Zolpidem as a Sleep Aid for Military Aviators.

PubMed

Sen Kew, Guan; See, Brian

2018-04-01

Zolpidem is a short-acting nonbenzodiazepine hypnotic that has been approved by the Republic of Singapore Air Force (RSAF) for aircrew sleep management since 2005. Prior to consuming zolpidem for operational reasons, each RSAF aircrew member is required to undergo a ground test to exclude operationally relevant adverse drug effects. This study describes the RSAF's zolpidem ground testing outcomes over a 12.5-yr period. This is a retrospective case series of 578 RSAF aircrew members who underwent zolpidem test dosing from 1 January 2005 to 30 June 2017. The median age was 29 yr (range, 19-54 yr) and the mean age was 30.1 yr ± 6.3 yr. Of the aircrew members, 568 (98.3%) were men and all were of Asian origin; 558 (96.5%) were medically cleared for the operational use of zolpidem. Among the 20 (3.5%) who failed zolpidem ground testing, next-day drowsiness (cumulative incidence, 1.04%), headache (cumulative incidence, 0.87%), and dizziness (cumulative incidence, 0.35%) were the most common causes of failure. None of the aircrew members reported abnormal sleep behaviors or major adverse drug events from zolpidem ingestion. Our results suggest a low occurrence of adverse effects among military aircrew members who undergo zolpidem test dosing prior to using the drug operationally. To our knowledge, this is the single largest published case series of zolpidem ground testing outcomes among Asian military aviators.Kew GS, See B. Zolpidem as a sleep aid for military aviators. Aerosp Med Hum Perform. 2018; 89(4):406-408.

Increased Reward-Related Behaviors during Sleep and Wakefulness in Sleepwalking and Idiopathic Nightmares.

PubMed

Perogamvros, Lampros; Aberg, Kristoffer; Gex-Fabry, Marianne; Perrig, Stephen; Cloninger, C Robert; Schwartz, Sophie

2015-01-01

We previously suggested that abnormal sleep behaviors, i.e., as found in parasomnias, may often be the expression of increased activity of the reward system during sleep. Because nightmares and sleepwalking predominate during REM and NREM sleep respectively, we tested here whether exploratory excitability, a waking personality trait reflecting high activity within the mesolimbic dopaminergic (ML-DA) system, may be associated with specific changes in REM and NREM sleep patterns in these two sleep disorders. Twenty-four unmedicated patients with parasomnia (12 with chronic sleepwalking and 12 with idiopathic nightmares) and no psychiatric comorbidities were studied. Each patient spent one night of sleep monitored by polysomnography. The Temperament and Character Inventory (TCI) was administered to all patients and healthy controls from the Geneva population (n = 293). Sleepwalkers were more anxious than patients with idiopathic nightmares (Spielberger Trait anxiety/STAI-T), but the patient groups did not differ on any personality dimension as estimated by the TCI. Compared to controls, parasomnia patients (sleepwalkers together with patients with idiopathic nightmares) scored higher on the Novelty Seeking (NS) TCI scale and in particular on the exploratory excitability/curiosity (NS1) subscale, and lower on the Self-directedness (SD) TCI scale, suggesting a general increase in reward sensitivity and impulsivity. Furthermore, parasomnia patients tended to worry about social separation persistently, as indicated by greater anticipatory worry (HA1) and dependence on social attachment (RD3). Moreover, exploratory excitability (NS1) correlated positively with the severity of parasomnia (i.e., the frequency of self-reported occurrences of nightmares and sleepwalking), and with time spent in REM sleep in patients with nightmares. These results suggest that patients with parasomnia might share common waking personality traits associated to reward-related brain functions

Functional Impairment in Adult Sleepwalkers: A Case-Control Study

PubMed Central

Lopez, Regis; Jaussent, Isabelle; Scholz, Sabine; Bayard, Sophie; Montplaisir, Jacques; Dauvilliers, Yves

2013-01-01

Study Objectives: To investigate the restorative quality of sleep and daytime functioning in sleepwalking adult patients in comparison with controls. Design: Prospective case-control study. Setting: Data were collected at the Sleep Disorders Center, Hôpital-Gui-de Chauliac, Montpellier, France between June 2007 and January 2011. Participants: There were 140 adult sleepwalkers (100 (median age 30 y, 55% male) in whom primary SW was diagnosed) who underwent 1 night of video polysomnography. All patients participated in a standardized clinical interview and completed a battery of questionnaires to assess clinical characteristics of parasomnia, daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and health-related quality of life. Results were compared with those of 100 sex- and age-matched normal controls. Interventions: N/A. Measurements and Results: Of the sleepwalkers, 22.3% presented with daily episodes and 43.5% presented with weekly episodes. Median age at sleepwalking onset was 9 y. Familial history of sleepwalking was reported in 56.6% of sleepwalkers and violent sleep related behaviors in 57.9%, including injuries requiring medical care for at least one episode in 17%. Significant associations were found between sleepwalking and daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and altered quality of life. Early-onset sleepwalkers had higher frequency of violent behaviors and injuries. Sleepwalkers with violent behaviors had higher frequency of sleep terrors and triggering factors, with greater alteration in health-related quality of life. Conclusion: Adult sleepwalking is a potentially serious condition that may induce violent behaviors, self-injury or injury to bed partners, sleep disruption, excessive daytime sleepiness, fatigue, and psychological distress, all of which affect health-related quality of life. Citation: Lopez R; Jaussent I; Scholz S; Bayard S; Montplaisir J; Dauvilliers Y. Functional impairment in

Functional impairment in adult sleepwalkers: a case-control study.

PubMed

Lopez, Regis; Jaussent, Isabelle; Scholz, Sabine; Bayard, Sophie; Montplaisir, Jacques; Dauvilliers, Yves

2013-03-01

To investigate the restorative quality of sleep and daytime functioning in sleepwalking adult patients in comparison with controls. Prospective case-control study. Data were collected at the Sleep Disorders Center, Hôpital-Gui-de Chauliac, Montpellier, France between June 2007 and January 2011. There were 140 adult sleepwalkers (100 (median age 30 y, 55% male) in whom primary SW was diagnosed) who underwent 1 night of video polysomnography. All patients participated in a standardized clinical interview and completed a battery of questionnaires to assess clinical characteristics of parasomnia, daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and health-related quality of life. Results were compared with those of 100 sex- and age-matched normal controls. N/A. Of the sleepwalkers, 22.3% presented with daily episodes and 43.5% presented with weekly episodes. Median age at sleepwalking onset was 9 y. Familial history of sleepwalking was reported in 56.6% of sleepwalkers and violent sleep related behaviors in 57.9%, including injuries requiring medical care for at least one episode in 17%. Significant associations were found between sleepwalking and daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and altered quality of life. Early-onset sleepwalkers had higher frequency of violent behaviors and injuries. Sleepwalkers with violent behaviors had higher frequency of sleep terrors and triggering factors, with greater alteration in health-related quality of life. Adult sleepwalking is a potentially serious condition that may induce violent behaviors, self-injury or injury to bed partners, sleep disruption, excessive daytime sleepiness, fatigue, and psychological distress, all of which affect health-related quality of life. Lopez R; Jaussent I; Scholz S; Bayard S; Montplaisir J; Dauvilliers Y. Functional impairment in adult sleepwalkers: a case-control study. SLEEP 2013;36(3):345-351.

The effect of zolpidem on sleep quality, stress status, and nondipping hypertension.

PubMed

Huang, Yuli; Mai, Weiyi; Cai, Xiaoyan; Hu, Yunzhao; Song, Yuanbin; Qiu, Ruofeng; Wu, Yanxian; Kuang, Jian

2012-03-01

Poor sleep quality and stress status have previously been shown to be closely associated with higher activation of the sympathetic nervous system and to be independent predictors of nondipping hypertension. This study aimed to evaluate the effects of the non-hypotensive sedative zolpidem on sleep quality, stress status, and nondipping hypertension. A total of 103 nondippers were defined as poor or good sleepers by the Pittsburgh Sleep Quality Index. They were randomized to receive zolpidem or placebo treatment for 30 days. Stress status was assessed by the Perceived Stress Scale, and levels of epinephrine and norepinephrine were examined to investigate the underlying mechanisms. Poor sleepers treated with zolpidem for 30 days showed significant improvements in sleep quality and stress levels (P<0.01). More nondippers were converted to dippers in the group of poor sleepers treated with zolpidem (11 of 22 patients, 50.0%) than in the placebo (2 of 23, 8.7%) (P<0.01). Epinephrine and norepinephrine levels were significantly reduced in poor sleepers treated with zolpidem (P<0.05). The results of this study suggest that zolpidem can improve sleep quality and stress status, and can convert nondippers with poor sleep quality into dippers. It may be an option for treating nondipping hypertensive patients with poor sleep quality. Copyright © 2011 Elsevier B.V. All rights reserved.

Pain in Sleepwalking: A Clinical Enigma.

PubMed

Lopez, Régis; Jaussent, Isabelle; Dauvilliers, Yves

2015-11-01

Sleepwalking is a disorder characterized by arousal specifically from slow wave sleep with dissociated brain activity that may be related to lower nociceptive state. Our objectives were to assess the frequency of chronic pain, headache, and migraine in sleepwalkers compared to controls, examine the impact and determinants of pain in sleepwalkers, and report analgesia frequency during injurious parasomnia episodes. Cross-sectional case-control study. Data were collected at the Sleep Disorders Center, Montpellier, France. One hundred patients with sleepwalking were assessed for disease characteristics, sleep (polysomnography, sleepiness, and insomnia), pain (chronic pain, multidimensional pain inventory, headache, and migraine), depressive symptoms, and quality of life compared to 100 adult controls. Pain perception was retrospectively assessed during injurious parasomnia episodes. Raw association data showed that lifetime headache, migraine, and chronic pain at time of study were significantly associated with sleepwalking (also called somnambulism). Compared to controls, sleepwalkers reported more frequent daytime sleepiness, and depressive and insomnia symptoms. After adjustments, sleepwalking was associated with increased risk for headache and migraine only. Compared to pain-free sleepwalkers, sleepwalkers with chronic pain were more likely to be older and to have greater daytime sleepiness, insomnia, and depressive symptoms, with no difference in polysomnography assessment. Of the 47 sleepwalkers with at least one previous violent parasomnia episode, 78.7% perceived no pain during episodes, allowing them to remain asleep despite injury. Our results highlight the clinical enigma of pain in sleepwalking patients with complaints of frequent chronic pain, migraine, and headache during wakefulness but who report retrospectively experience of analgesia during severe parasomnia episodes, suggesting a relationship between dissociated brain activity and nociceptive

Pain in Sleepwalking: A Clinical Enigma

PubMed Central

Lopez, Régis; Jaussent, Isabelle; Dauvilliers, Yves

2015-01-01

Study Objectives: Sleepwalking is a disorder characterized by arousal specifically from slow wave sleep with dissociated brain activity that may be related to lower nociceptive state. Our objectives were to assess the frequency of chronic pain, headache, and migraine in sleepwalkers compared to controls, examine the impact and determinants of pain in sleepwalkers, and report analgesia frequency during injurious parasomnia episodes. Design: Cross-sectional case-control study. Setting: Data were collected at the Sleep Disorders Center, Montpellier, France. Participants: One hundred patients with sleepwalking were assessed for disease characteristics, sleep (polysomnography, sleepiness, and insomnia), pain (chronic pain, multidimensional pain inventory, headache, and migraine), depressive symptoms, and quality of life compared to 100 adult controls. Pain perception was retrospectively assessed during injurious parasomnia episodes. Measurements and Results: Raw association data showed that lifetime headache, migraine, and chronic pain at time of study were significantly associated with sleepwalking (also called somnambulism). Compared to controls, sleepwalkers reported more frequent daytime sleepiness, and depressive and insomnia symptoms. After adjustments, sleepwalking was associated with increased risk for headache and migraine only. Compared to pain-free sleepwalkers, sleepwalkers with chronic pain were more likely to be older and to have greater daytime sleepiness, insomnia, and depressive symptoms, with no difference in polysomnography assessment. Of the 47 sleepwalkers with at least one previous violent parasomnia episode, 78.7% perceived no pain during episodes, allowing them to remain asleep despite injury. Conclusion: Our results highlight the clinical enigma of pain in sleepwalking patients with complaints of frequent chronic pain, migraine, and headache during wakefulness but who report retrospectively experience of analgesia during severe parasomnia

EEG Functional Connectivity Prior to Sleepwalking: Evidence of Interplay Between Sleep and Wakefulness.

PubMed

Desjardins, Marie-Ève; Carrier, Julie; Lina, Jean-Marc; Fortin, Maxime; Gosselin, Nadia; Montplaisir, Jacques; Zadra, Antonio

2017-04-01

Although sleepwalking (somnambulism) affects up to 4% of adults, its pathophysiology remains poorly understood. Sleepwalking can be preceded by fluctuations in slow-wave sleep EEG signals, but the significance of these pre-episode changes remains unknown and methods based on EEG functional connectivity have yet to be used to better comprehend the disorder. We investigated the sleep EEG of 27 adult sleepwalkers (mean age: 29 ± 7.6 years) who experienced a somnambulistic episode during slow-wave sleep. The 20-second segment of sleep EEG immediately preceding each patient's episode was compared with the 20-second segment occurring 2 minutes prior to episode onset. Results from spectral analyses revealed increased delta and theta spectral power in the 20 seconds preceding the episodes' onset as compared to the 20 seconds occurring 2 minutes before the episodes. The imaginary part of the coherence immediately prior to episode onset revealed (1) decreased delta EEG functional connectivity in parietal and occipital regions, (2) increased alpha connectivity over a fronto-parietal network, and (3) increased beta connectivity involving symmetric inter-hemispheric networks implicating frontotemporal, parietal and occipital areas. Taken together, these modifications in EEG functional connectivity suggest that somnambulistic episodes are preceded by brain processes characterized by the co-existence of arousal and deep sleep. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats

PubMed Central

Fox, Steven V; Gotter, Anthony L; Tye, Spencer J; Garson, Susan L; Savitz, Alan T; Uslaner, Jason M; Brunner, Joseph I; Tannenbaum, Pamela L; McDonald, Terrence P; Hodgson, Robert; Yao, Lihang; Bowlby, Mark R; Kuduk, Scott D; Coleman, Paul J; Hargreaves, Richard; Winrow, Christopher J; Renger, John J

2013-01-01

Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague–Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep. PMID:23722242

EEG Functional Connectivity Prior to Sleepwalking: Evidence of Interplay Between Sleep and Wakefulness

PubMed Central

Desjardins, Marie-Ève; Carrier, Julie; Lina, Jean-Marc; Fortin, Maxime; Gosselin, Nadia; Montplaisir, Jacques

2017-01-01

Abstract Study Objectives: Although sleepwalking (somnambulism) affects up to 4% of adults, its pathophysiology remains poorly understood. Sleepwalking can be preceded by fluctuations in slow-wave sleep EEG signals, but the significance of these pre-episode changes remains unknown and methods based on EEG functional connectivity have yet to be used to better comprehend the disorder. Methods: We investigated the sleep EEG of 27 adult sleepwalkers (mean age: 29 ± 7.6 years) who experienced a somnambulistic episode during slow-wave sleep. The 20-second segment of sleep EEG immediately preceding each patient’s episode was compared with the 20-second segment occurring 2 minutes prior to episode onset. Results: Results from spectral analyses revealed increased delta and theta spectral power in the 20 seconds preceding the episodes’ onset as compared to the 20 seconds occurring 2 minutes before the episodes. The imaginary part of the coherence immediately prior to episode onset revealed (1) decreased delta EEG functional connectivity in parietal and occipital regions, (2) increased alpha connectivity over a fronto-parietal network, and (3) increased beta connectivity involving symmetric inter-hemispheric networks implicating frontotemporal, parietal and occipital areas. Conclusions: Taken together, these modifications in EEG functional connectivity suggest that somnambulistic episodes are preceded by brain processes characterized by the co-existence of arousal and deep sleep. PMID:28204773

Sexsomnia: A case of sleep masturbation documented by video-polysomnography in a young adult male with sleepwalking.

PubMed

Yeh, Shih-Bin; Schenck, Carlos H

2016-01-01

The first case of video-polysomnography (vPSG) documented sleep masturbation in a male is reported, and the second reported case of shift work induced sexsomnia. A 20 y.o. soldier with childhood sleepwalking (SW) developed sleep masturbation and SW triggered by military shift work. vPSG documented two episodes of sleep masturbation from N2 sleep in the fourth sleep cycle and from N3 sleep during the fifth sleep cycle. There was no sleep-disordered breathing nor periodic limb movements. vPSG thus confirmed confusional arousals from NREM sleep as the cause of the masturbation. Bedtime clonazepam therapy controlled the SW but not the masturbation.

Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal

PubMed Central

Vandrey, Ryan; Smith, Michael T.; McCann, Una D.; Budney, Alan J.; Curran, Erin M.

2011-01-01

Background Sleep difficulty is a common symptom of cannabis withdrawal, but little research has objectively measured sleep or explored the effects of hypnotic medication on sleep during cannabis withdrawal. Methods Twenty daily cannabis users completed a within-subject crossover study. Participants alternated between periods of ad-libitum cannabis use and short-term cannabis abstinence (3 days). Placebo was administered at bedtime during one abstinence period (withdrawal test) and extended-release zolpidem, a non-benzodiazepine GABAA receptor agonist, was administered during the other. Polysomnographic (PSG) sleep architecture measures, subjective ratings, and cognitive performance effects were assessed each day. Results During the placebo-abstinence period, participants had decreased sleep efficiency, total sleep time, percent time spent in Stage 1 and Stage 2 sleep, REM latency and subjective sleep quality, as well as increased sleep latency and time spent in REM sleep compared with when they were using cannabis. Zolpidem attenuated the effects of abstinence on sleep architecture and normalized sleep efficiency scores, but had no effect on sleep latency. Zolpidem was not associated with any significant side effects or next-day cognitive performance impairments. Conclusions These data extend prior research that indicates abrupt abstinence from cannabis can lead to clinically significant sleep disruption in daily users. The findings also indicate that sleep disruption associated with cannabis withdrawal can be attenuated by zolpidem, suggesting that hypnotic medications might be useful adjunct pharmacotherapies in the treatment of cannabis use disorders. PMID:21296508

Effects of Zolpidem CR on Sleep and Nocturnal Ventilation in Patients with Heart Failure

PubMed Central

Gatti, Rodrigo C.; Burke, Patrick R.; Otuyama, Leonardo J.; Almeida, Dirceu R.; Tufik, Sergio; Poyares, Dalva

2016-01-01

Study Objective: This study aimed to evaluate the effects of zolpidem CR (controlled release) on sleep and nocturnal ventilation in patients with congestive heart failure, a population at risk for insomnia and poor sleep quality. Methods: Fifteen patients with heart failure (ischemic cardiomyopathy) and ejection fraction ≤ 45% in NYHA functional class I or II were evaluated with full polysomnography in a placebo-controlled, double-blind, randomized trial. Patients underwent three tests: (1) baseline polysomnography and, after randomization, (2) a new test with zolpidem CR 12.5 mg or placebo, and after 1 week, (3) a new polysomnography, crossing the “medication” used. Results: A 16% increase in total sleep time was found with the use of zolpidem CR and an increase in stage 3 NREM sleep (slow wave sleep). The apnea hypopnea index (AHI) did not change with zolpidem CR even after controlling for supine position; however, a slight but significant decrease was observed in lowest oxygen saturation compared with baseline and placebo conditions (83.60 ± 5.51; 84.43 ± 3.80; 80.71 ± 5.18, P = 0.002). Conclusion: Zolpidem CR improved sleep structure in patients with heart failure, did not change apnea hypopnea index, but slightly decreased lowest oxygen saturation. Citation: Gatti RC, Burke PR, Otuyama LJ, Almeida DR, Tufik S, Poyares D. Effects of zolpidem CR on sleep and nocturnal ventilation in patients with heart failure. SLEEP 2016;39(8):1501–1505. PMID:27166233

Zolpidem and Sleep in Pediatric Burn Patients with Attention Deficit/Hyperactivity Disorder.

PubMed

Cronin, Stephanie D; Gottschlich, Michele M; Gose, Lacy M; Kagan, Richard J

2015-01-01

Existing research shows that hospitalized patients, especially pediatric burn patients, are often sleep deprived. A pre-existing diagnosis of attention deficit/hyperactivity disorder (ADHD) further compounds a burn patient's inability to sleep. This retrospective study compared the effectiveness of zolpidem on patients with acute burns with ADHD (n = 23) and patients with acute burns without ADHD (n = 23). Effectiveness was defined based on the need for a change in the sleep medication or an increase in the zolpidem dose during the first 12 days of treatment. This study found that sleep dysfunction was similar in pediatric burn patients with and without a concurrent diagnosis of ADHD. Sixteen (69.6%) patients with and 13 (56.5%) patients without ADHD required a sleep medication change (p = 0.541). Further, while patients with ADHD required a sleep medication change (median = 5 days) sooner than those without ADHD (median = 9 days), it appears that zolpidem is not an effective drug for managing sleep in pediatric burn patients with or without ADHD.

Insomnia: Zolpidem Extended-Release for the Treatment of Sleep Induction and Sleep Maintenance Symptoms

PubMed Central

Doghramji, Paul P.

2007-01-01

Insomnia impairs daytime functioning or causes clinically significant daytime distress. The consequences of insomnia, if left untreated, may contribute to the risks of developing additional serious conditions, such as psychiatric illness, cardiovascular disease, or metabolic issues. Furthermore, some comorbidities associated with insomnia may be bidirectional in their causality because psychiatric and other medical problems can increase the risk for insomnia. Regardless of the serious consequences of inadequately treated insomnia, clinicians often do not inquire into their patients' sleep habits, and patients, in turn, are not forthcoming with details of their sleep difficulties. The continuing education of physicians and patients with regard to insomnia and currently available therapies for the treatment of insomnia is, therefore, essential. Insomnia may present as either a difficulty falling asleep, difficulty maintaining sleep, or waking too early without being able to return to sleep. Furthermore, these symptoms often change over time in an unpredictable manner. Therefore, when considering a sleep medication, one with efficacy for the treatment of multiple insomnia symptoms is recommended. A modified-release formulation of zolpidem, zolpidem extended-release, has been approved for the treatment of insomnia characterized by both difficulty in falling asleep and maintaining sleep. Here, we review studies supporting the use of zolpidem extended-release in the treatment of sleep-onset and sleep maintenance difficulties. PMID:17435620

Assessment and treatment of sleepwalking in clinical practice.

PubMed

Stallman, Helen M

2017-01-01

Sleepwalking is a relatively common and innocuous arousal disorder during non‑rapid eye movement sleep. This paper provides a review of the most recent science on sleepwalking to guide clinical decision-making. Most patients who sleepwalk do not require treatment, but comorbid sleep disorders that result in daytime tiredness, and behaviour and emotional problems require assessment and interventions. In the absence of clinical trials, tentative, low-risk treatments - scheduled waking and hypnosis - are suggested for sleepwalking that results in distress or violence towards others. People who sleepwalk and are violent may benefit from impulse-control interventions.

Effects of zolpidem on sleep architecture, night time ventilation, daytime vigilance and performance in heavy snorers.

PubMed Central

Quera-Salva, M A; McCann, C; Boudet, J; Frisk, M; Borderies, P; Meyer, P

1994-01-01

1. In a double-blind, crossover, placebo controlled trial, zolpidem 10 mg, a new imidazopyridine hypnotic drug, was administered in a single dose to 10 healthy non-obese heavy snorers. 2. Nocturnal polysomnography showed that zolpidem increased total sleep time, sleep efficiency and the percentage of stage 2. 3. Respiratory monitoring showed that zolpidem did not modify the percentage of total sleep time spent snoring. The percentages of total sleep time with a SaO2 < 4% of the baseline value and with a SaO2 < 90% and the mean SaO2 were also unchanged with zolpidem. The respiratory disturbance index was modestly increased by zolpidem although in all but one subject it remained < 5 with both treatments. 4. Zolpidem intake did not impair daytime vigilance and performance evaluated the day after. PMID:7917771

Effects of Zolpidem CR on Sleep and Nocturnal Ventilation in Patients with Heart Failure.

PubMed

Gatti, Rodrigo C; Burke, Patrick R; Otuyama, Leonardo J; Almeida, Dirceu R; Tufik, Sergio; Poyares, Dalva

2016-08-01

This study aimed to evaluate the effects of zolpidem CR (controlled release) on sleep and nocturnal ventilation in patients with congestive heart failure, a population at risk for insomnia and poor sleep quality. Fifteen patients with heart failure (ischemic cardiomyopathy) and ejection fraction ≤ 45% in NYHA functional class I or II were evaluated with full polysomnography in a placebo-controlled, double-blind, randomized trial. Patients underwent three tests: (1) baseline polysomnography and, after randomization, (2) a new test with zolpidem CR 12.5 mg or placebo, and after 1 week, (3) a new polysomnography, crossing the "medication" used. A 16% increase in total sleep time was found with the use of zolpidem CR and an increase in stage 3 NREM sleep (slow wave sleep). The apnea hypopnea index (AHI) did not change with zolpidem CR even after controlling for supine position; however, a slight but significant decrease was observed in lowest oxygen saturation compared with baseline and placebo conditions (83.60 ± 5.51; 84.43 ± 3.80; 80.71 ± 5.18, P = 0.002). Zolpidem CR improved sleep structure in patients with heart failure, did not change apnea hypopnea index, but slightly decreased lowest oxygen saturation. © 2016 Associated Professional Sleep Societies, LLC.

Sleepwalking associated with hyperthyroidism.

PubMed

Ajlouni, Kamel M; Ahmad, Azmi T; El-Zaheri, Mohamed M; Al-Zahiri, Mohammad M; Ammari, Fawwaz L; Jarrah, Nadim S; AbuJbara, Mousa A; Ajlouni, Heitham K; Daradkeh, Tewfik K

2005-01-01

To report several cases of hyperthyroidism in patients presenting with the unusual symptom of sleepwalking and to discuss the possible pathophysiologic basis for this novel association. After encountering and reporting the first case of new-onset somnambulism in a patient presenting with thyrotoxicosis at our institution, we routinely inquired about the sleep history of patients with thyrotoxicosis, questioning both the patients and family members when applicable. Those patients who actually had sleepwalking episodes coinciding with the onset of thyrotoxicosis underwent close follow-up, and the relationship between the sleepwalking and the results of thyroid function tests was analyzed. In addition, we reviewed the literature on psychiatric disorders and sleep problems, and the pathophysiologic rationale for a cause-and-effect relationship is discussed. We collected 8 cases of patients with new-onset sleepwalking episodes that coincided with the start of thyrotoxicosis. The disappearance of the sleepwalking with successful achievement of euthyroidism supports a cause-and-effect relationship. This hypothesis is further supported by the absence of a family history, the adult onset, and the relapse of sleepwalking in 2 of the patients when their thyrotoxicosis became poorly controlled as a result of noncompliance with medications and its subsequent disappearance with reachievement of euthyroidism. Of note, such a presentation was seen only in patients with thyrotoxicosis caused by diffuse toxic goiter or Graves' disease and never in patients with other causes of thyrotoxicosis. New-onset sleepwalking could be caused by thyrotoxicosis or, more specifically, by thyrotoxicosis resulting from diffuse toxic goiter. The mechanism is hypothesized to be related to the combination of prolongation of non-rapid eye movement sleep and the associated fatigue. Specific inquiry about this unusual presentation of thyrotoxicosis is encouraged, and more studies are needed to confirm

Zolpidem Ingestion, Automatisms, and Sleep Driving: A Clinical and Legal Case Series

PubMed Central

Poceta, J. Steven

2011-01-01

Study Objectives: To describe zolpidem-associated complex behaviors, including both daytime automatisms and sleep-related parasomnias. Methods: A case series of eight clinical patients and six legal defendants is presented. Patients presented to the author after an episode of confusion, amnesia, or somnambulism. Legal defendants were being prosecuted for driving under the influence, and the author reviewed the cases as expert witness for the defense. Potential predisposing factors including comorbidities, social situation, physician instruction, concomitant medications, and patterns of medication management were considered. Results: Patients and defendants exhibited abnormal behavior characterized by poor motor control and confusion. Although remaining apparently interactive with the environment, all reported amnesia for 3 to 5 hours. In some cases, the episodes began during daytime wakefulness because of accidental or purposeful ingestion of the zolpidem and are considered automatisms. Other cases began after ingestion of zolpidem at the time of going to bed and are considered parasomnias. Risk factors for both wake and sleep-related automatic complex behaviors include the concomitant ingestion of other sedating drugs, a higher dose of zolpidem, a history of parasomnia, ingestion at times other than bedtime or when sleep is unlikely, poor management of pill bottles, and living alone. In addition, similar size and shape of two medications contributed to accidental ingestion in at least one case. Conclusions: Sleep driving and other complex behaviors can occur after zolpidem ingestion. Physicians should assess patients for potential risk factors and inquire about parasomnias. Serious legal and medical complications can occur as a result of these forms of automatic complex behaviors. Citation: Poceta JS. Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med 2011;7(6):632-638. PMID:22171202

Adverse Reactions to Zolpidem: Case Reports and a Review of the Literature

PubMed Central

Miyaoka, Tsuyoshi; Tsuji, Seiichi; Inami, Yasushi; Nishida, Akira; Horiguchi, Jun

2010-01-01

Objective: Zolpidem, a nonbenzodiazepine hypnotic, is very effective and widely prescribed in clinical practice for the treatment of insomnia and is thought to have few adverse effects. However, zolpidem-induced adverse effects have begun to be reported in the literature, but few systemic descriptions of the adverse effects (especially for psychotic reactions) of zolpidem have been undertaken. In light of the accumulating reports of adverse reactions to zolpidem, we present 2 case reports of zolpidem-induced adverse effects and review the literature on this subject. Data Sources: Articles were selected by the authors on the basis of our experience and by a PubMed search using the terms zolpidem or side effects or adverse effects or adverse reactions. Study Selection and Data Extraction: Publications relevant to the objective of this article were obtained (1992–2010), and some adverse neuropsychiatric reactions were summarized. Data Synthesis: Zolpidem has been associated with the development of adverse neuropsychiatric reactions, such as hallucinations/sensory distortion, amnesia, sleepwalking/somnambulism, and nocturnal eating. The following 4 variables should be considered when prescribing zolpidem: (1) gender: women have been found to have a significantly higher serum zolpidem concentration than men; (2) zolpidem dose: the adverse reactions that develop are dose dependent; (3) protein binding affinity: a high proportion of zolpidem is protein bound; therefore, low serum albumin results in a higher level of free zolpidem leading to adverse psychiatric reactions; and (4) cytochrome P450 (CYP) isoenzyme inhibition: concomitant administration of zolpidem and other drugs may cause interactions that lead to increased concentrations of zolpidem. Conclusions: Zolpidem is clinically very effective in treating insomnia. However, while rare, zolpidem-induced unusual complex behavior may develop. Primary care physicians should be alert to the possible unusual complex

Precipitating factors of somnambulism: impact of sleep deprivation and forced arousals.

PubMed

Pilon, Mathieu; Montplaisir, Jacques; Zadra, Antonio

2008-06-10

Experimental attempts to induce sleepwalking with forced arousals during slow-wave sleep (SWS) have yielded mixed results in children and have not been investigated in adult patients. We hypothesized that the combination of sleep deprivation and external stimulation would increase the probability of inducing somnambulistic episodes in sleepwalkers recorded in the sleep laboratory. The main goal of this study was to assess the effects of forced arousals from auditory stimuli (AS) in adult sleepwalkers and control subjects during normal sleep and following post-sleep deprivation recovery sleep. Ten sleepwalkers and 10 controls were investigated. After a baseline night, participants were presented with AS at predetermined sleep stages either during normal sleep or recovery sleep following 25 hours of sleep deprivation. One week later, the conditions with AS were reversed. No somnambulistic episodes were induced in controls. When compared to the effects of AS during sleepwalkers' normal sleep, the presentation of AS during sleepwalkers' recovery sleep significantly increased their efficacy in experimentally inducing somnambulistic events and a significantly greater proportion of sleepwalkers (100%) experienced at least one induced episode during recovery SWS as compared to normal SWS (30%). There was no significant difference between the mean intensity of AS that induced episodes during sleepwalkers' SWS and the mean intensity of AS that awakened sleepwalkers and controls from SWS. Sleep deprivation and forced arousals during slow-wave sleep can induce somnambulistic episodes in predisposed adults. The results highlight the potential value of this protocol in establishing a video-polysomnographically based diagnosis for sleepwalking.

Electroencephalographic slow waves prior to sleepwalking episodes.

PubMed

Perrault, Rosemarie; Carrier, Julie; Desautels, Alex; Montplaisir, Jacques; Zadra, Antonio

2014-12-01

Recent studies have suggested that the onset of sleepwalking episodes may be preceded by fluctuations in slow-wave sleep electroencephalographic characteristics. However, whether or not such fluctuations are specific to sleepwalking episodes or generalized to all sleep-wake transitions in sleepwalkers remains unknown. The goal of this study was to compare spectral power for delta (1-4 Hz) and slow delta (0.5-1 Hz) as well as slow oscillation density before the onset of somnambulistic episodes versus non-behavioral awakenings recorded from the same group of sleepwalkers. A secondary aim was to describe the time course of observed changes in slow-wave activity and slow oscillations during the 3 min immediately preceding the occurrence of somnambulistic episodes. Twelve adult sleepwalkers were investigated polysomnographically during the course of one night. Slow-wave activity and slow oscillation density were significantly greater prior to patients' somnambulistic episodes as compared with non-behavioral awakenings. However, there was no evidence for a gradual increase over the 3 min preceding the episodes. Increased slow-wave activity and slow oscillation density appear to be specific to sleepwalking episodes rather than generalized to all sleep-wake transitions in sleepwalkers. Copyright © 2014 Elsevier B.V. All rights reserved.

The course and character of sleepwalking in adulthood: a clinical and polysomnographic study.

PubMed

Bušková, Jitka; Piško, Juraj; Pastorek, Lukáš; Šonka, Karel

2015-01-01

To describe characteristics of adult sleepwalking (potential triggers and correlates with polysomnography), 52 patients were interviewed regarding their sleepwalking episodes and underwent video-polysomnography on two consecutive nights. Sleepwalking history averaged 12 years and frequent episodes (more than once per week) occurred in 62%. Higher frequency was associated with earlier onset of sleepwalking (p < 0.005) and 53.8% reported dangerous sleepwalking behavior. The most common self-reported triggers were sleep deprivation and stressful events, while no specific trigger was reported in 37% of patients. More awakening from slow-wave sleep was associated with a higher frequency of sleepwalking episodes (p < 0.001). A longer history of sleepwalking was associated with more sleepwalking episodes, even without the presence of sleep comorbidities or other known precipitating factors.

Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening: a randomized placebo-controlled trial.

PubMed

Frey, Danielle J; Ortega, Justus D; Wiseman, Courtney; Farley, Claire T; Wright, Kenneth P

2011-01-01

To determine whether sleep inertia (grogginess upon awakening from sleep) with or without zolpidem impairs walking stability and cognition during awakenings from sleep. Three within-subject conditions hypnotic medication (zolpidem), placebo (sleep inertia), and wakefulness control randomized using balanced Latin square design. Sleep laboratory. Twelve older and 13 younger healthy adults. Five milligrams of zolpidem or placebo 10 minutes before scheduled sleep (double-blind: zolpidem or sleep inertia); placebo before sitting in bed awake for 2 hours after their habitual bedtime (single-blind: wakefulness control). Tandem walk on a beam and cognition, measured using computerized performance tasks, approximately 120 minutes after treatment. No participants stepped off the beam on 10 practice trials. Seven of 12 older adults stepped off the beam after taking zolpidem, compared with none after sleep inertia and three after wakefulness control. Fewer young adults stepped off the beam: three after taking zolpidem, one after sleep inertia, and none after wakefulness control. Number needed to harm analyses showed one tandem walk failure for every 1.7 (95% confidence interval (CI)=1.4-2.0) older and 5.5 (95% CI=5.2-5.8) younger adults treated with zolpidem. Cognition was significantly more impaired after zolpidem exposure than with wakefulness control in older and younger participants (working memory: older, -4.3 calculations, 95% CI=-7.0 to -1.7; younger, -12.4 calculations, 95% CI=-18.2 to -6.7; Stroop: older, 76-ms increase (95% CI=13.5-138.4 ms); younger, 126-ms increase, 95% CI=34.7-217.5 ms), whereas sleep inertia significantly impaired cognition in younger but not older participants. Zolpidem produced clinically significant balance and cognitive impairments upon awakening from sleep. Because impaired tandem walk predicts falls and hip fractures and because impaired cognition has important safety implications, use of nonbenzodiazepine hypnotic medications may have

Sleepiness in sleepwalking and sleep terrors: a higher sleep pressure?

PubMed

Carrillo-Solano, Marisol; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Groos, Elisabeth; Arnulf, Isabelle

2016-10-01

To identify the determinants of excessive daytime sleepiness in adults with sleepwalking or sleep terrors (SW/ST). We collected the charts of all consecutive adult patients admitted from 2012 to 2014 for SW/ST. They had completed the Paris Arousal Disorders Severity Scale and the Epworth Sleepiness Scale, and had undergone one (n = 34) or two consecutive (n = 124) nocturnal videopolysomnographies. The demographic, clinical, and sleep determinants of excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score of greater than 10) were analyzed. Almost half (46.8%) of the 158 adult patients with SW/ST reported excessive daytime sleepiness. They had shorter sleep onset latencies (in night 1 and night 2), shorter REM sleep latencies, longer total sleep time, and higher REM sleep percentages in night 2, but no greater clinical severity of the parasomnia than patients without sleepiness. The level of sleepiness correlated with the same measures (sleep onset latency on both nights, REM sleep onset latency, and total sleep time in night 2), plus the latency to N3. In the regression model, higher sleepiness was determined by shorter sleep onset latency on night 1, lower number of awakenings in N3 on night 1, and higher total sleep time on night 2. Daytime sleepiness in patients with SW/ST is not the consequence of disturbed sleep but is associated with a specific polygraphic phenotype (rapid sleep onset, long sleep time, lower numbers of awakenings on N3) that is suggestive of a higher sleep pressure that may contribute to incomplete arousal from N3. Copyright © 2015 Elsevier B.V. All rights reserved.

Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series.

PubMed

Poceta, J Steven

2011-12-15

To describe zolpidem-associated complex behaviors, including both daytime automatisms and sleep-related parasomnias. A case series of eight clinical patients and six legal defendants is presented. Patients presented to the author after an episode of confusion, amnesia, or somnambulism. Legal defendants were being prosecuted for driving under the influence, and the author reviewed the cases as expert witness for the defense. Potential predisposing factors including comorbidities, social situation, physician instruction, concomitant medications, and patterns of medication management were considered. Patients and defendants exhibited abnormal behavior characterized by poor motor control and confusion. Although remaining apparently interactive with the environment, all reported amnesia for 3 to 5 hours. In some cases, the episodes began during daytime wakefulness because of accidental or purposeful ingestion of the zolpidem and are considered automatisms. Other cases began after ingestion of zolpidem at the time of going to bed and are considered parasomnias. Risk factors for both wake and sleep-related automatic complex behaviors include the concomitant ingestion of other sedating drugs, a higher dose of zolpidem, a history of parasomnia, ingestion at times other than bedtime or when sleep is unlikely, poor management of pill bottles, and living alone. In addition, similar size and shape of two medications contributed to accidental ingestion in at least one case. Sleep driving and other complex behaviors can occur after zolpidem ingestion. Physicians should assess patients for potential risk factors and inquire about parasomnias. Serious legal and medical complications can occur as a result of these forms of automatic complex behaviors.

Conventional and power spectrum analysis of the effects of zolpidem on sleep EEG in patients with chronic primary insomnia.

PubMed

Monti, J M; Alvariño, F; Monti, D

2000-12-15

The purpose of this study was 1) to assess the effect of zolpidem or a placebo on sleep in two groups of insomniac patients with a diagnosis of moderate-to-severe chronic primary insomnia and 2) to determine the effect of zolpidem on sleep structure using spectral analysis. A randomized, double-blind, placebo-controlled trial. Sleep laboratory of the Department of Pharmacology and Therapeutics at the Clinics Hospital. 12 female outpatients with chronic primary insomnia. Zolpidem was given at a daily dose of 10 mg for 15 nights. The hypnotic drug reduced sleep latency and waking time after sleep onset, and increased total sleep time and sleep efficiency. Values corresponding to visually scored slow wave sleep (stage 3 and 4) showed no significant changes. All-night spectral analysis of the EEG revealed that power density in NREM sleep was significantly increased in the low frequency band (0.25-1.0 Hz) in the zolpidem group during the first 2-h interval. In agreement with previous findings obtained in patients with chronic primary insomnia, zolpidem significantly improved sleep induction and maintenance. Moreover, zolpidem increased power density in the 0.25-1.0 Hz band during short-term and intermediate-term treatment. Nevertheless, other frequency bands in the delta range showed a relative decrease which was not statistically significant.

Effects of GF-015535-00, a novel α1 GABA A receptor ligand, on the sleep-wake cycle in mice, with reference to zolpidem.

PubMed

Anaclet, Christelle; Zhang, Mei; Zhao, Chunmei; Buda, Colette; Seugnet, Laurent; Lin, Jian-Sheng

2012-01-01

Novel, safe, and efficient hypnotic compounds capable of enhancing physiological sleep are still in great demand in the therapy of insomnia. This study compares the sleep-wake effects of a new α1 GABA(A) receptor subunit ligand, GF-015535-00, with those of zolpidem, the widely utilized hypnotic compound. Nine C57Bl6/J male mice were chronically implanted with electrodes for EEG and sleep-wake monitoring. Each mouse received 3 doses of GF-015535-00 and zolpidem. Time spent in sleep-wake states and cortical EEG power spectra were analyzed. Both zolpidem and GF-015535-00 prominently enhanced slow wave sleep and paradoxical sleep in the mouse. However, as compared with zolpidem, GF-015535-00 showed several important differences: (1) a comparable sleep-enhancing effect was obtained with a 10 fold smaller dose; (2) the induced sleep was less fragmented; (3) the risk of subsequent wake rebound was less prominent; and (4) the cortical EEG power ratio between slow wave sleep and wake was similar to that of natural sleep and thus compatible with physiological sleep. The characteristics of the sleep-wake effects of GF-015535-00 in mice could be potentially beneficial for its use as a therapeutic compound in the treatment of insomnia. Further investigations are required to assess whether the same characteristics are conserved in other animal models and humans.

Effects on sleep stages and microarchitecture of caffeine and its combination with zolpidem or trazodone in healthy volunteers.

PubMed

Paterson, L M; Nutt, D J; Ivarsson, M; Hutson, P H; Wilson, S J

2009-07-01

Caffeine is the world's most popular stimulant and is known to disrupt sleep. Administration of caffeine can therefore be used in healthy volunteers to mimic the effects of insomnia and thus to test the hypnotic effects of medication. This study assessed the effects of caffeine on sleep architecture and electroencephalography (EEG) spectrum alone and in combination with two different sleep-promoting medications. Home polysomnography was performed in 12 healthy male volunteers in a double-blind study whereby subjects received placebo, caffeine (150 mg), caffeine plus zolpidem (10 mg) and caffeine plus trazodone (100 mg) at bedtime in a randomised crossover design. In addition to delaying sleep onset, caffeine decreased total sleep time (TST), sleep efficiency (SE) and stage 2 sleep without significantly altering wake after sleep onset or the number of awakenings. Zolpidem attenuated the caffeine-induced decrease in SE and increased spindle density in the caffeine plus zolpidem combination compared with placebo. Trazodone attenuated the decrease in SE and TST, and it also increased stage 3 sleep, decreased the number of awakenings and decreased the spindle density. No significant changes in rapid eye movement (REM) sleep were observed, neither was any significant alteration in slow wave activity nor other EEG spectral measures, although the direction of change was similar to that previously reported for caffeine and appeared to 'normalise' after trazodone. These data suggest that caffeine mimics some, but not all of the sleep disruption seen in insomnia and that its disruptive effects are differentially attenuated by the actions of sleep-promoting compounds with distinct mechanisms of action.

Prior sleep with zolpidem enhances the effect of caffeine or modafinil during 18 hours continuous work.

PubMed

Batéjat, Denise; Coste, Olivier; Van Beers, Pascal; Lagarde, Didier; Piérard, Christophe; Beaumont, Maurice

2006-05-01

Continuous military operations may disrupt sleep-wakefulness cycles, resulting in impaired performance and fatigue. We assessed the treatment efficacy of a hypnotic-psychostimulant combination to maintain sleep quality, performance, and alertness during a 42-h simulated military operation. A 6-h prophylactic sleep period with zolpidem (ZOL) followed by a 18-h continuous work period with administration at midway of 300 mg of slow release caffeine (CAF) or 200 mg of modafinil (MOD) was performed by eight healthy male subjects. Performance level was assessed with a reaction time test, a memory search test, a dual task, an attention test, and a computerized Stroop test. Cortical activation level was evaluated by the Critical Flicker Frequency test. Subjective sleepiness was evaluated using a visual analog scale and questionnaires. Effects of drugs on prophylactic and recovery sleep were also quantified from EEG recordings. CAF and MOD maintained performance and alertness throughout the 18-h work period. As shown by EEG recordings, ZOL improved prophylactic sleep without any deleterious effect on performance immediately after waking. As a result of its positive effects on prophylactic sleep, a lower pressure for slow wave sleep during recovery sleep was observed; nevertheless, zolpidem did not enhance the effects of either psychostimulant on performance. MOD and CAF may be of value in promoting performance and wakefulness during shiftwork or military operations while zolpidem improves prophylactic sleep quality without any deleterious effect after waking. We concluded that a zolpidem/ caffeine or modafinil combination could be useful in a context of environmental conditions not conducive to sleep.

Psychopathologic correlates of adult sleepwalking.

PubMed

Labelle, Marc-Antoine; Desautels, Alex; Montplaisir, Jacques; Zadra, Antonio

2013-12-01

Sleepwalking (SW) often has been associated with psychopathology, but the nature and magnitude of this relation remains unclear. The aim of our study was to investigate the presence of psychopathology in a large cohort of sleepwalkers and to determine if levels of psychopathology showed differential relations to specific characteristics of the disorder, including clinical history. One-hundred and five sleepwalkers (39 men, 66 women; mean age, 32.4±9.5years) referred to our sleep disorders clinic for chronic SW underwent a comprehensive clinical investigation that included an overnight polysomnography (PSG) assessment in 90% of cases. All participants also completed a series of questionnaires, including the Beck Depression Inventory, Second Revision (BDI-II), the Beck Anxiety Inventory (BAI), and the Symptom Checklist 90-Revised (SCL-90-R). The proportion of sleepwalkers who scored above the minimal clinical threshold on the BDI-II, BAI, and SCL-90-R was 27%, 40%, and 28%, respectively. Only 15% of sleepwalkers showed moderate to severe symptoms on the BDI-II and 19% on the BAI. Taken as a whole, these profiles are similar to those observed in the general adult population. The presence of psychopathology in sleepwalkers was associated with a negative family history for SW, a higher frequency of nightmares, and with potentially injurious behaviors enacted during somnambulistic episodes. A majority of adult sleepwalkers consulting for the disorder do not report clinically significant levels of depression or anxiety. Overall, sleepwalkers with and without psychopathology appear more similar than dissimilar. Copyright © 2013 Elsevier B.V. All rights reserved.

Zolpidem Overdose: A Dilemma in Mental Health.

PubMed

Jung, Minsoo

Sleeping pills are one of the most common drugs taken by adults when afflicted by insomnia. Adverse effects of pharmacotherapy, however, should not be overlooked, and monitoring is needed to check for an overdose of sleeping pills. We reviewed zolpidem overdose and patient suicide with benefits and disadvantages of pharmacotherapy. Cases of adverse effects concerning the central nervous system, including delirium and hallucination, as well as abnormal behavior during sleep, are commonly reported among patients who have taken zolpidem for more than 1 year. The serious problem of long-term prescription to medication can lead to a higher mortality rate of insomniac patients. An alternative to medication for treating insomnia is cognitive behavioral therapy, which can improve sleeping habits. Cognitive behavioral therapy induces patients to recognize and change the negative thoughts that affect their sleep. Medical providers should be aware of the adverse effects of sleep inducers and provide sufficient information to their patients about them. When establishing treatment plans, they should encourage patients to make the proper decisions and try to reduce the adverse effects of any medication as much as possible.

Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia

PubMed Central

Bettica, Paolo; Squassante, Lisa; Groeger, John A; Gennery, Brian; Winsky-Sommerer, Raphaelle; Dijk, Derk-Jan

2012-01-01

Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual orexin receptor antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABAA receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB–6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB–6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25–11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual orexin receptor antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem. PMID:22237311

Acute Effects of Zolpidem Extended-Release on Cognitive Performance and Sleep in Healthy Males After Repeated Nightly Use

PubMed Central

Kleykamp, Bethea A.; Griffiths, Roland R.; McCann, Una D.; Smith, Michael T.; Mintzer, Miriam Z.

2012-01-01

The extended-release formulation of zolpidem (Ambien CR®) is approved for the treatment of insomnia without a treatment duration limit. Acutely zolpidem impairs performance, and no research to date has examined whether tolerance develops to these performance impairments during nighttime awakening. The present double-blind, placebo-controlled study examined whether tolerance develops to zolpidem-induced acute performance impairment after repeated (22–30 days) nightly use. Effects of bedtime administration of zolpidem extended-release (ZOL; 12.5 mg) were tested on a battery of performance measures assessed during a forced nighttime awakening in 15 healthy male volunteers who completed overnight polysomnographic recording sessions in our laboratory at baseline and after approximately a month of at-home ZOL. As expected, bedtime ZOL administration was associated with changes in sleep architecture and impairments across all performance domains during nighttime testing (psychomotor function, attention, working memory, episodic memory, metacognition) with no residual next morning impairment. Tolerance did not develop to the observed ZOL-related impairments on any outcome. Possible evidence of acute abstinence effects following discontinuation of ZOL was observed on some performance and sleep outcomes. Overall, these findings suggest that performance is significantly impaired during nighttime awakening even after a month of nightly ZOL administration and these impairments could significantly impact safety should nighttime awakening require unimpaired functioning (e.g., driving; combat-related activities in the military). PMID:21928913

The antinociceptive effect of zolpidem and zopiclone in mice.

PubMed

Pick, Chaim G; Chernes, Yakov; Rigai, Tova; Rice, Kenner C; Schreiber, Shaul

2005-07-01

Zolpidem and zopiclone are two of a newer hypno-sedative class of drugs, the "Z compounds". Their use for the treatment of short-term insomnia has been expanding constantly during the last two decades. The "Z compounds" are considered to cause less significant rebound insomnia or tolerance than the conventional hypnotic benzodiazepines. Their possible antinociceptive effect and interaction with the opioid system has not been studied yet. Our results demonstrate a significant difference between the antinociceptive properties of zopiclone and zolpidem when injected s.c. in the hotplate analgesic assay in mice. Zopiclone induced a weak, dose-dependent antinociceptive effect, antagonized only by the alpha2-adrenergic receptor antagonist yohimbine. Zolpidem induced a weak, biphasic dose-dependent antinociceptive effect, antagonized primarily by the non-selective opioid antagonist naloxone and by yohimbine. The weak antinociceptive effect of both drugs, evident only at very high doses (far beyond those used clinically to induce sleep), implies no clinical use for zopiclone or zolpidem in the management of pain. However, the possible interaction of zolpidem with the opioid system should be further investigated (in behavioral models, which do not overlap with the acute-pain antinociception model we used), both for possible side effects in special populations (i.e. elderly) and for possible drug-drug interactions, in order to minimize possible hazards and maximize clinical beneficial effects of its use for sleep.

The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats.

PubMed

Yoshimoto, M; Higuchi, H; Kamata, M; Yoshida, K; Shimizu, T; Hishikawa, Y

1999-01-01

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.

Fight or flight? Dream content during sleepwalking/sleep terrors vs. rapid eye movement sleep behavior disorder.

PubMed

Uguccioni, Ginevra; Golmard, Jean-Louis; de Fontréaux, Alix Noël; Leu-Semenescu, Smaranda; Brion, Agnès; Arnulf, Isabelle

2013-05-01

Dreams enacted during sleepwalking or sleep terrors (SW/ST) may differ from those enacted during rapid eye movement sleep behavior disorder (RBD). Subjects completed aggression, depression, and anxiety questionnaires. The mentations associated with SW/ST and RBD behaviors were collected over their lifetime and on the morning after video polysomnography (PSG). The reports were analyzed for complexity, length, content, setting, bizarreness, and threat. Ninety-one percent of 32 subjects with SW/ST and 87.5% of 24 subjects with RBD remembered an enacted dream (121 dreams in a lifetime and 41 dreams recalled on the morning). These dreams were more complex and less bizarre, with a higher level of aggression in the RBD than in SW/ST subjects. In contrast, we found low aggression, anxiety, and depression scores during the daytime in both groups. As many as 70% of enacted dreams in SW/ST and 60% in RBD involved a threat, but there were more misfortunes and disasters in the SW/ST dreams and more human and animal aggressions in the RBD dreams. The response to these threats differed, as the sleepwalkers mostly fled from a disaster (and 25% fought back when attacked), while 75% of RBD subjects counterattacked when assaulted. The dreams setting included their bedrooms in 42% SW/ST dreams, though this finding was exceptional in the RBD dreams. Different threat simulations and modes of defense seem to play a role during dream-enacted behaviors (e.g., fleeing a disaster during SW/ST, counterattacking a human or animal assault during RBD), paralleling and exacerbating the differences observed between normal dreaming in nonrapid eye movement (NREM) vs rapid eye movement (REM) sleep. Copyright © 2013 Elsevier B.V. All rights reserved.

Somnambulism (sleepwalking).

PubMed

Remulla, Agnes; Guilleminault, Christian

2004-10-01

Somnambulism is an arousal parasomnia consisting of a series of complex behaviours that result in large movements in bed or walking during sleep. It occurs in 2-14% of children and 1.6-2.4% of adults. Occasional benign episodes are managed conservatively. However, recurrent sleepwalking with a risk of injury to self or others mandates immediate treatment with pharmacotherapy while awaiting work-up. The most commonly used medications are benzodiazepines, particularly clonazepam, with tricyclic antidepressants and serotonin selective re-uptake inhibitors also administered. Treatment of underlying causes such as obstructive sleep apnoea, upper airway resistance syndrome, restless legs syndrome and periodic limb movements, is currently the best approach and usually eliminates somnambulism in children and adults.

Is there a dissociative process in sleepwalking and night terrors?

PubMed Central

Hartman, D; Crisp, A; Sedgwick, P; Borrow, S

2001-01-01

The enduring and contentious hypothesis that sleepwalking and night terrors are symptomatic of a protective dissociative mechanism is examined. This is mobilised when intolerable impulses, feelings and memories escape, within sleep, the diminished control of mental defence mechanisms. They then erupt but in a limited motoric or affective form with restricted awareness and subsequent amnesia for the event. It has also been suggested that such processes are more likely when the patient has a history of major psychological trauma. In a group of 22 adult patients, referred to a tertiary sleep disorders service with possible sleepwalking/night terrors, diagnosis was confirmed both clinically and polysomnographically, and only six patients had a history of such trauma. More commonly these described sleepwalking/night terrors are associated with vivid dream-like experiences or behaviour related to flight from attack. Two such cases, suggestive of a dissociative process, are described in more detail.
The results of this study are presented largely on account of the negative findings. Scores on the dissociation questionnaire (DIS-Q) were normal, although generally higher in the small "trauma" subgroup. These were similar to scores characterising individuals with post-traumatic stress disorder. This "trauma" group also scored particularly highly on the anxiety, phobic, and depression scales of the Crown-Crisp experiential index. In contrast the "no trauma" group scored more specifically highly on the anxiety scale, along with major trends to high depression and hysteria scale scores. Two cases are presented which illustrate exceptional occurrence of later onset of sleepwalking/night terrors with accompanying post-traumatic symptoms during wakefulness. It is concluded that a history of major psychological trauma exists in only a minority of adult patients presenting with sleepwalking/night terror syndrome. In this subgroup trauma appears to dictate the subsequent content

A review of sleepwalking (somnambulism): the enigma of neurophysiology and polysomnography with differential diagnosis of complex partial seizures.

PubMed

Hughes, John R

2007-12-01

The goal of this report is to review all aspects of sleepwalking (SW), also known as somnambulism. Various factors seem to initiate SW, especially drugs, stress, and sleep deprivation. As an etiology, heredity is important, but other conditions include thyrotoxicosis, stress, and herpes simplex encephalitis. Psychological characteristics of sleepwalkers often include aggression, anxiety, panic disorder, and hysteria. Polysomnographic characteristics emphasize abnormal deep sleep associated with arousal and slow wave sleep fragmentation. In the differential diagnosis, the EEG is important to properly identify a seizure disorder, rather than SW. Associated disorders are Tourette's syndrome, sleep-disordered breathing, and migraine. Various kinds of treatment are discussed, as are legal considerations, especially murder during sleepwalking.

Zolpidem efficacy and safety in disorders of consciousness.

PubMed

Machado, Calixto; Estévez, Mario; Rodriguez-Rojas, Rafael

2018-01-01

Sutton and Clauss presented a detailed review about the effectiveness of zolpidem, discussing recoveries from brain damage due to strokes, trauma and hypoxia. A significant finding has been the unexpected and paradoxical increment of brain activity in vegetative state/unresponsive wakefulness syndrome (VS/UWS). On the contrary, zolpidem is considered one of the best sleep inducers in normal subjects. We have studied series of VS/UWS cases after zolpidem intake. We have demonstrated EEG activation, increment of BOLD signal in different brain regions, and an autonomic influence, mainly characterized by a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. As this autonomic imbalance might induce cardio- circulatory complications, which we didn't find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that the paradoxical arousing zolpidem effect might be certainly related to brain function improvement, we agree with Sutton and Clauss that future multicentre and multinational clinical trials should be developed, but under control of physiological indices.

Efficacy of Eight Months of Nightly Zolpidem: A Prospective Placebo-Controlled Study

PubMed Central

Randall, Surilla; Roehrs, Timothy A.; Roth, Thomas

2012-01-01

Study Objectives: To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic primary insomnia using polysomnography. Design: Randomized, double-blind, placebo-controlled clinical trial. Setting: Sleep disorders and research center. Participants: Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia. Interventions: Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. Measurements and Results: Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. Conclusions: In adults with primary insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Randall S; Roehrs TA; Roth T. Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study. SLEEP 2012;35(11):1551-1557. PMID:23115404

Involvement of the K+-Cl- co-transporter KCC2 in the sensitization to morphine-induced hyperlocomotion under chronic treatment with zolpidem in the mesolimbic system.

PubMed

Shibasaki, Masahiro; Masukawa, Daiki; Ishii, Kazunori; Yamagishi, Yui; Mori, Tomohisa; Suzuki, Tsutomu

2013-06-01

Benzodiazepines are commonly used as sedatives, sleeping aids, and anti-anxiety drugs. However, chronic treatment with benzodiazepines is known to induce dependence, which is considered related to neuroplastic changes in the mesolimbic system. This study investigated the involvement of K(+) -Cl(-) co-transporter 2 (KCC2) in the sensitization to morphine-induced hyperlocomotion after chronic treatment with zolpidem [a selective agonist of γ-aminobutyric acid A-type receptor (GABAA R) α1 subunit]. In this study, chronic treatment with zolpidem enhanced morphine-induced hyperlocomotion, which is accompanied by the up-regulation of KCC2 in the limbic forebrain. We also found that chronic treatment with zolpidem induced the down-regulation of protein phosphatase-1 (PP-1) as well as the up-regulation of phosphorylated protein kinase C γ (pPKCγ). Furthermore, PP-1 directly associated with KCC2 and pPKCγ, whereas pPKCγ did not associate with KCC2. On the other hand, pre-treatment with furosemide (a KCC2 inhibitor) suppressed the enhancing effects of zolpidem on morphine-induced hyperlocomotion. These results suggest that the mesolimbic dopaminergic system could be amenable to neuroplastic change through a pPKCγ-PP-1-KCC2 pathway by chronic treatment with zolpidem. © 2013 International Society for Neurochemistry.

EEG spectral power density profiles during NREM sleep for gaboxadol and zolpidem in patients with primary insomnia.

PubMed

Lundahl, Jonas; Deacon, Steve; Maurice, Damien; Staner, Luc

2012-08-01

There is significant interest in the functional significance and the therapeutic value of slow-wave sleep (SWS)-enhancing drugs. A prerequisite for studies of the functional differences is characterization of the electroencephalography (EEG) spectra following treatment in relevant patients. We evaluate for the first time gaboxadol and zolpidem treatments in insomniac patients using power spectra analysis. We carried out two randomized, double-blind, crossover studies. Study 1, 38 patients received gaboxadol 10 mg and 20 mg and zolpidem 10 mg; study 2, 23 patients received gaboxadol 5 mg and 15 mg. Treatments were administered during two nights and compared with placebo. Gaboxadol 10, 15 and 20 mg enhanced slow-wave activity (SWA) and theta power. In 1 Hz bins gaboxadol 10 and 20 mg enhanced power up to 9 Hz. In study 2, 15 mg gaboxadol showed a similar effect pattern. Zolpidem suppressed theta and alpha power, and increased sigma power, with no effect on SWA. In the 1 Hz bins zolpidem suppressed power between 5-10 Hz. Gaboxadol dose-dependently increased SWA and theta power in insomniac patients. In contrast, zolpidem did not affect SWA, reduced theta and alpha activity and enhanced sigma power. EEG spectral power differences may be consequences of the different mechanisms of action for zolpidem and the SWS-enhancing agent, gaboxadol.

[Life-threatening sleepwalking (Elpenor's syndrome) in a 10-year-old child].

PubMed

Madigand-Tordjman, M-A; Egler, P-J; Bertran, F; Jokic, M; Guénolé, F

2017-06-01

Though benign in the majority of cases, sleepwalking sometimes causes injuries due, among other causes, to falls. Such accidents can be life-threatening - a situation that has been termed Elpenor syndrome (in reference to an accident experienced by a character in Homer's epic The Odyssey) - in particular when entailing defenestration. This syndrome has been described in adults and adolescents; we report here a case in a child. This 10-year-old girl was admitted at night to our hospital after a 3-m fall at home. She was alert (Glasgow score, 15) at admission; a frontal wound and a deformation of the right wrist were noted. Brain CT scans showed a frontal skull fracture and frontal lobe contusion, wrist x-rays showed a displaced right fracture. The patient underwent urgent neurosurgery (wound excision and suture after reduction of skull fracture) and closed reduction and immobilization of the wrist fracture, both under general anesthesia. She underwent a psychiatric assessment in the intensive care unit 3 days after her fall. She was alert, well-oriented in time and space, and spoke fluently. She had no memory of her fall, only remembering going to bed in the evening before the accident and waking up in the ambulance on the way to the hospital. She displayed no sign of a concurrent mental illness and no suicidal ideas. Her parents reported that the evening of the accident she and her two brothers had all fallen asleep about 11:00 pm while watching TV, in the double bed of the guest room, placed just beside its window. At approximately 1:00 am, her father, who was going to bed and had just made noise in the hall, heard a cry from the guest room. He entered the room immediately and saw the opened window and his daughter lying on the outside ground; the brothers only awakened after the fall. The family had returned 2 days before from a 6-month stay in the United States, with jet-lag, sleep deprivation, and a disorganized sleep/wake rhythm in the patient. There was

Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism.

PubMed

Dang-Vu, Thien Thanh; Zadra, Antonio; Labelle, Marc-Antoine; Petit, Dominique; Soucy, Jean-Paul; Montplaisir, Jacques

2015-01-01

Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness.

Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism

PubMed Central

Dang-Vu, Thien Thanh; Zadra, Antonio; Labelle, Marc-Antoine; Petit, Dominique; Soucy, Jean-Paul; Montplaisir, Jacques

2015-01-01

Background Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. Methods Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. Results During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. Conclusions Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness. PMID:26241047

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem

PubMed Central

Roehrs, Timothy A.; Roth, Thomas

2016-01-01

Study Objectives: Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. Methods: To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23–70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. Results: Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. Conclusions: In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. Clincial Trials Registration: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Roehrs TA, Roth T. Gender differences in the efficacy and safety of chronic nightly zolpidem. J Clin Sleep Med 2016;12(3):319–325. PMID:26446253

Gender Differences in the Efficacy and Safety of Chronic Nightly Zolpidem.

PubMed

Roehrs, Timothy A; Roth, Thomas

2016-03-01

Studies have shown pharmacokinetic differences for hypnotics in women compared to men, but few studies have assessed either short-or long-term differences in efficacy and safety. To evaluate gender differences in the efficacy and safety of chronic nightly zolpidem (10 mg), we did a post hoc assessment of a large clinical trial. In the trial, participants with primary insomnia (n = 89), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia were randomized, double blind, to nightly zolpidem, 10 mg (n = 47) or placebo (n = 42) 30 minutes before bedtime nightly for 12 months. Polysomnographic sleep on 2 nights in months 1 and 8 and likelihood of next-day sleepiness, rebound insomnia, and dose escalation were evaluated in months 1, 4, and 12. Relative to placebo, zolpidem significantly increased sleep efficiency and reduced sleep latency and wake after sleep onset assessed at months 1 and 8, with no differences in efficacy between women and men and no diminution of efficacy over months. On a next-day multiple sleep latency test (MSLT), no residual sedation was observed for either women or men. No rebound insomnia or dose escalation was seen with no gender differences in either. In adults with primary insomnia, nightly zolpidem administration showed no gender differences in acute or chronic efficacy or in next-day sleepiness. Zolpidem remained efficacious and safe across 12 months. CLINCIAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. © 2016 American Academy of Sleep Medicine.

Effects of zolpidem and zopiclone on cognitive and attentional function in young healthy volunteers: an event-related potential study.

PubMed

Nakajima, T; Takazawa, S; Hayashida, S; Nakagome, K; Sasaki, T; Kanno, O

2000-02-01

The effects of zolpidem and zopiclone, non-benzodiazepine ultra-short-acting hypnotics, on cognitive function and vigilance level were investigated in the morning following nocturnal administration using event-related potentials (ERP) and a sleep latency test (SLT). Zopiclone significantly shortened the sleep latency the following morning, whereas zolpidem did not, perhaps due to the difference in the elimination half-lives between the compounds. No significant effect was observed for either drug on the ERP indices, including the P3, mismatch negativity and negative difference components. At a clinically prescribed dosage these sleep inducers have no remarkable effect on cognitive or attentional functions but increase sleepiness of the subjects.

Comparative effects of melatonin, zolpidem and diazepam on sleep, body temperature, blood pressure and heart rate measured by radiotelemetry in Wistar rats.

PubMed

Mailliet, F; Galloux, P; Poisson, D

2001-08-01

The role of melatonin (MLT) in mediating the sleep-wake cycle has been previously suspected of indicating that this substance could be a candidate for a new generation of hypnotics. We investigated whether MLT acted as a sleep promoter or a modulator of sleep temporal timing related to cardiovascular and body temperature (Tb) adaptations to sleep induction. The pharmacological effects of MLT on sleep were compared with zolpidem (ZP) and diazepam (DZ). The radiotelemetry system was used to record the electrocorticogram [slow wave sleep (SWS), paradoxical sleep (PS)], Tb, blood pressure and heart rate in six Wistar rats. DZ (3 mg/kg and 6 mg/kg), ZP (1, 3, 5 and 10 mg/kg) and MLT (2.5 and 5 mg/kg) were delivered intraperitoneally during light (L) and dark (D) periods. MLT increased the number of sleep cycles (L: 30%, D: 110%) and total duration (P<0.05) of PS (L: 70%, D: 150%). In return, ZP (10 mg/kg) presented no effect during L but increased total (40%) and mean duration (37%) of SWS during the D period. DZ modified mean duration of SWS (L: -27%, D: +26%) and increased total duration of SWS (+47%). ZP and DZ induced a more pronounced decrease in Tb than MLT but only DZ induced tachycardia and hypertension. We showed that MLT could not promote sleep and its cardiovascular adaptations despite hypothermia, but modulated the period of ultradian sleep cycles. DZ and ZP promoted sleep and induced hypothermia during the D period. Only DZ disrupted sleep architecture and induced adverse effects on cardiovascular parameters.

Design and in vitro evaluation of multiparticulate floating drug delivery system of zolpidem tartarate.

PubMed

Amrutkar, P P; Chaudhari, P D; Patil, S B

2012-01-01

Zolpidem tartarate is a non-benzodiazepine, sedative-hypnotic, which finds its major use in various types of insomnia. The present work relates to development of multiparticulate floating drug delivery system based on gas generation technique to prolong the gastric residence time and to increase the overall bioavailability. Modified release dosage form of zolpidem tartarate adapted to release over a predetermined time period, according to biphasic profile of dissolution, where the first phase is immediate release phase for inducing the sleep and the second phase is modified release phase for maintaining the sleep up to 10 h. The system consists of zolpidem tartarate layered pellets coated with effervescent layer and polymeric membrane. The floating ability and in vitro drug release of the system were dependent on amount of the effervescent agent (sodium bicarbonate) layered onto the drug layered pellets, and coating level of the polymeric membrane (Eudragit(®) NE 30D). The system could float completely within 5 min and maintain the floating over a period of 10 h. The multiparticulate floating delivery system of zolpidem tartarate with rapid floating and modified drug release was obtained. Copyright © 2011 Elsevier B.V. All rights reserved.

Scalp and Source Power Topography in Sleepwalking and Sleep Terrors: A High-Density EEG Study

PubMed Central

Castelnovo, Anna; Riedner, Brady A.; Smith, Richard F.; Tononi, Giulio; Boly, Melanie; Benca, Ruth M.

2016-01-01

Study Objectives: To examine scalp and source power topography in sleep arousals disorders (SADs) using high-density EEG (hdEEG). Methods: Fifteen adult subjects with sleep arousal disorders (SADs) and 15 age- and gender-matched good sleeping healthy controls were recorded in a sleep laboratory setting using a 256 channel EEG system. Results: Scalp EEG analysis of all night NREM sleep revealed a localized decrease in slow wave activity (SWA) power (1–4 Hz) over centro-parietal regions relative to the rest of the brain in SADs compared to good sleeping healthy controls. Source modelling analysis of 5-minute segments taken from N3 during the first half of the night revealed that the local decrease in SWA power was prominent at the level of the cingulate, motor, and sensori-motor associative cortices. Similar patterns were also evident during REM sleep and wake. These differences in local sleep were present in the absence of any detectable clinical or electrophysiological sign of arousal. Conclusions: Overall, results suggest the presence of local sleep differences in the brain of SADs patients during nights without clinical episodes. The persistence of similar topographical changes in local EEG power during REM sleep and wakefulness points to trait-like functional changes that cross the boundaries of NREM sleep. The regions identified by source imaging are consistent with the current neurophysiological understanding of SADs as a disorder caused by local arousals in motor and cingulate cortices. Persistent localized changes in neuronal excitability may predispose affected subjects to clinical episodes. Citation: Castelnovo A, Riedner BA, Smith RF, Tononi G, Boly M, Benca RM. Scalp and source power topography in sleepwalking and sleep terrors: a high-density EEG study. SLEEP 2016;39(10):1815–1825. PMID:27568805

The effects of diazepam and zolpidem on cocaine- and amphetamine-induced place preference.

PubMed

Meririnne, E; Kankaanpää, A; Lillsunde, P; Seppälä, T

1999-01-01

Drugs such as benzodiazepines, which enhance the effects of inhibitory neurotransmitter gamma-amino butyric acid (GABA), are known to modulate the mesocorticolimbic dopaminergic system, which is considered to mediate the rewarding effects of psychostimulants. The effects of diazepam, a benzodiazepine that binds unspecifically to omega 1- (omega1-) and omega2-receptors, and zolpidem, a nonbenzodiazepine drug that binds preferentially to omega1-receptors, on cocaine- and amphetamine-induced place preference were evaluated in Wistar rats. In tests using the counterbalanced method, neither diazepam (0.2, 1, and 5 mg/kg) nor zolpidem (2.5, 5, and 10 mg/kg) alone induced place preference or place aversion. Diazepam pretreatment prevented both cocaine- and amphetamine-induced (15 and 9 mg/kg, respectively) place preference; however, at doses that were earlier shown to cause sedation and amnesia, zolpidem failed to prevent either cocaine- or amphetamine-induced place preference. These results suggest that diazepam interferes with the rewarding properties of the psychostimulants, whereas zolpidem is less effective in this respect, possibly due to differential distribution of omega1- and omega2-receptors in the brain.

Not Only Sleepwalking But NREM Parasomnia Irrespective of the Type Is Associated with HLA DQB1*05:01.

PubMed

Heidbreder, Anna; Frauscher, Birgit; Mitterling, Thomas; Boentert, Matthias; Schirmacher, Anja; Hörtnagl, Paul; Schennach, Harald; Massoth, Christina; Happe, Svenja; Mayer, Geert; Young, Peter; Högl, Birgit

2016-04-15

Despite the high prevalence and clinical relevance of NREM parasomnias, data on supportive genetic markers are scarce, and mainly refer to sleepwalking only. We retrospectively analyzed clinical, polysomnographic, and HLA findings of 74 adults (37 men) with NREM parasomnia gathered from four neurological sleep centers. Parasomniac events were classified according to ICSD-2 criteria. HLA DQB1 genotyping was compared to regional-matched reference allele-frequencies. Fifty-six patients had more than 2 different parasomnia type: 11 sleepwalking, 4 sleep terrors, 3 confusional arousals only. Parasomniac events were documented during video-polysomnography (V-PSG) in 70% (49/70) of subjects (71.4% confusional arousals, 8.2% sleep terrors, 4.1% sleepwalking, 16.3% ≥ 2 NREM parasomnia types). Violent behavior during V-PSG occurred in 8.5% (6/71). NREM parasomnia onset was reported after the age of 30 years in 6.8% (5/74). The HLA DQB1*05:01 allele was present in 41% (29/71) compared to 24.2% in the regional-matched reference allele group (p < 0.05). This haplotype prevalence did not differ within the NREM parasomnia type. Epworth Sleepiness Score was 10 or higher in 28.6%. This is a large polysomnography-based case series of patients with NREM parasomnia. In patients with suspected sleepwalking or sleep terrors, polysomnography is highly useful in detecting arousals from NREM sleep as a marker of NREM parasomnia. We confirmed previous findings by demonstrating a high prevalence of the HLA DQB1*05:01 genotype for different types of NREM parasomnias. Our findings therefore support a common genetic background, and corroborate the importance of video-polysomnography in the work-up of parasomnia. © 2016 American Academy of Sleep Medicine.

Zolpidem and traffic safety - the importance of treatment compliance.

PubMed

Verster, Joris C; Volkerts, Edmund R; Olivier, Berend; Johnson, William; Liddicoat, Laura

2007-09-01

Zolpidem is among the most frequently prescribed hypnotic drugs for those who suffer from insomnia. Recent media reports drew attention to driving impairment after zolpidem misuse. This review summarizes the available data on the effects of recommended use and misuse of zolpidem on driving ability and traffic safety. Both experimental studies and roadside evidence were taken into account. From these studies it must be concluded that patients should fully comply with the prescription instructions of zolpidem, i.e. to take the medication just prior to a full 8 hours of uninterrupted sleep. If this strategy is adopted, zolpidem is a safe alternative to benzodiazpine hypnotics and zopiclone who do show significant driving impairment the morning following bedtime administration. However, to ensure traffic safety higher dosages than recommended (10 mg) or allowing less than 8 hours between zolpidem intake and actual operation of a motor vehicle should be avoided.

Sleep Talking (Somniloquy)

MedlinePlus

... Overview & Facts Symptoms & Risk Factors Diagnosis & Treatment Sleep Terrors Overview & Facts Symptoms & Risk Factors Diagnosis & Treatment Sleep ... radius: Email Print Parasomnias Confusional Arousals Sleepwalking Sleep Terrors Sleep Eating Disorder REM Sleep Behavior Disorder Sleep ...

Quetiapine-induced sleep-related eating disorder-like behavior: a case series.

PubMed

Tamanna, Sadeka; Ullah, M Iftekhar; Pope, Chelle R; Holloman, Garland; Koch, Christian A

2012-11-06

Somnambulism or sleepwalking is a disorder of arousal from non-rapid eye movement sleep. The prevalence of sleep-related eating disorder has been found to be approximately between 1% and 5% among adults. Many cases of medication-related somnambulism and sleep-related eating disorder-like behavior have been reported in the literature. Quetiapine, an atypical antipsychotic medication, has been associated with somnambulism but has not yet been reported to be associated with sleep-related eating disorder. Case 1 is a 51-year-old obese African American male veteran with a body mass index of 34.11kg/m2 and severe sleep apnea who has taken 150mg of quetiapine at bedtime for more than one year for depression. He developed sleepwalking three to four nights per week which resolved after stopping quetiapine while being compliant with bi-level positive pressure ventilation therapy. At one year follow-up, his body mass index was 32.57kg/m2.Case 2 is a 50-year-old African American female veteran with a body mass index of 30.5kg/m2 and mild sleep apnea who has taken 200mg of quetiapine daily for more than one year for depression. She was witnessed to sleepwalk three nights per week which resolved after discontinuing quetiapine while being treated with continuous positive airway pressure. At three months follow-up, her body mass index was 29.1kg/m2. These cases illustrate that quetiapine may precipitate complex motor behavior including sleep-related eating disorder and somnambulism in susceptible patients. Atypical antipsychotics are commonly used in psychiatric and primary care practice, which means the population at risk of developing parasomnia may often go unrecognized. It is important to recognize this potential adverse effect of quetiapine and, to prevent injury and worsening obesity, discuss this with the patients who are prescribed these medications.

Sleep Disorders

MedlinePlus

... Narcolepsy - daytime "sleep attacks" Nightmares, night terrors, sleepwalking, sleep talking, head banging, wetting the bed and grinding your teeth are kinds of sleep problems called parasomnias. There are treatments for most ...

Topiramate-induced somnambulism in a migraineur: a probable idiosyncratic adverse effect.

PubMed

Mathew, Thomas; Sarma, G R K; Nadig, Raghunandan; Varghese, Raji

2012-04-15

Somnambulism (sleepwalking) is a disorder of arousal that falls under "parasomnia" group and is more common in children. These phenomena occur as primary sleep events or secondary to systemic disease or can be drug induced. Medications that can cause sleepwalking include neuroleptics, hypnotics, lithium, amitriptyline, and β-blockers. This report presents an unusual adverse effect of topiramate on sleep in a patient with migraine.

Implication of mGlu5 receptor in the enhancement of morphine-induced hyperlocomotion under chronic treatment with zolpidem.

PubMed

Shibasaki, Masahiro; Ishii, Kazunori; Masukawa, Daiki; Ando, Koji; Ikekubo, Yuiko; Ishikawa, Yutori; Shibasaki, Yumiko; Mori, Tomohisa; Suzuki, Tsutomu

2014-09-05

Long-term exposure to zolpidem induces drug dependence, and it is well known that the balance between the GABAergic and glutamatergic systems plays a critical role in maintaining the neuronal network. In the present study, we investigated the interaction between GABAA receptor α1 subunit and mGlu5 receptor in the limbic forebrain including the N.Acc. after treatment with zolpidem for 7 days. mGlu5 receptor protein levels were significantly increased after treatment with zolpidem for 7 days, and this change was accompanied by the up-regulation of phospholipase Cβ1 and calcium/calmodulin-dependent protein kinase IIα, which are downstream of mGlu5 receptor in the limbic forebrain. To confirm that mGlu5 receptor is directly involved in dopamine-related behavior in mice following chronic treatment with zolpidem, we measured morphine-induced hyperlocomotion after chronic treatment with zolpidem in the presence or absence of an mGlu5 receptor antagonist. Although chronic treatment with zolpidem significantly enhanced morphine-induced hyperlocomotion, this enhancement of morphine-induced hyperlocomotion was suppressed by treating it with the mGlu5 receptor antagonist MPEP. These results suggest that chronic treatment with zolpidem caused neural plasticity in response to activation of the mesolimbic dopaminergic system accompanied by an increase in mGlu5 receptor. Copyright © 2014 Elsevier B.V. All rights reserved.

Topiramate-Induced Somnambulism in a Migraineur: A Probable Idiosyncratic Adverse Effect

PubMed Central

Mathew, Thomas; Sarma, G. R. K.; Nadig, Raghunandan; Varghese, Raji

2012-01-01

Somnambulism (sleepwalking) is a disorder of arousal that falls under “parasomnia” group and is more common in children. These phenomena occur as primary sleep events or secondary to systemic disease or can be drug induced. Medications that can cause sleepwalking include neuroleptics, hypnotics, lithium, amitriptyline, and β-blockers.1 This report presents an unusual adverse effect of topiramate on sleep in a patient with migraine. Citation: Mathew T; Sarma GRK; Nadig R; Varghese R. Topiramate-induced somnambulism in a migraineur: a probable idiosyncratic adverse effect. J Clin Sleep Med 2012;8(2):197-198. PMID:22505867

Sleepwalking episodes are preceded by arousal-related activation in the cingulate motor area: EEG current density imaging.

PubMed

Januszko, Piotr; Niemcewicz, Szymon; Gajda, Tomasz; Wołyńczyk-Gmaj, Dorota; Piotrowska, Anna Justyna; Gmaj, Bartłomiej; Piotrowski, Tadeusz; Szelenberger, Waldemar

2016-01-01

To investigate local arousal fluctuations in adults who received ICSD-2 diagnosis of somnambulism. EEG neuroimaging (eLORETA) was utilized to compare current density distribution for 4s epochs immediately preceding sleepwalking episode (from -4.0 s to 0 s) to the distribution during earlier 4s epochs (from -8.0 s to -4.0 s) in 20 EEG segments from 15 patients. Comparisons between eLORETA images revealed significant (t>4.52; p<0.05) brain activations before onset of sleepwalking, with greater current density within beta 3 frequency range (24-30 Hz) in Brodmann areas 33 and 24. Sleepwalking motor events are associated with arousal-related activation of cingulate motor area. These results support the notion of blurred boundaries between wakefulness and NREM sleep in sleepwalking. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Hypnotics in insomnia: the experience of zolpidem.

PubMed

MacFarlane, James; Morin, Charles M; Montplaisir, Jacques

2014-11-01

One of the most commonly prescribed medications to treat insomnia is zolpidem, a nonbenzodiazepine compound that is available as an immediate-release oral tablet formulation, an extended-release oral formulation, an oral spray formulation, and as sublingual formulations. The purpose of this review was to summarize the data currently available on the efficacy and safety of zolpidem in the treatment of insomnia among adults. Published studies on the use of zolpidem in the treatment of insomnia were identified by using combinations of relevant search terms in PubMed and Google Scholar. Studies were included if they were placebo- or active comparator-controlled studies, with the exception of trials on the long-term use of zolpidem. Studies were limited to those conducted in adults. Studies were not included if the patient population was small, if the study was not designed or powered to assess the efficacy or safety of zolpidem, if insomniac patients had a medical condition in addition to insomnia (with the exception of comorbid depression or anxiety for studies on comorbid insomnia), or if zolpidem was given concomitantly with any other therapy (with the exception of selective serotonin reuptake inhibitors for studies on comorbid insomnia). Twenty-five studies designed to evaluate the efficacy of zolpidem in insomnia and 51 studies reporting the safety of zolpidem in insomnia were included in this review. The studies discussed in this review report the efficacy and safety of zolpidem in both young adults and the elderly. It can be used for either bedtime or middle-of-the-night administration, over the short or long term, with minimal risk of withdrawal or abuse. The use of zolpidem is associated with rebound insomnia, complex sleep-related behaviors, and next-day residual effects (after middle-of-the-night dosing) on driving ability, memory, and psychomotor performance. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Complex dream-enacting behavior in sleepwalking.

PubMed

Pillmann, Frank

2009-02-01

Currently, dream-enacting behaviors are viewed as occurring typically in association with a REM-sleep behavior disorder. In some cases, dream-like mentation is found also in non-REM parasomnia. We report a case of complex and dramatic sleepwalking behavior in a 26-year-old adult male who tied his 4-month-old daughter to the clothesline in the attic of his house. The explanation of this seemingly senseless behavior, which was related to psychosocial stressors, was found in a detailed dream-like mentation that was reported by the patient. At the same time, an organic factor, namely, a worsening of the patient's asthma, was identified as the cause of an increased fragmentation of sleep. In some cases of non-REM parasomnia, detailed dream-like mentation may act as a bridge between psychosocial stressors and the specific parasomnic behavior.

Quetiapine-induced sleep-related eating disorder-like behavior: a case series

PubMed Central

2012-01-01

Introduction Somnambulism or sleepwalking is a disorder of arousal from non-rapid eye movement sleep. The prevalence of sleep-related eating disorder has been found to be approximately between 1% and 5% among adults. Many cases of medication-related somnambulism and sleep-related eating disorder-like behavior have been reported in the literature. Quetiapine, an atypical antipsychotic medication, has been associated with somnambulism but has not yet been reported to be associated with sleep-related eating disorder. Case presentation Case 1 is a 51-year-old obese African American male veteran with a body mass index of 34.11kg/m2 and severe sleep apnea who has taken 150mg of quetiapine at bedtime for more than one year for depression. He developed sleepwalking three to four nights per week which resolved after stopping quetiapine while being compliant with bi-level positive pressure ventilation therapy. At one year follow-up, his body mass index was 32.57kg/m2. Case 2 is a 50-year-old African American female veteran with a body mass index of 30.5kg/m2 and mild sleep apnea who has taken 200mg of quetiapine daily for more than one year for depression. She was witnessed to sleepwalk three nights per week which resolved after discontinuing quetiapine while being treated with continuous positive airway pressure. At three months follow-up, her body mass index was 29.1kg/m2. Conclusion These cases illustrate that quetiapine may precipitate complex motor behavior including sleep-related eating disorder and somnambulism in susceptible patients. Atypical antipsychotics are commonly used in psychiatric and primary care practice, which means the population at risk of developing parasomnia may often go unrecognized. It is important to recognize this potential adverse effect of quetiapine and, to prevent injury and worsening obesity, discuss this with the patients who are prescribed these medications. PMID:23130910

Temazepam, but not zolpidem, causes orthostatic hypotension in astronauts after spaceflight

NASA Technical Reports Server (NTRS)

Shi, Shang-Jin; Garcia, Kathleen M.; Meck, Janice V.

2003-01-01

Insomnia is a common symptom, not only in the adult population but also in many astronauts. Hypnotics, such as temazepam (a benzodiazepine) and zolpidem (an imidazopyridine), are often taken to relieve insomnia. Temazepam has been shown clinically to have hemodynamic side effects, particularly in the elderly; however, the mechanism is not clear. Zolpidem does not cause hemodynamic side effects. The purpose of this study was to determine whether the use of different hypnotics during spaceflight might contribute significantly to the high incidence of postflight orthostatic hypotension, and to compare the findings in astronauts with clinical research. Astronauts were separated into three groups: control (n = 40), temazepam (15 or 30 mg; n = 9), and zolpidem (5 or 10 mg; n = 8). In this study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand tests before spaceflight and on landing day. On landing day, systolic pressure decreased significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight when astronauts are hemodynamically compromised. Temazepam should not be the initial choice as a sleeping aid for astronauts. These results in astronauts may help to explain the hemodynamic side effects in the elderly who are also compromised. Zolpidem may be a better choice as a sleeping aid in these populations.

Prevalence of Sleepwalking: A Systematic Review and Meta-Analysis.

PubMed

Stallman, Helen M; Kohler, Mark

2016-01-01

Sleepwalking is thought to be a common arousal disorder; however, the epidemiology of this disorder has not yet been systematically examined. A systematic search of MEDLINE, CINAHL, EMBASE, PsycINFO, PubMed, and ScienceDirect was conducted for 'sleepwalking' OR 'somnambulism' in any field, to identify studies that reported the epidemiology of sleepwalking or sleepwalking disorders. Fifty-one studies assessed the prevalence rates of sleepwalking in a total sample of 100 490. The meta-analysis showed the estimated lifetime prevalence of sleepwalking was 6.9% (95% CI 4.6%-10.3%). The current prevalence rate of sleepwalking-within the last 12 months-was significantly higher in children 5.0% (95% CI 3.8%-6.5%) than adults 1.5% (95% CI 1.0%-2.3%). There was no evidence of developmental trends in sleepwalking across childhood. The significant risk of bias across all studies suggests these results should be used cautiously. Further epidemiological research that addresses methodological problems found in studies of sleepwalking to date is needed.

Self-reported sleepwalking in Australian senior secondary school students.

PubMed

Stallman, H M; Kohler, M; Wilson, A; Biggs, S; Dollman, J; Martin, J; Kennedy, D; Lushington, K

2016-09-01

Few studies have examined self-reported sleepwalking in older adolescents. The aim of this study was to examine the prevalence rates of sleepwalking in a one-month self-report period in Australian adolescents. Participants were 532 Australian adolescents in their final two years of secondary school. The prevalence of sleepwalking in the one-month self-report period was 2.9% (95% confidence interval (CI) 1.47-4.33) in this sample-1% reported sleepwalking at least once a week in the previous month. A significant proportion (17.5%) of the participants was unsure if they had sleepwalked. The results provide data on the self-reported prevalence rate of sleepwalking in older adolescents. Compared with the population data, this rate falls within the confidence intervals of child and adult prevalence rates of sleepwalking and is consistent with a decline in sleepwalking from childhood and adulthood. Further research is needed to explore how adolescents know they sleepwalk to understand the reliability of self-report measures. Copyright © 2016 Elsevier B.V. All rights reserved.

Some Sleep Drugs Can Impair Driving

MedlinePlus

... prescribed sleep medications. Some sleep drugs contain an extended-release form of zolpidem that stays in the ... the regular form. FDA is particularly concerned about extended-release forms of zolpidem. They are sold as ...

Long-Term Maintenance of Therapeutic Gains Associated With Cognitive-Behavioral Therapy for Insomnia Delivered Alone or Combined With Zolpidem.

PubMed

Beaulieu-Bonneau, Simon; Ivers, Hans; Guay, Bernard; Morin, Charles M

2017-03-01

To document the long-term sleep outcomes at 12 and 24 months after patients with chronic insomnia were treated with cognitive-behavioral therapy (CBT), either singly or combined with zolpidem medication. Participants were 160 adults with chronic insomnia. They were first randomized for a six-week acute treatment phase involving CBT alone or CBT combined with nightly zolpidem, and randomized for a six-month extended treatment phase involving CBT, no additional treatment, CBT combined with zolpidem as needed, or CBT with zolpidem tapered. This paper reports results of the 12- and 24-month follow-ups on the main outcome measures derived from the Insomnia Severity Index and sleep diaries. Clinical improvements achieved 6 months following the end of treatment were well-maintained in all four conditions, with insomnia remission rates ranging from 48% to 74% at the 12-month follow-up, and from 44% to 63% at the 24-month follow-up. Participants receiving CBT with zolpidem taper in the extended treatment phase had significantly better results than those receiving CBT with continued zolpidem as needed. The magnitude of improvements on sleep diary parameters was similar between conditions, with a slight advantage for the CBT with zolpidem taper condition. The addition of extended CBT did not alter the long-term outcome over improvements obtained during the initial 6-week CBT. The results suggest that CBT for insomnia, when delivered alone or in combination with medication, produce durable sleep improvements up to two years after completion of treatment. These long-term results indicate that even if a combined CBT plus medication approach provide an added benefit immediately after treatment, extending CBT while tapering medication produce better sustained improvements compared to continued use of medication as needed. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e

Sleep-related automatism and the law.

PubMed

Ebrahim, Irshaad Osman; Fenwick, Peter

2008-04-01

Crimes carried out during or arising from sleep highlight many difficulties with our current law and forensic sleep medicine clinical practice. There is a need for clarity in the law and agreement between experts on a standardised form of assessment and diagnosis in these challenging cases. We suggest that the time has come for a standardised, internationally recognised diagnostic protocol to be set as a minimum standard in all cases of suspected sleep-related forensic cases. The protocol of a full medical history, sleep history, psychiatric history, neuropsychiatric and psychometric examination and electroencephalography (EEG), should be routine. It should now be mandatory to carry out routine polysomnography (PSG) to establish the presence of precipitating and modulating factors. Sleepwalking is classified as insane automatism in England and Wales and sudden arousal from sleep in a non-sleepwalker as sane automatism. The recent case in England of R v. Lowe (2005) highlights these anomalies. Moreover, the word insanity stigmatises sleepwalkers and should be dropped. The simplest solution to these problems would be for the law to be changed so that there is only one category of defence for all sleep-related offences--not guilty by reason of sleep disorder. This was rejected by the House of Lords for cases of automatism due to epilepsy, and is likely to be rejected for sleepwalkers. Removing the categories of automatism (sane or insane) would be the best solution. Risk assessment is already standard practice in the UK and follow up, subsequent to disposal, by approved specialists should become part of the sentencing process. This will provide support for the defendant and protection of the public.

Arousability and Fall Risk During Forced Awakenings From Nocturnal Sleep Among Healthy Males Following Administration of Zolpidem 10 mg and Doxepin 6 mg: A Randomized, Placebo-Controlled, Four-Way Crossover Trial.

PubMed

Drake, Christopher L; Durrence, Heith; Cheng, Philip; Roth, Thomas; Pillai, Vivek; Peterson, Edward L; Singh, Meeta; Tran, Kieulinh Michelle

2017-07-01

To examine and compare the arousability threshold and fall risk upon awakening of doxepin (6 mg) versus zolpidem (10 mg). A total of 52 healthy adult males were included in a double-blind, placebo-controlled, four-way crossover study. The experimental procedure included four nights with polysomnography in the lab (zolpidem, doxepin, and their respective placebo conditions). Arousability was measured using an auditory awakening threshold delivered at the peak-plasma concentration for the active hypnotics and at matched times for the respective placebo conditions. Fall risk during the night was measured following awakening using the Berg Balance Scale and the Tandem Walk Task. Both arousability and fall risk were lower in the doxepin condition compared to the zolpidem condition. Furthermore, arousability and fall risk for doxepin did not differ significantly from the placebo conditions. A significantly greater proportion of participants in the zolpidem condition (63.5%) did not wake until receiving the loudest tone (110 dB) as compared to the doxepin (17.6%) and placebo conditions (17.3%, 5.8%). Results suggest that zolpidem has greater risks for balance and awakening threshold compared with low-dose doxepin. Future prospective studies should extend results to clinical samples with population-level risk of injury and arousability. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Prevalence of Sleepwalking: A Systematic Review and Meta-Analysis

PubMed Central

Kohler, Mark

2016-01-01

Sleepwalking is thought to be a common arousal disorder; however, the epidemiology of this disorder has not yet been systematically examined. A systematic search of MEDLINE, CINAHL, EMBASE, PsycINFO, PubMed, and ScienceDirect was conducted for ‘sleepwalking’ OR ‘somnambulism’ in any field, to identify studies that reported the epidemiology of sleepwalking or sleepwalking disorders. Fifty-one studies assessed the prevalence rates of sleepwalking in a total sample of 100 490. The meta-analysis showed the estimated lifetime prevalence of sleepwalking was 6.9% (95% CI 4.6%–10.3%). The current prevalence rate of sleepwalking—within the last 12 months—was significantly higher in children 5.0% (95% CI 3.8%–6.5%) than adults 1.5% (95% CI 1.0%–2.3%). There was no evidence of developmental trends in sleepwalking across childhood. The significant risk of bias across all studies suggests these results should be used cautiously. Further epidemiological research that addresses methodological problems found in studies of sleepwalking to date is needed. PMID:27832078

Twelve Months of Nightly Zolpidem Does Not Lead to Dose Escalation: A Prospective Placebo-Controlled Study

PubMed Central

Roehrs, Timothy A.; Randall, Surilla; Harris, Erica; Maan, Renee; Roth, Thomas

2011-01-01

Study Objectives: To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. Design: Randomized, double-blind, placebo-controlled, clinical trial. Setting: Outpatient with tri-monthly one-week, sleep laboratory assessments. Participants: Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32–64 yrs old, 14 men and 19 women. Interventions: Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color-coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. Results: Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self-administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self-administered. Conclusions: Zolpidem was preferred to placebo, but its self-administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation. Clinical Trial Registration: Safety and Efficacy of Chronic Hypnotic Use; # NCT01006525; http://www.clinicaltrials.gov/ Citation: Roehrs TA; Randall S; Harris E; Maan R; Roth T. Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo

Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson's Disease? The Potential Role of Zolpidem in the Treatment of Parkinson's Disease

PubMed Central

Daniele, Antonio; Panza, Francesco; Greco, Antonio; Logroscino, Giancarlo; Seripa, Davide

2016-01-01

At present, patients with advanced Parkinson's disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD. PMID:27293955

Clinically important drug interactions with zopiclone, zolpidem and zaleplon.

PubMed

Hesse, Leah M; von Moltke, Lisa L; Greenblatt, David J

2003-01-01

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The

Involvement of nitrergic system in anticonvulsant effect of zolpidem in lithium-pilocarpine induced status epilepticus: Evaluation of iNOS and COX-2 genes expression.

PubMed

Eslami, Seyyed Majid; Ghasemi, Maryam; Bahremand, Taraneh; Momeny, Majid; Gholami, Mahdi; Sharifzadeh, Mohammad; Dehpour, Ahmad Reza

2017-11-15

This study aims to investigate the role of zolpidem in lithium-pilocarpine induced status epilepticus (SE) and probable mechanisms involved in seizure threshold alteration. In the present study, lithium chloride (127mg/kg) was administered 20h prior to pilocarpine (60mg/kg) to induce SE in adult male Wistar rats. Different doses of zolpidem (0.1, 1, 2, 5, 10mg/kg) were injected 30min before pilocarpine administration. Furthermore, to find out whether nitric oxide (NO) plays a role in the observed effect, L-arginine and L-NAME were injected 15min before zolpidem. Afterward, we identified the particular NO isoform mediating the effect of zolpidem by injecting aminoguanidine (AG) and 7-Nitroindazole (7-NI) 15min prior to zolpidem. Moreover, in both 6 and 24h after pilocarpine injection, experimental groups underwent hippocampectomy to evaluate cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes expression by quantitative reverse transcription-PCR (qRT-PCR). Pre-treatment with zolpidem significantly prevented the onset of SE in a dose-dependent manner. AG and L-NAME significantly potentiated the anticonvulsant effect of zolpidem while L-arginine inverted this effect. Our qRT-PCR exerted that there was a continuous elevation of iNOS and COX-2 genes expression over 6 and 24h after pilocarpine administration in SE and L-arginine+Zolpidem groups while in AG/L-NAME+Zolpidem and zolpidem groups this upregulation was prevented. Our study indicates that zolpidem prevents the onset of SE through inhibition of iNOS/COX-2 genes upregulation following lithium-pilocarpine administration. Consistent with our results, we suggest that iNOS activation could be probably upstream of COX-2 gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.

A biopsychosocial model of violence when sleepwalking: review and reconceptualisation

PubMed Central

Bari, Andrea

2017-01-01

Summary Violence towards others during sleepwalking is relatively uncommon, but can result in serious injury or even death. Much of the research in this field has focused on the forensic consequences of violence during sleepwalking without sufficient attention to an understanding of the risk factors for violence during sleepwalking and the development of prevention and interventions based on these risk factors. This paper reviews the characteristics of impulsive violence in general and reconceptualises violence during sleepwalking as an extension of this prior vulnerability. We propose a biopsychosocial model of the risk for violence during sleepwalking that is supported through a review of empirical literature both within sleepwalking and violent behaviour more generally. Biological, psychological and social risk factors are hypothesised to mediate the relationship between sleepwalking and violence. Implications for prevention and treatment of this potentially fatal problem are discussed. Declaration of interest None. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID:28446961

Zolpidem prescribing and adverse drug reactions in hospitalized general medicine patients at a Veterans Affairs hospital.

PubMed

Mahoney, Jane E; Webb, Melissa J; Gray, Shelly L

2004-03-01

Zolpidem is prescribed for sleep disruption in hospitalized patients, but data on the incidence of adverse drug reactions (ADRs) are based largely on outpatient studies. Thus, the incidence of ADRs in hospitalized patients may be much higher. The goal of this study was to describe prescribing patterns of zolpidem for hospitalized medical patients aged 50 years, the incidence of ADRs possibly and probably associated with its use, and the factors associated with central nervous system (CNS) ADRs. This case series was conducted in 4 general medicine wards at a Veterans Affairs hospital and was a consecutive sample of patients aged 50 years who were hospitalized between 1993 and 1997 and received zolpidem as a hypnotic during hospitalization, but had not received it in the previous 3 months. Chart review was conducted by 2 evaluators. Data extracted from the medical records included admission demographic characteristics, medications, comorbidities, and levels of function in performing basic and instrumental activities of daily living. The main outcome measure was ADRs possibly or probably related to zolpidem use. The association between zolpidem and the occurrence of CNS ADRs (eg, confusion, dizziness, daytime somnolence) was analyzed separately. The review included 119 medical patients aged > or =50 years who had newly received zolpidem for sleep disruption during hospitalization. The median age of the population was 70 years; 86 (72.3%) patients were aged 65 years. The initial zolpidem dose was 5 mg in 42 patients (35.3%) and 10 mg in 77 patients (64.7%). Twenty-three patients had a respective 16 and 10 ADRs possibly and probably related to zolpidem use (19.3% incidence). Of a total of 26 ADRs, 21 (80.8%) were CNS ADRs, occurring with both zolpidem 5 mg (10.8% of users) and 10 mg (18.3% of users). On univariate analyses, the only factor significantly associated with a CNS ADR was functional impairment at baseline (P = 0.003). Zolpidem was discontinued in 38.8% of

[Sleep deprivation in somnambulism. Effect of arousal, deep sleep and sleep stage changes].

PubMed

Mayer, G; Neissner, V; Schwarzmayr, P; Meier-Ewert, K

1998-06-01

Diagnosis of parasomnias in the sleep laboratory is difficult since the nocturnal behavior reported by the patients often does not show up in the laboratory. To test the efficacy of sleep deprivation as a tool to provoke somnambulism we investigated ten patients (three women and seven men, mean age 27 +/- 3.4) with somnambulism. Their standard polysomnographies and videomonitored nocturnal behavior was compared to that of sex- and age-matched controls and to polysomnography and behavior after sleep deprivation. Patients with parasomnias and controls did not show significant differences in sleep parameters with the exception of longer arousal duration in controls, which was nonsignificant. In magnetic resonance tomography, patients with parasomnias did not reveal abnormality of the brain that might explain release of nocturnal behavior. Sleep deprivation led to significantly reduced number of arousals, reduced arousal index, significantly prolonged arousal duration and more stage shifts from all sleep stages (nonsignificant). Complex behavior during sleep increased under sleep deprivation, whereas sleepwalking did not increase. The majority of complex behavior during sleep is triggered by stage shifts and not by arousal in the sense of the arousal definition of the American Sleep Disorder Society. Complex behavior in sleep is stereotypical and nonviolent. Its complexity seems to depend on the duration and intensity of arousals. Sleep deprivation can be recommended as an efficacious method of increasing complex behavior in sleep, which is a preliminary stage of sleepwalking. Concerning the underlying pathology it seems to be important to register the quality and duration of stimuli that trigger arousals instead of focusing the number of arousals alone.

Mechanism of action of the hypnotic zolpidem in vivo

PubMed Central

Crestani, Florence; Martin, James R; Möhler, Hanns; Rudolph, Uwe

2000-01-01

Zolpidem is a widely used hypnotic agent acting at the GABAA receptor benzodiazepine site. On recombinant receptors, zolpidem displays a high affinity to α1-GABAA receptors, an intermediate affinity to α2- and α3-GABAA receptors and fails to bind to α5-GABAA receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying α1(H101R) mice, which possess zolpidem-insensitive α1-GABAA receptors, we show that the sedative action of zolpidem is exclusively mediated by α1-GABAA receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by α1-GABAA receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on α1-GABAA receptors and not on α2- or α3-GABAA receptors. PMID:11090095

Defending sleepwalkers with science and an illustrative case.

PubMed

Cartwright, Rosalind D; Guilleminault, Christian

2013-07-15

To test whether laboratory-based research differentiating sleepwalkers (SW) from controls (C) can be applied in an uncontrolled forensic case as evidence the alleged crime was committed during an arousal from sleep in which the mind is not fully conscious due to a SW disorder. A PSG study recorded 8 months after the defendant was charged was analyzed independently by spectral analysis. Slow wave activity (SWA) and cyclic alternating pattern (CAP) rates were computed. Clinical interviews and police records were reviewed for data re: the defendant's sleep prior to the event and use of drugs, alcohol, and stimulants. The SWA distribution was abnormally low and flat, significantly lower than published controls; in the first NREM cycle, CAP rate 55 was above normal. Two weeks of prior sleep deprivation was confirmed from interviews and defendant's observed daytime sleepiness. Caffeine intake the day before the event was calculated at 826 mg over 14 hours. Snoring and a mild breathing disorder were present in the PSG. Testimony based on spectral analysis of PSG recorded following an alleged criminal event supported a SW explanation for the non-rational behaviors charged. The defendant was acquitted of all charges and has been successfully treated.

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

PubMed

Rush, C R; Baker, R W; Rowlett, J K

2000-02-01

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5-15.0 mg), triazolam (0.0625-0.3750 mg), pentobarbital (25-150 mg), caffeine (100-600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines.

Gene expression in the rat cerebral cortex: comparison of recovery sleep and hypnotic-induced sleep.

PubMed

Wisor, J P; Morairty, S R; Huynh, N T; Steininger, T L; Kilduff, T S

2006-08-11

Most hypnotic medications currently on the market target some aspect of GABAergic neurotransmission. Although all such compounds increase sleep, these drugs differentially affect the activity of the cerebral cortex as measured by the electroencephalogram. Whereas benzodiazepine medications such as triazolam tend to suppress slow wave activity in the cortex, the GABA(B) ligand gamma-hydroxybutyrate greatly enhances slow wave activity and the non-benzodiazepine, zolpidem, which binds to the omega1 site on the GABA(A) receptor/Cl(-) ionophore complex, is intermediate in this regard. Our previous studies have demonstrated that a small number of genes exhibit increased expression in the cerebral cortex of the mouse and rat during recovery sleep after sleep deprivation: egr-3, fra-2, grp78, grp94, ngfi-b, and nr4a3. Using these genes as a panel of biomarkers associated with sleep, we asked whether hypnotic medications induce similar molecular changes in the rat cerebral cortex to those observed when both sleep continuity and slow wave activity are enhanced during recovery sleep. We find that, although each drug increases the expression of a subset of genes in the panel of biomarkers, no drug fully replicates the molecular changes in the cortex associated with recovery sleep. Furthermore, high levels of slow wave activity in the cortex are correlated with increased expression of fra-2 whereas the expression of grp94 is correlated with body temperature. These results demonstrate that sleep-related changes in gene expression may be affected by physiological covariates of sleep and wakefulness rather than by vigilance state per se.

Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

PubMed Central

Berdyyeva, Tamara; Otte, Stephani; Aluisio, Leah; Ziv, Yaniv; Burns, Laurie D.; Dugovic, Christine; Yun, Sujin; Ghosh, Kunal K.; Schnitzer, Mark J.; Lovenberg, Timothy; Bonaventure, Pascal

2014-01-01

Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal’s state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (∼65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders. PMID:25372144

Disorders of Arousal From Sleep and Violent Behavior: The Role of Physical Contact and Proximity

PubMed Central

Pressman, Mark R.

2007-01-01

Study Objectives: To review medical and legal case reports to determine how many appear to support the belief that violence against other individuals that occurs during Disorders of Arousal - sleepwalking, confusional arousal, and sleep terrors – is triggered by direct physical contact or close proximity to that individual and does not occur randomly or spontaneously. Design: Historical review of case reports in the medical and legal literature. Measurements and Results: A total of 32 cases drawn from medical and legal literature were reviewed. Each case contained a record of violence associated with Disorders of Arousal; in each, details of the violent behavior were available. Violent behaviors associated with provocations and/or close proximity were found to be present in 100% of confusional arousal patients and 81% of sleep terror patients. Violent behaviors were associated with provocation or close proximity in 40%–90% of sleepwalking cases, depending on whether the legal verdict and other factors were taken into account. Often the provocation was quite minor and the response greatly exaggerated. The specific manner in which the violence was triggered differed among sleepwalking, confusional arousals, and sleep terrors. Conclusions: In the cases reviewed, violent behavior directed against other individuals associated with Disorders of Arousal most frequently appeared to follow direct provocation by, or close proximity to, another individual. Sleepwalkers most often did not seek out victims, but rather the victims sought out or encountered the sleepwalker. These conclusions are tempered by several limitations: the selection of cases was not random and may not represent an accurate sample of violent behaviors associated with Disorders of Arousal. Also, final verdicts by juries in reported legal cases should not be confused with scientific proof of the presence or absence of sleepwalking. The pathophysiology of Disorders of Arousal with and without violent

A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.

PubMed

Erman, Milton K; Zammit, Gary; Rubens, Robert; Schaefer, Kendyl; Wessel, Thomas; Amato, David; Caron, Judy; Walsh, James K

2008-06-15

To evaluate the polysomnographic efficacy and the safety of a range of doses of eszopiclone relative to placebo in patients with primary insomnia. Zolpidem 10 mg was included as an active control. This multicenter, randomized, crossover study enrolled patients aged 21-64 years meeting the DSM-IV criteria for primary insomnia (n = 65). Patients received 2 nights treatment each with placebo, eszopiclone 1 mg, 2 mg, 2.5 mg, or 3 mg, and zolpidem 10 mg after randomization to one of 6 treatment sequences. Visits were separated by a 3-7 day washout. Objective efficacy was assessed by polysomnography (PSG). The primary endpoint was latency to persistent sleep (LPS); key secondary endpoints were sleep efficiency (SE) and wake time after sleep onset (WASO); other endpoints included wake time during sleep (WTDS) and number of awakenings (NAW), as well as patient-reported variables. LPS and SE were significantly different than placebo for all active treatments (p < 0.05 for all). Significant differences from placebo were noted in the 3 objective sleep maintenance measures (WASO, WTDS, and NAW) for eszopiclone 3 mg (p < 0.05), which was not the case for zolpidem 10 mg or the other eszopiclone doses. The incidence of central nervous system adverse events was 23.4% for zolpidem 10 mg, 6.2% to 12.5% for the eszopiclone doses, and 7.9% for placebo. Relative to placebo, all active treatments were effective in reducing LPS and increasing SE. Eszopiclone 3 mg was significantly different from placebo on the 3 PSG measures of sleep maintenance (WASO, WTDS, and NAW). Significant differences between zolpidem 10 mg and eszopiclone (2 mg or 3 mg) were not observed for PSG-measured outcomes, although the study was not powered to detect differences between the active drug conditions.

Hypersynchronous delta waves and somnambulism: brain topography and effect of sleep deprivation.

PubMed

Pilon, Mathieu; Zadra, Antonio; Joncas, Steve; Montplaisir, Jacques

2006-01-01

Hypersynchronous delta activity (HSD) is usually described as several continuous high-voltage delta waves (> or = 150 microV) in the sleep electroencephalogram of somnambulistic patients. However, studies have yielded varied and contradictory results. The goal of the present study was to evaluate HSD over different electroencephalographic derivations during the non-rapid eye movement (NREM) sleep of somnambulistic patients and controls during normal sleep and following 38 hours of sleep deprivation, as well as prior to sleepwalking episodes. N/A. Sleep disorders clinic. Ten adult sleepwalkers and 10 sex- and age-matched control subjects were investigated polysomnographically during a baseline night and following 38 hours of sleep deprivation. N/A. During normal sleep, sleepwalkers had a significantly higher ratio of HSD over the time spent in stage 2, 3 and 4 on frontal and central derivations when compared with controls. Sleep deprivation resulted in a significant increase in the ratio of the time in HSD over the time in stage 4 on the frontal lead in both groups and on the central lead in controls. There was no evidence for a temporal accumulation of HSD prior to the episodes. HSD shows a clear frontocentral gradient across all subjects during both baseline and recovery sleep and has relatively low specificity for the diagnosis of NREM parasomnias. Increases in HSD after sleep deprivation may reflect an enhancement of the homeostatic process underlying sleep regulation.

Disorders of arousal from sleep and violent behavior: the role of physical contact and proximity.

PubMed

Pressman, Mark R

2007-08-01

To review medical and legal case reports to determine how many appear to support the belief that violence against other individuals that occurs during Disorders of Arousal - sleepwalking, confusional arousal, and sleep terrors - is triggered by direct physical contact or close proximity to that individual and does not occur randomly or spontaneously. Historical review of case reports in the medical and legal literature. A total of 32 cases drawn from medical and legal literature were reviewed. Each case contained a record of violence associated with Disorders of Arousal; in each, details of the violent behavior were available. Violent behaviors associated with provocations and/or close proximity were found to be present in 100% of confusional arousal patients and 81% of sleep terror patients. Violent behaviors were associated with provocation or close proximity in 40%-90% of sleepwalking cases, depending on whether the legal verdict and other factors were taken into account. Often the provocation was quite minor and the response greatly exaggerated. The specific manner in which the violence was triggered differed among sleepwalking, confusional arousals, and sleep terrors. In the cases reviewed, violent behavior directed against other individuals associated with Disorders of Arousal most frequently appeared to follow direct provocation by, or close proximity to, another individual. Sleepwalkers most often did not seek out victims, but rather the victims sought out or encountered the sleepwalker. These conclusions are tempered by several limitations: the selection of cases was not random and may not represent an accurate sample of violent behaviors associated with Disorders of Arousal. Also, final verdicts by juries in reported legal cases should not be confused with scientific proof of the presence or absence of sleepwalking. The pathophysiology of Disorders of Arousal with and without violent behavior could be associated with normally occurring deactivation of the

Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users.

PubMed

Cruz, Hans G; Hoever, Petra; Chakraborty, Bijan; Schoedel, Kerri; Sellers, Edward M; Dingemanse, Jasper

2014-04-01

Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40 mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24 h post-dose in 33 evaluable subjects. Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p<0.001). Almorexant 200 mg showed significantly less 'Drug Liking' than both zolpidem doses (p<0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p<0.05), while almorexant 1,000 mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints. This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction.

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

PubMed Central

Hall-Porter, Janine M.; Schweitzer, Paula K.; Eisenstein, Rhody D.; Ahmed, Hasan Ali H.; Walsh, James K.

2014-01-01

Introduction: Numerous studies have demonstrated that sleep promotes memory consolidation, but there is little research on the effect of hypnotics on sleep-dependent memory consolidation. We compared bedtime administration of zolpidem-ER 12.5 mg (6- to 8-h duration of action), middle-of-the-night administration of zaleplon 10 mg (3- to 4-h duration of action), and placebo to examine the effect of different durations of hypnotic drug exposure on memory consolidation during sleep. Methods: Twenty-two participants with no sleep complaints underwent 3 conditions in a counterbalanced crossover study: (1) zolpidem-ER 12.5 mg (bedtime dosing), (2) zaleplon 10 mg (middle-of-the-night dosing), and (3) placebo. Memory testing was conducted before and after an 8-h sleep period, using a word pair association task (WPT; declarative memory) and a finger-tapping task (FTT; procedural memory). Results: ANOVA revealed a significant condition effect for the WPT (p = 0.025) and a trend for the FTT (p = 0.067), which was significant when sex was added to the model (p = 0.014). Improvement in memory performance following sleep was lower with bedtime dosing of zolpidem-ER compared to placebo and middle-of-the-night dosing of zaleplon. There were no differences between placebo and zaleplon. Conclusions: The results suggest that in some circumstances hypnotics may have the potential to reduce the degree of sleep-dependent memory consolidation and that drug-free sleep early in the night may ameliorate this effect. Citation: Hall-Porter JM; Schweitzer PK; Eisenstein RD; Ahmed HAH; Walsh JK. The effect of two benzodiazepine receptor agonist hypnotics on sleep-dependent memory consolidation. J Clin Sleep Med 2014;10(1):27-34. PMID:24426817

Factors that predispose, prime and precipitate NREM parasomnias in adults: clinical and forensic implications.

PubMed

Pressman, Mark R

2007-02-01

Sleepwalking and related disorders are the result of factors that predispose, prime and precipitate episodes. In the absence of one or more of these factors sleepwalking is unlikely to occur. Predisposition to sleepwalking is based on genetic susceptibility and has a familial pattern. Priming factors include conditions and substances that increase slow wave sleep (SWS) or make arousal from sleep more difficult. These factors include sleep deprivation, alcohol, medications, situational stress and fever among others. The patient with a genetic predisposition to sleepwalking and with priming factors still requires a precipitating factor or trigger to set the sleepwalking episode in motion. Classical theories of sleepwalking were based primarily on case reports. Recently some of these theories have been tested in the sleep laboratory. Experimental sleep deprivation studies of sleepwalkers generally report an increase in complex behaviors during SWS, although one prominent study reported the opposite effect. However, the generally accepted theory that alcohol and medications can induce sleepwalking episodes remains entirely based on clinical and forensic case reports. Alleged cases of alcohol related sleepwalking often involve individuals lacking the generally accepted characteristics of sleepwalkers but with very high blood alcohol levels that could in and of itself account for complex behaviors noted without the presence of sleepwalking. Further, the effects of high levels of alcohol dramatically decrease SWS, a finding inconsistent with sleepwalking. Case reports of medication-related induction of apparent sleepwalking most often present a complex medical and psychiatric history associated with multiple medications. These patients often lack the clinical history and other criteria currently required for the diagnosis of sleepwalking. The medication-related behaviors may instead represent some other condition in an awake, but impaired patient. Sleep laboratory

Zolpidem modulation of phasic and tonic GABA currents in the rat dorsal motor nucleus of the vagus

PubMed Central

Gao, Hong; Smith, Bret N.

2010-01-01

Zolpidem is a widely prescribed sleep aid with relative selectivity for GABAA receptors containing α1–3 subunits. We examined the effects of zolpidem on the inhibitory currents mediated by GABAA receptors using whole-cell patch-clamp recordings from DMV neurons in transverse brainstem slices from rat. Zolpidem prolonged the decay time of mIPSCs and of muscimol-evoked whole-cell GABAergic currents, and it occasionally enhanced the amplitude of mIPSCs. The effects were blocked by flumazenil, a benzodiazepine antagonist. Zolpidem also hyperpolarized the resting membrane potential, with a concomitant decrease in input resistance and action potential firing activity in a subset of cells. Zolpidem did not clearly alter the GABAA receptor-mediated tonic current (Itonic) under baseline conditions, but after elevating extracellular GABA concentration with nipecotic acid, a non-selective GABA transporter blocker, zolpidem consistently and significantly increased the tonic GABA current. This increase was suppressed by flumazenil and gabazine. These results suggest that α1–3 subunits are expressed in synaptic GABAA receptors on DMV neurons. The baseline tonic GABA current is likely not mediated by these same low affinity, zolpidem-sensitive GABAA receptors. However, when the extracellular GABA concentration is increased, zolpidem-sensitive extrasynaptic GABAA receptors containing α1–3 subunits contribute to the Itonic. PMID:20226798

Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil.

PubMed

Thornton, Stephen L; Negus, Elezer; Carstairs, Shaun D

2013-11-01

Zolpidem is a widely prescribed anti-insomnia agent. Although most pediatric zolpidem ingestions are benign, large ingestions can cause significant central nervous system (CNS) depression. Flumazenil has been reported to reverse the CNS effects of zolpidem. We describe a case of a large pediatric zolpidem ingestion resulting in profound CNS depression that responded to flumazenil administration. Serial zolpidem serum levels confirmed the ingestion. A 10-year-old boy with trisomy 21 presented to the emergency department 1 hour after he was found sedate with several zolpidem 5-mg tablets in his mouth. Seventeen tables (85 mg) were unaccounted for from a prescription bottle. He became unarousable approximately 2 hours after his ingestion. Flumazenil 0.2 mg intravenously was given with rapid return to his baseline mental status. He became resedate 1 hour later but was arousable. Sixteen hours after his presentation, he was asymptomatic. Serial zolpidem serum levels were obtained, showed an initial level of 310 ng/mL, and demonstrated zero-order kinetics. Zolpidem is an imidazopyridine, which binds to the benzodiazepine receptor. It is rapidly absorbed and has a short-half life. Unintentional pediatric ingestions of zolpidem are typically well tolerated. However, this case demonstrates that large ingestions may cause significant and prolonged CNS depression. Flumazenil, a benzodiazepine receptor antagonist, has been described to reverse the effects of zolpidem in adult ingestions. There are few published reports describing flumazenil use in pediatric ingestion patients. This case suggests that flumazenil may be an effective treatment for zolpidem-induced CNS depression in the pediatric patient.

Involvement of ATP-sensitive potassium channels and the opioid system in the anticonvulsive effect of zolpidem in mice.

PubMed

Sheikhi, Mehdi; Shirzadian, Armin; Dehdashtian, Amir; Amiri, Shayan; Ostadhadi, Sattar; Ghasemi, Mehdi; Dehpour, Ahmad Reza

2016-09-01

Zolpidem is a hypnotic medication that mainly exerts its function through activating γ-aminobutyric acid (GABA)A receptors. There is some evidence that zolpidem may have anticonvulsive effects. However, the mechanisms underlying this effect have not been elucidated yet. In the present study, we used the pentylentetrazole (PTZ)-induced generalized seizure model in mice to investigate whether zolpidem can affect seizure threshold. We also further evaluated the roles of ATP-sensitive potassium (KATP) channels as well as μ-opioid receptors in the effects of zolpidem on seizure threshold. Our data showed that zolpidem in a dose-dependent manner increased the PTZ-induced seizure threshold. The noneffective (i.e., did not significantly alter the PTZ-induced seizure threshold by itself) doses of KATP channel blocker (glibenclamide) and nonselective opioid receptor antagonist (naloxone) were able to inhibit the anticonvulsive effect of zolpidem. Additionally, noneffective doses of either KATP channel opener (cromakalim) or nonselective μ-opioid receptor agonist (morphine) in combination with a noneffective dose of zolpidem exerted a significant anticonvulsive effect on PTZ-induced seizures in mice. A combination of noneffective doses of naloxone and glibenclamide, which separately did not affect zolpidem effect on seizure threshold, inhibited the anticonvulsive effects of zolpidem. These results suggest a role for KATP channels and the opioid system, alone or in combination, in the anticonvulsive effects of zolpidem. Copyright © 2016 Elsevier Inc. All rights reserved.

Eszopiclone and Zolpidem Do Not Affect the Prevalence of the Low Arousal Threshold Phenotype

PubMed Central

Smith, Patrick R.; Sheikh, Karen L.; Costan-Toth, Camille; Forsthoefel, Derek; Bridges, Edward; Andrada, Teotimo F.; Holley, Aaron B.

2017-01-01

Study Objectives: We sought to determine whether non benzodiazepine sedative hypnotics (NBSH) reduce the occurrence of the low arousal threshold (LAT) phenotype. Methods: Consecutive patients with suspected obstructive sleep apnea (OSA) referred for polysomnography (PSG) had demographic and PSG data abstracted. LAT was estimated using PSG criteria. After adjusting for pretest probability (PTP) for OSA, we calculated the effect that premedication with NBSHs has on LAT prevalence. Results: Five hundred seventy-nine patients with a mean age and body mass index of 42.2 ± 10.1 y and 28.9 ± 4.5 kg/m2, respectively, had data available for analysis. Most patients (444, or 80.9%) had a LAT, and administering a NBSH (zolpidem or eszopiclone) on the same night as the PSG did not change LAT prevalence (NBSH: 339 (83.3%) versus no drug: 100 (80.6%); p = 0.50). Adjusting for PTP, neither administration of eszopiclone (odds ratio 0.80 (95% confidence interval: 0.33–2.0); 0.69) nor zolpidem (odds ratio 1.65 (95% confidence interval: 0.8–3.5); p = 0.19) reduced the odds that a patient had a LAT. NBSHs did not change the mean SpO2 nadir, percentage hypopneas, or apnea-hypopnea index. There was no association between zolpidem or eszopiclone dosing and SpO2 nadir (zolpidem: β = −0.69, p = 0.80; eszopiclone: β = −1.53, p = 0.68), percentage hypopneas (zolpidem: β = 2.2, p = 0.43; eszopiclone β = −6.2, p = 0.46), or apnea-hypopnea index (zolpidem: β = 3.1, p = 0.22; eszopiclone: β = 2.6, p = 0.39). Conclusions: The LAT is common in our population and NBSH premedication does not alter its occurrence. Further studies are needed to determine how the LAT can be optimally managed to improve OSA treatment. Citation: Smith PR, Sheikh KL, Costan-Toth C, Forsthoefel D, Bridges E, Andrada TF, Holley AB. Eszopiclone and zolpidem do not affect the prevalence of the low arousal threshold phenotype. J Clin Sleep Med. 2017;13(1):115–119. PMID:27784413

Spontaneous Adverse Event Reports Associated with Zolpidem in the United States 2003-2012.

PubMed

Wong, Carmen K; Marshall, Nathaniel S; Grunstein, Ronald R; Ho, Samuel S; Fois, Romano A; Hibbs, David E; Hanrahan, Jane R; Saini, Bandana

2017-02-15

Stimulated reporting occurs when patients and healthcare professionals are influenced or "stimulated" by media publicity to report specific drug-related adverse reactions, significantly biasing pharmacovigilance analyses. Among countries where the non-benzodiazepine hypnotic drug zolpidem is marketed, the United States experienced a comparable surge of media reporting during 2006-2009 linking the above drug with the development of complex neuropsychiatric sleep-related behaviors. However, the effect of this stimulated reporting in the United States Food and Drug Administration Adverse Event Reporting System has not been explored. Using disproportionality analyses, reporting odds ratios for zolpidem exposure and the following adverse events; parasomnia, movement-based parasomnia, nonmovement-based parasomnia, amnesia, hallucination, and suicidality were determined and compared to all other medications in the database, followed by specific comparison to the benzodiazepine hypnotic class, year-by-year from 2003 to 2012. Odds ratios were increased significantly during and after the period of media publicity for parasomnias, movement-based parasomnias, amnesias and hallucinations. We also observed that zolpidem adverse drug reaction (ADR) reports have higher odds for parasomnias, movement-based parasomnias, amnesias, hallucinations, and suicidality compared to all other drugs, even before the media publicity cluster. Although our results indicate that zolpidem reports have higher odds for the ADR of interest even before the media publicity cluster, negative media coverage greatly exacerbated the reporting of these adverse reactions. The effect of such reporting must be borne in mind when decisions around drugs which have been the subject of intense media publicity are made by health professionals or regulatory bodies. © 2017 American Academy of Sleep Medicine

Spontaneous Adverse Event Reports Associated with Zolpidem in the United States 2003–2012

PubMed Central

Wong, Carmen K.; Marshall, Nathaniel S.; Grunstein, Ronald R.; Ho, Samuel S.; Fois, Romano A.; Hibbs, David E.; Hanrahan, Jane R.; Saini, Bandana

2017-01-01

Study Objectives: Stimulated reporting occurs when patients and healthcare professionals are influenced or “stimulated” by media publicity to report specific drug-related adverse reactions, significantly biasing pharmacovigilance analyses. Among countries where the non-benzodiazepine hypnotic drug zolpidem is marketed, the United States experienced a comparable surge of media reporting during 2006–2009 linking the above drug with the development of complex neuropsychiatric sleep-related behaviors. However, the effect of this stimulated reporting in the United States Food and Drug Administration Adverse Event Reporting System has not been explored. Methods: Using disproportionality analyses, reporting odds ratios for zolpidem exposure and the following adverse events; parasomnia, movement-based parasomnia, nonmovement-based parasomnia, amnesia, hallucination, and suicidality were determined and compared to all other medications in the database, followed by specific comparison to the benzodiazepine hypnotic class, year-by-year from 2003 to 2012. Results: Odds ratios were increased significantly during and after the period of media publicity for parasomnias, movement-based parasomnias, amnesias and hallucinations. We also observed that zolpidem adverse drug reaction (ADR) reports have higher odds for parasomnias, movement-based parasomnias, amnesias, hallucinations, and suicidality compared to all other drugs, even before the media publicity cluster. Conclusions: Although our results indicate that zolpidem reports have higher odds for the ADR of interest even before the media publicity cluster, negative media coverage greatly exacerbated the reporting of these adverse reactions. The effect of such reporting must be borne in mind when decisions around drugs which have been the subject of intense media publicity are made by health professionals or regulatory bodies. Citation: Wong CK, Marshall NS, Grunstein RR, Ho SS, Fois RA, Hibbs DE, Hanrahan JR, Saini B

Temazepam, But Not Zolpidem, Causes Orthostatic Hypotension in Astronauts After Spaceflight

NASA Technical Reports Server (NTRS)

Shi, Shang-Jin; Garcia, Kathleen M.; Meck, Janice V.

2002-01-01

Many astronauts do not sleep well due to the difficult environment in space. Hypnotics such as temazepam or zolpidem are often taken while in space and/or the night prior to returning to Earth. Until now, no data have illustrated the effect of these sleeping medications on postflight hemodynamic responses. The purpose of this study was to determine if the use of different hypnotics during flight has any effect on cardiovascular responses to standing in astronauts upon returning to Earth's gravity.

Sleep and wakefulness in somnambulism: a spectral analysis study.

PubMed

Guilleminault, C; Poyares, D; Aftab, F A; Palombini, L; Abat, F

2001-08-01

The sleep structure and the dynamics of EEG slow-wave activity (SWA) were investigated in 12 young adults and age- and gender-matched controls. Polysomnography was performed in subjects with well-documented chronic sleepwalking and in matched controls. Blinded visual scoring was performed using the international criteria from the Rechtschaffen and Kales atlas [A manual of standardized technology, techniques and scoring systems for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service, Brain Research Institute, 1968.] and by determining the presence of microarousals as defined in the American Sleep Disorders Association (ASDA) atlas [Sleep 15 (1992) 173.]. An evaluation of SWA overnight was performed on total nocturnal sleep to determine if a difference existed between groups of subjects, since sleepwalking usually originates with slow-wave sleep. Investigation of the delta power in successive nonoverlapping 4-second windows in the 32 seconds just prior to EMG activity associated with a confusional arousal was also conducted. One central EEG lead was used for all analyses. Somnambulistic individuals experienced more disturbed sleep than controls during the first NREM-REM sleep cycle. They had a higher number of ASDA arousals and presented lower peak of SWA during the first cycle that led to a lower SWA decline overnight. When the investigation focused on the short segment immediately preceding a confusional arousal, they presented an important increase in the relative power of low delta (0.75-2 Hz) just prior to the confusional arousal. Sleepwalkers undergo disturbed nocturnal sleep at the beginning of the night. The increased power of low delta just prior to the confusional arousal experienced may not be related to Stages 3-4 NREM sleep. We hypothesize that it may be translated as a cortical reaction to brain activation.

A comparison of complex sleep behaviors with two short-acting Z-hypnosedative drugs in nonpsychotic patients

PubMed Central

Chen, Li-Fen; Lin, Ching-En; Chou, Yu-Ching; Mao, Wei-Chung; Chen, Yi-Chyan; Tzeng, Nian-Sheng

2013-01-01

Objective Complex sleep behaviors (CSBs) are classified as “parasomnias” in the International Classifcation of Sleep Disorders, Second Edition (ICSD-2). To realize the potential danger after taking two short-acting Z-hypnosedative drugs, we estimated the incidence of CSBs in nonpsychotic patients in Taiwan. Methods Subjects (N = 1,220) using zolpidem or zopiclone were enrolled from the psychiatric outpatient clinics of a medical center in Taiwan over a 16-month period in 2006–2007. Subjects with zolpidem (N = 1,132) and subjects with zopiclone (N = 88) were analyzed. All subjects completed a questionnaire that included demographic data and complex sleep behaviors after taking hypnotics. Results Among zolpidem and zopiclone users, 3.28% of patients reported incidents of somnambulism or amnesic sleep-related behavior problems. The incidence of CSBs with zolpidem and zopiclone were 3.27%, and 3.41%, respectively, which was signifcantly lower than other studies in Taiwan. Conclusion These results serve as a reminder for clinicians to make inquiries regarding any unusual performance of parasomnic activities when prescribing zolpidem or zopiclone. PMID:23976857

Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

PubMed Central

Jehle, J; Ficker, E; Wan, X; Deschenes, I; Kisselbach, J; Wiedmann, F; Staudacher, I; Schmidt, C; Schweizer, PA; Becker, R; Katus, HA; Thomas, D

2013-01-01

Background and Purpose Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels. Experimental Approach Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. Key Results Zolpidem caused acute hERG channel blockade in oocytes (IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I–V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. Conclusions and Implications Zolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose. PMID:23061993

Changes in cerebral metabolism in patients with a minimally conscious state responding to zolpidem

PubMed Central

Chatelle, Camille; Thibaut, Aurore; Gosseries, Olivia; Bruno, Marie-Aurélie; Demertzi, Athena; Bernard, Claire; Hustinx, Roland; Tshibanda, Luaba; Bahri, Mohamed A.; Laureys, Steven

2014-01-01

Background: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). Methods: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). Results: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. Conclusion: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS. PMID:25520636

Sleep problems in children and adolescents at pediatric clinics

PubMed Central

Kim, Dong Soon; Lee, Cho Long

2017-01-01

Purpose To investigate the frequency of childhood sleep problems at pediatric clinics in Seoul and Gyeonggi provinces. Methods Children (n=936) and their parents who visited 5 primary and 1 secondary pediatric outpatient clinics were invited to complete a Pediatric Sleep Questionnaire. Results Among patients, 901 (96.3%) answered questionnaires in sufficient detail for evaluation. The participant's mean age was 4.35±3.02 years (range, 0–18 years). The male to female ratio was 1:0.93 (466 boys, 435 girls). Habitual snoring (>3 day/week) was reported in 16.9% of the participants. The prevalence of habitual snoring in children <2 years and those between 2–5 years was 9% and 18%, respectively. Sleep disordered breathing was found in 15.1% (106 of 700) of children >2 years. Insomnia was reported in 13.2% of children. The prevalence of sleepwalking, night terrors, and bruxism, is 1.6%, 19%, and 21.1%, respectively. Snoring was associated with increased incidence of sleepwalking, night terrors, and bruxism. Age was associated with insomnia and habitual snoring (P<0.05). Insomnia was more prevalent in younger (21%) than in older children (6%). Snoring was more frequent in both preschool (34%) and school-aged children (33%). The frequency of sleep disordered breathing and insomnia did not vary significantly with gender. However, snoring was more prevalent in boys. Conclusion Sleep problems are frequent among children in Korea. Children with snoring have an increased risk of sleepwalking, night terror, and bruxism. Primary clinicians should consider children's sleep habits to improve their health. PMID:28592979

Controlled clinical trial of zolpidem for the treatment of insomnia associated with attention-deficit/ hyperactivity disorder in children 6 to 17 years of age.

PubMed

Blumer, Jeffrey L; Findling, Robert L; Shih, Weichung Joe; Soubrane, Christina; Reed, Michael D

2009-05-01

The goal was to evaluate the hypnotic efficacy of zolpidem at 0.25 mg/kg per day (maximum of 10 mg/day), compared with placebo, in children 6 through 17 years of age who were experiencing insomnia associated with attention-deficit/hyperactivity disorder. An 8-week, North American, multicenter, double-blind, placebo-controlled, parallel-group study was conducted. Patients underwent stratification according to age (6-11 years [N = 111] or 12-17 years [N = 90]) and were assigned randomly to receive treatment with the study drug or placebo (in a 2:1 ratio). The primary efficacy variable was latency to persistent sleep between weeks 3 and 6. Secondary efficacy variables also were assessed, and behavioral and cognitive components of attention-deficit/hyperactivity disorder were monitored. Safety was assessed on the basis of reports of adverse events, abnormal laboratory data, vital signs, and physical examination findings. The potential for next-day residual effects also was assessed. The baseline-adjusted mean change in latency to persistent sleep at week 4 did not differ significantly between the zolpidem and placebo groups (-20.28 vs -21.27 minutes). However, differences favoring zolpidem were observed for the older age group in Clinical Global Impression scores at weeks 4 and 8. No next-day residual effects of treatment were associated with zolpidem, and no rebound phenomena occurred after treatment discontinuation. Central nervous system and psychiatric disorders were the most-frequent treatment-emergent adverse events (>5%) that were observed more frequently with zolpidem than with placebo; these included dizziness, headache, and hallucinations. Ten (7.4%) patients discontinued zolpidem treatment because of adverse events. Zolpidem at a dose of 0.25 mg/kg per day to a maximum of 10 mg failed to reduce the latency to persistent sleep on polysomnographic recordings after 4 weeks of treatment in children and adolescents 6 through 17 years of age who had attention

Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study.

PubMed

Roth, Thomas; Krystal, Andrew; Steinberg, Frank J; Singh, Nikhilesh N; Moline, Margaret

2013-02-01

To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings. Multicenter randomized, double-blind, placebo-controlled, parallel-group. Outpatient. There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening). After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures. ZST significantly (P < 0.0001) decreased latency to sleep onset over 4 wk (baseline 68.1 min; ZST 38.2 min) compared with placebo (baseline 69.4 min; placebo 56.4 min). Ratings of morning sleepiness/alertness significantly (P = 0.0041) favored the ZST group on nights medication was taken but not on other nights. Participants in the ZST group took the study drug on 62% of nights during the 4 wk; members of the placebo group took study medication on 64% of nights. Adverse events were generally mild and at the same rate (19.3% of participants) in both groups. There were no treatment-related serious adverse events (SAEs), and one adverse event-related study discontinuation from the placebo group. Dosing/week did not increase across the study. 3.5 mg ZST used as needed significantly reduced latency to return to sleep in comparison with placebo in these patients with insomnia. Sleep quality was improved, and morning sleepiness/alertness scores also improved. ZST was well tolerated. These data demonstrate the utility of a sleep-promoting agent when used as needed in the MOTN. NCT00466193: "A Study of Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http

A single dose of hypnotic corrects sleep and EEG abnormalities in symptomatic Huntington's disease mice.

PubMed

Kantor, Sandor; Varga, Janos; Morton, A Jennifer

2016-06-01

Sleep and electroencephalogram abnormalities are prominent early features of Huntington's disease (HD) that typically appear before the onset of characteristic motor symptoms. The changes in sleep and electroencephalogram seen in HD patients are largely recapitulated in mouse models of HD such as transgenic R6/2 lines. To test whether or not drugs with hypnotic properties can correct the sleep and electroencephalogram abnormalities seen in HD mice, we treated male wild-type (WT; N = 7) and R6/2 mice (N = 9) acutely with intraperitoneal injections of vehicle, zolpidem (5, 10 or 20 mg/kg) or amitriptyline (5, 10 or 20 mg/kg), and then monitored their sleep-wake behavior. In R6/2 mice, both zolpidem and amitriptyline suppressed the abnormally high REM sleep amount and electroencephalographic gamma (30-46 Hz) oscillations in a dose-dependent manner. Amitriptyline's effect on sleep was similar in both genotypes, whereas zolpidem showed significant genotype differences. Zolpidem exerted a strong hypnotic effect in WT mice by increasing electroencephalographic delta power, doubling the mean bout duration and the total amount of non-rapid eye movement sleep. However, no such effect was seen in R6/2 mice. Our study demonstrates that the pathophysiological changes seen in sleep and electroencephalogram are not 'hard-wired' in HD brain and can be reversed even at late stages of the disease. The diminished hypnotic effect of zolpidem suggests that the GABAergic control of sleep-wake states is impaired in HD mice. A better understanding of the neurochemical basis underlying these abnormalities should lead to more effective and rational therapies for HD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Doctor Shopping Behavior for Zolpidem Among Insomnia Patients in Taiwan: A Nationwide Population-Based Study

PubMed Central

Lu, Tzu-Hsuan; Lee, Yen-Ying; Lee, Hsin-Chien; Lin, You-Meei

2015-01-01

Objectives: Although zolpidem is listed as a controlled drug in Taiwan, patients' behavior has not been restricted and has led to the problem of doctor shopping behavior (DSB), leading to overutilization of medical resources and excess spending. The National Health Insurance Administration in Taiwan has instituted a new policy to regulate physicians' prescribing behavior and decrease DSB. This retrospective study aimed to analyze the DSB for zolpidem by insomnia patients and assess related factors. Design and Participants: Data were extracted from the Longitudinal Health Insurance Database in Taiwan. Individuals with a diagnosis of insomnia who received more than one prescription of zolpidem in 2008 were followed for 24 mo. Doctor shopping was defined as ≥ 2 prescriptions by different doctors within ≥ 1 day overlapping in the duration of therapy. The percentage of zolpidem obtained through doctor shopping was used as an indicator of the DSB of each patient. Results: Among the 6,947 insomnia patients who were prescribed zolpidem, 1,652 exhibited DSB (23.78%). The average dose of zolpidem dispensed for each patient during 24 mo was 244.21 daily defined doses. The doctor shopping indicator (DSI) was 0.20 (standard deviation, 0.23) among patients with DSB. Younger age, chronic diseases, high number of diseases, higher premium status, high socioeconomic status, and fewer people served per practicing physicians were all factors significantly related to doctor shopping behavior. Conclusion: Doctor shopping for zolpidem appears to be an important issue in Taiwan. Implementing a proper referral system with efficient data exchange by physician or pharmacist-led medication reconciliation process might reduce DSB. Citation: Lu TH, Lee YY, Lee HC, Lin YM. Doctor shopping behavior for zolpidem among insomnia patients in Taiwan: a nationwide population-based study. SLEEP 2015;38(7):1039–1044. PMID:25761979

Retrospective Population Cohort Study on Hip Fracture Risk Associated with Zolpidem Medication

PubMed Central

Lin, Fang-Yu; Chen, Pei-Chun; Liao, Chun Hui; Hsieh, Yow-Wen; Sung, Fung-Chang

2014-01-01

Study Objective: Few studies have evaluated the hip fracture risk for zolpidem users. We assessed the risk for subjects taking zolpidem. Design: Population-based retrospective cohort study using claims data of a universal insurance system. Participants: We identified 6,978 patients newly prescribed for zolpidem in 2000-2001 age 18 y and older, and 27,848 nonusers frequency matched with sex, age, and date visiting a clinic. Measurements and Results: Both cohorts were followed up to the end of 2008 to measure the hip fracture incidence and risk, which considered factors such as sex, age, occupation, days of drug use, and osteoporosis status. The zolpidem users had a 2.23-fold higher hip fracture incidence than nonusers (3.10 versus 1.39 per 1,000 person-y). The risk increased with age for both cohorts. The elderly users had a 21-fold higher incidence than the younger users, or twofold higher than the elderly nonusers. Among 33 patients (20.4%) with hip fracture occurring during presumed medication days, which was accountable for an incidence of 1,083.0 per 1,000 person-y. Those taking the medicine for 8 days or longer had a moderately higher fracture rate than those taking it for less days (6.02 versus 4.48 per 100 person-times) with a ratio of 1.34 (95% confidence interval 0.42-4.56). Subjects with blue collar occupations were at a higher fracture risk. Conclusion: The hip fracture risk of zolpidem users is higher than that of nonusers. Fracture prevention awareness should be disseminated to the users. Citation: Lin FY; Chen PC; Liao CH; Hsieh YW; Sung FC. Retrospective population cohort study on hip fracture risk associated with zolpidem medication. SLEEP 2014;37(4):673-679. PMID:24899758

Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs

PubMed Central

Tannenbaum, Pamela L.; Stevens, Joanne; Binns, Jacquelyn; Savitz, Alan T.; Garson, Susan L.; Fox, Steven V.; Coleman, Paul; Kuduk, Scott D.; Gotter, Anthony L.; Marino, Michael; Tye, Spencer J.; Uslaner, Jason M.; Winrow, Christopher J.; Renger, John J.

2014-01-01

The ability to awaken from sleep in response to important stimuli is a critical feature of normal sleep, as is maintaining sleep continuity in the presence of irrelevant background noise. Dual orexin receptor antagonists (DORAs) effectively promote sleep across species by targeting the evolutionarily conserved wake-promoting orexin signaling pathway. This study in dogs investigated whether DORA-induced sleep preserved the ability to awaken appropriately to salient acoustic stimuli but remain asleep when exposed to irrelevant stimuli. Sleep and wake in response to DORAs, vehicle, GABA-A receptor modulators (diazepam, eszopiclone and zolpidem) and antihistamine (diphenhydramine) administration were evaluated in telemetry-implanted adult dogs with continuous electrocorticogram, electromyogram (EMG), electrooculogram (EOG), and activity recordings. DORAs induced sleep, but GABA-A modulators and antihistamine induced paradoxical hyperarousal. Thus, salience gating studies were conducted during DORA-22 (0.3, 1, and 5 mg/kg; day and night) and vehicle nighttime sleep. The acoustic stimuli were either classically conditioned using food reward and positive attention (salient stimulus) or presented randomly (neutral stimulus). Once conditioned, the tones were presented at sleep times corresponding to maximal DORA-22 exposure. In response to the salient stimuli, dogs woke completely from vehicle and orexin-antagonized sleep across all sleep stages but rarely awoke to neutral stimuli. Notably, acute pharmacological antagonism of orexin receptors paired with emotionally salient anticipation produced wake, not cataplexy, in a species where genetic (chronic) loss of orexin receptor signaling leads to narcolepsy/cataplexy. DORA-induced sleep in the dog thereby retains the desired capacity to awaken to emotionally salient acoustic stimuli while preserving uninterrupted sleep in response to irrelevant stimuli. PMID:24904334

Doctor Shopping Behavior for Zolpidem Among Insomnia Patients in Taiwan: A Nationwide Population-Based Study.

PubMed

Lu, Tzu-Hsuan; Lee, Yen-Ying; Lee, Hsin-Chien; Lin, You-Meei

2015-07-01

Although zolpidem is listed as a controlled drug in Taiwan, patients' behavior has not been restricted and has led to the problem of doctor shopping behavior (DSB), leading to overutilization of medical resources and excess spending. The National Health Insurance Administration in Taiwan has instituted a new policy to regulate physicians' prescribing behavior and decrease DSB. This retrospective study aimed to analyze the DSB for zolpidem by insomnia patients and assess related factors. Data were extracted from the Longitudinal Health Insurance Database in Taiwan. Individuals with a diagnosis of insomnia who received more than one prescription of zolpidem in 2008 were followed for 24 mo. Doctor shopping was defined as ≥ 2 prescriptions by different doctors within ≥ 1 day overlapping in the duration of therapy. The percentage of zolpidem obtained through doctor shopping was used as an indicator of the DSB of each patient. Among the 6,947 insomnia patients who were prescribed zolpidem, 1,652 exhibited DSB (23.78%). The average dose of zolpidem dispensed for each patient during 24 mo was 244.21 daily defined doses. The doctor shopping indicator (DSI) was 0.20 (standard deviation, 0.23) among patients with DSB. Younger age, chronic diseases, high number of diseases, higher premium status, high socioeconomic status, and fewer people served per practicing physicians were all factors significantly related to doctor shopping behavior. Doctor shopping for zolpidem appears to be an important issue in Taiwan. Implementing a proper referral system with efficient data exchange by physician or pharmacist-led medication reconciliation process might reduce DSB. © 2015 Associated Professional Sleep Societies, LLC.

The use of a non-benzodiazepine hypnotic sleep-aid (Zolpidem) in patients undergoing ACL reconstruction: a randomized controlled clinical trial.

PubMed

Tompkins, Marc; Plante, Matthew; Monchik, Keith; Fleming, Braden; Fadale, Paul

2011-05-01

Previous studies have addressed post-operative pain management after ACL reconstruction by examining the use of intra-articular analgesia and/or modification of anesthesia techniques. To our knowledge, however, no previous studies have evaluated the effect of zolpidem on post-operative narcotic requirements, pain, and fatigue in patients undergoing outpatient arthroscopic ACL reconstruction. The purpose of this prospective, blinded, randomized, controlled clinical study was to evaluate the effect of zolpidem on post-operative narcotic requirements, pain, and fatigue in patients undergoing outpatient arthroscopic ACL reconstruction. Twenty-nine patients undergoing arthroscopic ACL reconstruction were randomized to a treatment group or placebo group. Both groups received post-operative hydrocodone/acetaminophen bitartrate (Vicodin ES). Patients in the treatment group received a single dose of zolpidem for the first seven post-operative nights. Patients in the placebo group received a gelatin capsule similar in appearance to zolpidem. The amount of Vicodin used in each group, the amount of post-operative pain, and the amount of post-operative fatigue were analyzed. Following ACL reconstruction, a 28% reduction was seen in the total amount of narcotic consumed with zolpidem (P = 0.047) when compared to placebo. There were no significant differences in post-operative pain or fatigue levels between zolpidem and placebo. Adding zolpidem to the post-operative medication regimen after arthroscopic ACL reconstruction helps to lower the amount of narcotic pain medication required for adequate analgesia. Randomized controlled clinical trial, Level I.

Possible GABAergic modulation in the protective effect of zolpidem in acute hypoxic stress-induced behavior alterations and oxidative damage.

PubMed

Kumar, Anil; Goyal, Richa

2008-03-01

Hypoxia is an environmental stressor that is known to elicit alterations in both the autonomic nervous system and endocrine functions. The free radical or oxidative stress theory holds that oxidative reactions are mainly underlying neurodegenerative disorders. In fact among complex metabolic reactions occurring during hypoxia, many could be related to the formation of oxygen derived free radicals, causing a wide spectrum of cell damage. In present study, we investigated possible involvement of GABAergic mechanism in the protective effect of zolpidem against acute hypoxia-induced behavioral modification and biochemical alterations in mice. Mice were subjected to acute hypoxic stress for a period of 2 h. Acute hypoxic stress for 2 h caused significant impairment in locomotor activity, anxiety-like behavior, and antinocioceptive effect in mice. Biochemical analysis revealed a significant increased malondialdehyde, nitrite concentrations and depleted reduced glutathione and catalase levels. Pretreatment with zolpidem (5 and 10 mg/kg, i.p.) significantly improved locomotor activity, anti-anxiety effect, reduced tail flick latency and attenuated oxidative damage (reduced malondialdehyde, nitrite concentration, and restoration of reduced glutathione and catalase levels) as compared to stressed control (hypoxia) (P < 0.05). Besides, protective effect of zolpidem (5 mg/kg) was blocked significantly by picrotoxin (1.0 mg/kg) or flumazenil (2 mg/kg) and potentiated by muscimol (0.05 mg/kg) in hypoxic animals (P < 0.05). These effects were significant as compared to zolpidem (5 mg/kg) per se (P < 0.05). Present study suggest that the possible involvement of GABAergic modulation in the protective effect of zolpidem against hypoxic stress.

Zolpidem test and catatonia.

PubMed

Javelot, H; Michel, B; Steiner, R; Javelot, T; Cottencin, O

2015-12-01

There is no consensus regarding treatment of catatonia and the main recent therapeutic progress has been the development of the zolpidem diagnostic and therapeutic test. We report on the use of this test in one of our patients. Mr. S. suffered from a paranoid schizophrenia. Three episodes of catatonia are described to illustrate the effect of zolpidem in a patient for whom lorazepam was ineffective or inadequate. Zolpidem with appropriate testing appears to be a credible alternative to electroconvulsive therapy or increased lorazepam dosing and allows continuation of antipsychotic administration. © 2015 John Wiley & Sons Ltd.

Sibutramine-associated psychotic symptoms and zolpidem-induced complex behaviours: implications for patient safety.

PubMed

Wiglusz, Mariusz S; Cubała, Wiesław Jerzy; Nowak, Paweł; Jakuszkowiak-Wojten, Katarzyna; Landowski, Jerzy; Krysta, Krzysztof

2013-09-01

Sibutramine is a weight loss agent recently withdrawn from the European market due to cardiovascular risk concerns. It was used for long-term obesity treatment. Zolpidem is a short acting hypnotic agent commonly used in the treatment of insomnia. A number of case reports describing psychotic reaction to sibutramine were reported in the literature. We present a case of a 61-year-old Caucasian woman who developed two psychotic episodes related to sibutramine treatment. The second psychotic episode was complicated with complex behaviours after zolpidem use due to insomnia. Sibutramine and zolpidem discontinuation resulted in rapid resolution of psychotic symptoms. This case suggests a possibility of incidence of psychotic symptoms and complex behaviour disturbances in patients prescribed sibutramine or other monoaminergic reuptake inhibitors.

Examination of Zolpidem effects on AhR- and PXR-dependent expression of drug-metabolizing cytochromes P450 in primary cultures of human hepatocytes.

PubMed

Bachleda, Petr; Vrzal, Radim; Pivnicka, Jakub; Cvek, Boris; Dvorak, Zdenek

2009-12-01

A hypnotic drug Zolpidem is used in clinical practice for more than 25 years. Surprisingly, the effects of Zolpidem on the expression of drug-metabolizing cytochromes P450 (CYPs) were not examined yet. Recently, the unexpected capacity of several "old drugs", such as valproic acid or azoles, to induce CYPs was reported. Therefore, we tested whether Zolpidem induces the expression of important CYPs in primary cultures of human hepatocytes. Cells were treated for 24h with Zolpidem in therapeutic (0.1mg/L) and toxic (1mg/L) concentrations. The levels of CYP1A1, CYP1A2, CY2C9 and CYP3A4 mRNAs were not altered by Zolpidem, whereas model inducers dioxin and rifampicin significantly induced CYP1A and CYP2/3 gene expression, respectively. Consistently, Zolpidem did not activate aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), the key regulators of cytochromes P450s, as revealed by transient transfection gene reporter assays using HepG2 cells. We conclude Zolpidem be considered a safe drug with respect to the possible interactions through AhR- and PXR-dependent induction of drug-metabolizing CYPs.

Triazolam and zolpidem: effects on human memory and attentional processes.

PubMed

Mintzer, M Z; Griffiths, R R

1999-05-01

The imidazopyridine hypnotic zolpidem may produce less memory and cognitive impairment than classic benzodiazepines, due to its relatively low binding affinity for the benzodiazepine receptor subtypes found in areas of the brain which are involved in learning and memory. The study was designed to compare the acute effects of single oral doses of zolpidem (5, 10, 20 mg/70 kg) and the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) on specific memory and attentional processes. Drug effects on memory for target (i.e., focal) information and contextual information (i.e., peripheral details surrounding a target stimulus presentation) were evaluated using a source monitoring paradigm, and drug effects on selective attention mechanisms were evaluated using a negative priming paradigm, in 18 healthy volunteers in a double-blind, placebo-controlled, crossover design. Triazolam and zolpidem produced strikingly similar dose-related effects on memory for target information. Both triazolam and zolpidem impaired subjects' ability to remember whether a word stimulus had been presented to them on the computer screen or whether they had been asked to generate the stimulus based on an antonym cue (memory for the origin of a stimulus, which is one type of contextual information). The results suggested that triazolam, but not zolpidem, impaired memory for the screen location of picture stimuli (spatial contextual information). Although both triazolam and zolpidem increased overall reaction time in the negative priming task, only triazolam increased the magnitude of negative priming relative to placebo. The observed differences between triazolam and zolpidem have implications for the cognitive and pharmacological mechanisms underlying drug-induced deficits in specific memory and attentional processes, as well for the cognitive and brain mechanisms underlying these processes.

Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users

PubMed Central

Herrmann, Evan S.; Cooper, Ziva D.; Bedi, Gillinder; Ramesh, Divya; Reed, Stephanie C.; Comer, Sandra D.; Foltin, Richard W.; Haney, Margaret

2017-01-01

Rationale Each year over 300,000 individuals in the U.S. enter treatment for Cannabis Use Disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. Objective This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. Methods Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6% THC). On days 2–8, participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300), zolpidem (0 mg at 0900 and 1800 and 12.5 mg at 2300) or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3–4, when only inactive cannabis (0.0% THC) was available for self-administration. ‘Relapse’ was measured on days 5–8, when participants could self-administer active cannabis. Results Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. Conclusions Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted. PMID:27085870

Zolpidem

MedlinePlus

Zolpidem comes as a tablet (Ambien) and an extended-release (long-acting) tablet (Ambien CR) to take ... the tongue. If you are taking the tablets, extended-release tablets, sublingual tablets (Edluar), or oral spray, ...

Effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory model of relapse in cannabis users.

PubMed

Herrmann, Evan S; Cooper, Ziva D; Bedi, Gillinder; Ramesh, Divya; Reed, Stephanie C; Comer, Sandra D; Foltin, Richard W; Haney, Margaret

2016-07-01

Each year, over 300,000 individuals in the USA enter treatment for cannabis use disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6 % Δ(9)-tetrahydrocannabinol (THC)). On days 2-8, the participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300 hours), zolpidem (0 mg at 0900 and 1800, and 12.5 mg at 2300), or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3-4, when only inactive cannabis (0.0 % THC) was available for self-administration. "Relapse" was measured on days 5-8, when participants could self-administer active cannabis. Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted.

Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine.

PubMed

Cysneiros, R M; Farkas, D; Harmatz, J S; von Moltke, L L; Greenblatt, D J

2007-07-01

The kinetic and dynamic interaction of caffeine and zolpidem was evaluated in a double-blind, single-dose, six-way crossover study of 7.5 mg zolpidem (Z) or placebo (P) combined with low-dose caffeine (250 mg), high-dose caffeine (500 mg), or placebo. Caffeine coadministration modestly increased maximum plasma concentration (C(max)) and area under the plasma concentration-time curve of zolpidem by 30-40%, whereas zolpidem did not significantly affect the pharmacokinetics of caffeine or its metabolites. Compared to P+P, Z+P significantly increased sedation, impaired digit-symbol substitution test performance, slowed tapping speed and reaction time, increased EEG relative beta amplitude, and impaired delayed recall. Caffeine partially, but not completely, reversed most pharmacodynamic effects of zolpidem. Thus, caffeine only incompletely reverses zolpidem's sedative and performance-impairing effects, and cannot be considered as an antidote to benzodiazepine agonists.

An update on zolpidem abuse and dependence.

PubMed

Victorri-Vigneau, Caroline; Gérardin, Marie; Rousselet, Morgane; Guerlais, Marylène; Grall-Bronnec, Marie; Jolliet, Pascale

2014-01-01

In 2004, the health authorities (French National Agency for Medicines and Health Products Safety-ANSM) modified the summary of zolpidem characteristics. Particularly it now includes the sentence "a pharmacodependence may materialize." The current article aims to show that despite this modification, zolpidem continues to be associated with problematic drug use, as the official system (Center for Evaluation and Information on Pharmacodependence-Addictovigilance network) providing information on the abuse and dependence potential of drugs informs us. The authors reviewed the literature on this topic and analyzed French data from zolpidem's postmarketing period that were collected by the Addictovigilance network from 2003 to 2010. Postmarketing data and the 30 case reports yielded from the literature review highlight a significant dependence and abuse potential for zolpidem. This survey led to propose in stronger additional rules in France to try to mitigate the abuse potential of zolpidem.

Sleepwalking through history: medicine, arts, and courts of law.

PubMed

Umanath, Sharda; Sarezky, Daniel; Finger, Stanley

2011-10-01

Somnambulism, or sleepwalking, has always been of interest to theologians, writers, philosophers, physicians, and others fascinated by unusual behaviors. This parasomnia, which was defined less precisely in the past than it is today, has long been featured in medical dissertations and books of medicine. Further, Shakespeare, Bellini, and Brown, among others, incorporated it into their plays, operas, and novels. Because some somnambulists turned violent and committed other acts detrimental to society, sleepwalking also demanded attention from legal systems, and guidelines were set for whether somnambulists could be held responsible for their actions. This historical review focuses on these developments pertaining to somnambulism through the seventeenth, eighteenth, and nineteenth centuries.

Zolpidem is independently associated with increased risk of inpatient falls.

PubMed

Kolla, Bhanu Prakash; Lovely, Jenna K; Mansukhani, Meghna P; Morgenthaler, Timothy I

2013-01-01

Inpatient falls are associated with significant morbidity and increased healthcare costs. Zolpidem has been reported to decrease balance and is associated with falls. Yet, it is a commonly used hypnotic agent in the inpatient setting. Zolpidem use in hospitalized patients may be a significant and potentially modifiable risk factor for falling. To determine whether inpatients administered zolpidem are at greater risk of falling. Retrospective cohort study. Adult non-intensive care unit (non-ICU) inpatients at a tertiary care center. Adult inpatients who were prescribed zolpidem were identified. Electronic medical records were reviewed to capture demographics and other risk factors for falls. The fall rate was compared in those administered zolpidem versus those only prescribed zolpidem. Multivariate analyses were performed to determine whether zolpidem was independently associated with falls. The fall rate among patients who were prescribed and received zolpidem (n = 4962) was significantly greater than among patients who were prescribed but did not receive zolpidem (n = 11,358) (3.04% vs 0.71%; P < 0.001). Zolpidem use continued to remain significantly associated with increased fall risk after accounting for age, gender, insomnia, delirium status, dose of zolpidem, Charlson comorbidity index, Hendrich's fall risk score, length of hospital stay, presence of visual impairment, gait abnormalities, and dementia/cognitive impairment (adjusted odds ratio [OR] 4.37, 95% confidence interval [CI] = 3.34-5.76; P < 0.001). Additionally, patients taking zolpidem who experienced a fall did not differ from other hospitalized adult patients who fell in terms of age, opioids, antidepressants, sedative-antidepressants, antipsychotics, benzodiazepine, or antihistamine use. Zolpidem use was a strong, independent, and potentially modifiable risk factor for inpatient falls. Copyright © 2012 Society of Hospital Medicine.

Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

PubMed

Lionberger, Robert A; Raw, Andre S; Kim, Stephanie H; Zhang, Xinyuan; Yu, Lawrence X

2012-04-01

FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

Pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers.

PubMed

Vlase, Laurian; Popa, Adina; Neag, Maria; Muntean, Dana; Bâldea, Ioan; Leucuţa, Sorin E

2011-08-01

The objective of this study was to evaluate the pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers. The study consisted of 2 periods: period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem, and period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 400 mg carbamazepine. Between the 2 periods, the participants were treated for 15 days with a single daily dose of 400 mg carbamazepine. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using noncompartmental analysis. In the 2 periods of treatments, the mean peak plasma concentrations (C(max)) were 59 ng/mL (zolpidem alone) and 35 ng/mL (zolpidem after pretreatment with carbamazepine). The t(max), times taken to reach C(max), were 0.9 hours and 1.0 hour, respectively, and the total areas under the curve (AUC(0-∞)) were 234.9 ng·h/mL and 101.5 ng·h/mL, respectively. The half-life of zolpidem was 2.3 and 1.6 hours, respectively. Carbamazepine interacts with zolpidem in healthy volunteers and lowers its bioavailability by about 57%. The experimental data demonstrate the pharmacokinetic interaction between zolpidem and carbamazepine and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.

Zolpidem Use Associated With Increased Risk of Pyogenic Liver Abscess

PubMed Central

Liao, Kuan-Fu; Lin, Cheng-Li; Lai, Shih-Wei; Chen, Wen-Chi

2015-01-01

Abstract The purpose of this study was to explore the association between zolpidem use and pyogenic liver abscess in Taiwan. This was a population-based case-control study using the database of the Taiwan National Health Insurance Program since 2000 to 2011. We identified 1325 patients aged 20 to 84 years with the first-attack of pyogenic liver abscess as the cases, and 5082 patients without pyogenic liver abscess matched with sex, age, comorbidities, and index year of hospitalization for pyogenic liver abscess as the controls. Patients whose last remaining 1 tablet for zolpidem was noted ≤7 days before the date of admission for pyogenic liver abscess were defined as current use of zolpidem. Patients whose last remaining 1 tablet for zolpidem was noted >7 days before the date of admission for pyogenic liver abscess were defined as late use of zolpidem. Patients who never received 1 prescription for zolpidem were defined as never use of zolpidem. A multivariable unconditional logistic regression model was used to measure the odds ratio (OR) and 95% confidence interval (CI) to explore the association between zolpidem use and pyogenic liver abscess. After adjustment for possible confounding variables, the adjusted OR of pyogenic liver abscess was 3.89 for patients with current use of zolpidem (95% CI 2.89, 5.23), when compared with those with never use of zolpidem. The adjusted OR decreased to 0.85 for those with late use of zolpidem (95% CI 0.70, 1.03), but without statistical significance. Current use of zolpidem is associated with the increased risk of pyogenic liver abscess. Physicians should take the risk of pyogenic liver abscess into account when prescribing zolpidem. PMID:26266369

Zolpidem in progressive supranuclear palsy.

PubMed

Dash, Sandip K

2013-01-01

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder, characterized by motor symptoms, postural instability, personality changes, and cognitive impairment. There is no effective treatment for this disorder. Reduced neurotransmission of GABA in the striatum and globus pallidus may contribute to the symptoms of motor and cognitive symptoms seen in PSP. Zolpidem is a GABA agonist of the benzodiazepine subreceptor BZ1. Here a nondiabetic, normotensive case of PSP is (Progressive Supranuclear Palsy) described, which showed improvement in swallowing, speech, and gaze paresis after zolpidem therapy and possible mechanism of actions are discussed. However, more trials are needed with large number of patients to confirm the effectiveness of zolpidem in progressive supranuclear palsy.

Urine specimen detection of zolpidem use in patients with pain.

PubMed

Mann, Lindsey M; Atayee, Rabia S; Best, Brookie M; Morello, Candis M; Ma, Joseph D

2014-01-01

This study examined zolpidem and concurrent opioid, benzodiazepine, other central nervous system (CNS) depressants, and alcohol use. Urine specimens were analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Specimens were tested for zolpidem (n = 71,919) and separated into a provider-reported medication list documenting (n = 5,257) or not documenting zolpidem use (n = 66,662). Zolpidem-positive specimens were further separated into reported and unreported use cohorts. The total number of zolpidem-positive specimens in the reported and unreported use cohorts was 3,391 and 3,190, respectively. Non-informed prescribers were 4.4% (3,190/71,919) among the general population and 48.5% (3,190/6,581) when only zolpidem users were considered. In the zolpidem user population, the most common concurrent opioids in both cohorts were hydrocodone and oxycodone. Alprazolam and clonazepam were higher in the unreported use cohort (P ≤ 0.05). The unreported use cohort also had a higher detection of zolpidem plus a benzodiazepine (49.7 vs. 46%; P ≤ 0.05), zolpidem plus an opioid and a benzodiazepine (40.8% vs. 37.4%; P ≤ 0.05) and zolpidem plus an opioid, a benzodiazepine, and an other CNS depressant (12.9 vs. 10.9%; P ≤ 0.05). Concurrent use of zolpidem, an opioid, a benzodiazepine and an other CNS depressant is prevalent in a pain patient population. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Somnambulism: Emergency Department Admissions Due to Sleepwalking-Related Trauma.

PubMed

Sauter, Thomas C; Veerakatty, Sajitha; Haider, Dominik G; Geiser, Thomas; Ricklin, Meret E; Exadaktylos, Aristomenis K

2016-11-01

Somnambulism is a state of dissociated consciousness, in which the affected person is partially asleep and partially awake. There is pervasive public opinion that sleepwalkers are protected from hurting themselves. There have been few scientific reports of trauma associated with somnambulism and no published investigations on the epidemiology or trauma patterns associated with somnambulism. We included all emergency department (ED) admissions to University Hospital Inselspital, Berne, Switzerland, from January 1, 2000, until August 11, 2015, when the patient had suffered a trauma associated with somnambulism. Demographic data (age, gender, nationality) and medical data (mechanism of injury, final diagnosis, hospital admission, mortality and medication on admission) were included. Of 620,000 screened ED admissions, 11 were associated with trauma and sleepwalking. Two patients (18.2%) had a history of known non-rapid eye movement parasomnias. The leading cause of admission was falls. Four patients required hospital admission for orthopedic injuries needing further diagnostic testing and treatment (36.4%). These included two patients with multiple injuries (18.2%). None of the admitted patients died. Although sleepwalking seems benign in the majority of cases and most of the few injured patients did not require hospitalization, major injuries are possible. When patients present with falls of unknown origin, the possibility should be evaluated that they were caused by somnambulism.

Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury

PubMed Central

Williams, Shawniqua T; Conte, Mary M; Goldfine, Andrew M; Noirhomme, Quentin; Gosseries, Olivia; Thonnard, Marie; Beattie, Bradley; Hersh, Jennifer; Katz, Douglas I; Victor, Jonathan D; Laureys, Steven; Schiff, Nicholas D

2013-01-01

Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6–10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7–0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6–10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors. DOI: http://dx.doi.org/10.7554/eLife.01157.001 PMID:24252875

Zolpidem arousing effect in persistent vegetative state patients: autonomic, EEG and behavioral assessment.

PubMed

Machado, Calixto; Estévez, Mario; Rodríguez, Rafael; Pérez-Nellar, Jesús; Chinchilla, Mauricio; DeFina, Philip; Leisman, Gerry; Carrick, Frederick R; Melillo, Robert; Schiavi, Adam; Gutiérrez, Joel; Carballo, Maylén; Machado, Andrés; Olivares, Ana; Pérez-Cruz, Nuvia

2014-01-01

To study the Zolpidem arousing effect in persistent vegetative state (PVS) patients combining clinical evaluation, autonomic assessment by heart rate variability (HRV), and EEG records. We studied a group of 8 PVS patients and other 8 healthy control subjects, matched by age and gender. The patients and controls received drug or placebo in two experimental sessions, separated by 10-14 days. The first 30 minutes of the session were considered the basal record, and then Zolpidem was administered. All participants were evaluated clinically, by EEG, and by HRV during the basal record, and for 90 minutes after drug intake. We found in all patients, time-related arousing signs after Zolpidem intake: behavioral (yawns and hiccups), activation of EEG cortical activity, and a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. We demonstrated time-related arousing signs after Zolpidem intake. We discussed possible mechanisms to explain these patho-physiological findings regarding EEG cortical activation and an autonomic vagolytic drug effect. As this autonomic imbalance might induce cardiocirculatory complications, which we didn't find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that this arousing Zolpidem effect might be certainly related to brain function improvement, it should be particularly considered for the development of new neuro-rehabilitation programs in PVS cases. According to the literature review, we claim that this is the first report about the vagolitic effect of Zolpidem in PVS cases.

Enhancement of GABAergic transmission by zolpidem, an imidazopyridine with preferential affinity for type I benzodiazepine receptors.

PubMed

Biggio, G; Concas, A; Corda, M G; Serra, M

1989-02-28

The effect of zolpidem, an imidazopyridine derivative with high affinity at the type I benzodiazepine recognition site, on the function of the GABAA/ionophore receptor complex was studied in vitro. Zolpidem, mimicking the action of diazepam, increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced [35S]TBPS binding in rat cortical membrane preparations. Zolpidem was less effective than diazepam on the above parameters. Zolpidem induced a lower increase of [3H]GABA binding (23 vs. 35%) and muscimol-stimulated 36Cl- uptake (22 vs. 40%) and a smaller decrease of [35S]TBPS binding (47 vs. 77%) than diazepam. The finding that zolpidem enhanced the function of GABAergic synapses with an efficacy qualitatively and quantitatively different from that of diazepam suggests that this compound is a partial agonist at the benzodiazepine recognition site. Thus, our results are consistent with the view that the biochemical and pharmacological profile of a benzodiazepine recognition site ligand reflects its efficacy to enhance GABAergic transmission. Whether the preferential affinity of zolpidem at the type I site is involved in its atypical biochemical and pharmacological profile remains to be clarified.

Zolpidem dependence and withdrawal seizure--report of two cases.

PubMed

Wang, Liang-Jen; Ree, Shao-Chun; Chu, Chin-Lin; Juang, Yeong-Yuh

2011-03-01

Zolpidem is a non-benzodiazepine property which binds selectively to the ?1-GABAA receptors, and has been widely prescribed to patients suffering from insomnia. We report two cases of zolpidem dependence with withdrawal seizure in the Asian population. The first case is a 43-year-old woman who took zolpidem up to the dosage of 200 to 400 mg per night. The second case is a 35-year-old woman who even began to take zolpidem every 15 to 30 minutes to get euphoric and relaxed, and she gradually increased the dosage to 400 to 500mg per day. After abrupt discontinuation of zolpidem, both cases immediately developed anxiety, global insomnia, restlessness, and tonic seizure. The purpose of this case report is to suggest that clinicians should pay close attention to the potential of zolpidem tolerance, abuse and dependence. The possibility of withdrawal seizure cannot be excluded especially at high doses.

Intractable nausea caused by zolpidem withdrawal: a case report.

PubMed

Baruch, Edward; Vernon, Leonard F; Hasbun, Rafael J

2007-03-01

First launched in France in 1988, zolpidem (Ambien®) is a short-acting hypnotic agent. Early studies reported that that the development of physical dependence and tolerance to sedative-hypnotic drugs, such as the depressant and anticonvulsant effects evidenced with benzodiazepines, is not found with zolpidem. Direct to consumer advertising by the manufacturer continues to state that the risk for dependency is low; however, recent publications seem to contradict this. Additionally, adverse drug reactions affecting the central nervous system, gastrointestinal tract, and respiratory system have been reported. Other studies have examined the interactions of selective serotonin reuptake inhibitors and zolpidem as a possible cause of hallucinations. With continued physician marketing efforts touting the safety and efficacy of zolpidem, there is a high likelihood to overlook the risk of dependency and the symptoms related to zolpidem withdrawal. We report a case of a 41-year-old female who developed a dependency to zolpidem, who on her own decided to decrease her dosage, resulting in intractable nausea requiring hospitalization. Reported cases of zolpidem withdrawal have occurred with doses in excess of 160 mg per day, none of these have reported with intractable nausea as the sole symptom. In our reported case, although exceeding recommended dosage withdrawal phenomenon seemed to be severe after withdrawal from a comparatively low dose of zolpidem. Before zolpidem is prescribed, patient education should include warnings about the potential problems associated with dependency and abrupt discontinuation. Education about this common and likely underrecognized clinical phenomenon will help prevent future episodes and minimize the risk of misdiagnosis.

Evaluation of Automated and Semi-Automated Scoring of Polysomnographic Recordings from a Clinical Trial Using Zolpidem in the Treatment of Insomnia

PubMed Central

Svetnik, Vladimir; Ma, Junshui; Soper, Keith A.; Doran, Scott; Renger, John J.; Deacon, Steve; Koblan, Ken S.

2007-01-01

Objective: To evaluate the performance of 2 automated systems, Morpheus and Somnolyzer24X7, with various levels of human review/editing, in scoring polysomnographic (PSG) recordings from a clinical trial using zolpidem in a model of transient insomnia. Methods: 164 all-night PSG recordings from 82 subjects collected during 2 nights of sleep, one under placebo and one under zolpidem (10 mg) treatment were used. For each recording, 6 different methods were used to provide sleep stage scores based on Rechtschaffen & Kales criteria: 1) full manual scoring, 2) automated scoring by Morpheus 3) automated scoring by Somnolyzer24X7, 4) automated scoring by Morpheus with full manual review, 5) automated scoring by Morpheus with partial manual review, 6) automated scoring by Somnolyzer24X7 with partial manual review. Ten traditional clinical efficacy measures of sleep initiation, maintenance, and architecture were calculated. Results: Pair-wise epoch-by-epoch agreements between fully automated and manual scores were in the range of intersite manual scoring agreements reported in the literature (70%-72%). Pair-wise epoch-by-epoch agreements between automated scores manually reviewed were higher (73%-76%). The direction and statistical significance of treatment effect sizes using traditional efficacy endpoints were essentially the same whichever method was used. As the degree of manual review increased, the magnitude of the effect size approached those estimated with fully manual scoring. Conclusion: Automated or semi-automated sleep PSG scoring offers valuable alternatives to costly, time consuming, and intrasite and intersite variable manual scoring, especially in large multicenter clinical trials. Reduction in scoring variability may also reduce the sample size of a clinical trial. Citation: Svetnik V; Ma J; Soper KA; Doran S; Renger JJ; Deacon S; Koblan KS. Evaluation of automated and semi-automated scoring of polysomnographic recordings from a clinical trial using zolpidem

Somnambulism: Emergency Department Admissions Due to Sleepwalking-Related Trauma

PubMed Central

Sauter, Thomas C.; Veerakatty, Sajitha; Haider, Dominik G.; Geiser, Thomas; Ricklin, Meret E.; Exadaktylos, Aristomenis K.

2016-01-01

Introduction Somnambulism is a state of dissociated consciousness, in which the affected person is partially asleep and partially awake. There is pervasive public opinion that sleepwalkers are protected from hurting themselves. There have been few scientific reports of trauma associated with somnambulism and no published investigations on the epidemiology or trauma patterns associated with somnambulism. Methods We included all emergency department (ED) admissions to University Hospital Inselspital, Berne, Switzerland, from January 1, 2000, until August 11, 2015, when the patient had suffered a trauma associated with somnambulism. Demographic data (age, gender, nationality) and medical data (mechanism of injury, final diagnosis, hospital admission, mortality and medication on admission) were included. Results Of 620,000 screened ED admissions, 11 were associated with trauma and sleepwalking. Two patients (18.2%) had a history of known non-rapid eye movement parasomnias. The leading cause of admission was falls. Four patients required hospital admission for orthopedic injuries needing further diagnostic testing and treatment (36.4%). These included two patients with multiple injuries (18.2%). None of the admitted patients died. Conclusion Although sleepwalking seems benign in the majority of cases and most of the few injured patients did not require hospitalization, major injuries are possible. When patients present with falls of unknown origin, the possibility should be evaluated that they were caused by somnambulism. PMID:27833677

Sustained Sleep Fragmentation Induces Sleep Homeostasis in Mice

PubMed Central

Baud, Maxime O.; Magistretti, Pierre J.; Petit, Jean-Marie

2015-01-01

Study Objectives: Sleep fragmentation (SF) is an integral feature of sleep apnea and other prevalent sleep disorders. Although the effect of repetitive arousals on cognitive performance is well documented, the effects of long-term SF on electroencephalography (EEG) and molecular markers of sleep homeostasis remain poorly investigated. To address this question, we developed a mouse model of chronic SF and characterized its effect on EEG spectral frequencies and the expression of genes previously linked to sleep homeostasis including clock genes, heat shock proteins, and plasticity-related genes. Design: N/A. Setting: Animal sleep research laboratory. Participants : Sixty-six C57BL6/J adult mice. Interventions: Instrumental sleep disruption at a rate of 60/h during 14 days Measurements and Results: Locomotor activity and EEG were recorded during 14 days of SF followed by recovery for 2 days. Despite a dramatic number of arousals and decreased sleep bout duration, SF minimally reduced total quantity of sleep and did not significantly alter its circadian distribution. Spectral analysis during SF revealed a homeostatic drive for slow wave activity (SWA; 1–4 Hz) and other frequencies as well (4–40 Hz). Recordings during recovery revealed slow wave sleep consolidation and a transient rebound in SWA, and paradoxical sleep duration. The expression of selected genes was not induced following chronic SF. Conclusions: Chronic sleep fragmentation (SF) increased sleep pressure confirming that altered quality with preserved quantity triggers core sleep homeostasis mechanisms. However, it did not induce the expression of genes induced by sleep loss, suggesting that these molecular pathways are not sustainably activated in chronic diseases involving SF. Citation: Baud MO, Magistretti PJ, Petit JM. Sustained sleep fragmentation induces sleep homeostasis in mice. SLEEP 2015;38(4):567–579. PMID:25325477

[Physical performance and sedation: comparative study of the effects of a benzodiazepine (temazepam) and of a non-benzodiazepine hypnotic (zolpidem)].

PubMed

Gremion, G; Sutter-Weyrich, C; Rostan, A; Forster, A

1992-09-01

It is well-known that many athletes experience some form of precompetition stress that may result in insomnia during the night before their competition. Yet, sleep withdrawal even if only partial, has a negative influence on performance, particularly when the type of exercise requires good psychomotor performance The purpose of the present study was to investigate whether the intake of a hypnotic drug would have negative effects on physical performance capacity. The authors have compared the effects of oral temazepam, a medium half-life benzodiazepine vs oral zolpidem, a short half-life non-benzodiazepine drug, vs placebo. A randomized double-blind trial was used to assess endurance, resistance, strength and coordination in 26 athletes. The results did not show any differences between the three groups, neither in physical performance characteristic nor in coordination. It is concluded that as regards the performance capacity, there is no risk for stressed athletes to use sleep inducers the night before their competition.

[Sleep psychiatry].

PubMed

Chiba, Shigeru

2013-01-01

Sleep disorders are serious issues in modern society. There has been marked scientific interest in sleep for a century, with the discoveries of the electrical activity of the brain (EEG), sleep-wake system, rapid eye movement (REM) sleep, and circadian rhythm system. Additionally, the advent of video-polysomnography in clinical research has revealed some of the consequences of disrupted sleep and sleep deprivation in psychiatric disorders. Decades of clinical research have demonstrated that sleep disorders are intimately tied to not only physical disease (e. g., lifestyle-related disease) but psychiatric illness. According to The International Classification of Sleep Disorders (2005), sleep disorders are classified into 8 major categories: 1) insomnia, 2) sleep-related breathing disorders, 3) hypersomnias of central origin, 4) circadian rhythm sleep disorders, 5) parasomnias, 6) sleep-related movement disorders, 7) isolated symptoms, and 8) other sleep disorders. Several sleep disorders, including obstructive sleep apnea syndrome, restless legs syndrome, periodic limb movement disorder, sleepwalking, REM sleep behavior disorder, and narcolepsy, may be comorbid or possibly mimic numerous psychiatric disorders, and can even occur due to psychiatric pharmacotherapy. Moreover, sleep disorders may exacerbate underlying psychiatric disorders when left untreated. Therefore, psychiatrists should pay attention to the intimate relationship between sleep disorders and psychiatric symptoms. Sleep psychiatry is an academic field focusing on interrelations between sleep medicine and psychiatry. This mini-review summarizes recent findings in sleep psychiatry. Future research on the bidirectional relation between sleep disturbance and psychiatric symptoms will shed light on the pathophysiological view of psychiatric disorders and sleep disorders.

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

PubMed Central

Vlainić, Josipa; Jembrek, Maja Jazvinšćak; Vlainić, Toni; Štrac, Dubravka Švob; Peričić, Danka

2012-01-01

Aim: Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABAA receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABAA receptors following short and long-term exposure to zolpidem in vitro. Methods: Human embryonic kidney (HEK) 293 cells stably expressing recombinant α1β2γ2s GABAA receptors were exposed to zolpidem (1 and 10 μmol/L) for short-term (2 h daily for 1, 2, or 3 consecutive days) or long-term (continuously for 48 h). Radioligand binding studies were used to determine the parameters of [3H]flunitrazepam binding sites. Results: A single (2 h) or repeated (2 h daily for 2 or 3 d) short-term exposure to zolpidem affected neither the maximum number of [3H]flunitrazepam binding sites nor the affinity. In both control and short-term zolpidem treated groups, addition of GABA (1 nmol/L–1 mmol/L) enhanced [3H]flunitrazepam binding in a concentration-dependent manner. The maximum enhancement of [3H]flunitrazepam binding in short-term zolpidem treated group was not significantly different from that in the control group. In contrast, long-term exposure to zolpidem resulted in significantly increase in the maximum number of [3H]flunitrazepam binding sites without changing the affinity. Furthermore, long-term exposure to zolpidem significantly decreased the ability of GABA to stimulate [3H]flunitrazepam binding. Conclusion: The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive changes in GABAA receptors that could be related to the development of tolerance and dependence. PMID:22922343

Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic.

PubMed

Patat, A; Naef, M M; van Gessel, E; Forster, A; Dubruc, C; Rosenzweig, P

1994-10-01

Zolpidem is a new imidazopyridine-hypnotic that selectively binds to the central omega 1-receptor subtype. A double-blind, randomized, three-way, crossover placebo-controlled study was carried out in nine healthy male volunteers to assess the possible antagonism of central nervous system--depressant effects of zolpidem by flumazenil. Subjects received zolpidem (0.21 mg/kg) or placebo, intravenously, followed 17 minutes later by flumazenil (0.04 mg/kg) or placebo. Vigilance and performance were assessed by a trained anesthetist with use of ciliary reflex, response to a verbal instruction, subjective sedation, a tracking task, and a free recall task. Zolpidem produced a clinically relevant hypnotic effect in five subjects and significantly impaired performance in all nine subjects up to 90 minutes after dosing. Flumazenil rapidly antagonized clinical sedation in the five subjects who were asleep and significantly reversed the performance decrement within 3 minutes, without any escape phenomenon. Flumazenil did not change zolpidem plasma concentrations, confirming the pharmacodynamic nature of the interaction. Flumazenil may thus be a safe and effective antidote in patients with zolpidem overdosage.

Sleep violence--forensic science implications: polygraphic and video documentation.

PubMed

Mahowald, M W; Bundlie, S R; Hurwitz, T D; Schenck, C H

1990-03-01

During the past century, infrequent, anecdotal reports of sleep-related violence with forensic science implications have appeared. Recent rapid developments in the field of sleep-disorders medicine have resulted in greater understanding of a variety of sleep-related behaviors, and formal sleep-behavior monitoring techniques have permitted their documentation and classification. Sleep-related violence can be associated with a number of diagnosable and treatable sleep disorders, including (1) night terrors/sleepwalking, (2) nocturnal seizures, (3) rapid eye movement (REM) sleep-behavior disorder, (4) sleep drunkenness, and (5) psychogenic dissociative states occurring during the sleep period. Potentially violent automatized behavior, without consciousness, can and does occur during sleep. The violence resulting from these disorders may be misinterpreted as purposeful suicide, assault, or even homicide. Sleep-related violence must be added to the list of automatisms. A classification system of both waking and sleep-related automatic behavior is proposed, with recommendations for assessment of such behavior.

Sleep-inducing factors.

PubMed

García-García, Fabio; Acosta-Peña, Eva; Venebra-Muñoz, Arturo; Murillo-Rodríguez, Eric

2009-08-01

Kuniomi Ishimori and Henri Piéron were the first researchers to introduce the concept and experimental evidence for a chemical factor that would presumably accumulate in the brain during waking and eventually induce sleep. This substance was named hypnotoxin. Currently, the variety of substances which have been shown to alter sleep includes peptides, cytokines, neurotransmitters and some substances of lipidic nature, many of which are well known for their involvement in other biological activities. In this chapter, we describe the sleep-inducing properties of the vasoactive intestinal peptide, prolactin, adenosine and anandamide.

Sleep disorders in kidney disease.

PubMed

De Santo, R M; Perna, A; Di Iorio, B R; Cirillo, M

2010-03-01

Sleep disorders are common in patients with end stage renal disease receiving hemodialysis or peritoneal dialysis. However also a well functioning renal graft does not cure the poor sleep pattern which now emerges as a problem even in early chronic kidney disease (CKD). When patients are made aware for the first time of a disease such as CKD, which may brink to dialysis or at the best to a renal transplant patients begin to experience a disordered sleep. Sleeping disorders include insomnia (I), sleep apnoea (SAS), restless legs syndrome (RLS), periodic limb movement disorder (PLMD), excessive daily sleeping (EDS), sleepwalking, nightmares, and narcolepsy. Disordered sleep did not meet the clinical and scientific interest it deserves, in addition and we do not have a well defined solution for sleeping complaints. However, awareness that a poor sleep is associated with poor quality of life and carries an increase in mortality risk has recently stimulated interest in the field. There are many putative causes for a disordered sleep in chronic kidney disease and in end-stage renal disease. For a unifying hypothesis demographic factors, lifestyles, disease related factors, psychological factors, treatment related factors, and social factor must be taken into consideration.

The paradox of caffeine-zolpidem interaction: a network analysis.

PubMed

Myslobodsky, Michael

2009-10-01

A widely prescribed and potent short-acting hypnotic, zolpidem has become the mainstay for the treatment of middle-of-the-night sleeplessness. It is expected to be antagonized by caffeine. Paradoxically, in some cases caffeine appears to slightly enhance zolpidem sedation. The pharmacokinetic and pharmacodynamic nature of this odd effect remains unexplored. The purpose of this study is to reproduce a hypothetical molecular network recruited by caffeine when co-administered with zolpidem using Ingenuity Pathway Analysis. Thus generated, network drew attention to several possible contributors to caffeine sedation, such as tachykinin precursor 1, cannabinoid, and GABA receptors. The present overview is centered on the possibility that caffeine potentiation of zolpidem sedation does not involve a centralized interaction of specific neurotransmitters, but rather is contributed by its antioxidant capacity. It is proposed that by modifying the cellular redox state, caffeine ultimately reduces the pool of reactive oxygen species, thereby increasing the bioavailability of endogenous melatonin for interaction with zolpidem. This side effect of caffeine encourages further studies of multiple antioxidants as an attractive way to potentially increasing somnolence.

Clinically significant response to zolpidem in disorders of consciousness secondary to anti-N-methyl-D-aspartate receptor encephalitis in a teenager: a case report.

PubMed

Appu, Merveen; Noetzel, Michael

2014-03-01

Anti-N-methyl-d-aspartate receptor encephalitis has been associated with a prolonged neuropsychiatric phase that may last for months to years. We report the case of a 16-year-old girl who was diagnosed with anti-N-methyl-d-aspartate receptor encephalitis resulting from left ovarian mature teratoma 2 weeks after presentation with psychosis. Following tumor removal and immunotherapy, recovery from a minimally conscious state was accelerated significantly by zolpidem that was used for her sleep disturbance. Our patient was discharged home 8 weeks after admission with marked improvement in her neurological function. Zolpidem has been reported to improve arousal in disorders of consciousness but there are no previous reports of its benefit among patients with anti-N-methyl-d-aspartate receptor encephalitis. Zolpidem would be a reasonable consideration as an adjunctive treatment in anti-N-methyl-d-aspartate receptor encephalitis after tumor removal and immunotherapy to accelerate recovery and rehabilitation. Copyright © 2014 Elsevier Inc. All rights reserved.

Central nervous system side effects associated with zolpidem treatment.

PubMed

Toner, L C; Tsambiras, B M; Catalano, G; Catalano, M C; Cooper, D S

2000-01-01

Zolpidem is one of the newer medications developed for the treatment of insomnia. It is an imidazopyridine agent that is an alternative to the typical sedative-hypnotic agents. Zolpidem use is gaining favor because of its efficacy and its side effect profile, which is milder and less problematic than that of the benzodiazepines and barbiturates used to treat insomnia. Still, side effects are not uncommon with zolpidem use. We report a series of cases in which the patients developed delirium, nightmares and hallucinations during treatment with zolpidem. We will review its pharmacology, discuss previous reports of central nervous system side effects, examine the impact of drug interactions with concurrent use of antidepressants, examine gender differences in susceptibility to side effects, and explore the significance of protein binding in producing side effects.

Comorbid sleep disorders and suicide risk among children and adolescents with bipolar disorder.

PubMed

Stanley, Ian H; Hom, Melanie A; Luby, Joan L; Joshi, Paramjit T; Wagner, Karen D; Emslie, Graham J; Walkup, John T; Axelson, David A; Joiner, Thomas E

2017-12-01

Children and adolescents with bipolar disorder are at increased risk for suicide. Sleep disturbances are common among youth with bipolar disorder and are also independently implicated in suicide risk; thus, comorbid sleep disorders may amplify suicide risk in this clinical population. This study examined the effects of comorbid sleep disorders on suicide risk among youth with bipolar disorder. We conducted secondary analyses of baseline data from the Treatment of Early Age Mania (TEAM) study, a randomized controlled trial of individuals aged 6-15 years (mean ± SD = 10.2 ± 2.7 years) with DSM-IV bipolar I disorder (N = 379). Sleep disorders (i.e., nightmare, sleep terror, and sleepwalking disorders) and suicide risk were assessed via the WASH-U-KSADS and the CDRS-R, respectively. We constructed uncontrolled logistic regression models as well as models controlling for trauma history, a generalized anxiety disorder (GAD) diagnosis, and depression symptoms. Participants with a current comorbid nightmare disorder versus those without were nearly twice as likely to screen positive for suicide risk in an uncontrolled model and models controlling for trauma history, a GAD diagnosis, and depression symptoms. Neither a current comorbid sleep terror disorder nor a sleepwalking disorder was significantly associated with suicide risk. This pattern of findings remained consistent for both current and lifetime sleep disorder diagnoses. Youth with bipolar I disorder and a comorbid nightmare disorder appear to be at heightened suicide risk. Implications for assessment and treatment are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Patterns of zolpidem use among Iraq and Afghanistan veterans: A retrospective cohort analysis

PubMed Central

Amuan, Megan E.; Jaramillo, Carlos A.; Eapen, Blessen C.

2018-01-01

Background Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of zolpidem use. Objective To examine the prevalence and correlates of zolpidem exposure in Iraq and Afghanistan Veterans (IAVs). Methods A retrospective cohort study of zolpidem prescriptions was performed with National Veterans Health Administration (VHA) data. We gathered national VA inpatient, outpatient, and pharmacy data files for IAV’s who received VA care between fiscal years (FY) 2013 and 2014. The VA pharmacy database was used to identify the prevalence of long term (>30 days), high-dose zolpidem exposure (>10mg immediate-release; >12.5mg extended-release) and other medications received in FY14. Baseline characteristics (demographics, diagnoses) were identified in FY13. Bivariate and multivariable analyses were used to examine the demographic, clinical, and medication correlates of zolpidem use. Results Of 493,683 IAVs who received VHA care in FY 2013 and 2014, 7.6% (n = 37,422) were prescribed zolpidem in FY 2014. Women had lower odds of high-dose zolpidem exposure than men. The majority (77.3%) of IAVs who received zolpidem prescriptions had long-term use with an average days’ supply of 189.3 days and a minority (0.9%) had high-dose exposure. In multivariable analyses, factors associated with long-term zolpidem exposure included age greater than 29 years old, PTSD, insomnia, Selim Index, physical 2–3 conditions, opioids, antidepressants, benzodiazepines, atypical antipsychotics, and stimulants. High dose exposure was associated with PTSD, depression, substance use disorder, insomnia, benzodiazepines, atypical antipsychotics, and stimulant prescriptions. Conclusion The current practices of insomnia pharmacotherapy in IAVs fall short of the clinical guidelines and may reflect high-risk zolpidem prescribing practices that put Iraq and Afghanistan Veterans at risk for adverse effects

Patterns of zolpidem use among Iraq and Afghanistan veterans: A retrospective cohort analysis.

PubMed

Shayegani, Ramona; Song, Kangwon; Amuan, Megan E; Jaramillo, Carlos A; Eapen, Blessen C; Pugh, Mary Jo

2018-01-01

Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of zolpidem use. To examine the prevalence and correlates of zolpidem exposure in Iraq and Afghanistan Veterans (IAVs). A retrospective cohort study of zolpidem prescriptions was performed with National Veterans Health Administration (VHA) data. We gathered national VA inpatient, outpatient, and pharmacy data files for IAV's who received VA care between fiscal years (FY) 2013 and 2014. The VA pharmacy database was used to identify the prevalence of long term (>30 days), high-dose zolpidem exposure (>10mg immediate-release; >12.5mg extended-release) and other medications received in FY14. Baseline characteristics (demographics, diagnoses) were identified in FY13. Bivariate and multivariable analyses were used to examine the demographic, clinical, and medication correlates of zolpidem use. Of 493,683 IAVs who received VHA care in FY 2013 and 2014, 7.6% (n = 37,422) were prescribed zolpidem in FY 2014. Women had lower odds of high-dose zolpidem exposure than men. The majority (77.3%) of IAVs who received zolpidem prescriptions had long-term use with an average days' supply of 189.3 days and a minority (0.9%) had high-dose exposure. In multivariable analyses, factors associated with long-term zolpidem exposure included age greater than 29 years old, PTSD, insomnia, Selim Index, physical 2-3 conditions, opioids, antidepressants, benzodiazepines, atypical antipsychotics, and stimulants. High dose exposure was associated with PTSD, depression, substance use disorder, insomnia, benzodiazepines, atypical antipsychotics, and stimulant prescriptions. The current practices of insomnia pharmacotherapy in IAVs fall short of the clinical guidelines and may reflect high-risk zolpidem prescribing practices that put Iraq and Afghanistan Veterans at risk for adverse effects of zolpidem and poor health outcomes.

Modafinil and zolpidem use by emergency medicine residents.

PubMed

McBeth, Brian D; McNamara, Robert M; Ankel, Felix K; Mason, Emily J; Ling, Louis J; Flottemesch, Thomas J; Asplin, Brent R

2009-12-01

The objective was to assess the prevalence and patterns of modafinil and zolpidem use among emergency medicine (EM) residents and describe side effects resulting from use. A voluntary, anonymous survey was distributed in February 2006 to EM residents nationally in the context of the national American Board of Emergency Medicine in-training examination. Data regarding frequency and timing of modafinil and zolpidem use were collected, as well as demographic information, reasons for use, side effects, and perceived dependence. A total of 133 of 134 residency programs distributed the surveys (99%). The response rate was 56% of the total number of EM residents who took the in-training examination (2,397/4,281). Past modafinil use was reported by 2.4% (57/2,372) of EM residents, with 66.7% (38/57) of those using modafinil having initiated their use during residency. Past zolpidem use was reported by 21.8% (516/2,367) of EM residents, with 15.3% (362/2,367) reporting use in the past year and 9.3% (221/2,367) in the past month. A total of 324 of 516 (62.8%) of zolpidem users initiated use during residency. Side effects were commonly reported by modafinil users (31.0%)-most frequent were palpitations, insomnia, agitation, and restlessness. Zolpidem users reported side effects (22.6%) including drowsiness, dizziness, headache, hallucinations, depression/mood lability, and amnesia. Zolpidem use is common among EM residents, with most users initiating use during residency. Modafinil use is relatively uncommon, although most residents using have also initiated use during residency. Side effects are commonly reported for both of these agents, and long-term safety remains unclear.

Parasomnias and isolated sleep symptoms in Parkinson's disease: a questionnaire study on 661 patients.

PubMed

Ylikoski, Ari; Martikainen, Kirsti; Partinen, Markku

2014-11-15

Sleep disorders are among the most common non-motor symptoms in Parkinson's disease. The prevalence of parasomnias and their association with other symptoms were studied in a questionnaire study among 1447 randomly selected Parkinson patients, aged 43 to 89 years. The response rate was 59.0% and of these 77% had answered to all questions that were used in the analyses (N = 661). The prevalence of REM sleep behavior disorder (RBD) evaluated by the RBDSQ ≥ 6 was 39.0%. The occurrences of other parasomnias (≥ 1/week) in patients with PD were: nightmares 17.2%, night terrors 3.9%, sleepwalking 1.8%, enuresis 21.0%, and hallucinations 15.3%. Occurrences (≥ 1/week) of the isolated sleep symptoms were: nocturnal sweating 28.8%, bruxism 4.7%, and sleep talking 21.7%. Association of RBD with sleepwalking (parasomnia overlap disorder) was found in 1.7% of all PD patients. Adjusted logistic regression analysis showed that weekly nightmares (OR 12.5; 95% CI 5.3 to 29.7), hallucinations (OR 5.1; 2.1 to 12.4), sleep talking (OR 11.6; 5.9 to 22.8), male gender (OR 1.9; 1.1 to 3.1), and restless legs syndrome (OR 4.7; 1.7 to 13.2) associated with the presence of RBD. Parkinson patients with RBD have often also other parasomnias and/or isolated sleep symptoms. Copyright © 2014 Elsevier B.V. All rights reserved.

Zolpidem 10 mg given at daytime is not antagonized by 300 mg caffeine in man.

PubMed

Mattila, M J; Nurminen, M L; Vainio, P; Vanakoski, J

1998-07-01

Caffeine counteracts various effects of traditional benzodiazepines (BZDs). As zolpidem, a short-acting hypnotic, is an atypical GABAA-BZD agonist, we investigated when caffeine would counteract the effects of zolpidem as well. In daytime study I, zolpidem 10 mg (capsule) and caffeine 150 or 300 mg (in decaffeinated coffee) were given, alone and in combinations, to parallel groups (n = 15-17) of healthy students in double-blind and placebo-controlled manner. Objective and subjective tests were done before and 45 min and 90 min after intake. Ranked delta values (changes from baseline) were analysed by one-way contrast ANOVA and Scheffe's tests. In daytime study II, four healthy subjects took zolpidem 10 mg alone, and together with blinded caffeine 250 mg or (at -45 min) erythromycin 750 mg. Objective and subjective effects were measured and plasma zolpidem concentrations assayed at baseline and 45 min and 90 min after zolpidem intake. In study I, practice effects after placebo (ad + 30%) were seen for letter cancellation and digit symbol substitution but not for flicker fusion tests. Zolpidem alone significantly impaired (P < 0.05 vs delta placebo) letter cancellation and digit symbol substitution at 45 min and 90 min, lowered the flicker fusion threshold at 45 min, and caused subjective drowsiness, mental slowness, clumsiness and feeling of poor performance. Caffeine alone showed a non-significant trend to improve objective performance. The combined effects of zolpidem and either dose of caffeine matched those measured after zolpidem alone. Zolpidem + caffeine 300 mg was not stronger than zolpidem + caffeine 150 mg in impairing immediate memory and causing subjective sedation. In study II, zolpidem caused objective and subjective sedation; neither caffeine nor erythromycin modulated the effects of zolpidem or plasma zolpidem concentrations. The sedative effects of 10 mg of zolpidem are not antagonized by 150-300 mg of caffeine in pharmacodynamic or pharmacokinetic

Toxicology and characteristics of deaths involving zolpidem in New South Wales, Australia 2001-2010.

PubMed

Darke, Shane; Deady, Mark; Duflou, Johan

2012-09-01

All cases presenting to the New South Wales Department of Forensic Medicine between January 1, 2001 and September 31, 2010 in which zolpidem was detected, were retrieved. A total of 91 cases were identified. The mean age was 49.4 years, 65.9% were male, and 61.5% were suicides. Zolpidem was a factor contributing to death in 35 (37.3%) cases, of which 31 (34.1%) involved zolpidem toxicity. The median blood zolpidem concentration was 0.20 mg/L (range 0.05-3.50 mg/L), with no significant gender difference. Drug toxicity cases involving zolpidem had significantly higher median blood zolpidem concentrations than other cases (0.50 vs. 0.10 mg/L). In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide. © 2012 American Academy of Forensic Sciences.

Association between zolpidem use and glaucoma risk: a Taiwanese population-based case-control study.

PubMed

Ho, Yi-Hao; Chang, Yue-Cune; Huang, Wei-Cheng; Chen, Hsin-Yi; Lin, Che-Chen; Sung, Fung-Chang

2015-01-01

To date, the relationship between zolpidem use and subsequent risk of glaucoma in a Taiwanese population has not been assessed. We used data from the National Health Insurance system to investigate whether zolpidem use was related to glaucoma risk. A 1:4 matched case-control study was conducted. The cases were patients newly diagnosed with glaucoma from 2001 to 2010. The controls were randomly selected non-glaucoma subjects matched by sex and age (± 5 years). Zolpidem exposure and/or the average dosage of zolpidem used (mg/year) were evaluated. Medical comorbidities were considered as confounding factors. Multiple logistic regression models were used to evaluate the potential risk of zolpidem exposure on glaucoma with/without adjustment for the effects of confounding variables. The exposure rate of zolpidem use in the glaucoma group was significantly higher than that of the control group (2.8% vs. 2.0%, P < 0.0001). The adjusted odds ratio (OR) of the risk of glaucoma for those with zolpidem use vs. those without was 1.19 (95% confidence interval [CI], 1.02-1.38). Compared to non-zolpidem users, zolpidem users with an average dose of more than 200 mg/year had significantly increased risk of glaucoma (OR 1.31, 95% CI 1.03-1.68). This study suggests that the use of zolpidem might increase the risk of subsequent glaucoma. Further confirmatory studies are recommended to clarify this important issue.

Association Between Zolpidem Use and Glaucoma Risk: A Taiwanese Population-Based Case-Control Study

PubMed Central

Ho, Yi-Hao; Chang, Yue-Cune; Huang, Wei-Cheng; Chen, Hsin-Yi; Lin, Che-Chen; Sung, Fung-Chang

2015-01-01

Background To date, the relationship between zolpidem use and subsequent risk of glaucoma in a Taiwanese population has not been assessed. Methods We used data from the National Health Insurance system to investigate whether zolpidem use was related to glaucoma risk. A 1:4 matched case-control study was conducted. The cases were patients newly diagnosed with glaucoma from 2001 to 2010. The controls were randomly selected non-glaucoma subjects matched by sex and age (±5 years). Zolpidem exposure and/or the average dosage of zolpidem used (mg/year) were evaluated. Medical comorbidities were considered as confounding factors. Multiple logistic regression models were used to evaluate the potential risk of zolpidem exposure on glaucoma with/without adjustment for the effects of confounding variables. Results The exposure rate of zolpidem use in the glaucoma group was significantly higher than that of the control group (2.8% vs. 2.0%, P < 0.0001). The adjusted odds ratio (OR) of the risk of glaucoma for those with zolpidem use vs. those without was 1.19 (95% confidence interval [CI], 1.02–1.38). Compared to non-zolpidem users, zolpidem users with an average dose of more than 200 mg/year had significantly increased risk of glaucoma (OR 1.31, 95% CI 1.03–1.68). Conclusions This study suggests that the use of zolpidem might increase the risk of subsequent glaucoma. Further confirmatory studies are recommended to clarify this important issue. PMID:25720944

Association Between Zolpidem Use and Glaucoma Risk: A Taiwanese Population-Based Case-Control Study.

PubMed

Ho, Yi-Hao; Chang, Yue-Cune; Huang, Wei-Cheng; Chen, Hsin-Yi; Lin, Che-Chen; Sung, Fung-Chang

2014-08-23

Background: To date, the relationship between zolpidem use and subsequent risk of glaucoma in a Taiwanese population has not been assessed.Methods: We used data from the National Health Insurance system to investigate whether zolpidem use was related to glaucoma risk. A 1:4 matched case-control study was conducted. The cases were patients newly diagnosed with glaucoma from 2001 to 2010. The controls were randomly selected non-glaucoma subjects matched by sex and age (±5 years). Zolpidem exposure and/or the average dosage of zolpidem used (mg/year) were evaluated. Medical comorbidities were considered as confounding factors. Multiple logistic regression models were used to evaluate the potential risk of zolpidem exposure on glaucoma with/without adjustment for the effects of confounding variables.Results: The exposure rate of zolpidem use in the glaucoma group was significantly higher than that of the control group (2.8% vs. 2.0%, P < 0.0001). The adjusted odds ratio (OR) of the risk of glaucoma for those with zolpidem use vs. those without was 1.19 (95% confidence interval [CI], 1.02-1.38). Compared to non-zolpidem users, zolpidem users with an average dose of more than 200 mg/year had significantly increased risk of glaucoma (OR 1.31, 95% CI 1.03-1.68).Conclusions: This study suggests that the use of zolpidem might increase the risk of subsequent glaucoma. Further confirmatory studies are recommended to clarify this important issue.

The Development of Sleep Medicine: A Historical Sketch

PubMed Central

Schulz, Hartmut; Salzarulo, Piero

2016-01-01

For centuries the scope of sleep disorders in medical writings was limited to those disturbances which were either perceived by the sleeper him- or herself as troublesome, such as insomnia, or which were recognized by an observer as strange behavioral acts during sleep, such as sleepwalking or sleep terrors. Awareness of other sleep disorders, which are caused by malfunction of a physiological system during sleep, such as sleep-related respiratory disorders, were widely unknown or ignored before sleep monitoring techniques became available, mainly in the second half of the 20th century. Finally, circadian sleep-wake disorders were recognized as a group of disturbances by its own only when chronobiology and sleep research began to interact extensively in the last two decades of the 20th century. Sleep medicine as a medical specialty with its own diagnostic procedures and therapeutic strategies could be established only when key findings in neurophysiology and basic sleep research allowed a breakthrough in the understanding of the sleeping brain, mainly since the second half of the last century. Citation: Schulz H, Salzarulo P. The development of sleep medicine: a historical sketch. J Clin Sleep Med 2016;12(7):1041–1052. PMID:27250813

Child temperament, parenting discipline style, and daytime behavior in childhood sleep disorders.

PubMed

Owens-Stively, J; Frank, N; Smith, A; Hagino, O; Spirito, A; Arrigan, M; Alario, A J

1997-10-01

Fifty-two children without significant sleep disturbance seen at a primary care clinic for well-child care were compared on measures of temperament, parenting style, daytime behavior, and overall sleep disturbance to three diagnostic subgroups identified in a pediatric sleep clinic: children with obstructive sleep apnea (n = 33), parasomnias (night terrors, sleepwalking, etc.) (n = 16), and behavioral sleep disorders (limit-setting disorder, etc.) (n = 31). The mean age of the entire sample was 5.7 years. Temperamental emotionality in the behavioral sleep disorders group was associated with a higher level of sleep disturbance (p < .001); parenting laxness was associated with sleep disturbance in the general pediatric population (p < .01); and intense and negative temperament characteristics seemed to be associated with clinically significant behavioral sleep disturbances. Ineffective parenting styles and daytime disruptive behaviors were more likely to be associated with the milder sleep disturbances found in children in a primary care setting.

Risk of Parkinson's disease following zolpidem use: a retrospective, population-based cohort study.

PubMed

Huang, Hui-Chun; Tsai, Chon-Haw; Muo, Chih-Hsin; Lin, Kang-Hsu; Lu, Ming-Kuei; Sung, Fung-Chang; Kao, Chia-Hung

2015-01-01

To evaluate the influence of long-term zolpidem use on the incidence of developing Parkinson's disease. 2,961 subjects who used zolpidem for the first time longer than 3 months between 1998 and 2000 were identified in the National Health Insurance system of Taiwan. Subjects without a history of zolpidem use were randomly selected as a comparison cohort and frequency matched to zolpidem users based on age, sex, and index date. The diagnosis of Parkinson's disease was based on the criteria of the International Classification of Diseases, Ninth Revision, Clinical Modification. Its incidence until the end of 2009 was calculated and its hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression models and Kaplan-Meier analysis. The overall incidence of Parkinson's disease was greater among zolpidem users than in the comparison cohort (HR = 1.88; 95% CI, 1.45-2.45). However, there was no difference in Parkinson's disease incidence between these 2 cohorts after 5 years of observation. The risk of Parkinson's disease increased with increasing zolpidem dose, with an HR of 0.70 for low-dose users (< 400 mg/y) and 2.94 for high-dose users (≥ 1,600 mg/y). The incidence of Parkinson's disease was greater in subjects using zolpidem only (HR = 2.35; 95% CI, 1.66-3.33) compared to those using benzodiazepines only (HR = 1.31; 95% CI, 0.91-1.90). By stratified analysis, zolpidem use with concurrent depression (HR = 4.79) increased the risk of Parkinson's disease compared to that of zolpidem users without concurrent depression. Zolpidem use might unmask preclinical Parkinson's disease, especially in patients with depression. However, large population-based, unbiased, randomized trials are warranted to confirm this finding. © Copyright 2015 Physicians Postgraduate Press, Inc.

Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations.

PubMed

Von Moltke, L L; Greenblatt, D J; Granda, B W; Duan, S X; Grassi, J M; Venkatakrishnan, K; Harmatz, J S; Shader, R I

1999-07-01

To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings. Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. The metabolic product termed M-3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC50 ) of 0.61 microm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by approximately 40%, somewhat less than anticipated based on the IC50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels. The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition.

Relationship of Zolpidem and Cancer Risk: A Taiwanese Population-Based Cohort Study

PubMed Central

Kao, Chia-Hung; Sun, Li-Min; Liang, Ji-An; Chang, Shih-Ni; Sung, Fung-Chang; Muo, Chih-Hsin

2012-01-01

Objective To evaluate the relationship between the use of zolpidem and subsequent cancer risk in Taiwanese patients. Methods We used data from the National Health Insurance system of Taiwan to investigate whether use of zolpidem was related to cancer risk. For the study cohort, we identified 14,950 patients who had received a first prescription for zolpidem from January 1, 1998, through December 31, 2000. For each zolpidem user, we selected randomly 4 comparison patients without a history of using zolpidem who were frequency-matched by sex, age, and year of the index date. Incidence rates of all cancers and selected site-specific cancers were measured by the end of 2009, and related hazard ratios (HRs) and 95% confidence intervals (CIs) of the cancer were measured as well. Results The risk of developing any cancer was greater in patients using zolpidem than in nonusers (HR, 1.68; 95% CI, 1.55-1.82). The stratified analysis showed that the overall HR for high-dosage zolpidem (≥300 mg/y) was 2.38. The site-specific cancer risk was the highest for oral cancer (HR, 2.36; 95% CI, 1.57-3.56), followed by kidney cancer, esophageal cancer, breast cancer, liver cancer, lung cancer, and bladder cancer (HR, 1.60; 95% CI, 1.06-2.41). Men were at higher risk than women. Conclusion This population-based study revealed some unexpected findings, suggesting that the use of zolpidem may be associated with an increased risk of subsequent cancer. Further large-scale and in-depth investigations in this area are warranted. PMID:22560522

Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations

PubMed Central

von Moltke, Lisa L; Greenblatt, David J; Granda, Brian W; Duan, Su Xiang; Grassi, Jeffrey M; Venkatakrishnan, Karthik; Harmatz, Jerold S; Shader, Richard I

1999-01-01

Aims To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings. Methods Kinetic properties of zolpidem biotransformation to its three hydroxylated metabolites were studied in vitro using human liver microsomes and heterologously expressed individual human cytochromes. Results The metabolic product termed M-3 accounted for more than 80% of net intrinsic clearance by liver microsomes in vitro. Microsomes containing human cytochromes CYP1A2, 2C9, 2C19, 2D6, and 3 A4 expressed by cDNA-transfected human lymphoblastoid cells mediated zolpidem metabolism in vitro. The kinetic profile for zolpidem metabolite formation by each individual cytochrome was combined with estimated relative abundances based on immunological quantification, yielding projected contributions to net intrinsic clearance of: 61% for 3 A4, 22% for 2C9, 14% for 1A2, and less than 3% for 2D6 and 2C19. These values were consistent with inhibitory effects of ketoconazole and sulfaphenazole on zolpidem biotransformation by liver microsomes. Ketoconazole had a 50% inhibitory concentration (IC50) of 0.61 μm vs formation of the M-3 metabolite of zolpidem in vitro; in a clinical study, ketoconazole coadministration reduced zolpidem oral clearance by ≈40%, somewhat less than anticipated based on the IC50 value and total plasma ketoconazole levels, but much more than predicted based on unbound plasma ketoconazole levels. Conclusions The incomplete dependence of zolpidem clearance on CYP3A activity has clinical implications for susceptibility to metabolic inhibition. PMID:10383565

Is "poor sleep" too vague a concept for rational treatment?

PubMed

Declerck, A C

1994-01-01

Poor sleep is a common complaint, accounting for 4-5% of all general practitioner consultations. Disorders of initiating sleep are overrated by patients compared with disorders of maintaining sleep, despite the greater effect of the latter on daytime performance. There is frequently a discrepancy between subjective observations and objective measurements of sleep. General practitioners should pay attention to sleep disorders lasting more than three weeks and should bear in mind that poor sleep is a symptom, the underlying cause of which needs to be determined. Good coordination of endogenous biorhythms and external life and working circumstances can positively influence sleeping patterns. Sleep onset latency determines the amount of deep sleep and, thus, the duration and stability of core sleep. General practitioners usually prescribe a single type of benzodiazepine drug with a half-life of 5-10 h for sleep disorders. Such drugs cause the patient to fall asleep quickly, to have a considerable period of uninterrupted sleep with little waking and to wake in the morning with a subjective feeling of having slept well. A number of less desirable changes can occur, however, that may produce, for example, anxiety dreams, increased snoring and sleep apnoea periods at night, and weakness of muscles during the day. The third generation of hypnotic agents produce less undesirable changes than the second generation. Zolpidem (an imidazoypridine), one such agent, seems to provide an effective treatment for insomnia without inducing undesirable side-effects.

Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes

PubMed Central

Norman, Jessica L; Fixen, Danielle R; Saseen, Joseph J; Saba, Laura M; Linnebur, Sunny A

2017-01-01

Background: Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women. Objectives: The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem. Methods: Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients’ records was also evaluated. Results: A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%–50%, p = 0.23), elderly men (34%–40%, p = 0.53), and elderly women (60%–74%, p = 0.14), but the change was only significant in young women (42%–70%, p = 0.0045). Conclusion: After Food and Drug Administration–mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system

Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes.

PubMed

Norman, Jessica L; Fixen, Danielle R; Saseen, Joseph J; Saba, Laura M; Linnebur, Sunny A

2017-01-01

Women have higher morning serum zolpidem concentrations than men after taking an evening dose, potentially leading to increased risk of harm. On 19 April 2013, the United States Food and Drug Administration required labeling changes for zolpidem, recommending an initial dose of no greater than 5 mg (immediate release) or 6.25 mg (controlled release) per night in women. The primary objective of this study was to compare prescribing practices before and after the 2013 zolpidem labeling change. A secondary objective was to evaluate serious adverse events potentially related to zolpidem. Electronic medical records of adults receiving care through the University of Colorado Health system were accessed for study inclusion if patients were provided a first-time prescription for zolpidem either prior to or after the Food and Drug Administration labeling change. Patients were randomly chosen from eight strata based on age, gender, and date of zolpidem initiation (before/after the labeling change). Demographic and zolpidem prescribing data were collected. Low-dose zolpidem was considered 5 mg (immediate release) or 6.25 mg (controlled release) daily or less. Documentation of potentially related serious adverse events within the patients' records was also evaluated. A total of 400 patients were included in the study. The overall percentage of patients prescribed low-dose zolpidem increased from 44% to 58% after the labeling change (p = 0.0020). In a pre-specified subgroup analysis, the percentage of patients prescribed low-dose zolpidem increased in all groups, including young men (38%-50%, p = 0.23), elderly men (34%-40%, p = 0.53), and elderly women (60%-74%, p = 0.14), but the change was only significant in young women (42%-70%, p = 0.0045). After Food and Drug Administration-mandated labeling changes for zolpidem in 2013, the percentage of overall patients in our health system, and specifically young women, with initial prescriptions for low

Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults.

PubMed

Finkle, William D; Der, Jane S; Greenland, Sander; Adams, John L; Ridgeway, Gregory; Blaschke, Terrance; Wang, Zixia; Dell, Richard M; VanRiper, Kurt B

2011-10-01

To determine whether zolpidem is a safer alternative to benzodiazepines. Retrospective cohort study. Community based. Health maintenance organization members with an initial prescription for zolpidem (n = 43,343), alprazolam (n = 103,790), lorazepam (n = 150,858), or diazepam (n = 93,618). Zolpidem and benzodiazepine prescriptions were identified from pharmacy databases. Rates of nonvertebral fractures and hip fractures requiring hospitalization were compared before and after an initial prescription for each treatment, adjusting for confounders using doubly robust estimation. In patients aged 65 and older, the rates of nonvertebral fractures and dislocations were similar in the pre- treatment intervals. The rate ratios (RRs) for the 90-day posttreatment interval relative to the pretreatment interval were 2.55 (95% confidence interval (CI) = 1.78-3.65; P < .001) for zolpidem, 1.14 (95% CI = 0.80-1.64; P = .42) for alprazolam, 1.53 (95% CI = 1.23-1.91; P < .001) for lorazepam, and 1.97 (95% CI = 1.22-3.18; P = .01) for diazepam. The ratio of RRs (RRR)-the RR in the posttreatment period adjusted for the corresponding RR in the pretreatment period-were 2.23 (95% CI = 1.36-3.66; P = .006) for zolpidem relative to alprazolam, 1.68 (95% CI = 1.12-2.53; P = .02) for zolpidem relative to lorazepam, and 1.29 (95% CI = 0.72-2.30; P = .32) for zolpidem relative to diazepam. The RRs decreased with time from the initial prescription (trend P < .001), as would be expected if the association is causal. In older adults, the risk of injury with zolpidem exceeded that with alprazolam and lorazepam and was similar to that with diazepam. If the associations are causal, then the high incidence of these fractures implies that these treatment induce a substantial number of fractures and consequential costs. Further study of the association is imperative. © 2011, Copyright the Authors Journal compilation © 2011, The American Geriatrics Society.

Cerebral blood perfusion after treatment with zolpidem and flumazenil in the baboon.

PubMed

Clauss, Ralf P; Dormehl, Irene C; Kilian, Elmaré; Louw, Werner K A; Nel, Wally H; Oliver, Douglas W

2002-01-01

Previous studies have shown that zolpidem (CAS 82626-48-0) can lead to improved perfusion in damaged brain tissue. Zolpidem belongs to the imidazopyridine chemical class and it illicits its pharmacological action via the gamma-aminobutyric acid (GABA) receptor system through stimulation of particularly the omega 1 receptors and to a lesser extent omega 2 receptors. Previously it was reported that no cerebral blood flow effects were observed in normal baboons after treatment with zolpidem, whereas an asymmetric regional increase in cerebral blood flow was observed in a neurologically abnormal baboon. In this study, the effect of a combination of the benzodiazepine receptor antagonist flumazenil (CAS 78755-81-4) and zolpidem on brain perfusion was examined by the 99mTc-hexamethyl-propylene amine oxime (99mTc-HMPAO) split dose brain single photon emission computed tomography (SPECT). Four normal baboons and the neurologically abnormal baboon from the previous zolpidem study were examined. In the current study the asymmetric changes observed after zolpidem--only treatment in the abnormal baboon was attenuated by flumazenil intervention. A decreased brain blood flow was observed after combination treatment of zolpidem and flumazenil in the normal baboons. The involvement of the omega receptors is suggested by these results. Up- or down-regulation of omega receptors may also contribute to the observed responses in the abnormal baboon and a brain injured patient.

REM sleep behavior disorder and other sleep disturbances in Disney animated films.

PubMed

Iranzo, Alex; Schenck, Carlos H; Fonte, Jorge

2007-08-01

During a viewing of Disney's animated film Cinderella (1950), one author (AI) noticed a dog having nightmares with dream-enactment that strongly resembled RBD. This prompted a study in which all Disney classic full-length animated films and shorts were analyzed for other examples of RBD. Three additional dogs were found with presumed RBD in the classic films Lady and the Tramp (1955) and The Fox and the Hound (1981), and in the short Pluto's Judgment Day (1935). These dogs were elderly males who would pant, whine, snuffle, howl, laugh, paddle, kick, and propel themselves while dreaming that they were chasing someone or running away. In Lady and the Tramp the dog was also losing both his sense of smell and his memory, two associated features of human RBD. These four films were released before RBD was first formally described in humans and dogs. In addition, systematic viewing of the Disney films identified a broad range of sleep disorders, including nightmares, sleepwalking, sleep related seizures, disruptive snoring, excessive daytime sleepiness, insomnia and circadian rhythm sleep disorder. These sleep disorders were inserted as comic elements. The inclusion of a broad range of accurately depicted sleep disorders in these films indicates that the Disney screenwriters were astute observers of sleep and its disorders.

Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study.

PubMed

Kao, Chia-Hung; Sun, Li-Min; Liang, Ji-An; Chang, Shih-Ni; Sung, Fung-Chang; Muo, Chih-Hsin

2012-05-01

To evaluate the relationship between the use of zolpidem and subsequent cancer risk in Taiwanese patients. We used data from the National Health Insurance system of Taiwan to investigate whether use of zolpidem was related to cancer risk. For the study cohort, we identified 14,950 patients who had received a first prescription for zolpidem from January 1, 1998, through December 31, 2000. For each zolpidem user, we selected randomly 4 comparison patients without a history of using zolpidem who were frequency-matched by sex, age, and year of the index date. Incidence rates of all cancers and selected site-specific cancers were measured by the end of 2009, and related hazard ratios (HRs) and 95% confidence intervals (CIs) of the cancer were measured as well. The risk of developing any cancer was greater in patients using zolpidem than in nonusers (HR, 1.68; 95% CI, 1.55-1.82). The stratified analysis showed that the overall HR for high-dosage zolpidem (≥300 mg/y) was 2.38. The site-specific cancer risk was the highest for oral cancer (HR, 2.36; 95% CI, 1.57-3.56), followed by kidney cancer, esophageal cancer, breast cancer, liver cancer, lung cancer, and bladder cancer (HR, 1.60; 95% CI, 1.06-2.41). Men were at higher risk than women. This population-based study revealed some unexpected findings, suggesting that the use of zolpidem may be associated with an increased risk of subsequent cancer. Further large-scale and in-depth investigations in this area are warranted. Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.

PubMed

de Haas, S L; Schoemaker, R C; van Gerven, J M A; Hoever, P; Cohen, A F; Dingemanse, J

2010-11-01

Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

Zolpidem (Ambien): a pediatric case series.

PubMed

Kurta, D L; Myers, L B; Krenzelok, E P

1997-01-01

In 1993, the nonbenzodiazepine sedative-hypnotic zolpidem tartrate (Ambien) was approved for use in the US. Zolpidem has an imidazopyridine structure and possesses a rapid onset of action and a short half-life. The toxic threshold and profile have not been well established in the pediatric population. All pediatric zolpidem exposures reported to a regional poison information center over 24 months were reviewed retrospectively from the American Association of Poison Control Centers Toxic Exposure Surveillance System data collection forms. Twelve pediatric zolpidem exposures were reported. Seven were unintentional (ages 20 mon-5 y) and five were intentional misuse/suicide (ages 12-16 y). The regional poison information center was contacted within 1 h in ten cases with onset of symptoms within 10 to 60 min (mean 31.6 min). One child had no effect with 2.5 mg. As little as 5 mg caused symptoms with minor outcome in six unintentional ingestions (5-30 mg). Minor to moderate symptoms were reported 1-4 h after intentional ingestions (12.5-150 mg). The duration of symptoms in the unintentional cases ranged from less than 60 min up to 4 h (mean 2.4 h) and 6-10 h (mean 7.5 h) in the intentional exposures. Treatment consisted of observation (4), syrup of ipecac (1), lavage and activated charcoal (1), activated charcoal alone (5), and unknown (1). Due to the very rapid onset of central nervous system symptoms in children, emesis is not a treatment option. Supportive care, activated charcoal in large ingestions, and observation until symptoms resolve may be sufficient in most pediatric cases.

Measurement of cerebral perfusion after zolpidem administration in the baboon model.

PubMed

Clauss, R P; Dormehl, I C; Oliver, D W; Nel, W H; Kilian, E; Louw, W K

2001-01-01

A recent report showed that zolpidem (CAS 82626-48-0) can lead to the arousal of a semi-comatosed patient. Zolpidem is clinically used for the treatment of insomnia. It belongs to the imidazopyridine chemical class and is a non benzodiazepine drug. It illicits its pharmacological action via the GABA receptor system through stimulation of particularly the omega 1 receptors. In this study, the effect of zolpidem on brain perfusion was examined by 99mTc hexamethyl-propylene amine oxime (HMPAO) split dose brain SPECT on four normal baboons and in one baboon with abnormal neurological behaviour. The global and regional brain perfusion was not significantly affected in the normal brains. In some regions of the abnormal baboon brain, however, there was a disproportionate increase in perfusion after zolpidem.

Zolpidem reduces the blood oxygen level-dependent signal during visual system stimulation.

PubMed

Licata, Stephanie C; Lowen, Steven B; Trksak, George H; Maclean, Robert R; Lukas, Scott E

2011-08-15

Zolpidem is a short-acting imidazopyridine hypnotic that binds at the benzodiazepine binding site on specific GABA(A) receptors to enhance fast inhibitory neurotransmission. The behavioral and receptor pharmacology of zolpidem has been studied extensively, but little is known about its neuronal substrates in vivo. In the present within-subject, double-blind, and placebo-controlled study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) at 3 Tesla was used to assess the effects of zolpidem within the brain. Healthy participants (n=12) were scanned 60 min after acute oral administration of zolpidem (0, 5, 10, or 20mg), and changes in BOLD signal were measured in the visual cortex during presentation of a flashing checkerboard. Heart rate and oxygen saturation were monitored continuously throughout the session. Zolpidem (10 and 20mg) reduced the robust visual system activation produced by presentation of this stimulus, but had no effects on physiological activity during the fMRI scan. Zolpidem's modulation of the BOLD signal within the visual cortex is consistent with the abundant distribution of GABA(A) receptors localized in this region, as well as previous studies showing a relationship between increased GABA-mediated neuronal inhibition and a reduction in BOLD activation. Copyright © 2011 Elsevier Inc. All rights reserved.

[Single and combining effects of Calculus Bovis and zolpidem on inhibitive neurotransmitter of rat striatum corpora].

PubMed

Liu, Ping; He, Xinrong; Guo, Mei

2010-04-01

To investigate the correlation effects between single or combined administration of Calculus Bovis or zolpidem and changes of inhibitive neurotransmitter in rat striatum corpora. Sampling from rat striatum corpora was carried out through microdialysis. The content of two inhibitive neurotransmitters in rat corpus striatum- glycine (Gly) and gama aminobutyric acid (GABA), was determined by HPLC, which involved pre-column derivation with orthophthaladehyde, reversed-phase gradient elution and fluorescence detection. GABA content of rat striatum corpora in Calculus Bovis group was significantly increased compared with saline group (P < 0.01). GABA content of zolpidem group and Calculus Boris plus zolpidem group were increased largely compared with saline group as well (P < 0.05). GABA content of Calculus Bovis group was higher than combination group (P < 0.05). GABA content of zolpidem group was not significantly different from combination group. Gly content of Calculus Bovis or zolpidem group was markedly increased compared with saline group or combination group (P < 0.05). Contents of two inhibitive neurotransmitters in rat striatum corpora were all significantly increased in Calculus Bovis group, zolpidem group and combination group. The magnitude of increase was lower in combination group than in Calculus Bovis group and Zolpidem group, suggesting that Calculus Bovis promoted encephalon inhibition is more powerful than zolpidem. The increase in two inhibitive neurotransmitters did not show reinforcing effect in combination group, suggesting that Calculus Bovis and zolpidem may compete the same receptors. Therefore, combination of Calculus Bovis containing drugs and zolpidem has no clinical significance. Calculus Bovis shouldn't as an aperture-opening drugs be used for resuscitation therapy.

Symptom Presentation and Prescription of Sleep Medications for Veterans With Posttraumatic Stress Disorder.

PubMed

Greenbaum, Mark A; Neylan, Thomas C; Rosen, Craig S

2017-02-01

This study tested whether sleep medications prescribed to veterans diagnosed with posttraumatic stress disorder (PTSD) are being targeted to patients who report more severe insomnia or nightmares. Secondary analysis of survey and pharmacy data was conducted in samples of veterans from two periods: from 2006 to 2008 and from 2009 to 2013. Logistic regression tested associations between self-reported insomnia and nightmare severity, and being prescribed trazodone, prazosin, zolpidem, and benzodiazepines, controlling for PTSD severity and other covariates. In both samples, insomnia severity independently predicted trazodone receipt, and nightmare severity independently predicted prazosin receipt. In the later study, insomnia severity predicted receipt of zolpidem. Veterans in the later sample were more likely to receive trazodone, prazosin, and non-benzodiazepine hypnotics, and less likely to receive benzodiazepines than those in the earlier sample. Further research is needed to evaluate and optimize pharmacological and psychosocial treatments for sleep problems among veterans with PTSD.

Zolpidem displays heterogeneity in its binding to the nonhuman primate benzodiazepine receptor in vivo.

PubMed

Schmid, L; Bottlaender, M; Fuseau, C; Fournier, D; Brouillet, E; Mazière, M

1995-10-01

The distinctive pharmacological activity of zolpidem in rats compared with classical benzodiazepines has been related to its differential affinity for benzodiazepine receptor (BZR) subtypes. By contrast, in nonhuman primates the pharmacological activity of zolpidem was found to be quite similar to that of classical BZR agonists. In an attempt to explain this discrepancy, we examined the ability of zolpidem to differentiate BZR subtypes in vivo in primate brain using positron emission tomography. The BZRs were specifically labeled with [11C]flumazenil. Radiotracer displacement by zolpidem was monophasic in cerebellum and neocortex, with in vivo Hill coefficients close to 1. Conversely, displacement of [11C]flumazenil was biphasic in hippocampus, amygdala, septum, insula, striatum, and pons, with Hill coefficients significantly smaller than 1, suggesting two different binding sites for zolpidem. In these cerebral regions, the half-maximal inhibitory doses for the high-affinity binding site were similar to those found in cerebellum and neocortex and approximately 100-fold higher for the low-affinity binding site. The low-affinity binding site accounted for < 32% of the specific [11C]-flumazenil binding. Such zolpidem binding characteristics contrast with those reported for rodents, where three different binding sites were found. Species differences in binding characteristics may explain why zolpidem has a distinctive pharmacological activity in rodents, whereas its pharmacological activity in primates is quite similar to that of classical BZR agonists, except for the absence of severe effects on memory functions, which may be due to the lack of substantial zolpidem affinity for a distinct BZR subtype in cerebral structures belonging to the limbic system.

Sleep Disorders: Insomnia.

PubMed

Burman, Deepa

2017-09-01

Insomnia is the most common type of sleep disorder in the family medicine population. It is defined as a persistent difficulty initiating or maintaining sleep, or a report of nonrestorative sleep, accompanied by related daytime impairment. Insomnia is a significant public health problem because of its high prevalence and management challenges. There is increasing evidence of a strong association between insomnia and various medical and psychiatric comorbidities. Diagnosis of insomnia and treatment planning rely on a thorough sleep history to address contributing and precipitating factors as well as maladaptive behaviors resulting in poor sleep. Using a sleep diary or sleep log is more accurate than patient recall to determine sleep patterns. A sleep study is not routinely indicated for evaluation of insomnia. Cognitive behavioral therapy for insomnia (CBT-I) is the mainstay of treatment and is a safe and effective approach. The key challenge of CBT-I is the lack of clinicians to implement it. The newer generation nonbenzodiazepines (eg, zolpidem, zaleplon) are used as first-line pharmacotherapy for chronic insomnia. Newer drugs active on targets other than the gamma-aminobutyric acid receptor are now available, but clear treatment guidelines are needed. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Aging induced ER stress alters sleep and sleep homeostasis

PubMed Central

Brown, Marishka K.; Chan, May T.; Zimmerman, John E.; Pack, Allan I.; Jackson, Nicholas E.; Naidoo, Nirinjini

2014-01-01

Alterations in the quality, quantity and architecture of baseline and recovery sleep have been shown to occur during aging. Sleep deprivation induces endoplasmic reticular (ER) stress and upregulates a protective signaling pathway termed the unfolded protein response (UPR). The effectiveness of the adaptive UPR is diminished by age. Previously, we showed that endogenous chaperone levels altered recovery sleep in Drosophila melanogaster. We now report that acute administration of the chemical chaperone sodium 4-phenylbutyrate (PBA) reduces ER stress and ameliorates age-associated sleep changes in Drosophila. PBA consolidates both baseline and recovery sleep in aging flies. The behavioral modifications of PBA are linked to its suppression of ER stress. PBA decreased splicing of x-box binding protein 1 (XBP1) and upregulation of phosphorylated elongation initiation factor 2 α (p-eIF2α), in flies that were subjected to sleep deprivation. We also demonstrate that directly activating ER stress in young flies fragments baseline sleep and alters recovery sleep. Alleviating prolonged/sustained ER stress during aging contributes to sleep consolidation and improves recovery sleep/ sleep debt discharge. PMID:24444805

Three cases of zolpidem dependence treated with fluoxetine: the serotonin hypothesis.

PubMed

Liappas, Ioannis A; Malitas, Petros N; Dimopoulos, Nikolaos P; Gitsa, Olympia E; Liappas, Alexandros I; Nikolaou, Chrisoula K; Christodoulou, Georgios N

2003-04-01

Zolpidem is an imidazopyridine hypnotic that is believed to act selectively at alpha(1) subunit-containing gamma-aminobutyric acid type A (GABA(A)) receptors and thus to have minimal abuse and dependence potential. We present three cases of zolpidem abuse and dependence in which the drug was used not for sedation but for stimulation and anxiolysis. All of the patients were treated with fluoxetine (a selective serotonin reuptake inhibitor) and managed to discontinue the abuse and remain abstinent from the drug. The efficacy of this kind of medication on the abuse of a GABAergic agonist, in this case dependence on zolpidem, leads to a serotonergic and GABAergic system interaction hypothesis.

Scalp and Source Power Topography in Sleepwalking and Sleep Terrors: A High-Density EEG Study.

PubMed

Castelnovo, Anna; Riedner, Brady A; Smith, Richard F; Tononi, Giulio; Boly, Melanie; Benca, Ruth M

2016-10-01

To examine scalp and source power topography in sleep arousals disorders (SADs) using high-density EEG (hdEEG). Fifteen adult subjects with sleep arousal disorders (SADs) and 15 age- and gender-matched good sleeping healthy controls were recorded in a sleep laboratory setting using a 256 channel EEG system. Scalp EEG analysis of all night NREM sleep revealed a localized decrease in slow wave activity (SWA) power (1-4 Hz) over centro-parietal regions relative to the rest of the brain in SADs compared to good sleeping healthy controls. Source modelling analysis of 5-minute segments taken from N3 during the first half of the night revealed that the local decrease in SWA power was prominent at the level of the cingulate, motor, and sensori-motor associative cortices. Similar patterns were also evident during REM sleep and wake. These differences in local sleep were present in the absence of any detectable clinical or electrophysiological sign of arousal. Overall, results suggest the presence of local sleep differences in the brain of SADs patients during nights without clinical episodes. The persistence of similar topographical changes in local EEG power during REM sleep and wakefulness points to trait-like functional changes that cross the boundaries of NREM sleep. The regions identified by source imaging are consistent with the current neurophysiological understanding of SADs as a disorder caused by local arousals in motor and cingulate cortices. Persistent localized changes in neuronal excitability may predispose affected subjects to clinical episodes. © 2016 Associated Professional Sleep Societies, LLC.

FMRFamide signaling promotes stress-induced sleep in Drosophila

PubMed Central

Lenz, Olivia; Xiong, Jianmei; Nelson, Matthew D.; Raizen, David M.; Williams, Julie A.

2015-01-01

Enhanced sleep in response to cellular stress is a conserved adaptive behavior across multiple species, but the mechanism of this process is poorly understood. Drosophila melanogaster increases sleep following exposure to septic or aseptic injury, and Caenorhabditis elegans displays sleep-like quiescence following exposure to high temperatures that stress cells. We show here that, similar to C. elegans, Drosophila responds to heat stress with an increase in sleep. In contrast to Drosophila infection-induced sleep, heat-induced sleep is not sensitive to the time-of-day of the heat pulse. Moreover, the sleep response to heat stress does not require Relish, the NFκB transcription factor that is necessary for infection-induced sleep, indicating that sleep is induced by multiple mechanisms from different stress modalities. We identify a sleep-regulating role for a signaling pathway involving FMRFamide neuropeptides and their receptor FR. Animals mutant for either FMRFamide or for the FMRFamide receptor (FR) have a reduced recovery sleep in response to heat stress. FR mutants, in addition, show reduced sleep responses following infection with Serratia marcescens, and succumb to infection at a faster rate than wild-type controls. Together, these findings support the hypothesis that FMRFamide and its receptor promote an adaptive increase in sleep following stress. Because an FMRFamide-like neuropeptide plays a similar role in C. elegans, we propose that FRMFamide neuropeptide signaling is an ancient regulator of recovery sleep which occurs in response to cellular stress. PMID:25668617

FMRFamide signaling promotes stress-induced sleep in Drosophila.

PubMed

Lenz, Olivia; Xiong, Jianmei; Nelson, Matthew D; Raizen, David M; Williams, Julie A

2015-07-01

Enhanced sleep in response to cellular stress is a conserved adaptive behavior across multiple species, but the mechanism of this process is poorly understood. Drosophila melanogaster increases sleep following exposure to septic or aseptic injury, and Caenorhabditis elegans displays sleep-like quiescence following exposure to high temperatures that stress cells. We show here that, similar to C. elegans, Drosophila responds to heat stress with an increase in sleep. In contrast to Drosophila infection-induced sleep, heat-induced sleep is not sensitive to the time-of-day of the heat pulse. Moreover, the sleep response to heat stress does not require Relish, the NFκB transcription factor that is necessary for infection-induced sleep, indicating that sleep is induced by multiple mechanisms from different stress modalities. We identify a sleep-regulating role for a signaling pathway involving FMRFamide neuropeptides and their receptor FR. Animals mutant for either FMRFamide or for the FMRFamide receptor (FR) have a reduced recovery sleep in response to heat stress. FR mutants, in addition, show reduced sleep responses following infection with Serratia marcescens, and succumb to infection at a faster rate than wild-type controls. Together, these findings support the hypothesis that FMRFamide and its receptor promote an adaptive increase in sleep following stress. Because an FMRFamide-like neuropeptide plays a similar role in C. elegans, we propose that FRMFamide neuropeptide signaling is an ancient regulator of recovery sleep which occurs in response to cellular stress. Copyright © 2015 Elsevier Inc. All rights reserved.

The Association Between the Use of Zolpidem and the Risk of Alzheimer's Disease Among Older People.

PubMed

Cheng, Hui-Ting; Lin, Fang-Ju; Erickson, Steven R; Hong, Jin-Liern; Wu, Chung-Hsuen

2017-11-01

To evaluate the association between zolpidem use and the risk of Alzheimer's disease among older people. A retrospective cohort study using data from 2001 to 2011 from the National Health Insurance Research Database. Taiwan. A total of 6,922 patients aged 65 years or older enrolled from January 2002 to December 2004 (the enrollment period). Zolpidem users were identified as patients who used zolpidem during the enrollment period. The index date was the date of the first zolpidem prescription. Dosage of zolpidem use was defined using cumulative defined daily dose (cDDD) based on the cumulative dosage that patients took within one year after the index date (grouped as: less than 28, 28-90, 91-180, and more than 180 cDDD). The occurrence of Alzheimer's disease was defined as the time period from the end of one year after the index date to the date of the Alzheimer's disease diagnosis. The propensity score was used to adjust the measured confounders of Alzheimer's disease. Cox proportional hazards models were used to evaluate the association between zolpidem use and the incidence of Alzheimer's disease. Zolpidem users with a high cumulative dose (>180 cDDD) in the first year after initiation had a significantly greater risk of Alzheimer's disease than non-zolpidem users (HR = 2.97, 95% CI = 1.61-5.49) and low cumulative dose (<28 cDDD) users (HR = 4.18, 95% CI = 1.77-9.86). We found the use of a high cumulative dose of zolpidem was associated with an increased risk of Alzheimer's disease among older people living in Taiwan. It is advised to use caution when considering long-term use of zolpidem in older patients. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Zolpidem improves neuropsychiatric symptoms and motor dysfunction in a patient with Parkinson's disease after deep brain stimulation.

PubMed

Huang, Hung-Yu; Hsu, Yi-Ting; Wu, Yu-Chin; Chiou, Shang-Ming; Kao, Chia-Hung; Tsai, Mu-Chieh; Tsai, Chon-Haw

2012-06-01

To illustrate the beneficial effect of zolpidem on the neuropsychiatric and motor symptoms in a patient with Parkinson disease (PD) after bilateral subthalamic nucleus deep brain stimulation. The 61-year-old housewife was diagnosed to have PD for 12 years with initial presentation of clumsiness and rest tremor of right limbs. She was referred to our hospital in March 2009 due to shortening of drug beneficial period since 3 years ago and on-phase dyskinesia in recent 2 years. Bilateral STN DBS was conducted on 18 June, 2009. Fluctuating spells of mental confusion were developed on the next day after surgery. Electric stimuli via DBS electrodes were delivered with parameters of 2 volts, 60 μs, 130 Hz on bilateral STN 32 days after DBS. The incoherent behaviors and motor fluctuation remained to occur. The beneficial effect of zolpidem on her neuropsychiatric and motor symptoms was detected incidentally in early July 2009. She could chat normally with her caregiver and walk with assistance after taking zolpidem. The beneficial period may last for 2 hours. Zolpidem was then given in dosage of 10 mg three times per day. The neuropsychiatric inventory was scored 56 during zolpidem 'off' and 30 during zolpidem 'on'. To understand the intriguing feature, we conducted FDG-PET during 'off' and 'on' zolpidem conditions. The results revealed that the metabolism was decreased in the right frontal, parietal cortex and caudate nucleus during zolpidem 'off'. These cool spots can be partially restored by zolpidem. Zolpidem ameliorated the neuropsychiatric and parkinsonian motor symptom in the PD patient. Since GABAA benzodiazepine receptors are widely distributed throughout the central nervous system, zolpidem probably acts via modulating structures lying within the cortico-subcortical loop or by direct effect on these cortical regions.

Sleep and Sex: What Can Go Wrong? A Review of the Literature on Sleep Related Disorders and Abnormal Sexual Behaviors and Experiences

PubMed Central

Schenck, Carlos H.; Arnulf, Isabelle; Mahowald, Mark W.

2007-01-01

Study Objectives: To formulate the first classification of sleep related disorders and abnormal sexual behaviors and experiences. Design: A computerized literature search was conducted, and other sources, such as textbooks, were searched. Results: Many categories of sleep related disorders were represented in the classification: parasomnias (confusional arousals/sleepwalking, with or without obstructive sleep apnea; REM sleep behavior disorder); sleep related seizures; Kleine-Levin syndrome (KLS); severe chronic insomnia; restless legs syndrome; narcolepsy; sleep exacerbation of persistent sexual arousal syndrome; sleep related painful erections; sleep related dissociative disorders; nocturnal psychotic disorders; miscellaneous states. Kleine-Levin syndrome (78 cases) and parasomnias (31 cases) were most frequently reported. Parasomnias and sleep related seizures had overlapping and divergent clinical features. Thirty-one cases of parasomnias (25 males; mean age, 32 years) and 7 cases of sleep related seizures (4 males; mean age, 38 years) were identified. A full range of sleep related sexual behaviors with self and/or bed partners or others were reported, including masturbation, sexual vocalizations, fondling, sexual intercourse with climax, sexual assault/rape, ictal sexual hyperarousal, ictal orgasm, and ictal automatism. Adverse physical and/or psychosocial effects from the sleepsex were present in all parasomnia and sleep related seizure cases, but pleasurable effects were reported by 5 bed partners and by 3 patients with sleep related seizures. Forensic consequences were common, occurring in 35.5% (11/31) of parasomnia cases, with most (9/11) involving minors. All parasomnias cases reported amnesia for the sleepsex, in contrast to 28.6% (2/7) of sleep related seizure cases. Polysomnography (without penile tumescence monitoring), performed in 26 of 31 parasomnia cases, documented sexual moaning from slow wave sleep in 3 cases and sexual intercourse during

Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study

PubMed Central

Thonnard, Marie; Gosseries, Olivia; Demertzi, Athena; Lugo, Zulay; Vanhaudenhuyse, Audrey; Bruno, Marie-Aurélie; Chatelle, Camille; Thibaut, Aurore; Charland-Verville, Vanessa; Habbal, Dina; Schnakers, Caroline; Laureys, Steven

2013-01-01

Summary Zolpidem has been reported as an “awakening drug” in some patients with disorders of consciousness (DOC). We here present the results of a prospective open-label study in chronic DOC patients. Sixty patients (35±15 years; 18 females; mean time since insult ± SD: 4±5.5 years; 31 with traumatic etiology) with a diagnosis of vegetative state/unresponsive wakefulness syndrome (n=28) or minimally conscious state (n=32) were behaviorally assessed using the Coma Recovery Scale-Revised (CRS-R) before and one hour after administration of 10 mg of zolpidem. At the group level, the diagnosis did not change after intake of zolpidem (p=0.10) and CRS-R total scores decreased (p=0.01). Twelve patients (20%) showed improved behaviors and/or CRS-R total scores after zolpidem administration but in only one patient was the diagnosis after zolpidem intake found to show a significant improvement (functional object use), which suggested a change of diagnosis. However, in this patient, a double-blind placebo-controlled trial was performed in order to better specify the effects of zolpidem, but the patient, on this trial, failed to show any clinical improvements. The present open-label study therefore failed to show any clinically significant improvement (i.e., change of diagnosis) in any of the 60 studied chronic DOC patients. PMID:24598393

Zolpidem, a clinical hypnotic that affects electronic transfer, alters synaptic activity through potential GABA receptors in the nervous system without significant free radical generation.

PubMed

Kovacic, Peter; Somanathan, Ratnasamy

2009-01-01

Zolpidem (trade name Ambien) has attracted much interest as a sleep-inducing agent and also in research. Attention has been centered mainly on receptor binding and electrochemistry in the central nervous system which are briefly addressed herein. A novel integrated approach to mode of action is presented. The pathways to be discussed involve basicity, reduction potential, electrostatics, cell signaling, GABA receptor binding, electron transfer (ET), pharmacodynamics, structure activity relationships (SAR) and side effects. The highly conjugated pyridinium salt formed by protonation of the amidine moiety is proposed to be the active form acting as an ET agent. Extrapolation of reduction potentials for related compounds supports the premise that zolpidem may act as an ET species in vivo. From recent literature reports, electrostatics is believed to play a significant role in drug action. The pyridinium cation displays molecular electrostatic potential which may well play a role energetically or as a bridging mechanism. An SAR analysis points to analogy with other physiologically active xenobiotics, namely benzodiazepines and paraquat in the conjugated iminium category. Inactivity of metabolites indicates that the parent is the active form of zolpidem. Absence of reactive oxygen species and oxidative stress is in line with minor side effects. In contrast, generally, the prior literature contains essentially no discussion of these fundamental biochemical relationships. Pharmacodynamics may play an important role. Concerning behavior at the blood-brain barrier, useful insight can be gained from investigations of the related cationic anesthetics that are structurally related to acetyl choline. Evidently, the neutral form of the drug penetrates the neuronal membrane, with the salt form operating at the receptor. The pathways of zolpidem have several clinical implications since the agent affects sedation, electroencephalographic activity, oxidative metabolites and

The influence of serotonin depletion on rat behavior in the Vogel test and brain 3H-zolpidem binding.

PubMed

Nazar, M; Siemiatkowski, M; Bidziński, A; Członkowska, A; Sienkiewicz-Jarosz, H; Płaźnik, A

1999-01-01

The influence of p-chlorophenylalanine (p-CPA) and 5,7-dihydroxytryptamine (5,7-DHT)-induced serotonin depletion on rat behavior as well as on zolpidem's the behavioral effects and binding to some brain areas of zolpidem, was examined with the help of Vogel's punished drinking test and autoradiography, respectively. Moreover, changes in the serotonin levels and turnover rate were studied in the forebrain and brainstem of rats pretreated with various ligands at the benzodiazepine (BDZ) receptors (midazolam, bretazenil, abecarnil, zolpidem). These drugs were given at doses shown previously to significantly disinhibit animal behavior suppressed by punishment in the Vogel test (Nazar et al., 1997). It was found that serotonin decrease in the frontal cortex and hippocampus after p-CPA significantly and inversely correlated with rat behavior controlled by fear in the VT. p-CPA produced an anticonflict activity in the absence of effect on spontaneous drinking, pain threshold and motility of animals. All applied benzodiazepine receptor ligands decreased the 5-HT turnover rate in the frontal cortex and hippocampus, whereas in the brainstem only abecarnil and zolpidem diminished 5-hydroxyindoleacetic acid levels. This part of the study replicated earlier data with neurotoxins and indicated that the anxiolytic-like effect of 5-HT depletion in some models of anxiety did not depend on changes in animal appetitive behavior or stimulus control. Moreover, the fact that all nonselective and selective (zolpidem) agonists of the type 1 benzodiazepine receptors seemed to produce the same anticonflict effect and decreasing 5-HT turnover indicates that this subtype of benzodiazepine receptor may be important for the interaction between brain 5-HT and GABA/BDZ systems. Accordingly, it was found that serotonin decrease enhanced the anticonflict effect of zolpidem in the Vogel test and increased 3H-zolpidem binding to the occipital cortex and substantia nigra. Altogether, the present study

Zolpidem reduces the blood oxygen level-dependent signal during visual system stimulation

PubMed Central

Licata, Stephanie C.; Lowen, Steven B.; Trksak, George H.; MacLean, Robert R.; Lukas, Scott E.

2011-01-01

Zolpidem is a short-acting imidazopyridine hypnotic that binds at the benzodiazepine binding site on specific GABAA receptors to enhance fast inhibitory neurotransmission. The behavioral and receptor pharmacology of zolpidem has been studied extensively, but little is known about its neuronal substrates in vivo. In the present within-subject, double-blind, and placebo-controlled study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) at 3 Tesla was used to assess the effects of zolpidem within the brain. Healthy participants (n=12) were scanned 60 minutes after acute oral administration of zolpidem (0, 5, 10, or 20 mg), and changes in BOLD signal were measured in the visual cortex during presentation of a flashing checkerboard. Heart rate and oxygen saturation were monitored continuously throughout the session. Zolpidem (10 and 20 mg) reduced the robust visual system activation produced by presentation of this stimulus, but had no effects on physiological activity during the fMRI scan. Zolpidem’s modulation of the BOLD signal within the visual cortex is consistent with the abundant distribution of GABAA receptors localized in this region, as well as previous studies showing a relationship between increased GABA-mediated neuronal inhibition and a reduction in BOLD activation. PMID:21640782

Sexsomnia: A Specialized Non-REM Parasomnia?

PubMed

Dubessy, Anne-Laure; Leu-Semenescu, Smaranda; Attali, Valérie; Maranci, Jean-Baptiste; Arnulf, Isabelle

2017-02-01

To describe patients with sexsomnia and to contrast their clinical and sleep measures with those of healthy controls and sleepwalkers. Subjects referred for sexsomnia and for sleepwalking/night terror were interviewed, completed the Paris Arousal Disorder Severity Scale (PADSS), and were monitored 1-2 nights with video-polysomnography. Seventeen patients (70.6% male, aged 17-76 years) had sexsomnia, with amnestic fondling of the bed partner (n = 11), complete sexual intercourse (n = 8), masturbation (n = 8), and spontaneous orgasm (n = 1). The sexual behaviors were more direct during sleep than during wakefulness (n = 12), leading to 6 sexual assaults, including intra-conjugal rape (n = 3), assault of a family member (n = 2), rape of a friend (n = 1), and forensic consequences (n = 2). In 47% of sexsomnia patients, there was a history or current occurrences of sleepwalking/night terrors. Patients with sexsomnia had more N3 awakenings than healthy matched controls and the same amount as regular sleepwalkers. Half of them presented evidence of cortico-cortical dissociation, including concomitant slow (mostly frontal) and rapid (mostly temporal and occipital) electroencephalography (EEG) rhythms, with concomitant N3 penile erection in 1 case. Of 89 sleepwalkers, 10% had previous episodes of amnestic sexual behaviors, with a higher PADSS-A score and a trend of a higher total PADSS score than the 80 sleepwalkers without sexsomnia. In this single-center series, we confirmed the male predominance of sexsomnias and its potential for severe clinical and forensic consequences. The results suggest a continuum of regular sleepwalking, sleepwalking with occasional sexsomnia, and quasi-exclusive sexsomnia. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Aging induced endoplasmic reticulum stress alters sleep and sleep homeostasis.

PubMed

Brown, Marishka K; Chan, May T; Zimmerman, John E; Pack, Allan I; Jackson, Nicholas E; Naidoo, Nirinjini

2014-06-01

Alterations in the quality, quantity, and architecture of baseline and recovery sleep have been shown to occur during aging. Sleep deprivation induces endoplasmic reticular (ER) stress and upregulates a protective signaling pathway termed the unfolded protein response. The effectiveness of the adaptive unfolded protein response is diminished by age. Previously, we showed that endogenous chaperone levels altered recovery sleep in Drosophila melanogaster. We now report that acute administration of the chemical chaperone sodium 4-phenylbutyrate (PBA) reduces ER stress and ameliorates age-associated sleep changes in Drosophila. PBA consolidates both baseline and recovery sleep in aging flies. The behavioral modifications of PBA are linked to its suppression of ER stress. PBA decreased splicing of X-box binding protein 1 and upregulation of phosphorylated elongation initiation factor 2 α, in flies that were subjected to sleep deprivation. We also demonstrate that directly activating ER stress in young flies fragments baseline sleep and alters recovery sleep. Alleviating prolonged or sustained ER stress during aging contributes to sleep consolidation and improves recovery sleep or sleep debt discharge. Copyright © 2014 Elsevier Inc. All rights reserved.

The sleepwalking/night terrors syndrome in adults.

PubMed Central

Crisp, A. H.

1996-01-01

A third of a million adults in the UK sleepwalk while a million suffer from night terrors. In both conditions the individual is unaware of the fullness of their surroundings and is totally focussed in their concern or activity. Doctors are only likely to become involved if the individual comes to harm or seeks help or if other people are inconvenienced or threatened. The constitutional basis of the disorder is beyond doubt, although the actual expression may be related to stressful life-events resulting from an individual's personality, relationships and circumstances. Treatment may include the provision of a secure environment, counselling, and the use of benzodiazepines and serotonin re-uptake inhibitors. PMID:8977941

Temporal changes in postural sway caused by ultrashort-acting hypnotics: triazolam and zolpidem.

PubMed

Nakamura, M; Ishii, M; Niwa, Y; Yamazaki, M; Ito, H

2005-01-01

Two ultrashort-acting hypnotics, triazolam 0.25 mg and zolpidem 10 mg, were studied for their effects on equilibrium function in humans. Eight healthy male subjects participated in a double-blind, placebo-controlled study after informed consent. They subjected to static equilibrium tests, oculomotor tests and an assay of drug concentrations in the blood. Zolpidem was statistically significant in postural sway in tandem stance test, as defined by parametric values of tracing sum length and polygonal area of foot pressure center measured by a gait analysis system. In the tandem stance test, triazolam was statistically significant in postural sway only as defined by the polygonal area. However, in the Romberg test, the only statistically significant difference in zolpidem use was observed in polygonal area values. Blood concentrations of triazolam and zolpidem were found to closely correlate with the extent of postural sway in both tandem stance and Romberg tests. In this study, zolpidem with minimal muscle-relaxant effect incurred imbalance more extensively than triazolam, which is known for its effect of muscle relaxation. In addition, gaze deviation nystagmus was observed only in zolpidem use in 5 of 8 subjects (62.5%). From these results, it is suggested that in the use of hypnotics, sway derives from the suppression of the central nervous system relevant to awakening rather than from muscle relaxation. The prior reference to blood concentrations of hypnotics should help improve safety care in minimizing loss of balance control and possible fall. Copyright 2005 S. Karger AG, Basel.

Residual effect of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades.

PubMed

Bocca, M L; Le Doze, F; Etard, O; Pottier, M; L'Hoste, J; Denise, P

1999-04-01

Studies report contradictory results concerning the residual effects of zolpidem and zopiclone. Moreover, residual effects of these compounds on healthy subjects have not yet been simultaneously assessed. The present study with healthy subjects investigated the residual effects of zolpidem 10 mg and zopiclone 7.5 mg on driving performance and on ocular saccade and compared them to those under flunitrazepam 1 mg and placebo. The study involved 16 subjects divided into two groups, a 9:00 a.m. group and a 11:00 a.m. group, in a balanced, double-blind, cross-over design. In the 9:00 a.m. group, zolpidem had no residual effects while zopiclone and flunitrazepam both impaired driving performance (P < 0.001 for both) and increased saccadic latency (P < 0.005; P = 0.052, respectively). Zopiclone impaired driving performance 5 times less than did flunitrazepam. In the 11:00 a.m. group, zolpidem and zopiclone had no residual effects, while flunitrazepam increased saccadic latency (P = 0.065) but did not impair driving performance. Zopiclone and flunitrazepam had residual effects in the first part of the morning, whereas zolpidem had no residual effects. The hierarchical character of the effects of the molecules differed according to the test administered. This is probably linked more to drug-induced specific alterations than to different sensitivities of the tests.

Efficacy of Zolpidem for Dystonia: A Study Among Different Subtypes

PubMed Central

Miyazaki, Yoshimichi; Sako, Wataru; Asanuma, Kotaro; Izumi, Yuishin; Miki, Tetsuro; Kaji, Ryuji

2012-01-01

Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor. PMID:22529836

The correlation between concentrations of zolpidem and benzodiazepines in segmental hair samples and use patterns.

PubMed

Kim, Hyojeong; Lee, Sangeun; In, Sanghwan; Park, Meejung; Cho, Sungnam; Shin, Junguk; Lee, Hunjoo; Han, Eunyoung

2018-01-01

The aim of this study was to investigate the correlation between histories of zolpidem and benzodiazepines use and their concentrations in hair as determined by segmental hair analysis, that is, by analyzing hair samples taken 0-1, 1-2, 2-3, 3-4, 4-5, and 5-6cm etc. and 0-3cm from the scalp, and whole hair. Of the 23 hair samples examined, 18 were collected from patients in a rehabilitation program and five were from patients that had taken zolpidem only once by prescription. All 23 patients provided written informed consent after reviewing the research plan, described their zolpidem and benzodiazepines use histories accurately, and provided hair samples, which were weighed, washed, cut into lengths of <1mm, and extracted in 100% methanol for 16h (diazepam-d 5 was used as an internal standard). Extracts were evaporated under reduced pressure and reconstituted with aqueous methanol (1:1 v/v). These extracts (10μL) were analyzed by Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). The method used was validated by determining LOD, LOQ, calibration curves, intra- and inter-accuracies, precisions, matrix effects, process efficiencies, extraction efficiencies, and processed sample stabilities. Five hundred and ninety-five 1cm hair segments showed 61.59% positive probability and 86.71% negative probability of quality correlation between zolpidem and benzodiazepines use and concentrations in hair. Good qualitative correlations were observed between drug use and detection in hair. False positivity and false negativity were very low. Of the hair samples taken from patients in a rehabilitation program, subject nos. 4, 5, and 12 had correlation coefficients of 0.68, 0.54 and 0.71, respectively, for relationships between zolpidem use and concentration of zolpidem in hair. For the 5 patients taking only a single dose of zolpidem (10mg), the average zolpidem concentrations in hair were 20, 15 and 40pg/mg after 5, 30 and 60 days, respectively. This study shows a

Oxidative metabolism of limbic structures after acute administration of diazepam, alprazolam and zolpidem.

PubMed

González-Pardo, Héctor; Conejo, Nélida M; Arias, Jorge L

2006-08-30

The effects of acute administration of two benzodiazepines and a non-benzodiazepine hypnotic on behavior and brain metabolism were evaluated in rats. After testing the behavioral action of the benzodiazepines on the open field and the elevated plus-maze, the effects of the three drugs on neuronal metabolism of particular limbic regions were measured using cytochrome c oxidase (CO) histochemistry. Diazepam (5 mg/kg i.p.) and alprazolam (0.5 mg/kg i.p.) induced clear anxiolytic effects and a decrease in locomotion, whereas zolpidem (2 mg/kg i.p.) caused an intense hypnotic effect. The anxiolytic effects of alprazolam were distinguishable from diazepam due to the pharmacological and clinical profile of this triazolobenzodiazepine. CO activity decreased significantly in almost all the limbic regions evaluated after zolpidem administration. However, significant prominent decreases in CO activity were found after diazepam treatment in the medial mammillary nucleus, anteroventral thalamus, cingulate cortex, dentate gyrus and basolateral amygdala. Alprazolam caused similar decreases in CO activity, with the exception of the prelimbic and cingulate cortices, where significant increases were detected. In agreement with previous studies using other functional mapping techniques, our results indicate that particular benzodiazepines and non-benzodiazepine hypnotics induce selective changes in brain oxidative metabolism.

Involvement of the α1-adrenoceptor in sleep-waking and sleep loss-induced anxiety behavior in zebrafish.

PubMed

Singh, A; Subhashini, N; Sharma, S; Mallick, B N

2013-08-15

Sleep is a universal phenomenon in vertebrates, and its loss affects various behaviors. Independent studies have reported that sleep loss increases anxiety; however, the detailed mechanism is unknown. Because sleep deprivation increases noradrenalin (NA), which modulates many behaviors and induces patho-physiological changes, this study utilized zebrafish as a model to investigate whether sleep loss-induced increased anxiety is modulated by NA. Continuous behavioral quiescence for at least 6s was considered to represent sleep in zebrafish; although some authors termed it as a sleep-like state, in this study we have termed it as sleep. The activity of fish that signified sleep-waking was recorded in light-dark, during continuous dark and light; the latter induced sleep loss in fish. The latency, number of entries, time spent and distance travelled in the light chamber were assessed in a light-dark box test to estimate the anxiety behavior of normal, sleep-deprived and prazosin (PRZ)-treated fish. Zebrafish showed increased waking during light and complete loss of sleep upon continuous exposure to light for 24h. PRZ significantly increased sleep in normal fish. Sleep-deprived fish showed an increased preference for dark (expression of increased anxiety), and this effect was prevented by PRZ, which increased sleep as well. Our findings suggest that sleep loss-induced anxiety-like behavior in zebrafish is likely to be mediated by NA's action on the α1-adrenoceptor. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Association of zolpidem use and subsequent increased risk of epilepsy: a population-based, case-control study.

PubMed

Harnod, Tomor; Wang, Yu-Chiao; Sung, Fung-Chang; Kao, Chia-Hung

2014-10-01

To evaluate the impact of long-term zolpidem use on the subsequent risk of epilepsy. We used data from the National Health Insurance system of Taiwan to conduct a population-based case-control study. We identified 4,972 newly diagnosed epilepsy patients (ICD-9-CM code 345) for the period of 2005-2010 as cases. For each epilepsy case, 4 controls without a history of epilepsy were randomly selected from the rest of the population. Zolpidem was used as a predictor of epilepsy. Patients with epilepsy exhibited an adjusted odds ratio (OR) of 1.86 (95% CI, 1.70-2.03) and were, therefore, more strongly associated with zolpidem exposure than control patients were. The adjusted OR of epilepsy increased with the increase of mean zolpidem exposure (g/y). Compared with the OR of nonusers, the adjusted OR was 1.64 (95% CI, 1.44-1.86) for those who had taken < 1.0 g/y of zolpidem and 2.38 (95% CI, 2.06-2.74) for those who had taken ≥ 20.0 g/y of zolpidem. An adjusted OR of 3.55 (95% CI, 2.94-4.28) was noted to be associated with epilepsy when users had stopped taking the drug less than 7 days earlier. The estimated risk declined to an OR of 1.62 (95% CI, 1.47-1.78) when users had stopped taking the drug more than 90 days earlier. This population-based, retrospective case-control study revealed a possible increase in epilepsy risk with zolpidem use, at either typical or supratherapeutic doses. These findings might stimulate public interest in safety issues regarding zolpidem use. © Copyright 2014 Physicians Postgraduate Press, Inc.

Medicolegal aspects of complex behaviours arising from the sleep period: a review and guide for the practising sleep physician.

PubMed

Morrison, Ian; Rumbold, John M M; Riha, Renata L

2014-06-01

This review is aimed at summarizing the current state of knowledge regarding parasomnias, which have been implicated in medicolegal cases as well as providing guidance to those working within common-law jurisdictions regarding the technical aspects of the law. Sleepwalking and sexsomnia as a defence are being raised more frequently in criminal cases and there has been public debate on their validity. Unfortunately, expert evidence on forensic sleep disorders continues to be heavily opinion-based with the potential for miscarriages of justice seen in recent highly publicized cases. There is an apparent inertia in research into violent sleep disorders. We review the current state of forensic sleep science in the United Kingdom (UK) and abroad and discuss the need to formulate guidelines based on available evidence. We also highlight the pressing necessity for more research in this area as well as the need to reform the law, which is the subject of a recent Criminal Law Commission report in the United Kingdom. In time, this will facilitate the efficient, proportionate, and just disposal of violence arising from sleep, thus benefitting both society and the individual sufferer. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hypnotherapy in the treatment of chronic combat-related PTSD patients suffering from insomnia: a randomized, zolpidem-controlled clinical trial.

PubMed

Abramowitz, Eitan G; Barak, Yoram; Ben-Avi, Irit; Knobler, Haim Y

2008-07-01

This study evaluated the benefits of add-on hypnotherapy in patients with chronic PTSD. Thirty-two PTSD patients treated by SSRI antidepressants and supportive psychotherapy were randomized to 2 groups: 15 patients in the first group received Zolpidem 10 mg nightly for 14 nights, and 17 patients in the hypnotherapy group were treated by symptom-oriented hypnotherapy, twice-a-week 1.5-hour sessions for 2 weeks. All patients completed the Stanford Hypnotic Susceptibility Scale, Form C, Beck Depression Inventory, Impact of Event Scale, and Visual Subjective Sleep Quality Questionnaire before and after treatment. There was a significant main effect of the hypnotherapy treatment with PTSD symptoms as measured by the Posttraumatic Disorder Scale. This effect was preserved at follow-up 1 month later. Additional benefits for the hypnotherapy group were decreases in intrusion and avoidance reactions and improvement in all sleep variables assessed.

Retrospective population cohort study on hip fracture risk associated with zolpidem medication.

PubMed

Lin, Fang-Yu; Chen, Pei-Chun; Liao, Chun Hui; Hsieh, Yow-Wen; Sung, Fung-Chang

2014-04-01

Few studies have evaluated the hip fracture risk for zolpidem users. We assessed the risk for subjects taking zolpidem. Population-based retrospective cohort study using claims data of a universal insurance system. We identified 6,978 patients newly prescribed for zolpidem in 2000-2001 age 18 y and older, and 27,848 nonusers frequency matched with sex, age, and date visiting a clinic. Both cohorts were followed up to the end of 2008 to measure the hip fracture incidence and risk, which considered factors such as sex, age, occupation, days of drug use, and osteoporosis status. The zolpidem users had a 2.23-fold higher hip fracture incidence than nonusers (3.10 versus 1.39 per 1,000 person-y). The risk increased with age for both cohorts. The elderly users had a 21-fold higher incidence than the younger users, or twofold higher than the elderly nonusers. Among 33 patients (20.4%) with hip fracture occurring during presumed medication days, which was accountable for an incidence of 1,083.0 per 1,000 person-y. Those taking the medicine for 8 days or longer had a moderately higher fracture rate than those taking it for less days (6.02 versus 4.48 per 100 person-times) with a ratio of 1.34 (95% confidence interval 0.42-4.56). Subjects with blue collar occupations were at a higher fracture risk. The hip fracture risk of zolpidem users is higher than that of nonusers. Fracture prevention awareness should be disseminated to the users.

Sleep Is Critical for Remote Preconditioning-Induced Neuroprotection.

PubMed

Brager, Allison J; Yang, Tao; Ehlen, J Christopher; Simon, Roger P; Meller, Robert; Paul, Ketema N

2016-11-01

Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities ( Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome. © 2016 Associated Professional Sleep Societies, LLC.

Zolpidem for the Treatment of Neurologic Disorders: A Systematic Review.

PubMed

Bomalaski, Martin N; Claflin, Edward S; Townsend, Whitney; Peterson, Mark D

2017-09-01

Given its selective action on the ω1 subtype of the γ-aminobutyric acid A receptor, zolpidem tartrate presents a potential treatment mechanism for other neurologic disorders. To synthesize studies that used zolpidem to treat neurologic disorders. Eligibility criteria included any published English-language article that examined the use of zolpidem for noninsomnia neurologic disorders in humans for all dates up to March 20, 2015. Searched databases included PubMed, Scopus, Web of Science Core Collection, the Cochrane Library, EMBASE, CENTRAL, and clinicaltrials.gov. Publication bias was mitigated by searching clinicaltrials.gov for unpublished studies. Two rounds of screening were performed based on title and then abstract, and coding was performed by 2 coders. All methods followed the PRISMA Reporting Guidelines for systematic reviews of the literature. The initial search produced 2314 articles after removing duplicates. After exclusion based on a review of abstracts, 67 articles remained for full manuscript review. Thirty-one studies treated movement disorders, 22 treated disorders of consciousness, and 14 treated other neurologic conditions, including stroke, traumatic brain injury, encephalopathy, and dementia. Study designs included case reports (n = 28), case series (n = 8), single-patient interventional (n = 13), pretest and posttest (n = 9), randomized clinical trials (n = 9), and crossover studies (n = 5). Only 11 studies had more than 10 participants. Effects of zolpidem were wide ranging (eg, improvement on the JFK Coma Recovery Scale-Revised, the Unified Parkinson Disease Rating Scale, and the Burke-Fahn-Marsden Dystonia Rating Scale) and generally lasted 1 to 4 hours before the participant returned to baseline. Sedation was the most common adverse effect. Zolpidem has been observed to transiently treat a large variety of neurologic disorders, most often related to movement disorders and disorders of consciousness. Much of what

Prevalence of Sleep Disorders Among Primary School Children.

PubMed

Gupta, Ravi; Goel, Deepak; Kandpal, S D; Mittal, Nidhi; Dhyani, Mohan; Mittal, Manish

2016-11-01

To screen symptoms of sleep disorders among primary school children. Four schools from urban area and four rural schools were included in this study. Symptoms of sleep disorders were assessed using the validated Hindi version of Childhood Sleep Habit Questionnaire in 8-13 y old children. Comparison was made between urban and rural group and between boys and girls. Descriptive statistics was calculated. Mean age of the subjects included in this study was 8.9 ± 1.5 y. Boys and girls were equally distributed, however, rural sample was smaller. More than one awakening each night was found in 12.2 % children. In the whole group, prevalence of bed-wetting was 8.7 %, sleep-talking 20.9 %, sleep-walking 3.2 %, teeth grinding 15.4 % and night terrors 8.4 %. Daytime sleepiness was reported by 25.5 % and napping by 56.4 %. 17.3 % used to fall asleep in unusual circumstances and the teacher or the friend in 6.9 % students noticed it. Snoring was reported by 11.4 % children, and 6.3 % reportedly struggled to breathe during sleep. Domicile and gender did not affect prevalence of parasomnia, however, symptoms of sleep apnea were more frequent among rural children. Daytime sleepiness was more common among rural children as compared to urban. Symptoms of sleep disorders are prevalent among primary school children. Common disorders are parasomnia, sleep apnea and daytime sleepiness.

Analysis of zolpidem in postmortem fluids and tissues using ultra-performance liquid chromatography-mass spectrometry.

DOT National Transportation Integrated Search

2014-02-01

Zolpidem is a nonbenzodiazepine sedative hypnotic drug used for the short-term treatment of insomnia. Its : use is common and wide-spread. While quite effective in producing sedation, zolpidem has potentially : hazardous side effects when put in the ...

What Does the Sleeping Brain Say? Syntax and Semantics of Sleep Talking in Healthy Subjects and in Parasomnia Patients.

PubMed

Arnulf, Isabelle; Uguccioni, Ginevra; Gay, Frederick; Baldayrou, Etienne; Golmard, Jean-Louis; Gayraud, Frederique; Devevey, Alain

2017-11-01

Speech is a complex function in humans, but the linguistic characteristics of sleep talking are unknown. We analyzed sleep-associated speech in adults, mostly (92%) during parasomnias. The utterances recorded during night-time video-polysomnography were analyzed for number of words, propositions and speech episodes, frequency, gaps and pauses (denoting turn-taking in the conversation), lemmatization, verbosity, negative/imperative/interrogative tone, first/second person, politeness, and abuse. Two hundred thirty-two subjects (aged 49.5 ± 20 years old; 41% women; 129 with rapid eye movement [REM] sleep behavior disorder and 87 with sleepwalking/sleep terrors, 15 healthy subjects, and 1 patient with sleep apnea speaking in non-REM sleep) uttered 883 speech episodes, containing 59% nonverbal utterance (mumbles, shouts, whispers, and laughs) and 3349 understandable words. The most frequent word was "No": negations represented 21.4% of clauses (more in non-REM sleep). Interrogations were found in 26% of speech episodes (more in non-REM sleep), and subordinate clauses were found in 12.9% of speech episodes. As many as 9.7% of clauses contained profanities (more in non-REM sleep). Verbal abuse lasted longer in REM sleep and was mostly directed toward insulting or condemning someone, whereas swearing predominated in non-REM sleep. Men sleep-talked more than women and used a higher proportion of profanities. Apparent turn-taking in the conversation respected the usual language gaps. Sleep talking parallels awake talking for syntax, semantics, and turn-taking in conversation, suggesting that the sleeping brain can function at a high level. Language during sleep is mostly a familiar, tensed conversation with inaudible others, suggestive of conflicts. © Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society]. All rights reserved. For permissions, please email: journals.permissions@oup.com

A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: a proton MRS study at 4 T.

PubMed

Licata, Stephanie C; Jensen, J Eric; Penetar, David M; Prescot, Andrew P; Lukas, Scott E; Renshaw, Perry F

2009-05-01

Zolpidem is a nonbenzodiazepine sedative/hypnotic that acts at GABA(A) receptors to influence inhibitory neurotransmission throughout the central nervous system. A great deal is known about the behavioral effects of this drug in humans and laboratory animals, but little is known about zolpidem's specific effects on neurochemistry in vivo. We evaluated how acute administration of zolpidem affected levels of GABA, glutamate, glutamine, and other brain metabolites. Proton magnetic resonance spectroscopy ((1)H MRS) at 4 T was employed to measure the effects of zolpidem on brain chemistry in 19 healthy volunteers. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires were administered periodically throughout the experimental session to assess subjective mood states. Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of "dizzy," "nauseous," "confused," and "bad effects" were increased relative to placebo, as were ratings on the sedation/intoxication (PCAG) and psychotomimetic/dysphoria (LSD) scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and "dizzy." Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and "dizzy" may be a function of zolpidem's interaction with alpha1GABA(A) receptors in the cerebellum, projecting through the vestibular system to the thalamus.

Effect of sleep-inducing music on sleep in persons with percutaneous transluminal coronary angiography in the cardiac care unit.

PubMed

Ryu, Min-Jung; Park, Jeong Sook; Park, Heeok

2012-03-01

The study compared the effect of earplug-delivered sleep-inducing music on sleep in persons with percutaneous transluminal coronary angiography in the cardiac care unit. Diverse types of music have been claimed to improve sleeping elsewhere, but relatively little is known in South Korea. Most studies investigating the effect of sleep-inducing music on sleep have involved persons with insomnia, even though many persons with cardiovascular disease in the intensive care unit suffer from sleeping problems. There is a need to investigate the effect of sleep-inducing music on sleep disorders in persons with percutaneous transluminal coronary angiography in the cardiac care unit. An experimental research design was used. Data collection was conducted in the cardiac care unit of K University Hospital in D city, from 3 September-4 October 2010. Fifty-eight subjects participated and were randomly assigned to the experimental group (earplug-delivered sleep-inducing music for 52 min beginning at 10:00 pm, while wearing an eyeshield, n = 29) and the control group (no music, but earplugs and eyeshield worn, n = 29). The quantity and quality of sleep were measured using questionnaires at 7 am the next morning for each group. Participants in the experimental group reported that the sleeping quantity and quality were significantly higher than control group (t = 3·181, p = 0·002, t = 5·269, p < 0·001, respectively). Sleep-inducing music significantly improved sleep in patients with percutaneous transluminal coronary angiography at a cardiac care unit. Offering earplugs and playing sleep-inducing music may be a meaningful and easily enacted nursing intervention to improve sleep for intensive care unit patients. Nurses working at cardiac care unit can use music to improve sleeping in clients with percutaneous transluminal coronary angiography. © 2011 Blackwell Publishing Ltd.

An Increased Risk of Reversible Dementia May Occur After Zolpidem Derivative Use in the Elderly Population

PubMed Central

Shih, Hsin-I; Lin, Che-Chen; Tu, Yi-Fang; Chang, Chia-Ming; Hsu, Hsiang-Chin; Chi, Chih-Hsien; Kao, Chia-Hung

2015-01-01

Abstract We evaluate the effects of zolpidem use to develop dementia or Alzheimer disease from the Taiwan National Health Insurance Research Database (NHIRD). A retrospective population-based nested case–control study. Newly diagnosed dementia patients 65 years and older and controls were sampled. A total of 8406 dementia and 16,812 control subjects were enrolled from Taiwan NHIRD during 2006 to 2010. The relationships between zolpidem use and dementia were measured using odds and adjusted odds ratios. The relationship between the average cumulative doses for zolpidem and dementia was also analyzed. Zolpidem alone or with other underlying diseases, such as hypertension, diabetes, and stroke, was significantly associated with dementia after controlling for potential confounders, such as age, sex, coronary artery disease, diabetes, anti-hypertension drugs, stroke, anticholesterol statin drugs, depression, anxiety, benzodiazepine, anti-psychotic, and anti-depressant agents’ use (Adjusted OR = 1.33, 95% CI 1.24–1.41). Zolpidem use also has significant dose–response effects for most of the types of dementia. In patient with Alzheimer diseases, the effects of zolpidem among patients with Alzheimer's disease remained obscure. The adjusted OR for patients whose cumulative exposure doses were between 170 and 819 mg/year (adjusted OR: 1.65, 95% CI 1.08–2.51, P = 0.0199) was significant; however, the effects for lower and higher cumulative dose were not significant. Zolpidem used might be associated with increased risk for dementia in elderly population. Increased accumulative dose might have higher risk to develop dementia, especially in patients with underlying diseases such as hypertension, diabetes, and stroke. PMID:25929937

Clinical syndrome associated with zolpidem ingestion in dogs: 33 cases (January 1998-July 2000).

PubMed

Richardson, Jill A; Gwaltney-Brant, Sharon M; Albretsen, Jay C; Khan, Safdar A; Porter, Jessica A

2002-01-01

Zolpidem is a nonbenzodiazepine hypnotic of the imidazopyridine class that is used to treat insomnia in humans. Zolpidem binds selectively to the benzodiazepine omega-1 receptor and increases the frequency of chloride channel opening, which results in inhibition of neuronal excitation. A retrospective study was conducted of zolpidem ingestion in dogs that were reported to the ASPCA Animal Poison Control Center (APCC) between January 1998 and July 2000. Data analysis included amount ingested, clinical effects, and time of onset of signs. Thirty-three reports of zolpidem ingestion in dogs (ranging in age from 5 months to 16 years) were evaluated. Approximate ingested dosages ranged from 0.24 to 21 mg/kg. Clinical signs reported included ataxia (18 dogs; 54.5%), hyperactivity (10 dogs; 30.3%), vomiting (7 dogs; 21.2%), and lethargy (5 dogs; 15.2%), as well as panting, disorientation, nonspecific behavior disorder, and hypersalivation (4 dogs each sign; 12.1%). Other signs reported include tachycardia, tremors, apprehension, vocalization, hypersalivation, weakness, and hyperesthesia. In 85% percent of reports, clinical signs developed within 1 hour and usually resolved within 12 hours. Although central nervous system (CNS) depression is reported as a primary effect of zolpidem in humans and would also be expected in dogs, information obtained from this study indicates that some dogs may exhibit a paradoxical excitation reaction. This effect appears to vary among individual dogs.

Interleukin-1 receptor (IL-1R) mediates epilepsy-induced sleep disruption.

PubMed

Huang, Tzu-Rung; Jou, Shuo-Bin; Chou, Yu-Ju; Yi, Pei-Lu; Chen, Chun-Jen; Chang, Fang-Chia

2016-11-22

Sleep disruptions are common in epilepsy patients. Our previous study demonstrates that homeostatic factors and circadian rhythm may mediate epilepsy-induced sleep disturbances when epilepsy occurs at different zeitgeber hours. The proinflammatory cytokine, interleukin-1 (IL-1), is a somnogenic cytokine and may also be involved in epileptogenesis; however, few studies emphasize the effect of IL-1 in epilepsy-induced sleep disruption. We herein hypothesized that IL-1 receptor type 1 (IL-1R1) mediates the pathogenesis of epilepsy and epilepsy-induced sleep disturbances. We determined the role of IL-1R1 by using IL-1R1 knockout (IL-1R1 -/- KO) mice. Our results elucidated the decrease of non-rapid eye movement (NREM) sleep during the light period in IL-1R -/- mice and confirmed the somnogenic role of IL-1R1. Rapid electrical amygdala kindling was performed to induce epilepsy at the particular zeitgeber time (ZT) point, ZT13. Our results demonstrated that seizure thresholds induced by kindling stimuli, such as the after-discharge threshold and successful kindling rates, were not altered in IL-1R -/- mice when compared to those obtained from the wildtype mice (IL-1R +/+ mice). This result suggests that IL-1R1 is not involved in kindling-induced epileptogenesis. During sleep, ZT13 kindling stimulation significantly enhanced NREM sleep during the subsequent 6 h (ZT13-18) in wildtype mice, and sleep returned to the baseline the following day. However, the kindling-induced sleep alteration was absent in the IL-1R -/- KO mice. These results indicate that the IL-1 signal mediates epilepsy-induced sleep disturbance, but dose not participate in kindling-induced epileptogenesis.

Pharmacology for sleep disturbance in PTSD.

PubMed

Lipinska, Gosia; Baldwin, David S; Thomas, Kevin G F

2016-03-01

Symptoms of sleep disturbance, particularly nightmares and insomnia, are a central feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that specific treatment of PTSD-related sleep disturbance improves other symptoms of the disorder, which in turn suggests that such disturbance may be fundamental to development and maintenance of the disorder. This mini-review focuses on pharmacological treatment of sleep disturbance in adult PTSD (specifically, studies testing the efficacy of antidepressants, adrenergic inhibiting agents, antipsychotics and benzodiazepine and non-benzodiazepine hypnotics). We conclude that only prazosin, an adrenergic inhibiting agent, has had its efficacy established by multiple randomised controlled trials. There is also high-level evidence supporting use of eszopiclone, as well as risperidone and olanzapine as adjunct therapy. Antidepressants such as sertraline, venlafaxine and mirtazapine, benzodiazepines such as alprazolam and clonazepam and non-benzodiazepine hypnotics such as zolpidem appear ineffective in treating PTSD-related sleep disturbance. Most studies that report reduced frequency of nightmares and insomnia also report decreases in overall symptom severity. Such findings suggest that (i) sleep disruption is central to PTSD; (ii) treating sleep disruption may be an effective way to address other symptoms of the disorder and (iii) PTSD symptoms tend to cluster together in predictable ways. Copyright © 2016 John Wiley & Sons, Ltd.

Hypnotherapy for sleep disorders.

PubMed

Ng, Beng-Yeong; Lee, Tih Shih

2008-08-01

Hypnosis can be defined as a procedure during which changes in sensations, perceptions, thoughts, feelings or behaviour are suggested. Hypnosis can be used to amplify whatever it is about therapy that makes it therapeutic. It permits a wide range of choices regarding where and how to intervene in the patient's problems. In this paper, we set out to examine the rationale of using hypnotherapy to manage various types of sleep disorders, and to explore the techniques, strategies and hypnotic scripts employed by various hypnotherapists. We also examine the research data available on the efficacy of hypnosis in the treatment of sleep disorders. Acute and chronic insomnia often respond to relaxation and hypnotherapy approaches, along with sleep hygiene instructions. Hypnotherapy has also helped with nightmares and sleep terrors. There are several reports of successful use of hypnotherapy for parasomnias, specifically for head and body rocking, bedwetting and sleepwalking. Hypnosis is a specialised technique, not a therapy itself, and should be used as an adjunctive intervention within a complete psychological and medical treatment package. Most of the literature is limited to case reports or studies with such a small sample that at times it is very difficult to interpret the results. There is a major placebo effect, so uncontrolled trials are of limited value. It is hard to perform a randomised, double-blind, controlled trial to evaluate hypnotherapy given that cooperation and rapport between patient and therapist is needed to achieve a receptive trance state.

Sleep, chronic pain, and opioid risk for apnea.

PubMed

Marshansky, Serguei; Mayer, Pierre; Rizzo, Dorrie; Baltzan, Marc; Denis, Ronald; Lavigne, Gilles J

2017-07-19

Pain is an unwelcome sleep partner. Pain tends to erode sleep quality and alter the sleep restorative process in vulnerable patients. It can contribute to next-day sleepiness and fatigue, affecting cognitive function. Chronic pain and the use of opioid medications can also complicate the management of sleep disorders such as insomnia (difficulty falling and/or staying asleep) and sleep-disordered breathing (sleep apnea). Sleep problems can be related to various types of pain, including sleep headache (hypnic headache, cluster headache, migraine) and morning headache (transient tension type secondary to sleep apnea or to sleep bruxism or tooth grinding) as well as periodic limb movements (leg and arm dysesthesia with pain). Pain and sleep management strategies should be personalized to reflect the patient's history and ongoing complaints. Understanding the pain-sleep interaction requires assessments of: i) sleep quality, ii) potential contributions to fatigue, mood, and/or wake time functioning; iii) potential concomitant sleep-disordered breathing (SDB); and more importantly; iv) opioid use, as central apnea may occur in at-risk patients. Treatments include sleep hygiene advice, cognitive behavioral therapy, physical therapy, breathing devices (continuous positive airway pressure - CPAP, or oral appliance) and medications (sleep facilitators, e.g., zolpidem; or antidepressants, e.g., trazodone, duloxetine, or neuroleptics, e.g., pregabalin). In the presence of opioid-exacerbated SDB, if the dose cannot be reduced and normal breathing restored, servo-ventilation is a promising avenue that nevertheless requires close medical supervision. Copyright © 2017 Elsevier Inc. All rights reserved.

Parasomnias

MedlinePlus

... Overview & Facts Symptoms & Risk Factors Diagnosis & Treatment Sleep Terrors Overview & Facts Symptoms & Risk Factors Diagnosis & Treatment Sleep ... the night. Parasomnias include: Sleepwalking Confusional Arousals Sleep Terrors Sleep Eating Disorder REM Sleep Behavior Disorder Nightmare ...

Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem.

PubMed

Chouinard, G; Lefko-Singh, K; Teboul, E

1999-08-01

1. The benzodiazepines are among the most frequently prescribed of all drugs and have been used for their anxiolytic, anticonvulsant, and sedative/hypnotic properties. Since absorption rates, volumes of distribution, and elimination rates differ greatly among the benzodiazepine derivatives, each benzodiazepine has a unique plasma concentration curve. Although the time to peak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect. The importance of alpha and beta half-lives in the actions of benzodiazepines is discussed. 2. The role of cytochrome P450 isozymes in the metabolism of benzodiazepines and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed. 3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extensive metabolism, with hydroxylation and dealkylation being the major pathways. Pharmacokinetic interactions of buspirone with other coadministered drugs seem to be minimal. 4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, and decarboxylation of zopiclone occur, and zolpidem undergoes oxidation of methyl groups and hydroxylation of a position on the imidazolepyridine ring system. Zopiclone has a chiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug-drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interactions of zolpidem with coadministered drugs; however, it has been reported to affect the Cmax and clearance of chlorpromazepine and to decrease metabolism of the antiviral agent ritonavin. Since CYP3A4 has been reported to play an important role in metabolism of zolpidem, possible interactions with drugs which are substrates and/or inhibitors of that CYP isozyme should be considered.

Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

PubMed

Piergies, A A; Sainati, S; Roth-Schechter, B

1997-04-01

To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). Clinical Pharmacology Unit within a teaching hospital. Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

Stability of sleep disorders from preschool to first grade and their bidirectional relationship with psychiatric symptoms.

PubMed

Steinsbekk, Silje; Wichstrøm, Lars

2015-05-01

To examine the prevalence and stability of DSM-4-defined sleep disorders from preschool to first grade and to explore the bidirectional relationship between sleep disorders and symptoms of psychiatric disorders. All children born in 2003 or 2004 in Trondheim, Norway, who attended regular community health checkups for 4-year-olds, were invited to participate (97.2% attendance; 82.0% consent rate, n = 2475) in this study. The authors recruited a screen-stratified subsample of 1250 children and interviewed 994 parents (79.6%) using a structured diagnostic interview (the Preschool Age Psychiatric Assessment). Two years later, 795 of the parents completed the interview. There was stability in insomnia (adjusted odds ratio [OR] = 4.03, confidence interval [CI] = 2.83-5.75) and sleepwalking (adjusted OR = 19.28, CI = 4.53-82.10), whereas none of the children with hypersomnia or nightmare disorder at age 4 had the same disorder 2 years later. Insomnia increased the risk for developing symptoms of conduct disorder, major depressive disorder (MDD), and social phobia when the initial levels of insomnia were adjusted for. Symptoms of attention-deficit hyperactivity disorder, oppositional defiant disorder, and MDD at age 4 were statistically linked to insomnia at age 6. Sleepwalking predicted later separation anxiety disorder, whereas hypersomnia was unrelated to symptoms of psychiatric disorders. Insomnia is a prevalent and stable disorder in children and is bidirectionally related to psychiatric symptoms.

Sleep disturbance induces neuroinflammation and impairment of learning and memory.

PubMed

Zhu, Biao; Dong, Yuanlin; Xu, Zhipeng; Gompf, Heinrich S; Ward, Sarah A P; Xue, Zhanggang; Miao, Changhong; Zhang, Yiying; Chamberlin, Nancy L; Xie, Zhongcong

2012-12-01

Hospitalized patients can develop cognitive function decline, the mechanisms of which remain largely to be determined. Sleep disturbance often occurs in hospitalized patients, and neuroinflammation can induce learning and memory impairment. We therefore set out to determine whether sleep disturbance can induce neuroinflammation and impairment of learning and memory in rodents. Five to 6-month-old wild-type C57BL/6J male mice were used in the studies. The mice were placed in rocking cages for 24 h, and two rolling balls were present in each cage. The mice were tested for learning and memory function using the Fear Conditioning Test one and 7 days post-sleep disturbance. Neuroinflammation in the mouse brain tissues was also determined. Of the Fear Conditioning studies at one day and 7 days after sleep disturbance, twenty-four hour sleep disturbance decreased freezing time in the context test, which assesses hippocampus-dependent learning and memory; but not the tone test, which assesses hippocampus-independent learning and memory. Sleep disturbance increased pro-inflammatory cytokine IL-6 levels and induced microglia activation in the mouse hippocampus, but not the cortex. These results suggest that sleep disturbance induces neuroinflammation in the mouse hippocampus, and impairs hippocampus-dependent learning and memory in mice. Pending further studies, these findings suggest that sleep disturbance-induced neuroinflammation and impairment of learning and memory may contribute to the development of cognitive function decline in hospitalized patients. Copyright © 2012 Elsevier Inc. All rights reserved.

Sleep problems and internet addiction among children and adolescents: a longitudinal study.

PubMed

Chen, Yi-Lung; Gau, Susan Shur-Fen

2016-08-01

Although the literature has documented associations between sleep problems and internet addiction, the temporal direction of these relationships has not been established. The purpose of this study is to evaluate the bidirectional relationships between sleep problems and internet addiction among children and adolescents longitudinally. A four-wave longitudinal study was conducted with 1253 children and adolescents in grades 3, 5 and 8 from March 2013 to January 2014. The sleep problems of the student participants were measured by parental reports on the Sleep Habit Questionnaire, which catalogues early insomnia, middle insomnia, disturbed circadian rhythm, periodic leg movements, sleep terrors, sleepwalking, sleep talking, nightmares, bruxism, snoring and sleep apnoea. The severity of internet addiction was measured by students' self-reports on the Chen Internet Addiction Scale. Based on the results of time-lag models, dyssomnias (odds ratio = 1.31), especially early and middle insomnias (odds ratio = 1.74 and 2.24), sequentially predicted internet addiction, and internet addiction sequentially predicted disturbed circadian rhythm (odds ratio = 2.40), regardless of adjustment for gender and age. This is the first study to demonstrate the temporal relationship of early and middle insomnia predicting internet addiction, which subsequently predicts disturbed circadian rhythm. These findings imply that treatment strategies for sleep problems and internet addiction should vary according to the order of their occurrence. © 2016 European Sleep Research Society.

Marine Aviation Weapons and Tactics Squadron One (MAWTS-1): Sleep, Fatigue, and Aviator Performance Study

DTIC Science & Technology

2008-12-01

hypnotics , referred to as “go and no-go” pills, respectively, that help aviators maintain alertness and performance or acquire restorative sleep...Stimulants used in the aviation community are amphetamines, caffeine, and modafinil. Hypnotics may include temazepam, zolpidem, and possibly melatonin...Both stimulants and hypnotics may be available through prescriptions or over-the-counter, but the flight surgeon must always approve any medication

In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A.

PubMed

Polasek, Thomas M; Sadagopal, Janani S; Elliot, David J; Miners, John O

2010-03-01

To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitro-in vivo extrapolation; IV-IVE). A co- vs. pre-incubation strategy was used to quantify time-dependent inhibition of human liver microsomal (HLM) and recombinant CYP3A4 (rCYP3A4) by zolpidem. Experiments involving a 10-fold dilution step were employed to determine the kinetic constants of inactivation (K (I) and k (inact)) and to assess the in vitro mechanism-based inactivation (MBI) criteria. Inactivation data were entered into the Simcyp population-based ADME simulator to predict the increase in the area under the plasma concentration-time curve (AUC) for orally administered midazolam. Consistent with MBI, the inhibitory potency of zolpidem toward CYP3A was increased following pre-incubation. In HLMs, the concentration required for half maximal inactivation (K (I)) was 122 microM and the maximal rate of inactivation (k (inact)) was 0.094 min(-1). In comparison, K (I) and k (inact) values with rCYP3A4 were 50 microM and 0.229 min(-1), respectively. Zolpidem fulfilled all other in vitro MBI criteria, including irreversible inhibition. The mean oral AUC for midazolam in healthy volunteers was predicted to increase 1.1- to 1.7-fold due to the inhibition of metabolic clearance by zolpidem. Elderly subjects were more sensitive to the interaction, with mean increases in midazolam AUC of 1.2- and 2.2-fold for HLM IV-IVE and rCYP3A4 IV-IVE, respectively. Zolpidem is a relatively weak mechanism-based inactivator of human CYP3A in vitro. Zolpidem is unlikely to act as a significant perpetrator of metabolic interactions involving CYP3A.

Lithium Prevents REM Sleep Deprivation-Induced Impairments on Memory Consolidation

PubMed Central

Ota, Simone M.; Moreira, Karin Di Monteiro; Suchecki, Deborah; Oliveira, Maria Gabriela M.; Tiba, Paula A.

2013-01-01

Background: Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. Objective: To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. Design: Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. Subjects: Wistar male rats weighing 300-400 g. Results: Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. Conclusion: Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained. Citation: Ota SM; Moreira KDM; Suchecki D; Oliveira MGM; Tiba PA. Lithium prevents REM sleep deprivation-induced impairments on memory consolidation. SLEEP 2013;36(11):1677-1684. PMID:24179301

Effect of zolpidem on human cytochrome P450 activity, and on transport mediated by P-glycoprotein.

PubMed

von Moltke, Lisa L; Weemhoff, James L; Perloff, Michael D; Hesse, Leah M; Harmatz, Jerold S; Roth-Schechter, Barbara F; Greenblatt, David J

2002-12-01

The influence of high concentrations of zolpidem (100 microM, corresponding to approximately 200 times maximum therapeutic concentrations) on the activity of six human Cytochrome P450 (CYP) enzymes was evaluated in a model system using human liver microsomes. Zolpidem produced negligible or weak inhibition of human CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. Transport of rhodamine 123, presumed to be mediated mainly by the energy-dependent efflux transport protein P-glycoprotein, was studied in a cell culture system using a human intestinal cell line. High concentrations of zolpidem (100 microM), exceeding the usual therapeutic range by more than 100-fold, produced only modest impairment of rhodamine 123 transport. The findings indicate that zolpidem is very unlikely to cause clinical drug interactions attributable to impairment of CYP activity or P-gp mediated transport. Copyright 2002 John Wiley & Sons, Ltd.

Sleep and dream habits in a sample of French college students who report no sleep disorders.

PubMed

Vallat, Raphael; Eskinazi, Mickael; Nicolas, Alain; Ruby, Perrine

2018-02-06

There is a lack of up-to-date data on sleep and dream habits of college students. To fill in this gap, we used an online questionnaire sent to the student mailing lists of two major universities of Lyon (Lyon 1 and Lyon 2) for the recruitment of an functional magnetic resonance imaging study with sleep disorders as exclusion criteria. In the sample (1,137 French college students, 411 males, mean age = 22.2 ± 2.4 years, body mass index = 22.0 ± 3.2 kg m -2 ), on average, the participants reported spending about 8 hr in bed during weekdays, 9 hr during the weekends, and 90.9% of them reported no difficulty falling asleep. Less than 0.4% of students reported to have sleep-walking episodes regularly, but nearly 7% reported regular sleep-talking episodes. The average dream recall frequency was about 3 mornings per week with a dream in mind. Dream recall frequency was positively correlated with the clarity of dream content and the frequency of lucid dreaming, and was negatively correlated with age. Fourteen percent of the students reported frequent lucid dreams, and 6% reported frequent recurrent dreams. We found a gender effect for several sleep and dream parameters, including dream recall frequency and time in bed, both of which were higher in women than in men. We have also observed differences between academic disciplines, namely humanities students (Lyon 2) reported spending more time in bed than sciences students (Lyon 1). These results confirm a gender difference for several sleep and dream parameters, and suggest a link between academic disciplines and sleep duration. © 2018 European Sleep Research Society.

Zolpidem Use and the Risk of Injury: A Population-Based Follow-Up Study

PubMed Central

Lin, Ching-Chun; Wang, Li-Hsuan; Kang, Jiunn-Horng

2013-01-01

Background While an association between zolpidem use and fracture and road accident was previously proposed, this study aimed to further explore the frequency and risk of a wide spectrum of injuries in subjects prescribed with zolpidem in Taiwan. Methods We identified 77,036 subjects who received Zolpidem treatment between 2005 and 2007. We randomly selected 77,036 comparison subjects who were frequency-matched based-on their demographic profiles. We individually tracked each subject for a 90-day period to identify those who subsequently suffered an injury. Cox proportional hazards regressions were performed to calculate the hazard ratio of injury between the two groups. Results The incidence rate of injury during the 90-day follow-up period for the total subjects was 18.11 (95% CI = 17.69–18.54) per 100 person-years; this was 24.35 (95% CI = 23.66–25.05) and 11.86 (95% CI = 11.39–12.36) for the study and comparison cohort, respectively. After adjusting for demographic variables, the hazard ratio (HR) of injury during the 90-day follow-up period for study subjects was 1.83 (95% CI = 1.73–1.94) that of comparison subjects. Additionally, compared to comparison subjects, the adjusted HR of injury during the 90-day follow-up period for study subjects who were prescribed Zolpidem for >30 days was as high as 2.17 (95% CI = 2.05–2.32). The adjusted HR of injury to blood vessels for study subjects was particularly high when compared to comparison subjects (HR = 6.34; 95% CI = 1.37–29.38). Conclusions We found that patients prescribed with Zolpidem were at a higher risk for a wide range of injuries. PMID:23826304

Comparison of snoring sounds between natural and drug-induced sleep recorded using a smartphone.

PubMed

Koo, Soo Kweon; Kwon, Soon Bok; Moon, Ji Seung; Lee, Sang Hoon; Lee, Ho Byung; Lee, Sang Jun

2018-08-01

Snoring is an important clinical feature of obstructive sleep apnea (OSA), and recent studies suggest that the acoustic quality of snoring sounds is markedly different in drug-induced sleep compared with natural sleep. However, considering differences in sound recording methods and analysis parameters, further studies are required. This study explored whether acoustic analysis of drug-induced sleep is useful as a screening test that reflects the characteristics of natural sleep in snoring patients. The snoring sounds of 30 male subjects (mean age=41.8years) were recorded using a smartphone during natural and induced sleep, with the site of vibration noted during drug-induced sleep endoscopy (DISE); then, we compared the sound intensity (dB), formant frequencies, and spectrograms of snoring sounds. Regarding the intensity of snoring sounds, there were minor differences within the retrolingual level obstruction group, but there was no significant difference between natural and induced sleep at either obstruction site. There was no significant difference in the F 1 and F 2 formant frequencies of snoring sounds between natural sleep and induced sleep at either obstruction site. Compared with natural sleep, induced sleep was slightly more irregular, with a stronger intensity on the spectrogram, but the spectrograms showed the same pattern at both obstruction sites. Although further studies are required, the spectrograms and formant frequencies of the snoring sounds of induced sleep did not differ significantly from those of natural sleep, and may be used as a screening test that reflects the characteristics of natural sleep according to the obstruction site. Copyright © 2017 Elsevier B.V. All rights reserved.

Objective daytime sleepiness in patients with somnambulism or sleep terrors.

PubMed

Lopez, Régis; Jaussent, Isabelle; Dauvilliers, Yves

2014-11-25

To objectively measure daytime sleepiness and to assess for clinical and polysomnographic determinants of mean sleep latency in adult patients with somnambulism (sleepwalking [SW]) or sleep terrors (ST) compared with controls. Thirty drug-free adult patients with primary SW or ST, and age-, sex-, and body mass index-matched healthy controls underwent a standardized clinical interview, completed questionnaires including the Epworth Sleepiness Scale, and underwent one night of video polysomnography followed by the Multiple Sleep Latency Test (MSLT). Excessive daytime sleepiness defined as Epworth Sleepiness Scale score >10 was reported in 66.7% of patients and 6.7% of controls. The temporal pattern of sleep latencies in individual MSLT trials differed between patients and controls, with progressive increased sleep latency in patients across the trials in contrast to a "U curve" for controls. We did not find between-group differences regarding the mean sleep latency on the 5 MSLT trials, but did observe reduced sleep latencies in patients for the first 2 trials. Despite increased slow-wave sleep disruptions found in patients (i.e, more micro-arousals and hypersynchronous high-voltage delta waves arousals), we did not find polysomnographic characteristic differences when comparing sleepy patients for either subjective or objective daytime sleepiness on the MSLT compared with alert patients. Excessive daytime sleepiness is a common complaint in subjects with SW or ST and shorter sleep latencies in the early morning hours. Despite an increased slow-wave sleep fragmentation found in these patients, we did not identify any association with the level of daytime sleepiness. © 2014 American Academy of Neurology.

Murdering while Asleep: Clinical and Forensic Issues.

ERIC Educational Resources Information Center

Gilmore, John Vaughn

On the basis of the relevant research literature, this article discusses adult sleepwalking disorders, and focuses particularly on the documented cases of violence occurring during sleepwalking. Important diagnostic elements are reviewed, including family history, age of onset, gender, stages of sleep, impairments in memory and judgment, automatic…

Aripiprazole-induced sleep-related eating disorder: a case report.

PubMed

Kobayashi, Nobuyuki; Takano, Masahiro

2018-04-05

Sleep-related eating disorder is characterized by parasomnia with recurrent episodes of nocturnal eating or drinking during the main sleep period. Several drugs, including atypical antipsychotics, induce sleep-related eating disorder. However, aripiprazole has not previously been associated with sleep-related eating disorder. A 41-year-old Japanese man visited our clinic complaining of depression. The patient was treated with sertraline, which was titrated up to 100 mg for 4 weeks. A sleep inducer and an anxiolytic were coadministered. His depressive mood slightly improved, but it continued for an additional 4 months. Subsequently, aripiprazole (3 mg) was added as an adjunctive therapy. After 3 weeks, the patient's mother found that the patient woke up and ate food at night. The next morning, the patient was amnesic for this event, felt full, and wondered why the bags of food were empty. This episode lasted for 2 days. The patient gained 5 kg during these 3 weeks. After the aripiprazole dose was reduced to 1.5 mg, the patient's nocturnal eating episodes rapidly and completely disappeared. To the best of our knowledge, this is first report of sleep-related eating disorder induced by aripiprazole, and it indicates that this disorder should be considered a possible side effect of aripiprazole. Although aripiprazole is used mainly in patients with schizophrenia, its recently documented use as an adjunctive therapy in patients with depression might induce hitherto unknown side effects.

Oscillatory brain activity in spontaneous and induced sleep stages in flies.

PubMed

Yap, Melvyn H W; Grabowska, Martyna J; Rohrscheib, Chelsie; Jeans, Rhiannon; Troup, Michael; Paulk, Angelique C; van Alphen, Bart; Shaw, Paul J; van Swinderen, Bruno

2017-11-28

Sleep is a dynamic process comprising multiple stages, each associated with distinct electrophysiological properties and potentially serving different functions. While these phenomena are well described in vertebrates, it is unclear if invertebrates have distinct sleep stages. We perform local field potential (LFP) recordings on flies spontaneously sleeping, and compare their brain activity to flies induced to sleep using either genetic activation of sleep-promoting circuitry or the GABA A agonist Gaboxadol. We find a transitional sleep stage associated with a 7-10 Hz oscillation in the central brain during spontaneous sleep. Oscillatory activity is also evident when we acutely activate sleep-promoting neurons in the dorsal fan-shaped body (dFB) of Drosophila. In contrast, sleep following Gaboxadol exposure is characterized by low-amplitude LFPs, during which dFB-induced effects are suppressed. Sleep in flies thus appears to involve at least two distinct stages: increased oscillatory activity, particularly during sleep induction, followed by desynchronized or decreased brain activity.

Interleukin 1 receptor contributes to methamphetamine- and sleep deprivation-induced hypersomnolence

PubMed Central

Schmidt, Michelle A.; Wisor, Jonathan P.

2014-01-01

Methamphetamine-induced wakefulness is dependent on monoamine transporter blockade. Subsequent to methamphetamine-induced wakefulness, the amount of time spent asleep and the depth of sleep are increased relative to baseline sleep. The mechanisms that drive methamphetamine-induced hypersomnolence are not fully understood. We recently observed that methamphetamine exposure elevates the expression of the sleep-promoting cytokine, interleukin-1 β in CD11b-positive monocytes within the brain. Here, we sought to determine whether activation of the interleukin 1 receptor (IL1R) drives the increase in the depth and amount of sleep that occurs subsequent to methamphetamine-induced wakefulness. IL1R-deficient mice and wild type control mice were subjected to systemic methamphetamine (1 and 2mg/kg) and saline treatments. The wake-promoting effect of methamphetamine was modestly potentiated by IL1R-deficiency. Additionally, the increase in time spent in NREMS subsequent to methamphetamine-induced wakefulness in wild type mice was abolished in IL1R-deficient mice. The increase in time spent asleep after 3 h of behaviorally enforced wakefulness was also abolished in IL1R-deficient mice. Increases in EEG slow wave activity triggered by methamphetamine and sleep deprivation were of equal magnitude in IL1R-deficient and wild type mice. These data demonstrate that IL1R activation contributes to hypersomnolence that occurs after sleep loss, whether that sleep loss is triggered pharmacologically by methamphetamine or through behavioral sleep deprivation. PMID:22387068

Sleep-Related Violence and Sexual Behavior in Sleep: A Systematic Review of Medical-Legal Case Reports

PubMed Central

Ingravallo, Francesca; Poli, Francesca; Gilmore, Emma V.; Pizza, Fabio; Vignatelli, Luca; Schenck, Carlos H.; Plazzi, Giuseppe

2014-01-01

Objective: To review systematically medical-legal cases of sleep-related violence (SRV) and sexual behavior in sleep (SBS). Search Methods: We searched Pubmed and PsychINFO (from 1980 to 2012) with pre-specified terms. We also searched reference lists of relevant articles. Selection Criteria: Case reports in which a sleep disorder was purported as the defense during a criminal trial and in which information about the forensic evaluation of the defendant was provided. Data Extraction and Analysis: Information about legal issues, defendant and victim characteristics, circumstantial factors, and forensic evaluation was extracted from each case. A qualitative-comparative assessment of cases was performed. Results: Eighteen cases (9 SRV and 9 SBS) were included. The charge was murder or attempted murder in all SRV cases, while in SBS cases the charge ranged from sexual touching to rape. The defense was based on sleepwalking in 11 of 18 cases. The trial outcome was in favor of the defendant in 14 of 18 cases. Defendants were relatively young males in all cases. Victims were usually adult relatives of the defendants in SRV cases and unrelated young girls or adolescents in SBS cases. In most cases the criminal events occurred 1-2 hours after the defendant's sleep onset, and both proximity and other potential triggering factors were reported. The forensic evaluations widely differed from case to case. Conclusion: SRV and SBS medical-legal cases did not show apparent differences, except for the severity of the charges and the victim characteristics. An international multidisciplinary consensus for the forensic evaluation of SRV and SBS should be developed as an urgent priority. Citation: Ingravallo F, Poli F, Gilmore EV, Pizza F, Vignatelli L, Schenck CH, Plazzi G. Sleep-related violence and sexual behavior in sleep: a systematic review of medical-legal case reports. J Clin Sleep Med 2014;10(8):927-935. PMID:25126042

L-carnitine prevents memory impairment induced by chronic REM-sleep deprivation.

PubMed

Alzoubi, Karem H; Rababa'h, Abeer M; Owaisi, Amani; Khabour, Omar F

2017-05-01

Sleep deprivation (SD) negatively impacts memory, which was related to oxidative stress induced damage. L-carnitine is a naturally occurring compound, synthesized endogenously in mammalian species and known to possess antioxidant properties. In this study, the effect of L-carnitine on learning and memory impairment induced by rapid eye movement sleep (REM-sleep) deprivation was investigated. REM-sleep deprivation was induced using modified multiple platform model (8h/day, for 6 weeks). Simultaneously, L-carnitine was administered (300mg/kg/day) intraperitoneally for 6 weeks. Thereafter, the radial arm water maze (RAWM) was used to assess spatial learning and memory. Additionally, the hippocampus levels of antioxidant biomarkers/enzymes: reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD) and thiobarbituric acid reactive substance (TBARS) were assessed. The results showed that chronic REM-sleep deprivation impaired both short- and long-term memory (P<0.05), whereas L-carnitine treatment protected against this effect. Furthermore, L-carnitine normalized chronic REM-sleep deprivation induced reduction in the hippocampus ratio of GSH/GSSG, activity of catalase, GPx, and SOD. No change was observed in TBARS among tested groups (P>0.05). In conclusion, chronic REM-sleep deprivation induced memory impairment, and treatment with L-carnitine prevented this impairment through normalizing antioxidant mechanisms in the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Plasticity-Related Gene Expression During Eszopiclone-Induced Sleep.

PubMed

Gerashchenko, Dmitry; Pasumarthi, Ravi K; Kilduff, Thomas S

2017-07-01

Experimental evidence suggests that restorative processes depend on synaptic plasticity changes in the brain during sleep. We used the expression of plasticity-related genes to assess synaptic plasticity changes during drug-induced sleep. We first characterized sleep induced by eszopiclone in mice during baseline conditions and during the recovery from sleep deprivation. We then compared the expression of 18 genes and two miRNAs critically involved in synaptic plasticity in these mice. Gene expression was assessed in the cerebral cortex and hippocampus by the TaqMan reverse transcription polymerase chain reaction and correlated with sleep parameters. Eszopiclone reduced the latency to nonrapid eye movement (NREM) sleep and increased NREM sleep amounts. Eszopiclone had no effect on slow wave activity (SWA) during baseline conditions but reduced the SWA increase during recovery sleep (RS) after sleep deprivation. Gene expression analyses revealed three distinct patterns: (1) four genes had higher expression either in the cortex or hippocampus in the group of mice with increased amounts of wakefulness; (2) a large proportion of plasticity-related genes (7 out of 18 genes) had higher expression during RS in the cortex but not in the hippocampus; and (3) six genes and the two miRNAs showed no significant changes across conditions. Even at a relatively high dose (20 mg/kg), eszopiclone did not reduce the expression of plasticity-related genes during RS period in the cortex. These results indicate that gene expression associated with synaptic plasticity occurs in the cortex in the presence of a hypnotic medication. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Low dose quetiapine in the treatment of an adolescent with somnambulism: a case report.

PubMed

Gill, Jesjeet Singh; Pillai, Subash Kumar; Koh, Ong Hui; Jambunathan, Stephen Thevanathan

2011-06-01

Somnambulism or sleepwalking is a sleep disorder of arousal. Compared to in adults, pediatric and adolescent sleep disorders is still under-researched and poorly described. We report the successful use of low dose quietiapine, an atypical antipsychotic, in the treatment of a 15-year-old Indian male who presented with significant somnambulism. To the best of our knowledge, this is the first report on the use of quetiapine for the treatment of somnambulism in the literature. The presence of high voltage delta waves in sleepwalkers has been offered as a possible explanation for the patho-physiology of sleepwalking Quetiapine has been reported to decrease brain delta activity, and we postulate that this may be the mechanism on how it was beneficial for our patient.

Neuropeptide glutamic acid-isoleucine (NEI)-induced paradoxical sleep in rats.

PubMed

Fujimoto, Moe; Fukuda, Satoru; Sakamoto, Hidetoshi; Takata, Junko; Sawamura, Shigehito

2017-01-01

Neuropeptideglutamic acid-isoleucine (NEI) as well as melanin concentrating hormone (MCH) is cleaved from the 165 amino acid protein, prepro-melanin concentrating hormone (prepro-MCH). Among many physiological roles of MCH, we demonstrated that intracerebroventricular (icv) injection of MCH induced increases in REM sleep episodes as well as in non REM sleep episodes. However, there are no studies on the effect of NEI on the sleep-wake cycle. As for the sites of action of MCH for induction of REM sleep, the ventrolateral periaqueductal gray (vlPAG) has been reported to be one of its site of action. Although MCH neurons contain NEI, GABA, MCH, and other neuropeptides, we do not know which transmitter(s) might induce REM sleep by acting on the vlPAG. Thus, we first examined the effect of icv injection of NEI on the sleep-wake cycle, and investigated how microinjection of either NEI, MCH, or GABA into the vlPAG affected REM sleep in rats. Icv injection of NEI (0.61μg/5μl: n=7) significantly increased the time spent in REM episodes compared to control (saline: 5μl; n=6). Microinjection of either NEI (61ng/0.2μl: n=7), MCH (100ng/0.2μl: n=6) or GABA (250mM/0.2μl: n=7) into the vlPAG significantly increased the time spent in REM episodes and the AUC. Precise hourly analysis of REM sleep also revealed that after those microinjections, NEI and MCH increased REM episodes at the latter phase, compared to GABA which increased REM episodes at the earlier phase. This result suggests that NEI and MCH may induce sustained REM sleep, while GABA may initiate REM sleep. In conclusion, our findings demonstrate that NEI, a cleaved peptide from the same precursor, prepro-MCH, as MCH, induce REM sleep at least in part through acting on the vlPAG. Copyright © 2016 Elsevier Inc. All rights reserved.

Lithium prevents REM sleep deprivation-induced impairments on memory consolidation.

PubMed

Ota, Simone M; Moreira, Karin Di Monteiro; Suchecki, Deborah; Oliveira, Maria Gabriela M; Tiba, Paula A

2013-11-01

Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pre-training sleep deprivation. Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. Wistar male rats weighing 300-400 g. Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained.

Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey

PubMed Central

Victorri-Vigneau, Caroline; Dailly, Eric; Veyrac, Gwenaëlle; Jolliet, Pascale

2007-01-01

Aim To show that the nonbenzodiazepine hypnotic zolpidem has a higher abuse potential than previously documented. Method An official enquiry was carried out by the Nantes Centre for Evaluation and Information on Pharmacodependence (CEIP). The authors made a review of literature and analysed French data corresponding to the drug's postmarketing period collected by the CEIP network from 1993 to 2002. Results The literature review yielded mixed results concerning the behavioural effects of zolpidem. Data from the CEIP and the 53 literature case reports highlight significant dependence and abuse potential of zolpidem. Conclusions This study adds to the growing evidence that zolpidem has the potential for abuse and dependence. As a consequence, the French drug monograph has been modified by the French Health Authorities. PMID:17324242

Media Coverage of FDA Drug Safety Communications about Zolpidem: A Quantitative and Qualitative Analysis.

PubMed

Woloshin, Steve; Schwartz, Lisa M; Dejene, Sara; Rausch, Paula; Dal Pan, Gerald J; Zhou, Esther H; Kesselheim, Aaron S

2017-05-01

FDA issues Drug Safety Communications (DSCs) to alert health care professionals and the public about emerging safety information affecting prescription and over-the-counter drugs. News media may amplify DSCs, but it is unclear how DSC messaging is transmitted through the media. We conducted a content analysis of the lay media coverage reaching the broadest audience to characterize the amount and content of media coverage of two zolpidem DSCs from 2013. After the first DSC, zolpidem news stories increased from 19 stories/week in the preceding 3 months to 153 following its release. Most (81%) appeared in the lay media, and 64% focused on the DSC content. After the second DSC, news stories increased from 24 stories/week in the preceding 3 months to 39 following. Among the 100 unique lay media news stories, at least half correctly reported three key DSC messages: next-day impairment and drowsiness as common safety hazards, lower doses for some but not all zolpidem products, and women's higher risk for impairment. Other DSC messages were reported in fewer than one-third of stories, such as the warning that impairment can happen even when people feel fully awake. The first-but not the second-zolpidem DSC generated high-profile news coverage. The finding that some messages were widely reported but others were not emphasizes the importance of ensuring translation of key DSC content.

Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system.

PubMed

Mahapatra, Anjan Kumar; Sameeraja, N H; Murthy, P N

2015-06-01

Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation.

Impact of Expanding ELISA Screening in DUID Investigations to Include Carisoprodol/Meprobamate and Zolpidem.

PubMed

Lu, Aileen; Scott, Karen S; Chan-Hosokawa, Aya; Logan, Barry K

2017-03-01

In 2013, the National Safety Council's Alcohol Drugs and Impairment Division added zolpidem and carisoprodol and its metabolite meprobamate to the list of Tier 1 drugs that should be tested for in all suspected drug impaired driving and motor vehicle fatality investigations. We describe the validation of an enzyme linked immunosorbent assays (ELISA) for both drugs in whole blood, and the utilization of the ELISA to assess their positivity in a sample of 322 suspected impaired driving cases that was retrospectively screened using the validated assays. The occurrence of carisoprodol/meprobamate was found to be 1.2%, and for zolpidem, 1.6%. In addition, we analyzed a large dataset (n = 1,672) of Driving Under the Influence of Drugs (DUID) test results from a laboratory performing high volume DUID testing to assess the frequency of detection of both drugs after implementing the expanded NSC scope. Carisoprodol or meprobamate were found positive in 5.9% (n = 99) of these samples, while zolpidem was found positive in 5.3% (n = 89) in drivers who in many cases had been found to be negative for other drugs. Carisoprodol and zolpidem are both potent CNS depressants and are appropriate additions to the recommended NSC scope of testing. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Quantitation of zolpidem in biological fluids by electro-driven microextraction combined with HPLC-UV analysis.

PubMed

Yaripour, Saeid; Mohammadi, Ali; Esfanjani, Isa; Walker, Roderick B; Nojavan, Saeed

2018-01-01

In this study, for the first time, an electro-driven microextraction method named electromembrane extraction combined with a simple high performance liquid chromatography and ultraviolet detection was developed and validated for the quantitation of zolpidem in biological samples. Parameters influencing electromembrane extraction were evaluated and optimized. The membrane consisted of 2-ethylhexanol immobilized in the pores of a hollow fiber. As a driving force, a 150 V electric field was applied to facilitate the analyte migration from the sample matrix to an acceptor solution through a supported liquid membrane. The pHs of donor and acceptor solutions were optimized to 6.0 and 2.0, respectively. The enrichment factor was obtained >75 within 15 minutes. The effect of carbon nanotubes (as solid nano-sorbents) on the membrane performance and EME efficiency was evaluated. The method was linear over the range of 10-1000 ng/mL for zolpidem (R 2 >0.9991) with repeatability ( %RSD) between 0.3 % and 7.3 % ( n = 3). The limits of detection and quantitation were 3 and 10 ng/mL, respectively. The sensitivity of HPLC-UV for the determination of zolpidem was enhanced by electromembrane extraction. Finally, the method was employed for the quantitation of zolpidem in biological samples with relative recoveries in the range of 60-79 %.

Combined effects of methamphetamine and zolpidem on performance and mood during simulated night shift work.

PubMed

Hart, Carl L; Haney, Margaret; Nasser, Jennifer; Foltin, Richard W

2005-07-01

Individuals who work irregular or rotating shifts often use stimulants and sedatives to offset shift-change-related mood and performance decrements. During this simulated shift work study the acute effects of the stimulant, methamphetamine were examined, and the effects of the hypnotic, zolpidem, and the combination were assessed during the shift after drug administration. Eight volunteers completed this 21-day, within-participant, residential laboratory study during which they received a single oral methamphetamine dose (0 or 10 mg) 1 h after waking, i.e., before task performance, and a single oral zolpidem dose (0 or 10 mg) 1 h before bedtime under 2 shift conditions: day shift and night shift. When participants received placebo at both dosing times, performance on some psychomotor tasks (e.g., the digit-symbol substitution task) and on some measures of mood (e.g., ratings of "Energetic") were disrupted during the night shift, relative to the day shift. Methamphetamine alone eliminated virtually all shift-related disruptions, while zolpidem alone and the drug combination produced few effects. These data indicate that shift changes produce performance impairments and mood alterations that are improved by a single low to moderate dose of methamphetamine. Zolpidem, given alone or in combination with methamphetamine, did not alleviate most shift-change mood and performance effects.

Analysis of Zolpidem in Postmortem Fluids and Tissues Using Ultra-Performance Liquid Chromatography-Mass Spectrometry

DTIC Science & Technology

2014-02-01

16. Abstract Zolpidem is a nonbenzodiazepine sedative hypnotic drug used for the short-term treatment of insomnia. Its use is common and wide-spread...Classif. (of this page) 21. No. of Pages 22. Price Unclassified Unclassified 15 Form DOT F 1700.7 (8-72) Reproduction of completed page authorized iii...INTRODUCTION Zolpidem is a nonbenzodiazepine sedative hypnotic drug used to treat insomnia by slowing the activity in the brain. It is prescribed as a short

Multiple sleep latency measures in narcolepsy and behaviourally induced insufficient sleep syndrome.

PubMed

Marti, Isabelle; Valko, Philipp O; Khatami, Ramin; Bassetti, Claudio L; Baumann, Christian R

2009-12-01

Short mean latencies to the first epoch of non-rapid eye movement sleep stage 1 (NREM1) and the presence of >or= 2 sleep onset REM (SOREM) periods on multiple sleep latency test (MSLT) occur in both narcolepsy-cataplexy (NC) and behaviourally induced insufficient sleep syndrome (BIISS). It is not known whether specific MSLT findings help differentiate the two disorders. We analyzed MSLT data including sleep latencies to and between different sleep stages of 60 age-, gender- and body mass index (BMI)-matched subjects (hypocretin-deficient NC, actigraphy-confirmed BIISS, healthy controls: each 20). Mean latency (in minutes) to NREM1 sleep was significantly shorter in NC (1.8+/-1.5) than in BIISS (4.7+/-2.1, p<0.001) and controls (11.4+/-3.3, p<0.001). Mean latency to NREM2 sleep was similar in NC (8.6+/-4.7) and BIISS (8.1+/-2.7, p=0.64); latency to either NREM2 or rapid eye movement (REM) sleep (i.e., the sum of the sleep latency to NREM1 and the duration of the first NREM1 sleep sequence), however, was shorter in NC (4.4+/-2.9) than in BIISS (7.9+/-3.5, p<0.001). Referring to all naps with SOREM periods, the sequence NREM1-REM-NREM2 was more common (71%) in NC than in BIISS (15%, p<0.001), reflecting the shorter latency from NREM1 to NREM2 in BIISS (3.7+/-2.5) than in NC (6.1+/-5.9, p<0.001). Our findings show that both sleepiness (as measured by NREM1 sleep latency) and REM sleep propensity are higher in NC than in BIISS. Furthermore, our finding of frequent REM sleep prior to NREM2 sleep in NC is in line with the recent assumption of an insufficient NREM sleep intensity in NC. Together with detailed clinical interviews, sleep logs, actigraphy, and nocturnal polysomnography, mean sleep latencies to NREM1

A therapeutic dose of zolpidem reduces thalamic GABA in healthy volunteers: A proton MRS study at 4 Tesla

PubMed Central

Licata, Stephanie C.; Jensen, J. Eric; Penetar, David M.; Prescot, Andrew P.; Lukas, scott E.; Renshaw, Perry F.

2009-01-01

Background Zolpidem is a non-benzodiazepine sedative/hypnotic that acts at GABAA receptors to influence inhibitory neurotransmission throughout the central nervous system. A great deal is known about the behavioral effects of this drug in humans and laboratory animals, but little is known about zolpidem’s specific effects on neurochemistry in vivo. Objectives We evaluated how acute administration of zolpidem affected levels of GABA, glutamate, glutamine, and other brain metabolites. Methods Proton magnetic resonance spectroscopy (1H MRS) at 4 Tesla was employed to measure the effects of zolpidem on brain chemistry in 19 healthy volunteers. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires were administered periodically throughout the experimental session to assess subjective mood states. Results Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of “dizzy”, “nauseous”, “confused”, and “bad effects” were increased relative to placebo, as were ratings on the sedation/intoxication (PCAG) and psychotomimetic/dysphoria (LSD) scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and “dizzy”. Conclusions Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and “dizzy” may be a function of zolpidem’s interaction with α1GABAA receptors in the cerebellum, projecting through the vestibular system to the thalamus. PMID:19125238

Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol.

PubMed

Helms, Christa M; Rogers, Laura S M; Waters, Courtney A; Grant, Kathleen A

2008-07-01

The subtypes of gamma-aminobutyric acid (GABA)(A) receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABA(A) receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing alpha(1), alpha(2/3), and alpha(5) subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for alpha(4/6)-containing receptors, higher affinity for alpha(5)- and lower, but equal, affinity for alpha(1)- and alpha(2/3)-, containing GABA(A) receptors, and antagonizes the discriminative stimulus effects of ethanol. This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval. Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (>or=80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose-response curve to the right in all monkeys showing generalization. Analysis of apparent pK(B) from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro15-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol. Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABA(A) receptors that contain alpha(1) subunits, however, antagonism by Ro15-4513 of zolpidem generalization

Endoscopic examination of obstructive sleep apnea syndrome patients during drug-induced sleep.

PubMed

Iwanaga, Koichi; Hasegawa, Kiyokazu; Shibata, Nobuhiro; Kawakatsu, Kenji; Akita, Yasutaka; Suzuki, Kenji; Yagisawa, Mikio; Nishimura, Tadao

2003-01-01

Sixty patients diagnosed with obstructive sleep apnea syndrome (OSAS) underwent uvulopalatopharyngoplasty (UPPP). The effects of surgery were studied based on endoscopic findings during drug-induced sleep and determination of the apnea-hypopnea index (AHI) before and after the operation. Changes in the form of the airway during sleep in the recumbent position were observed, and the role of upper airway endoscopy in the diagnosis and surgical treatment of OSAS was determined. The site of airway obstruction during sleep induced by i.v. injection of 10 mg of diazepam was classified into five types, and changes in AHI and the site of airway obstruction were compared before and after surgery. Changes in airway morphology during sleep in the supine and recumbent positions were also compared before surgery. The postoperative improvement rate was 74.4% for the soft palatal type of obstruction, 76.2% for the tonsillar type, 53.3% for the circumferential palatal type and 34.0% for the mixed type. Treatment produced excellent or good effects for the soft palatal and tonsillar types of obstruction. However, many patients with the circumferential palatal and mixed types of obstruction showed only some improvement or no change. Good airway morphology was maintained in the recumbent position by patients with the soft palatal type of obstruction. With the circumferential palatal and mixed types of obstruction, improvement can be expected from operations which include surgical treatment of the posterior pharyngeal wall or lateral funiculus, or with midline laser glossectomy. A good operative outcome can be predicted in patients showing improvement of apnea in the recumbent position preoperatively.

Virus-mediated swapping of zolpidem-insensitive with zolpidem-sensitive GABA(A) receptors in cortical pyramidal cells.

PubMed

Sumegi, Mate; Fukazawa, Yugo; Matsui, Ko; Lorincz, Andrea; Eyre, Mark D; Nusser, Zoltan; Shigemoto, Ryuichi

2012-04-01

Recently developed pharmacogenetic and optogenetic approaches, with their own advantages and disadvantages, have become indispensable tools in modern neuroscience. Here, we employed a previously described knock-in mouse line (GABA(A)Rγ2(77I)lox) in which the γ2 subunit of the GABA(A) receptor (GABA(A)R) was mutated to become zolpidem insensitive (γ2(77I)) and used viral vectors to swap γ2(77I) with wild-type, zolpidem-sensitive γ2 subunits (γ2(77F)). The verification of unaltered density and subcellular distribution of the virally introduced γ2 subunits requires their selective labelling. For this we generated six N- and six C-terminal-tagged γ2 subunits, with which cortical cultures of GABA(A)Rγ2(−/−) mice were transduced using lentiviruses. We found that the N-terminal AU1 tag resulted in excellent immunodetection and unimpaired synaptic localization. Unaltered kinetic properties of the AU1-tagged γ2 ((AU1)γ2(77F)) channels were demonstrated with whole-cell patch-clamp recordings of spontaneous IPSCs from cultured cells. Next, we carried out stereotaxic injections of lenti- and adeno-associated viruses containing Cre-recombinase and the (AU1)γ2(77F) subunit (Cre-2A-(AU1)γ2(77F)) into the neocortex of GABA(A)Rγ2(77I)lox mice. Light microscopic immunofluorescence and electron microscopic freeze-fracture replica immunogold labelling demonstrated the efficient immunodetection of the AU1 tag and the normal enrichment of the (AU1)γ2(77F) subunits in perisomatic GABAergic synapses. In line with this,miniature and action potential-evoked IPSCs whole-cell recorded from transduced cells had unaltered amplitudes, kinetics and restored zolpidem sensitivity. Our results obtained with a wide range of structural and functional verification methods reveal unaltered subcellular distributions and functional properties of γ2(77I) and (AU1)γ2(77F) GABA(A)Rs in cortical pyramidal cells. This transgenic–viral pharmacogenetic approach has the advantage that it

Prescription of Zolpidem and the Risk of Fatal Motor Vehicle Collisions: A Population-Based, Case-Crossover Study from South Korea.

PubMed

Yang, Bo Ram; Kim, Ye-Jee; Kim, Mi-Sook; Jung, Sun-Young; Choi, Nam-Kyong; Hwang, Byungkwan; Park, Byung-Joo; Lee, Joongyub

2018-05-23

Zolpidem is one of the most frequently used hypnotics worldwide, but associations with serious adverse effects such as motor vehicle collisions have been reported. The objective of this study was to evaluate the association of fatal motor vehicle collisions with a prescription for zolpidem, considering the context of the motor vehicle collisions. We conducted a case-crossover study, where each case served as its own control, by linking data about fatal motor vehicle collisions from the Korean Road Traffic Authority between 2010 and 2014 with national health insurance data. The case period was defined as 1 day before the fatal motor vehicle collisions, and was matched to four control periods at 90-day intervals. Conditional logistic regression was performed to calculate the odds ratio for fatal motor vehicle collisions associated with zolpidem exposure, and odds ratios were adjusted for time-varying exposure to confounding medications. A stratified analysis was performed by age group (younger than 65 years or not), the Charlson Comorbidity Index, and whether patients were new zolpidem users. Among the 714 subjects, the adjusted odds ratio for a fatal motor vehicle collision associated with a prescription for zolpidem the previous day was 1.48 (95% confidence interval 1.06-2.07). After stratification, a significantly increased risk was observed in subjects with a high Charlson Comorbidity Index (odds ratio 1.81; 95% confidence interval 1.16-2.84), the younger age group (odds ratio: 1.62; 95% confidence interval 1.03-2.56), and new zolpidem users (odds ratio 2.37; 95% confidence interval 1.40-4.00). A prescription for zolpidem on the previous day was significantly related to an increased risk of fatal motor vehicle collisions in this population-based case-crossover study.

Brain prolactin is involved in stress-induced REM sleep rebound.

PubMed

Machado, Ricardo Borges; Rocha, Murilo Ramos; Suchecki, Deborah

2017-03-01

REM sleep rebound is a common behavioural response to some stressors and represents an adaptive coping strategy. Animals submitted to multiple, intermittent, footshock stress (FS) sessions during 96h of REM sleep deprivation (REMSD) display increased REM sleep rebound (when compared to the only REMSD ones, without FS), which is correlated to high plasma prolactin levels. To investigate whether brain prolactin plays a role in stress-induced REM sleep rebound two experiments were carried out. In experiment 1, rats were either not sleep-deprived (NSD) or submitted to 96h of REMSD associated or not to FS and brains were evaluated for PRL immunoreactivity (PRL-ir) and determination of PRL concentrations in the lateral hypothalamus and dorsal raphe nucleus. In experiment 2, rats were implanted with cannulas in the dorsal raphe nucleus for prolactin infusion and were sleep-recorded. REMSD associated with FS increased PRL-ir and content in the lateral hypothalamus and all manipulations increased prolactin content in the dorsal raphe nucleus compared to the NSD group. Prolactin infusion in the dorsal raphe nucleus increased the time and length of REM sleep episodes 3h after the infusion until the end of the light phase of the day cycle. Based on these results we concluded that brain prolactin is a major mediator of stress-induced REMS. The effect of PRL infusion in the dorsal raphe nucleus is discussed in light of the existence of a bidirectional relationship between this hormone and serotonin as regulators of stress-induced REM sleep rebound. Copyright © 2016 Elsevier Inc. All rights reserved.

Sleep-related violence and sexual behavior in sleep: a systematic review of medical-legal case reports.

PubMed

Ingravallo, Francesca; Poli, Francesca; Gilmore, Emma V; Pizza, Fabio; Vignatelli, Luca; Schenck, Carlos H; Plazzi, Giuseppe

2014-08-15

To review systematically medical-legal cases of sleep-related violence (SRV) and sexual behavior in sleep (SBS). We searched Pubmed and PsychINFO (from 1980 to 2012) with pre-specified terms. We also searched reference lists of relevant articles. Case reports in which a sleep disorder was purported as the defense during a criminal trial and in which information about the forensic evaluation of the defendant was provided. Information about legal issues, defendant and victim characteristics, circumstantial factors, and forensic evaluation was extracted from each case. A qualitative-comparative assessment of cases was performed. Eighteen cases (9 SRV and 9 SBS) were included. The charge was murder or attempted murder in all SRV cases, while in SBS cases the charge ranged from sexual touching to rape. The defense was based on sleepwalking in 11 of 18 cases. The trial outcome was in favor of the defendant in 14 of 18 cases. Defendants were relatively young males in all cases. Victims were usually adult relatives of the defendants in SRV cases and unrelated young girls or adolescents in SBS cases. In most cases the criminal events occurred 1-2 hours after the defendant's sleep onset, and both proximity and other potential triggering factors were reported. The forensic evaluations widely differed from case to case. SRV and SBS medical-legal cases did not show apparent differences, except for the severity of the charges and the victim characteristics. An international multidisciplinary consensus for the forensic evaluation of SRV and SBS should be developed as an urgent priority.

Somnambulism: clinical aspects and pathophysiological hypotheses.

PubMed

Zadra, Antonio; Desautels, Alex; Petit, Dominique; Montplaisir, Jacques

2013-03-01

Somnambulism, or sleepwalking, can give rise to a wide range of adverse consequences and is one of the leading causes of sleep-related injury. Accurate diagnosis is crucial for proper management and imperative in an ever-increasing number of medicolegal cases implicating sleep-related violence. Unfortunately, several widely held views of sleepwalking are characterised by key misconceptions, and some established diagnostic criteria are inconsistent with research findings. The traditional idea of somnambulism as a disorder of arousal might be too restrictive and a comprehensive view should include the idea of simultaneous interplay between states of sleep and wakefulness. Abnormal sleep physiology, state dissociation, and genetic factors might explain the pathophysiology of the disorder. Copyright © 2013 Elsevier Ltd. All rights reserved.

Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction

PubMed Central

Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

2016-01-01

Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction. PMID:26235983

Quantitation of zolpidem in biological fluids by electro-driven microextraction combined with HPLC-UV analysis

PubMed Central

Yaripour, Saeid; Mohammadi, Ali; Esfanjani, Isa; Walker, Roderick B.; Nojavan, Saeed

2018-01-01

In this study, for the first time, an electro-driven microextraction method named electromembrane extraction combined with a simple high performance liquid chromatography and ultraviolet detection was developed and validated for the quantitation of zolpidem in biological samples. Parameters influencing electromembrane extraction were evaluated and optimized. The membrane consisted of 2-ethylhexanol immobilized in the pores of a hollow fiber. As a driving force, a 150 V electric field was applied to facilitate the analyte migration from the sample matrix to an acceptor solution through a supported liquid membrane. The pHs of donor and acceptor solutions were optimized to 6.0 and 2.0, respectively. The enrichment factor was obtained >75 within 15 minutes. The effect of carbon nanotubes (as solid nano-sorbents) on the membrane performance and EME efficiency was evaluated. The method was linear over the range of 10-1000 ng/mL for zolpidem (R2 >0.9991) with repeatability ( %RSD) between 0.3 % and 7.3 % (n = 3). The limits of detection and quantitation were 3 and 10 ng/mL, respectively. The sensitivity of HPLC-UV for the determination of zolpidem was enhanced by electromembrane extraction. Finally, the method was employed for the quantitation of zolpidem in biological samples with relative recoveries in the range of 60-79 %. PMID:29805344

C. elegans Stress-Induced Sleep Emerges from the Collective Action of Multiple Neuropeptides.

PubMed

Nath, Ravi D; Chow, Elly S; Wang, Han; Schwarz, Erich M; Sternberg, Paul W

2016-09-26

The genetic basis of sleep regulation remains poorly understood. In C. elegans, cellular stress induces sleep through epidermal growth factor (EGF)-dependent activation of the EGF receptor in the ALA neuron. The downstream mechanism by which this neuron promotes sleep is unknown. Single-cell RNA sequencing of ALA reveals that the most highly expressed, ALA-enriched genes encode neuropeptides. Here we have systematically investigated the four most highly enriched neuropeptides: flp-7, nlp-8, flp-24, and flp-13. When individually removed by null mutation, these peptides had little or no effect on stress-induced sleep. However, stress-induced sleep was abolished in nlp-8; flp-24; flp-13 triple-mutant animals, indicating that these neuropeptides work collectively in controlling stress-induced sleep. We tested the effect of overexpression of these neuropeptide genes on five behaviors modulated during sleep-pharyngeal pumping, defecation, locomotion, head movement, and avoidance response to an aversive stimulus-and we found that, if individually overexpressed, each of three neuropeptides (nlp-8, flp-24, or flp-13) induced a different suite of sleep-associated behaviors. These overexpression results raise the possibility that individual components of sleep might be specified by individual neuropeptides or combinations of neuropeptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rapidly-progressive catatonia responsive to zolpidem in a patient with ovarian teratoma-associated paraneoplastic encephalitis.

PubMed

Amorim, Edilberto; McDade, Eric M

2016-08-01

Psychiatric symptoms and catatonia are key components of the clinical presentation of paraneoplastic encephalitis; additionally symptoms can be long-lasting and often difficult to treat. We report a 73-year-old patient with rapidly progressive catatonia not responsive to immunotherapy, tumor resection, electroconvulsive therapy, or benzodiazepines who had significant improvement after zolpidem administration. This report suggests that zolpidem is an option in the treatment of patients with refractory catatonia and paraneoplastic encephalitis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Modeling aircraft noise induced sleep disturbance

NASA Astrophysics Data System (ADS)

McGuire, Sarah M.

occurrence of rapid eye movements, sleep spindles, and slow wave sleep. Using these features an approach for classifying sleep stages every one second during the night was developed. From observation of the results of the sleep stage classification, it was determined how to add faster dynamics to the nonlinear dynamic model. Slow and fast REM activity are modeled separately and the activity in the gamma frequency band of the EEG signal is used to model both spontaneous and noise-induced awakenings. The nonlinear model predicts changes in sleep structure similar to those found by other researchers and reported in the sleep literature and similar to those found in obtained survey data. To compare sleep disturbance model predictions, flight operations data from US airports were obtained and sleep disturbance in communities was predicted for different operations scenarios using the modified Markov model, the nonlinear dynamic model, and other aircraft noise awakening models. Similarities and differences in model predictions were evaluated in order to determine if the use of the developed sleep structure model leads to improved predictions of the impact of nighttime noise on communities.

A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

PubMed

Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

2011-12-01

Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.

Validation of a method for the determination of zolpidem in human plasma using LC with fluorescence detection.

PubMed

Ring, P R; Bostick, J M

2000-04-01

A sensitive and selective high-performance liquid chromatography (HPLC) method was developed for the determination of zolpidem in human plasma. Zolpidem and the internal standard (trazodone) were extracted from human plasma that had been made basic. The basic sample was loaded onto a conditioned Bond Elut C18 cartridge, rinsed with water and eluted with methanol. Forty microliters were then injected onto the LC system. Separation was achieved on a C18 column (150 x 4.6 mm, 5 microm) with a mobile phase composed of acetonitrile:50 mM potassium phosphate monobasic at pH 6.0 (4:6, v/v). Detection was by fluorescence, with excitation at 254 nm and emission at 400 nm. The retention times of zolpidem and internal standard were approximately 4.7 and 5.3 min, respectively. The LC run time was 8 min. The assay was linear in concentration range 1-400 ng/ml for zolpidem in human plasma. The analysis of quality control samples for zolpidem (3, 30, and 300 ng/ml) demonstrated excellent precision with relative standard deviations (RSD) of 3.7, 4.6, and 3.0%, respectively (n = 18). The method was accurate with all intraday (n = 6) and overall (n = 18) mean concentrations within 5.8% from nominal at all quality control sample concentrations. This method was also performed using a Gilson Aspec XL automated sample processor and autoinjector. The samples were manually fortified with internal standard and made basic. The aspec then performed the solid phase extraction and made injections of the samples onto the LC system. Using the automated procedure for analysis, quality control samples for zolpidem (3, 30, and 300 ng/ml) demonstrated acceptable precision with RSD values of 9.0, 4.9, and 5.1%, respectively (n = 12). The method was accurate with all intracurve (n = 4) and overall (n = 12) mean values being less than 10.8% from nominal at all quality control sample concentrations.

Cellular stress induces a protective sleep-like state in C. elegans.

PubMed

Hill, Andrew J; Mansfield, Richard; Lopez, Jessie M N G; Raizen, David M; Van Buskirk, Cheryl

2014-10-20

Sleep is recognized to be ancient in origin, with vertebrates and invertebrates experiencing behaviorally quiescent states that are regulated by conserved genetic mechanisms. Despite its conservation throughout phylogeny, the function of sleep remains debated. Hypotheses for the purpose of sleep include nervous-system-specific functions such as modulation of synaptic strength and clearance of metabolites from the brain, as well as more generalized cellular functions such as energy conservation and macromolecule biosynthesis. These models are supported by the identification of synaptic and metabolic processes that are perturbed during prolonged wakefulness. It remains to be seen whether perturbations of cellular homeostasis in turn drive sleep. Here we show that under conditions of cellular stress, including noxious heat, cold, hypertonicity, and tissue damage, the nematode Caenorhabditis elegans engages a behavioral quiescence program. The stress-induced quiescent state displays properties of sleep and is dependent on the ALA neuron, which mediates the conserved soporific effect of epidermal growth factor (EGF) ligand overexpression. We characterize heat-induced quiescence in detail and show that it is indeed dependent on components of EGF signaling, providing physiological relevance to the behavioral effects of EGF family ligands. We find that after noxious heat exposure, quiescence-defective animals show elevated expression of cellular stress reporter genes and are impaired for survival, demonstrating the benefit of stress-induced behavioral quiescence. These data provide evidence that cellular stress can induce a protective sleep-like state in C. elegans and suggest that a deeply conserved function of sleep is to mitigate disruptions of cellular homeostasis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hypoglycaemia and somnambulism: a case report.

PubMed

Cebrián, S; Gimeno, O; Orozco, D; Pertusa, S

2012-12-01

Sleepwalking (somnambulism) is a sleep disorder classified as a parasomnia. Sleepwalkers develop motor activities that may be simple or complex: they can get out of bed, walk, urinate and even leave the house while remaining unconscious and unable to communicate. It is difficult to wake a sleepwalker, but it is not dangerous - as many people think. Sleepwalking cases have been caused by jet lag, the consumption of narcotics, sedatives and alcohol, cardiac problems such as arrhythmias, and other medical conditions, including epilepsy, asthma and apnoea. In a quick search of the literature, only one case due to hypoglycaemia has been reported, describing a patient with type 1 diabetes whose sleepwalking was triggered by nocturnal hypoglycaemia. Our present case was similar, and our report also describes how it occurred and how the condition was remedied. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Influence of serial electrical stimulations of perifornical and posterior hypothalamic orexin-containing neurons on regulation of sleep homeostasis and sleep-wakefulness cycle recovery from experimental comatose state and anesthesia-induced deep sleep.

PubMed

Chijavadze, E; Chkhartishvili, E; Babilodze, M; Maglakelidze, N; Nachkebia, N

2013-11-01

The work was aimed for the ascertainment of following question - whether Orexin-containing neurons of dorsal and lateral hypothalamic, and brain Orexinergic system in general, are those cellular targets which can speed up recovery of disturbed sleep homeostasis and accelerate restoration of sleep-wakefulness cycle phases during some pathological conditions - experimental comatose state and/or deep anesthesia-induced sleep. Study was carried out on white rats. Modeling of experimental comatose state was made by midbrain cytotoxic lesions at intra-collicular level.Animals were under artificial respiration and special care. Different doses of Sodium Ethaminal were used for deep anesthesia. 30 min after comatose state and/or deep anesthesia induced sleep serial electrical stimulations of posterior and/or perifornical hypothalamus were started. Stimulation period lasted for 1 hour with the 5 min intervals between subsequent stimulations applied by turn to the left and right side hypothalamic parts.EEG registration of cortical and hippocampal electrical activity was started immediately after experimental comatose state and deep anesthesia induced sleep and continued continuously during 72 hour. According to obtained new evidences, serial electrical stimulations of posterior and perifornical hypothalamic Orexin-containing neurons significantly accelerate recovery of sleep homeostasis, disturbed because of comatose state and/or deep anesthesia induced sleep. Speed up recovery of sleep homeostasis was manifested in acceleration of coming out from comatose state and deep anesthesia induced sleep and significant early restoration of sleep-wakefulness cycle behavioral states.

Ventilatory response to induced auditory arousals during NREM sleep.

PubMed

Badr, M S; Morgan, B J; Finn, L; Toiber, F S; Crabtree, D C; Puleo, D S; Skatrud, J B

1997-09-01

Sleep state instability is a potential mechanism of central apnea/hypopnea during non-rapid eye movement (NREM) sleep. To investigate this postulate, we induced brief arousals by delivering transient (0.5 second) auditory stimuli during stable NREM sleep in eight normal subjects. Arousal was determined according to American Sleep Disorders Association (ASDA) criteria. A total of 96 trials were conducted; 59 resulted in cortical arousal and 37 did not result in arousal. In trials associated with arousal, minute ventilation (VE) increased from 5.1 +/- 1.24 minutes to 7.5 +/- 2.24 minutes on the first posttone breath (p = 0.001). However, no subsequent hypopnea or apnea occurred as VE decreased gradually to 4.8 +/- 1.5 l/minute (p > 0.05) on the fifth posttone breath. Trials without arousal did not result in hyperpnea on the first breath nor subsequent hypopnea. We conclude that 1) auditory stimulation resulted in transient hyperpnea only if associated with cortical arousal; 2) hypopnea or apnea did not occur following arousal-induced hyperpnea in normal subjects; 3) interaction with fluctuating chemical stimuli or upper airway resistance may be required for arousals to cause sleep-disordered breathing.

Treatment of GABA from Fermented Rice Germ Ameliorates Caffeine-Induced Sleep Disturbance in Mice

PubMed Central

Mabunga, Darine Froy N.; Gonzales, Edson Luck T.; Kim, Hee Jin; Choung, Se Young

2015-01-01

γ-Aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is involved in sleep physiology. Caffeine is widely used psychoactive substance known to induce wakefulness and insomnia to its consumers. This study was performed to examine whether GABA extracts from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice, without affecting spontaneous locomotor activity and motor coordination. Indeed, caffeine (10 mg/kg, i.p.) delayed sleep onset and reduced sleep duration of mice. Conversely, rice germ ferment extracts-GABA treatment (10, 30, or 100 mg/kg, p.o.), especially at 100 mg/kg, normalized the sleep disturbance induced by caffeine. In locomotor tests, rice germ ferment extracts-GABA slightly but not significantly reduced the caffeine-induced increase in locomotor activity without affecting motor coordination. Additionally, rice germ ferment extracts-GABA per se did not affect the spontaneous locomotor activity and motor coordination of mice. In conclusion, rice germ ferment extracts-GABA supplementation can counter the sleep disturbance induced by caffeine, without affecting the general locomotor activities of mice. PMID:25995826

Low-frequency electroacupuncture suppresses focal epilepsy and improves epilepsy-induced sleep disruptions.

PubMed

Yi, Pei-Lu; Lu, Chin-Yu; Jou, Shuo-Bin; Chang, Fang-Chia

2015-07-07

The positive effects of acupuncture at Feng-Chi acupoints on treating epilepsy and insomnia have been well-documented in ancient Chinese literature. However, there is a lack of scientific evidence to elucidate the underlying mechanisms behind these effects. Our previous study demonstrated that high-frequency (100 Hz) electroacupuncture (EA) at Feng-Chi acupoints deteriorates both pilocarpine-induced focal epilepsy and sleep disruptions. This study investigated the effects of low-frequency (10 Hz) EA on epileptic activities and epilepsy-induced sleep disruptions. In rats, the Feng-Chi acupoint is located 3 mm away from the center of a line between the two ears. Rats received 30 min of 10 Hz EA stimuli per day before each day's dark period for three consecutive days. Our results indicated that administration of pilocarpine into the left CeA at the beginning of the dark period induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep during the consequent light period. Low-frequency (10 Hz) EA at Feng-Chi acupoints suppressed pilocarpine-induced epileptiform EEGs, and this effect was in turn blocked by naloxone (a broad-spectrum opioid receptor antagonist), but not by naloxonazine (a μ-receptor antagonist), naltrindole (a δ-receptor antagonist) and nor-binaltorphimine (a κ-receptor antagonist). Ten Hz EA enhanced NREM sleep during the dark period, and this enhancement was blocked by all of the opioid receptor antagonists. On the other hand, 10 Hz EA reversed pilocarpine-induced NREM suppression during the light period, and the EA's effect on the sleep disruption was only blocked by naloxonazine. These results indicate that low-frequency EA stimulation of Feng-Chi acupoints is beneficial in improving epilepsy and epilepsy-induced sleep disruptions, and that opioid receptors in the CeA mediate EA's therapeutic effects.

The hypnotic zolpidem increases the synchrony of BOLD signal fluctuations in widespread brain networks during a resting paradigm

PubMed Central

Licata, Stephanie C.; Nickerson, Lisa D.; Lowen, Steven B.; Trksak, George H.; MacLean, Robert R.; Lukas, Scott E.

2013-01-01

Networks of brain regions having synchronized fluctuations of the blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) time-series at rest, or “resting state networks” (RSNs), are emerging as a basis for understanding intrinsic brain activity. RSNs are topographically consistent with activity-related networks subserving sensory, motor, and cognitive processes, and studying their spontaneous fluctuations following acute drug challenge may provide a way to understand better the neuroanatomical substrates of drug action. The present within-subject double-blind study used BOLD fMRI at 3T to investigate the functional networks influenced by the non-benzodiazepine hypnotic zolpidem (Ambien®). Zolpidem is a positive modulator of γ-aminobutyric acidA (GABAA) receptors, and engenders sedative effects that may be explained in part by how it modulates intrinsic brain activity. Healthy participants (n= 12) underwent fMRI scanning 45 min after acute oral administration of zolpidem (0, 5, 10, or 20 mg), and changes in BOLD signal were measured while participants gazed at a static fixation point (i.e., at rest). Data were analyzed using group independent component analysis (ICA) with dual regression and results indicated that compared to placebo, the highest dose of zolpidem increased functional connectivity within a number of sensory, motor, and limbic networks. These results are consistent with previous studies showing an increase in functional connectivity at rest following administration of the positive GABAA receptor modulators midazolam and alcohol, and suggest that investigating how zolpidem modulates intrinsic brain activity may have implications for understanding the etiology of its powerful sedative effects. PMID:23296183

Sleep Loss as a Factor to Induce Cellular and Molecular Inflammatory Variations

PubMed Central

Hurtado-Alvarado, Gabriela; Castillo-García, Stephanie Ariadne; Hernández, María Eugenia; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier; Gómez-González, Beatriz

2013-01-01

A reduction in the amount of time spent sleeping occurs chronically in modern society. Clinical and experimental studies in humans and animal models have shown that immune function is impaired when sleep loss is experienced. Sleep loss exerts a strong regulatory influence on peripheral levels of inflammatory mediators of the immune response. An increasing number of research projects support the existence of reciprocal regulation between sleep and low-intensity inflammatory response. Recent studies show that sleep deficient humans and rodents exhibit a proinflammatory component; therefore, sleep loss is considered as a risk factor for developing cardiovascular, metabolic, and neurodegenerative diseases (e.g., diabetes, Alzheimer's disease, and multiple sclerosis). Circulating levels of proinflammatory mediators depend on the intensity and duration of the method employed to induce sleep loss. Recognizing the fact that the concentration of proinflammatory mediators is different between acute and chronic sleep-loss may expand the understanding of the relationship between sleep and the immune response. The aim of this review is to integrate data from recent published reports (2002–2013) on the effects of sleep loss on the immune response. This review may allow readers to have an integrated view of the mechanisms involved in central and peripheral deficits induced by sleep loss. PMID:24367384

Experimental Sleep Restriction Facilitates Pain and Electrically Induced Cortical Responses

PubMed Central

Matre, Dagfinn; Hu, Li; Viken, Leif A.; Hjelle, Ingri B.; Wigemyr, Monica; Knardahl, Stein; Sand, Trond; Nilsen, Kristian Bernhard

2015-01-01

Study Objectives: Sleep restriction (SR) has been hypothesized to sensitize the pain system. The current study determined whether experimental sleep restriction had an effect on experimentally induced pain and pain-elicited electroencephalographic (EEG) responses. Design: A paired crossover study. Intervention: Pain testing was performed after 2 nights of 50% SR and after 2 nights with habitual sleep (HS). Setting: Laboratory experiment at research center. Participants: Self-reported healthy volunteers (n = 21, age range: 18–31 y). Measurements and Results: Brief high-density electrical stimuli to the forearm skin produced pinprick-like pain. Subjective pain ratings increased after SR, but only in response to the highest stimulus intensity (P = 0.018). SR increased the magnitude of the pain-elicited EEG response analyzed in the time-frequency domain (P = 0.021). Habituation across blocks did not differ between HS and SR. Event-related desynchronization (ERD) was reduced after SR (P = 0.039). Pressure pain threshold of the trapezius muscle region also decreased after SR (P = 0.017). Conclusion: Sleep restriction (SR) increased the sensitivity to pressure pain and to electrically induced pain of moderate, but not low, intensity. The increased electrical pain could not be explained by a difference in habituation. Increased response magnitude is possibly related to reduced processing within the somatosensory cortex after partial SR. Citation: Matre D, Hu L, Viken LA, Hjelle IB, Wigemyr M, Knardahl S, Sand T, Nilsen KB. Experimental sleep restriction facilitates pain and electrically induced cortical responses. SLEEP 2015;38(10):1607–1617. PMID:26194577

Glucose Induces Slow-Wave Sleep by Exciting the Sleep-Promoting Neurons in the Ventrolateral Preoptic Nucleus: A New Link between Sleep and Metabolism.

PubMed

Varin, Christophe; Rancillac, Armelle; Geoffroy, Hélène; Arthaud, Sébastien; Fort, Patrice; Gallopin, Thierry

2015-07-08

Sleep-active neurons located in the ventrolateral preoptic nucleus (VLPO) play a crucial role in the induction and maintenance of slow-wave sleep (SWS). However, the cellular and molecular mechanisms responsible for their activation at sleep onset remain poorly understood. Here, we test the hypothesis that a rise in extracellular glucose concentration in the VLPO can promote sleep by increasing the activity of sleep-promoting VLPO neurons. We find that infusion of a glucose concentration into the VLPO of mice promotes SWS and increases the density of c-Fos-labeled neurons selectively in the VLPO. Moreover, we show in patch-clamp recordings from brain slices that VLPO neurons exhibiting properties of sleep-promoting neurons are selectively excited by glucose within physiological range. This glucose-induced excitation implies the catabolism of glucose, leading to a closure of ATP-sensitive potassium (KATP) channels. The extracellular glucose concentration monitors the gating of KATP channels of sleep-promoting neurons, highlighting that these neurons can adapt their excitability according to the extracellular energy status. Together, these results provide evidence that glucose may participate in the mechanisms of SWS promotion and/or consolidation. Although the brain circuitry underlying vigilance states is well described, the molecular mechanisms responsible for sleep onset remain largely unknown. Combining in vitro and in vivo experiments, we demonstrate that glucose likely contributes to sleep onset facilitation by increasing the excitability of sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO). We find here that these neurons integrate energetic signals such as ambient glucose directly to regulate vigilance states accordingly. Glucose-induced excitation of sleep-promoting VLPO neurons should therefore be involved in the drowsiness that one feels after a high-sugar meal. This novel mechanism regulating the activity of VLPO neurons reinforces the

Treatments for somnambulism in adults: assessing the evidence.

PubMed

Harris, Melanie; Grunstein, Ronald R

2009-08-01

Somnambulism, or sleepwalking, is a parasomnia of non-rapid eye movement (NREM) sleep where movement behaviours usually confined to wakefulness are displayed during sleep. Generally, if sleepwalking is causing distress or danger in spite of safety measures, medical or psychological treatment is indicated. Clinicians will need to assess the evidence for treatment options. MEDLINE, EMBASE, PsycINFO and the Ovid Evidence-Based Medicine Reviews (EBM) multifile databases were searched. No properly powered rigorous controlled trials were found for treatment of sleepwalking in adults. Seven reports described small trials with some kind of control arm, or retrospective case series which included 30 or more patients. With no high quality evidence to underpin recommendations for treatments of somnambulism, full discussion with patients is advised. Adequately powered, well-designed clinical trials are now needed, and multi-centre collaborations may be required to obtain the sample sizes required.

Brain tumor presenting as somnambulism in an adolescent.

PubMed

Prashad, Priya S; Marcus, Carole L; Brown, Lawrence W; Dlugos, Dennis J; Feygin, Tamara; Harding, Brian N; Heuer, Gregory G; Mason, Thornton B Alexander

2013-09-01

Sleepwalking is typically a benign and self-limited non-rapid eye movement parasomnia of childhood. We describe an unusual 15-year-old boy referred to our sleep center for new-onset sleepwalking. An overnight polysomnogram was normal from a respiratory standpoint, but a concurrent extended electroencephalogram montage showed frequent epileptiform discharges from the right parietal-temporal region and two electroclinical seizures arising from the right-frontal-central-temporal region during sleep. Magnetic resonance imaging scan revealed a right parasagittal parietal region lesion consistent with a low-grade neoplasm, and surgical resection of the lesion demonstrated a right parietal dysembryoplastic neuroepithelial tumor. Complex partial seizures and sleepwalking remitted completely with anticonvulsant therapy following surgery. This patient highlights the differential diagnosis of nocturnal events appearing to be typical parasomnias, especially when they arise abruptly at an older age. Copyright © 2013 Elsevier Inc. All rights reserved.

Hypnotic Effect of Ocimum basilicum on Pentobarbital-Induced Sleep in Mice.

PubMed

Askari, Vahid Reza; Baradaran Rahimi, Vafa; Ghorbani, Ahmad; Rakhshandeh, Hassan

2016-07-01

Sleep disorders are accompanied by several complications, and currently used soporific drugs can induce unwanted effects such as psychomotor impairment, tolerance, amnesia, and rebound insomnia. The present study was carried out to investigate if Ocimum basilicum has a sleep-prolonging effect. This work was an experimental study on 72 mice which were randomly divided into 9 groups: saline (control); diazepam (3 mg/kg, positive control); hydro-alcoholic extract (HAE) of Ocimum basilicum (25, 50, or 100 mg/kg); ethyl acetate fraction (EAF, 50 mg/kg); n-butanol fraction (NBF, 50 mg/kg); water fraction (WF, 50 mg/kg); and saline containing 10% DMSO (vehicle for EAF and NBF). All the test compounds were injected intraperitoneally (IP) 30 minutes before pentobarbital administration (30 mg/kg). Duration and latency of pentobarbital-induced sleep were recorded. Also, LD50 of HAE was determined and the cytotoxicity of HAE was tested on neural and fibroblast cells using the MTT assay. HAE increased the duration of pentobarbital-induced sleep at doses of 25, 50, and 100 mg/kg (P < 0.001). The hypnotic effect of HAE was comparable to that induced by diazepam. Similarly, WF, EAF, and NBF at 50 mg/kg could increase sleep duration. The sleep latency was decreased by HAE (P < 0.01 - P < 0.001) and NBF (P < 0.001), but not by WF and EAF. The LD50 value for HAE was found to be 2.4 g/kg. HAE had no effect on the viability of neuronal PC12 cells and L929 fibroblast cells. The present data demonstrated that Ocimum basilicum potentiates sleeping behaviors without any cytotoxicity. The main component (s) responsible for the hypnotic effects of this plant is most likely a non-polar agent (s) which is found in NBF. Isolation of the active constituents may yield a novel sedative drug.

Flurbiprofen in rapid eye movement sleep deprivation induced hyperalgesia.

PubMed

Gürel, Elif Ezgi; Ural, Keremcan; Öztürk, Gülnur; Öztürk, Levent

2014-04-10

Rapid eye movement (REM) sleep deprivation induces hyperalgesia in healthy rats. Here, we evaluated the effects of flurbiprofen, an anti-inflammatory and neuroprotective agent, on the increased thermal responses observed in REM sleep deprived rats. Forty female rats were divided into four groups following 96-hour REM sleep deprivation: intraperitoneal injections of placebo, and flurbiprofen 5 mg/kg, 15 mg/kg and 40 mg/kg were made in CONT (n=10), FBP5, FBP15 and FBP40 groups respectively. Pain threshold measurements were performed three times at baseline (0.hour), at the end of REM sleep deprivation (96.hour) and at 1 h after injections (97.hour) by hot plate and tail-flick tests. REM sleep deprivation induced a significant decrease in pain thresholds of all rats (hotplate: 0.hour vs 96.hour, 9.75±2.85 vs 5.10±2.02, p<0.001; tail flick: 0.hour vs 96.hour, 11.92±4.62 vs 7.92±5.15, p<0.001). Flurbiprofen in 15 mg/kg and 40 mg/kg doses significantly improved pain tolerance measured by tail flick test (tail flick in FBP15 and FBP40 groups: 96.hour vs 97.hour, 7.01±4.97 vs 8.34±3.61 and 5.06±1.57 vs 7.04±2.49, p<0.05 for both). 96 h of REM sleep deprivation resulted in reduced pain thresholds in both hot plate and tail flick tests. Flurbiprofen was used for the first time in a rat model of REM sleep deprivation, and it provided anti-nociceptive effects in 15 mg/kg and 40 mg/kg doses. Flurbiprofen may have the potential for treatment of painful syndromes accompanying insomnia or sleep loss. Copyright © 2014 Elsevier Inc. All rights reserved.

Zolpidem Overdose: A Medical and Ethical Dilemma.

PubMed

Shuaib, Waqas; Beatrice, Cristina; Abazid, Ahmad G

Acute altered mental status can be caused by a broad range of etiologies, including cerebrovascular, neurologic, traumatic, metabolic, infectious, psychiatric, medications, etc. We present a case of a 53-year-old healthcare professional with an acute altered mental status after a trip to Africa. The patient was extensively worked up for infectious, cardiovascular, and neurologic etiologies, and all results were within normal limits. Further history revealed an overdose of a self-medicated hypnotic (zolpidem) for insomnia. The patient was conservatively managed and discharged on trazadone for insomnia.

A New Model to Study Sleep Deprivation-Induced Seizure

PubMed Central

Lucey, Brendan P.; Leahy, Averi; Rosas, Regine; Shaw, Paul J.

2015-01-01

Background and Study Objectives: A relationship between sleep and seizures is well-described in both humans and rodent animal models; however, the mechanism underlying this relationship is unknown. Using Drosophila melanogaster mutants with seizure phenotypes, we demonstrate that seizure activity can be modified by sleep deprivation. Design: Seizure activity was evaluated in an adult bang-sensitive seizure mutant, stress sensitive B (sesB9ed4), and in an adult temperature sensitive seizure mutant seizure (seits1) under baseline and following 12 h of sleep deprivation. The long-term effect of sleep deprivation on young, immature sesB9ed4 flies was also assessed. Setting: Laboratory. Participants: Drosophila melanogaster. Interventions: Sleep deprivation. Measurements and Results: Sleep deprivation increased seizure susceptibility in adult sesB9ed4/+ and seits1 mutant flies. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB9ed4/+ flies were given the anti-seizure drug, valproic acid. In contrast to adult flies, sleep deprivation during early fly development resulted in chronic seizure susceptibility when sesB9ed4/+ became adults. Conclusions: These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity. Citation: Lucey BP, Leahy A, Rosas R, Shaw PJ. A new model to study sleep deprivation-induced seizure. SLEEP 2015;38(5):777–785. PMID:25515102

Dexmedetomidine-induced sedation does not mimic the neurobehavioral phenotypes of sleep in Sprague Dawley rat.

PubMed

Garrity, Abigail G; Botta, Simhadri; Lazar, Stephanie B; Swor, Erin; Vanini, Giancarlo; Baghdoyan, Helen A; Lydic, Ralph

2015-01-01

Dexmedetomidine is used clinically to induce states of sedation that have been described as homologous to nonrapid eye movement (NREM) sleep. A better understanding of the similarities and differences between NREM sleep and dexmedetomidine-induced sedation is essential for efforts to clarify the relationship between these two states. This study tested the hypothesis that dexmedetomidine-induced sedation is homologous to sleep. This study used between-groups and within-groups designs. University of Michigan. Adult male Sprague Dawley rats (n = 40). Independent variables were administration of dexmedetomidine and saline or Ringer's solution (control). Dependent variables included time spent in states of wakefulness, sleep, and sedation, electroencephalographic (EEG) power, adenosine levels in the substantia innominata (SI), and activation of pCREB and c-Fos in sleep related forebrain regions. Dexmedetomidine significantly decreased time spent in wakefulness (-49%), increased duration of sedation (1995%), increased EEG delta power (546%), and eliminated the rapid eye movement (REM) phase of sleep for 16 h. Sedation was followed by a rebound increase in NREM and REM sleep. Systemically administered dexmedetomidine significantly decreased (-39%) SI adenosine levels. Dialysis delivery of dexmedetomidine into SI did not decrease adenosine level. Systemic delivery of dexmedetomidine did not alter c-Fos or pCREB expression in the horizontal diagonal band, or ventrolateral, median, and medial preoptic areas of the hypothalamus. Dexmedetomidine significantly altered normal sleep phenotypes, and the dexmedetomidine-induced state did not compensate for sleep need. Thus, in the Sprague Dawley rat, dexmedetomidine-induced sedation is characterized by behavioral, electrographic, and immunohistochemical phenotypes that are distinctly different from similar measures obtained during sleep. © 2014 Associated Professional Sleep Societies, LLC.

Potentiating Effects of Lactuca sativa on Pentobarbital-Induced Sleep.

PubMed

Ghorbani, Ahmad; Rakhshandeh, Hassan; Sadeghnia, Hamid Reza

2013-01-01

Traditionally, Lactuca sativa (lettuce) has been recommended for its hypnotic property. The present study was planned to investigate sleep-prolonging effect of this plant. The hydro-alcoholic extract (HAE) of lettuce and its water fraction (WF), ethyl acetate fraction (EAF), and n-butanol fraction (NBF) were administrated (IP) to mice 30 min before the pentobarbital injection. Moreover, both in-vivo and in-vitro toxicity of the extracts were determined. The quality of HAE and NBF was also evaluated using HPLC fingerprint. The HAE prolonged the pentobarbital-induced sleep duration at dose of 400 mg/Kg. The NBF was the only fraction which could increase the sleep duration and decrease sleep latency. The effects of NBF were comparable to those of induced by diazepam. The LD50-value for HAE was found to be 4.8 g/Kg. No neurotoxic effect was observed either by HAE or by its fractions in cultured PC12 neuron-like cells. The results suggest that lettuce potentiates pentobarbital hypnosis without major toxic effect. The main component(s) responsible for this effect is most likely to be non-polar agent(s) which found in NBF of this plant.

Potentiating Effects of Lactuca sativa on Pentobarbital-Induced Sleep

PubMed Central

Ghorbani, Ahmad; Rakhshandeh, Hassan; Sadeghnia, Hamid Reza

2013-01-01

Traditionally, Lactuca sativa (lettuce) has been recommended for its hypnotic property. The present study was planned to investigate sleep-prolonging effect of this plant. The hydro-alcoholic extract (HAE) of lettuce and its water fraction (WF), ethyl acetate fraction (EAF), and n-butanol fraction (NBF) were administrated (IP) to mice 30 min before the pentobarbital injection. Moreover, both in-vivo and in-vitro toxicity of the extracts were determined. The quality of HAE and NBF was also evaluated using HPLC fingerprint. The HAE prolonged the pentobarbital-induced sleep duration at dose of 400 mg/Kg. The NBF was the only fraction which could increase the sleep duration and decrease sleep latency. The effects of NBF were comparable to those of induced by diazepam. The LD50-value for HAE was found to be 4.8 g/Kg. No neurotoxic effect was observed either by HAE or by its fractions in cultured PC12 neuron-like cells. The results suggest that lettuce potentiates pentobarbital hypnosis without major toxic effect. The main component(s) responsible for this effect is most likely to be non-polar agent(s) which found in NBF of this plant. PMID:24250615

Evaluation of a new computerized psychometric test battery: Effects of zolpidem and caffeine.

PubMed

Pilli, Raveendranadh; Naidu, Mur; Pingali, Usharani; Shobha, Jc

2013-10-01

To evaluate the effects of centrally active drugs using a new indigenously developed automated psychometric test system and compare the results with that obtained using pencil- and paper-based techniques. The tests were standardized in 24 healthy participants. Reproducibility of the test procedure was evaluated by performing the tests by a single experimenter on two occasions (interday reproducibility). To evaluate the sensitivity of the tests, the effects of zolpidem (5 mg) and caffeine (500 mg) versus placebo were studied in 24 healthy participants in a randomized, double-blind three-way crossover design. Psychometric tests were performed at baseline and at 1, 2, and 3 h after administration of study medication. The effects of zolpidem and caffeine on the psychomotor performance were most pronounced 1 h after administration. At this time, a significant impairment of performance in the simple reaction test (SRT), choice discrimination test (CDT), digit symbol substitution test (DSST), digit vigilance test (DVT), and card sorting test (CST) was observed with zolpidem. In contrast, caffeine showed a significant improvement in performance in CDT and DVT only. The results suggest that the tests of the computerized system are more sensitive and reliable then the pencil and paper tests in detecting the effects of central acting agents and are suitable for use in clinical areas to conduct studies with patients.

Simultaneous ESI-APCI+ ionization and fragmentation pathways for nine benzodiazepines and zolpidem using single quadrupole LC-MS.

PubMed

Galaon, Toma; Vacaresteanu, Catalina; Anghel, Dan-Florin; David, Victor

2014-05-01

Nine important 1,4-benzodiazepines and zolpidem were characterized by liquid chromatography-mass spectrometry using a multimode ionization source able to generate ions using both electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI), and a single quadrupole mass analyzer. An optimum chromatographic separation was applied for all target compounds in less than 8 minutes using a Zorbax Eclipse Plus column (100 × 4.6 mm, 3.5 µm) kept at 35°C and a 0.3% HCOOH/ACN/IPA (61:34:5) mobile phase pumped at 1 ml/min. Optimization of LC-MS method generated low limit of quantitation (LOQ) values situated in the range 0.3-20.5 ng/ml. Comparison between differences in method sensitivity, under specified chromatographic conditions, when using ESI-only, APCI-only, and simultaneous ESI-APCI ionization with such a multimode source was discussed. Mixed ESI-APCI(+) mode proved to be the most sensitive ionization generating an average 35% detector response increase compared to ESI-only ionization and 350% detector response increase with respect to APCI-only ionization. Characterization of the nine benzodiazepines and zolpidem concerning their MS fragmentation pathway following 'in-source' collision-induced dissociation is discussed in detail and some general trends regarding these fragmentations are set. Copyright © 2013 John Wiley & Sons, Ltd.

Dose-dependent EEG effects of zolpidem provide evidence for GABA(A) receptor subtype selectivity in vivo.

PubMed

Visser, S A G; Wolters, F L C; van der Graaf, P H; Peletier, L A; Danhof, M

2003-03-01

Zolpidem is a nonbenzodiazepine GABA(A) receptor modulator that binds in vitro with high affinity to GABA(A) receptors expressing alpha(1) subunits but with relatively low affinity to receptors expressing alpha(2), alpha(3), and alpha(5) subunits. In the present study, it was investigated whether this subtype selectivity could be detected and quantified in vivo. Three doses (1.25, 5, and 25 mg) of zolpidem were administered to rats in an intravenous infusion over 5 min. The time course of the plasma concentrations was determined in conjunction with the change in the beta-frequency range of the EEG as pharmacodynamic endpoint. The concentration-effect relationship of the three doses showed a dose-dependent maximum effect and a dose-dependent potency. The data were analyzed for one- or two-site binding using two pharmacodynamic models based on 1) the descriptive model and 2) a novel mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for GABA(A) receptor modulators that aims to separates drug- and system-specific properties, thereby allowing the estimation of in vivo affinity and efficacy. The application of two-site models significantly improved the fits compared with one-site models. Furthermore, in contrast to the descriptive model, the mechanism-based PK/PD model yielded dose-independent estimates for affinity (97 +/- 40 and 33,100 +/- 14,800 ng x ml(-1)). In conclusion, the mechanism-based PK/PD model is able to describe and explain the observed dose-dependent EEG effects of zolpidem and suggests the subtype selectivity of zolpidem in vivo.

Hypnotic Effect of Ocimum basilicum on Pentobarbital-Induced Sleep in Mice

PubMed Central

Askari, Vahid Reza; Baradaran Rahimi, Vafa; Ghorbani, Ahmad; Rakhshandeh, Hassan

2016-01-01

Background Sleep disorders are accompanied by several complications, and currently used soporific drugs can induce unwanted effects such as psychomotor impairment, tolerance, amnesia, and rebound insomnia. Objectives The present study was carried out to investigate if Ocimum basilicum has a sleep-prolonging effect. Materials and Methods This work was an experimental study on 72 mice which were randomly divided into 9 groups: saline (control); diazepam (3 mg/kg, positive control); hydro-alcoholic extract (HAE) of Ocimum basilicum (25, 50, or 100 mg/kg); ethyl acetate fraction (EAF, 50 mg/kg); n-butanol fraction (NBF, 50 mg/kg); water fraction (WF, 50 mg/kg); and saline containing 10% DMSO (vehicle for EAF and NBF). All the test compounds were injected intraperitoneally (IP) 30 minutes before pentobarbital administration (30 mg/kg). Duration and latency of pentobarbital-induced sleep were recorded. Also, LD50 of HAE was determined and the cytotoxicity of HAE was tested on neural and fibroblast cells using the MTT assay. Results HAE increased the duration of pentobarbital-induced sleep at doses of 25, 50, and 100 mg/kg (P < 0.001). The hypnotic effect of HAE was comparable to that induced by diazepam. Similarly, WF, EAF, and NBF at 50 mg/kg could increase sleep duration. The sleep latency was decreased by HAE (P < 0.01 - P < 0.001) and NBF (P < 0.001), but not by WF and EAF. The LD50 value for HAE was found to be 2.4 g/kg. HAE had no effect on the viability of neuronal PC12 cells and L929 fibroblast cells. Conclusions The present data demonstrated that Ocimum basilicum potentiates sleeping behaviors without any cytotoxicity. The main component (s) responsible for the hypnotic effects of this plant is most likely a non-polar agent (s) which is found in NBF. Isolation of the active constituents may yield a novel sedative drug. PMID:27651944

Genetic Dissociation of Daily Sleep and Sleep Following Thermogenetic Sleep Deprivation in Drosophila.

PubMed

Dubowy, Christine; Moravcevic, Katarina; Yue, Zhifeng; Wan, Joy Y; Van Dongen, Hans P A; Sehgal, Amita

2016-05-01

Sleep rebound-the increase in sleep that follows sleep deprivation-is a hallmark of homeostatic sleep regulation that is conserved across the animal kingdom. However, both the mechanisms that underlie sleep rebound and its relationship to habitual daily sleep remain unclear. To address this, we developed an efficient thermogenetic method of inducing sleep deprivation in Drosophila that produces a substantial rebound, and applied the newly developed method to assess sleep rebound in a screen of 1,741 mutated lines. We used data generated by this screen to identify lines with reduced sleep rebound following thermogenetic sleep deprivation, and to probe the relationship between habitual sleep amount and sleep following thermogenetic sleep deprivation in Drosophila. To develop a thermogenetic method of sleep deprivation suitable for screening, we thermogenetically stimulated different populations of wake-promoting neurons labeled by Gal4 drivers. Sleep rebound following thermogenetically-induced wakefulness varies across the different sets of wake-promoting neurons that were stimulated, from very little to quite substantial. Thermogenetic activation of neurons marked by the c584-Gal4 driver produces both strong sleep loss and a substantial rebound that is more consistent within genotypes than rebound following mechanical or caffeine-induced sleep deprivation. We therefore used this driver to induce sleep deprivation in a screen of 1,741 mutagenized lines generated by the Drosophila Gene Disruption Project. Flies were subjected to 9 h of sleep deprivation during the dark period and released from sleep deprivation 3 h before lights-on. Recovery was measured over the 15 h following sleep deprivation. Following identification of lines with reduced sleep rebound, we characterized baseline sleep and sleep depth before and after sleep deprivation for these hits. We identified two lines that consistently exhibit a blunted increase in the duration and depth of sleep after

Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues Sleep Disturbances Induced by Early-Life Obesity.

PubMed

Gazea, Mary; Patchev, Alexandre V; Anderzhanova, Elmira; Leidmaa, Este; Pissioti, Anna; Flachskamm, Cornelia; Almeida, Osborne F X; Kimura, Mayumi

2018-01-10

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep-wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep-wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep-wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3-36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep-wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep. SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY 3-36 can reverse this neurochemical imbalance and

Experimental Sleep Restriction Facilitates Pain and Electrically Induced Cortical Responses.

PubMed

Matre, Dagfinn; Hu, Li; Viken, Leif A; Hjelle, Ingri B; Wigemyr, Monica; Knardahl, Stein; Sand, Trond; Nilsen, Kristian Bernhard

2015-10-01

Sleep restriction (SR) has been hypothesized to sensitize the pain system. The current study determined whether experimental sleep restriction had an effect on experimentally induced pain and pain-elicited electroencephalographic (EEG) responses. A paired crossover study. Pain testing was performed after 2 nights of 50% SR and after 2 nights with habitual sleep (HS). Laboratory experiment at research center. Self-reported healthy volunteers (n = 21, age range: 18-31 y). Brief high-density electrical stimuli to the forearm skin produced pinprick-like pain. Subjective pain ratings increased after SR, but only in response to the highest stimulus intensity (P = 0.018). SR increased the magnitude of the pain-elicited EEG response analyzed in the time-frequency domain (P = 0.021). Habituation across blocks did not differ between HS and SR. Event-related desynchronization (ERD) was reduced after SR (P = 0.039). Pressure pain threshold of the trapezius muscle region also decreased after SR (P = 0.017). Sleep restriction (SR) increased the sensitivity to pressure pain and to electrically induced pain of moderate, but not low, intensity. The increased electrical pain could not be explained by a difference in habituation. Increased response magnitude is possibly related to reduced processing within the somatosensory cortex after partial SR. © 2015 Associated Professional Sleep Societies, LLC.

Melatonin attenuates dextran sodium sulfate induced colitis with sleep deprivation: possible mechanism by microarray analysis.

PubMed

Chung, Sook Hee; Park, Young Sook; Kim, Ok Soon; Kim, Ja Hyun; Baik, Haing Woon; Hong, Young Ok; Kim, Sang Su; Shin, Jae-Ho; Jun, Jin-Hyun; Jo, Yunju; Ahn, Sang Bong; Jo, Young Kwan; Son, Byoung Kwan; Kim, Seong Hwan

2014-06-01

Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract. It can be aggravated by stress, like sleep deprivation, and improved by anti-inflammatory agents, like melatonin. We aimed to investigate the effects of sleep deprivation and melatonin on inflammation. We also investigated genes regulated by sleep deprivation and melatonin. In the 2% DSS induced colitis mice model, sleep deprivation was induced using modified multiple platform water bath. Melatonin was injected after induction of colitis and colitis with sleep deprivation. Also mRNA was isolated from the colon of mice and analyzed via microarray and real-time PCR. Sleep deprivation induced reduction of body weight, and it was difficult for half of the mice to survive. Sleep deprivation aggravated, and melatonin attenuated the severity of colitis. In microarrays and real-time PCR of mice colon tissues, mRNA of adiponectin and aquaporin 8 were downregulated by sleep deprivation and upregulated by melatonin. However, mRNA of E2F transcription factor (E2F2) and histocompatibility class II antigen A, beta 1 (H2-Ab1) were upregulated by sleep deprivation and downregulated by melatonin. Melatonin improves and sleep deprivation aggravates inflammation of colitis in mice. Adiponectin, aquaporin 8, E2F2 and H2-Ab1 may be involved in the inflammatory change aggravated by sleep deprivation and attenuated by melatonin.

Genetic Dissociation of Daily Sleep and Sleep Following Thermogenetic Sleep Deprivation in Drosophila

PubMed Central

Dubowy, Christine; Moravcevic, Katarina; Yue, Zhifeng; Wan, Joy Y.; Van Dongen, Hans P.A.; Sehgal, Amita

2016-01-01

Study Objectives: Sleep rebound—the increase in sleep that follows sleep deprivation—is a hallmark of homeostatic sleep regulation that is conserved across the animal kingdom. However, both the mechanisms that underlie sleep rebound and its relationship to habitual daily sleep remain unclear. To address this, we developed an efficient thermogenetic method of inducing sleep deprivation in Drosophila that produces a substantial rebound, and applied the newly developed method to assess sleep rebound in a screen of 1,741 mutated lines. We used data generated by this screen to identify lines with reduced sleep rebound following thermogenetic sleep deprivation, and to probe the relationship between habitual sleep amount and sleep following thermogenetic sleep deprivation in Drosophila. Methods: To develop a thermogenetic method of sleep deprivation suitable for screening, we thermogenetically stimulated different populations of wake-promoting neurons labeled by Gal4 drivers. Sleep rebound following thermogenetically-induced wakefulness varies across the different sets of wake-promoting neurons that were stimulated, from very little to quite substantial. Thermogenetic activation of neurons marked by the c584-Gal4 driver produces both strong sleep loss and a substantial rebound that is more consistent within genotypes than rebound following mechanical or caffeine-induced sleep deprivation. We therefore used this driver to induce sleep deprivation in a screen of 1,741 mutagenized lines generated by the Drosophila Gene Disruption Project. Flies were subjected to 9 h of sleep deprivation during the dark period and released from sleep deprivation 3 h before lights-on. Recovery was measured over the 15 h following sleep deprivation. Following identification of lines with reduced sleep rebound, we characterized baseline sleep and sleep depth before and after sleep deprivation for these hits. Results: We identified two lines that consistently exhibit a blunted increase in the

Ursolic acid enhances pentobarbital-induced sleeping behaviors via GABAergic neurotransmission in mice.

PubMed

Jeon, Se Jin; Park, Ho Jae; Gao, Qingtao; Pena, Irene Joy Dela; Park, Se Jin; Lee, Hyung Eun; Woo, Hyun; Kim, Hee Jin; Cheong, Jae Hoon; Hong, Eunyoung; Ryu, Jong Hoon

2015-09-05

Prunella vulgaris is widely used as a herbal medicine for cancers, inflammatory diseases, and other infections. Although it has long been used, few studies have examined its effects on central nervous system function. Here, we first observed that ethanolic extracts of P. vulgaris (EEPV) prolonged pentobarbital-induced sleep duration in mice. It is known that EEPV consists of many active components including triterpenoid (ursolic acid and oleanolic acid), which have many biological activities. Therefore, we evaluated which EEPV components induced sleep extension in pentobarbital-mediated sleeping model in mice. Surprisingly, despite their structural similarity and other common functions such as anti-inflammation, anti-cancer, and tissue protection, only ursolic acid enhanced sleep duration in pentobarbital-treated mice. These results were attenuated by bicuculline treatment, which is a GABAA receptor antagonist. The present results suggest that ursolic acid from P. vulgaris enhances sleep duration through GABAA receptor activation and could be a therapeutic candidate for insomnia treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Academic Performance among Adolescents with Behaviorally Induced Insufficient Sleep Syndrome

PubMed Central

Lee, Yu Jin; Park, Juhyun; Kim, Soohyun; Cho, Seong-Jin; Kim, Seog Ju

2015-01-01

Study Objectives: The present study investigated academic performance among adolescents with behaviorally induced insufficient sleep syndrome (BISS) and attempted to identify independent predictors of academic performance among BISS-related factors. Methods: A total of 51 students with BISS and 50 without BISS were recruited from high schools in South Korea based on self-reported weekday sleep durations, weekend oversleep, and the Epworth Sleepiness Scale (ESS). Participants reported their academic performance in the form of class quartile ranking. The Korean version of the Composite Scale (KtCS) for morningness/eveningness, the Beck Depression Inventory (BDI) for depression, and the Barratt Impulsiveness Scale-II (BIS-II) for impulsivity were administered. Results: Adolescents with BISS reported poorer academic performance than adolescents without BISS (p = 0.02). Adolescents with BISS also exhibited greater levels of eveningness (p < 0.001), depressive symptoms (p < 0.001), and impulsiveness (p < 0.01). Longer weekend oversleep predicted poorer academic performance among adolescents with BISS even after controlling for ESS, KtCS, BDI, and BIS-II (β = 0.42, p < 0.01). Conclusions: BISS among adolescents is associated with poor academic performance and that sleep debt, as represented by weekend oversleep, predicts poorer academic performance independent of depression, impulsiveness, weekday sleep duration, daytime sleepiness, and morningness/eveningness among adolescents with BISS. Citation: Lee YJ, Park J, Kim S, Cho SJ, Kim SJ. Academic performance among adolescents with behaviorally induced insufficient sleep syndrome. J Clin Sleep Med 2015;11(1):61–68. PMID:25515277

Brief Report: Behaviorally Induced Insufficient Sleep Syndrome in Older Adolescents: Prevalence and Correlates

ERIC Educational Resources Information Center

Pallesen, Stale; Saxvig, Ingvild West; Molde, Helge; Sorensen, Eli; Wilhelmsen-Langeland, Ane; Bjorvatn, Bjorn

2011-01-01

The aim of the present study was to investigate the prevalence of "behaviorally induced insufficient sleep syndrome (BIISS)" which is a newly defined hypersomnia, among adolescents. BIISS is characterized by excessive daytime sleepiness, short habitual sleep duration and sleeping considerably longer than usual during weekend/vacations.…

[Pharmacology of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (II). Sleep-inducing activity and effect on the motor system].

PubMed

Yamamoto, K; Matsushita, A; Sawada, T; Naito, Y; Yoshimura, K; Takesue, H; Utsumi, S; Kawasaki, K; Hirono, S; Koshida, H

1984-07-01

The sleep-inducing activity and effect on the motor system of the 1H-1,2,4-triazolyl benzophenone derivative 450191-S were examined behaviorally, electroencephalographically and electro-physiologically with various species of animals and were compared with those of diazepam, nitrazepam, estazolam and triazolam. In the rhesus monkey, rabbit and rat with chronically indwelling brain electrodes, 0.6 to 3 mg/kg, p.o. of 450191-S caused a shorter latency of sleep onset, an increase of and a stable continuity of slow wave deep sleep (SWDS) with higher amplitude, and the appearance of clear spindle bursts in the slow wave light sleeping (SWLS) state with little muscle relaxation. Animals treated with nitrazepam and/or estazolam showed a smaller increase in SWDS and its unstable continuity with remarkable disturbance of gait. The doses needed to induce sleep in the rhesus monkey were 0.6 to 1 mg/kg p.o. for 450191-S, 3 mg/kg for nitrazepam, 1 mg/kg for estazolam and 0.3 mg/kg for triazolam. The cat treated with 450191-S showed the phenomena caused by benzodiazepines (BDZ), i.e., behavioral excitation and decrease of frequencies in the hippocampal theta waves. The suppressive effects of 450191-S on the EEG arousal reaction and/or blood pressure elevation induced by hypothalamic stimulation in the rabbit suggested that the inhibitory effects acted on the posterior hypothalamus to the limbic system. The inhibitory effect of 450191-S on the amygdaloid kindling in the rat was as potent as those of diazepam and nitrazepam. Successive daily oral administration of both 3 mg/kg of 450191-S and/or 3 to 6 mg/kg of nitrazepam for 15 days in the rabbit caused slight decrease of SWDS and increase of fast wave (REM) sleep (FWS). During the withdrawal period of both compounds, a slight but insignificant increase in the waking state was noticed for 1 to 2 days, but not a rebound increase of FWS. Intravenously administered 450191-S showed the same action as BDZ on the spinal reflex and the

Sleep complaints: Whenever possible, avoid the use of sleeping pills.

PubMed

2008-10-01

(1) Most sleep complaints involve difficulties in getting to sleep or staying asleep, or not feeling refreshed on awakening. Misconceptions and worrying over the lack of sleep and its consequences can contribute to reinforcing these disorders; (2) How can patients who complain of poor-quality sleep be helped, without resorting to treatments that can have adverse effects? To answer this question, we conducted a systematic review of the literature based on the standard Prescrire procedure; (3) One effective approach is to explain the basic physiology of sleep, to discuss misconceptions, and to adopt a strategy of "stimulus control". This method has a similar efficacy to prescribing a benzodiazepine. and the effect is longer lasting; (4) Moderate, regular physical exercise, especially in the morning, seems to help some patients, but the evidence is weak; (5) Some clinical trials of phytotherapy have shown a positive risk-benefit balance of weak aqueous or hydroalcoholic valerian extracts. Efficacy is limited, however; (6) A meta-analysis of placebo-controlled trials showed that benzodiazepines and related drugs increase the duration of sleep and help patients to fall asleep sooner. However, none of these trials provides comparative data spanning periods of more than two weeks. Efficacy is uncertain in the longer term, as patients quickly develop a tolerance to the hypnotic effects of benzodiazepines; (7) The adverse effects of benzodiazepines include frequent memory disorders, daytime drowsiness, falls, fractures and road accidents, and a withdrawal syndrome after treatment cessation. Related drugs such as zolpidem and zopiclone provoke similar adverse effects; (8) Sedative antihistamines have not been as well-evaluated as benzodiazepines in this setting. Small comparative trials of doxylamine and diphenhydramine showed no major difference in efficacy versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness

Dissociative Disorders

MedlinePlus

... use disorders Depression and anxiety disorders Post-traumatic stress disorder Personality disorders Sleep disorders, including nightmares, insomnia and sleepwalking Eating disorders Physical symptoms such as ...

Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol.

PubMed

Tuk, Bert; van Gool, Toon; Danhof, Meindert

2002-06-01

The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ1 receptor subtype selective agonist zolpidem have been determined in the rat in vivo, using an integrated pharmacokinetic-pharmacodynamic approach. Ethanol was administered as a constant rate infusion resulting in constant plasma concentrations of 0.5 g/l. The pharmacokinetics and pharmacodynamics of midazolam, bretazenil, and zolpidem were determined following an intravenous infusion of 5.0, 2.5, and 18 mg/kg respectively. The amplitude in the 11.5-30 Hz frequency band of the EEG was used as measure of the pharmacological effect. For each of the benzodiazepines the concentration-EEG effect relationship could be described by the sigmoid Emax pharmacodynamic model. Significant differences in both EC50 and Emax were observed. The values of the EC50 were 76 +/- 11, 12 +/- 3, and 512 +/- 116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the Emax were 113 +/- 9, 44 +/- 3, and 175 +/- 10 microV/s. In the presence of ethanol the values of the EC50 of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for Emax and Hill-factor were unchanged Due to a large interindividual variability no significant change in EC50 was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant KPD for all three drugs, indicating that changes in EC50 can be explained entirely by a change in the apparent affinity constant KPD without concomitant changes in the efficacy parameter ePD and the stimulus-effect relationship. The findings of this study show that the pharmacodynamic interactions with a low dose of ethanol in vivo are qualitatively and quantitatively similar for benzodiazepine receptor full agonists, partial agonists, and benzodiazepine BZ1 receptor subtype selective

Main neuroendocrine features and therapy in primary sleep troubles.

PubMed

Amihăesei, Ioana Cristina; Mungiu, O C

2012-01-01

approximately a quarter of the adult population. Secondary insomnia is associated with chronic heart and/or lung diseases, medication which interfere with onset or duration of sleep, constant change of the sleep habits, restless leg syndrome, etc. Besides lifestyle changes and cogn itive-behavioral therapy, in the treatment of insomnia are used hypnotic medicines, advised to be prescribed on short-term cures of one or two weeks. Benzodiazepines are inducing and maintaining sleep. Longer use is responsible for severe side effects--dependency and withdrawal syndrome, daytime drowsiness and dizziness, low blood pressure, memory troubles and change in the melatonin secretion during night-time period. For these reasons were created non-benzodiazepines hypnotics--zolpidem, zaleplon, which are as effective as benzodiazepines, but have fewer side effects. Nevertheless the use of these hypnotics is also restricted to 7-10 days. Zopiclone (Imovane) another short-acting non-benzodiazepine hypnotic has a different chemical structure, but a pharmacologic profile similar to that of the benzod iazepines; the treatment should be of maximum four weeks. Besides generally known concerns related to the use of hypnotics (residual sedative effects, memory impairment, rebound insomnia, abuse, dose escalation, dependency and withdrawal problems) it was signaled a risk of death associated with the use of current hypnotic medications.

Chronic Sleep Fragmentation During the Sleep Period Induces Hypothalamic Endoplasmic Reticulum Stress and PTP1b-Mediated Leptin Resistance in Male Mice

PubMed Central

Hakim, Fahed; Wang, Yang; Carreras, Alba; Hirotsu, Camila; Zhang, Jing; Peris, Eduard; Gozal, David

2015-01-01

Background: Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction. Methods: Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP −/+ transgenic mice. Results: Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP −/+ mice. Conclusions: Sleep fragmentation (SF) induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of endoplasmic reticulum (ER) stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target. Citation: Hakim F, Wang Y, Carreras A, Hirotsu C, Zhang J, Peris E, Gozal D. Chronic sleep

Common High Altitudes Illnesses a Primer for Healthcare Provider

PubMed Central

Mohsenin, Vahid

2015-01-01

Exposure to high altitude imposes significant strain on cardiopulmonary system and the brain. As a consequence, sojourners to high altitude frequently experience sleep disturbances, often reporting restless and sleepless nights. At altitudes above 3,000 meters (9,800 ft) almost all healthy subjects develop periodic breathing especially during NREM sleep. Sleep architecture gradually improves with increased NREM and REM sleep despite persistence of periodic breathing. The primary reason for periodic breathing at high altitude is a hypoxic-induced increase in chemoreceptor sensitivity to changes in PaCO2 – both above and below eupnea, leading to periods of apnea and hyperpnea. Acetazolamide improves sleep by reducing the periodic breathing through development of metabolic acidosis and induced hyperventilation decreasing the plant gain and widening the PCO2 reserve. This widening of the PCO2 reserve impedes development of central apneas during sleep. Benzodiazepines and GABA receptor antagonist such as zolpidem improve sleep without affecting breathing pattern or cognitive functions. PMID:27057512

Synthesis and in vivo evaluation of [11C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors.

PubMed

Dumont, Filip; Waterhouse, Rikki N; Montoya, Julie A; Mattner, Filomena; Katsifis, Andrew; Kegeles, Lawrence S; Laruelle, Marc

2003-05-01

The synthesis and evaluation of [(11)C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors, is reported herein. The reaction of desmethylzolpidem with [(11)C] methyl iodide afforded the title compound [(11)C]zolpidem in a yield of 19.19 +/- 3.23% in 41 +/- 2 min in specific activities of 0.995-1.19 Ci/micromol (1.115 +/- 0.105 Ci/micromol) (n = 3; decay corrected, EOB). The amount of radioactivity in the brain after tail vein injection in male Wistar rats was low, and the regional distribution was homogeneous and not consistent with the known distribution of the central benzodiazepine receptors. The frontal cortex/cerebellum ratio was not significantly greater than one (1.007 +/- 0.266 at 5 min) and did not increase from 5 to 40 min post-injection. A PET brain imaging study in one baboon confirmed the results obtained in rats. Therefore, it can be concluded that [(11)C]zolpidem is not a suitable tracer for in vivo visualization of central benzodiazepine receptors.

Sleep-Active Neurons: Conserved Motors of Sleep

PubMed Central

Bringmann, Henrik

2018-01-01

Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The “motor” of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness. These sleep-inducing neurons are themselves controlled by inhibitory or activating upstream pathways, which act as the “drivers” of the sleep motor: arousal inhibits “sleep-active” neurons whereas various sleep-promoting “tiredness” pathways converge onto sleep-active neurons to depolarize them. This review provides the first overview of sleep-active neurons across the major model animals. The occurrence of sleep-active neurons and their regulation by upstream pathways in both vertebrate and invertebrate species suggests that these neurons are general and ancient components that evolved early in the history of nervous systems. PMID:29618588

No effect of odor-induced memory reactivation during REM sleep on declarative memory stability

PubMed Central

Cordi, Maren J.; Diekelmann, Susanne; Born, Jan; Rasch, Björn

2014-01-01

Memory reactivations in hippocampal brain areas are critically involved in memory consolidation processes during sleep. In particular, specific firing patterns of hippocampal place cells observed during learning are replayed during subsequent sleep and rest in rodents. In humans, experimentally inducing hippocampal memory reactivations during slow-wave sleep (but not during wakefulness) benefits consolidation and immediately stabilizes declarative memories against future interference. Importantly, spontaneous hippocampal replay activity can also be observed during rapid eye movement (REM) sleep and some authors have suggested that replay during REM sleep is related to processes of memory consolidation. However, the functional role of reactivations during REM sleep for memory stability is still unclear. Here, we reactivated memories during REM sleep and examined its consequences for the stability of declarative memories. After 3 h of early, slow-wave sleep (SWS) rich sleep, 16 healthy young adults learned a 2-D object location task in the presence of a contextual odor. During subsequent REM sleep, participants were either re-exposed to the odor or to an odorless vehicle, in a counterbalanced within subject design. Reactivation was followed by an interference learning task to probe memory stability after awakening. We show that odor-induced memory reactivation during REM sleep does not stabilize memories against future interference. We propose that the beneficial effect of reactivation during sleep on memory stability might be critically linked to processes characterizing SWS including, e.g., slow oscillatory activity, sleep spindles, or low cholinergic tone, which are required for a successful redistribution of memories from medial temporal lobe regions to neocortical long-term stores. PMID:25225474

Venlafaxine-induced REM sleep behavioral disorder presenting as two fractures.

PubMed

Ryan Williams, R; Sandigo, Gustavo

2017-10-01

Rapid eye movement (REM) sleep behavioral disorder is characterized by the absence of muscular atonia during REM sleep. In this disorder, patients can violently act out their dreams, placing them at risk for traumatic fractures during these episodes. REM sleep behavioral disorder (RBD) can be a sign of future neurodegenerative disease and has also been found to be a side effect of certain psychiatric medications. We present a case of venlafaxine-induced RBD in a 55 year old female who presented with a 13 year history of intermittent parasomnia and dream enactment in addition to a recent history of two fractures requiring intervention.

Positive effects of β-amyrin on pentobarbital-induced sleep in mice via GABAergic neurotransmitter system.

PubMed

Jeon, Se Jin; Park, Ho Jae; Gao, Qingtao; Lee, Hyung Eun; Park, Se Jin; Hong, Eunyoung; Jang, Dae Sik; Shin, Chan Young; Cheong, Jae Hoon; Ryu, Jong Hoon

2015-09-15

Sleep loss, insomnia, is considered a sign of imbalance of physiological rhythm, which can be used as pre-clinic diagnosis of various neuropsychiatric disorders. The aim of the present study is to understand the pharmacological actions of α- or β-amyrin, natural triterpene compound, on the sleep in mice. To analyze the sleeping behavior, we used the well-known pentobarbital-induced sleeping model after single administration of either α- or β-amyrin. The sleeping onset time was remarkably decreased and duration was prolonged by β-amyrin (1, 3, or 10mg/kg) but not by α-amyrin (1, 3, or 10mg/kg). These effects were significantly blocked by GABAA receptor antagonist, bicuculline. Moreover, β-amyrin increased brain GABA level compared to the vehicle administration. Overall, the present study suggests that β-amyrin would enhance the total sleeping behavior in pentobarbital-induced sleeping model via the activation of GABAergic neurotransmitter system through GABA content in the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparison of dexmedetomidine and propofol used for drug-induced sleep endoscopy in patients with obstructive sleep apnea syndrome.

PubMed

Kuyrukluyıldız, Ufuk; Binici, Orhan; Onk, Didem; Ayhan Celik, Serap; Torun, Mumtaz Taner; Unver, Edhem; Ozcicek, Adalet; Alagol, Aysin

2015-01-01

Backround: Surgical operations are alternative treatments in persons with Obstructive Sleep Apnea Syndrome who cannot tolerate continuous positive airway pressure therapy. Drug-Induced Sleep Endoscopy is a method with which somnolence is pharmacologically induced and collapse is evaluated through nasal endoscopy in patients with Obstructive Sleep Apnea Syndrome. We aimed to evaluate efficiency of dexmedetomidine or propofol used for sedation in patients undergoing drug-induced sleep endoscopy. A total of 40 patients aged between 18 and 65 years old in the ASA STATUS I-II group were included in the study. After premedicatıon wıth midazolam 0.05 mg/kg intravenously, patients were randomly divided into two groups and administered intravenous (iv) propofol with the loading dose of 0.7 mg/kg for 10 minutes, followed 0.5 mg/kg/h infusion (Group P); or dexmedetomidine with the loading dose of 1 mcg/kg for 10 minutes, followed by 0.3 mcg/kg/h infusion (Group D). Haemodynamic and respiratuary parameters, Bispectral index score, Ramsey sedation score, time to achieve sufficient sedation, surgeon's and patients' satisfaction, postoperative Aldrete score and side effects were recorded. Time to achieve sufficient sedation, Bispectral index scores at 5, 10 and 15th. minutes intraoperatively, first Aldrete score in the recovery room, SpO2 values and respiratory rates all over the surgical procedure and in the recovery room were found lower in Group P (P<0.05). Bispectral index scores, mean arterial pressure and heart rate in the recovery room were significantly lower in Group D (P<0.05). Dexmedetomidine may be preferred as a safer agent with respecting to respiratory function compared with propofol in obstructive sleep apnea patients who known to be susceptible to hypoxia and hypercarbia.

Comparison of dexmedetomidine and propofol used for drug-induced sleep endoscopy in patients with obstructive sleep apnea syndrome

PubMed Central

Kuyrukluyıldız, Ufuk; Binici, Orhan; Onk, Didem; Ayhan Celik, Serap; Torun, Mumtaz Taner; Unver, Edhem; Ozcicek, Adalet; Alagol, Aysin

2015-01-01

Backround: Surgical operations are alternative treatments in persons with Obstructive Sleep Apnea Syndrome who cannot tolerate continuous positive airway pressure therapy. Drug-Induced Sleep Endoscopy is a method with which somnolence is pharmacologically induced and collapse is evaluated through nasal endoscopy in patients with Obstructive Sleep Apnea Syndrome. Aims: We aimed to evaluate efficiency of dexmedetomidine or propofol used for sedation in patients undergoing drug-induced sleep endoscopy. Methods: A total of 40 patients aged between 18 and 65 years old in the ASA STATUS I-II group were included in the study. After premedicatıon wıth midazolam 0.05 mg/kg intravenously, patients were randomly divided into two groups and administered intravenous (iv) propofol with the loading dose of 0.7 mg/kg for 10 minutes, followed 0.5 mg/kg/h infusion (Group P); or dexmedetomidine with the loading dose of 1 mcg/kg for 10 minutes, followed by 0.3 mcg/kg/h infusion (Group D). Haemodynamic and respiratuary parameters, Bispectral index score, Ramsey sedation score, time to achieve sufficient sedation, surgeon’s and patients’ satisfaction, postoperative Aldrete score and side effects were recorded. Results: Time to achieve sufficient sedation, Bispectral index scores at 5, 10 and 15th. minutes intraoperatively, first Aldrete score in the recovery room, SpO2 values and respiratory rates all over the surgical procedure and in the recovery room were found lower in Group P (P<0.05). Bispectral index scores, mean arterial pressure and heart rate in the recovery room were significantly lower in Group D (P<0.05). Conclusion: Dexmedetomidine may be preferred as a safer agent with respecting to respiratory function compared with propofol in obstructive sleep apnea patients who known to be susceptible to hypoxia and hypercarbia. PMID:26131153

Dorsal Raphe Serotonin Neurons Mediate CO2-Induced Arousal from Sleep.

PubMed

Smith, Haleigh R; Leibold, Nicole K; Rappoport, Daniel A; Ginapp, Callie M; Purnell, Benton S; Bode, Nicole M; Alberico, Stephanie L; Kim, Young-Cho; Audero, Enrica; Gross, Cornelius T; Buchanan, Gordon F

2018-02-21

Arousal from sleep in response to CO 2 is a critical protective phenomenon. Dysregulation of CO 2 -induced arousal contributes to morbidity and mortality from prevalent diseases, such as obstructive sleep apnea and sudden infant death syndrome. Despite the critical nature of this protective reflex, the precise mechanism for CO 2 -induced arousal is unknown. Because CO 2 is a major regulator of breathing, prevailing theories suggest that activation of respiratory chemo- and mechano-sensors is required for CO 2 -induced arousal. However, populations of neurons that are not involved in the regulation of breathing are also chemosensitive. Among these are serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) that comprise a component of the ascending arousal system. We hypothesized that direct stimulation of these neurons with CO 2 could cause arousal from sleep independently of enhancing breathing. Dialysis of CO 2 -rich acidified solution into DRN, but not medullary raphe responsible for modulating breathing, caused arousal from sleep. Arousal was lost in mice with a genetic absence of 5-HT neurons, and with acute pharmacological or optogenetic inactivation of DRN 5-HT neurons. Here we demonstrate that CO 2 can cause arousal from sleep directly, without requiring enhancement of breathing, and that chemosensitive 5-HT neurons in the DRN critically mediate this arousal. Better understanding mechanisms underlying this protective reflex may lead to interventions to reduce disease-associated morbidity and mortality. SIGNIFICANCE STATEMENT Although CO 2 -induced arousal is critical to a number of diseases, the specific mechanism is not well understood. We previously demonstrated that serotonin (5-HT) neurons are important for CO 2 -induced arousal, as mice without 5-HT neurons do not arouse to CO 2 Many have interpreted this to mean that medullary 5-HT neurons that regulate breathing are important in this arousal mechanism. Here we found that direct application of CO 2

'Il Sonnambulo' by Michele Carafa: A Forgotten Romantic Opera with Sleepwalking.

PubMed

Riva, Michele Augusto; Mazzocchi, Caterina; Cesana, Giancarlo; Finger, Stanley

2016-01-01

Romantic operas provide a useful tool for historians to understand the perception of some medical disorders that existed during the nineteenth century. Somnambulism was still a mysterious condition during this time, since its pathogenesis was unknown. Hence, it comes as no surprise that somnambulism features in a number of operas, the best known of which are Verdi's 'Macbeth' and Bellini's 'La Sonnambula', both the subject of recent scholarship. Here we examine a more obscure opera in which sleepwalking is depicted. Dating from 1824, 'Il Sonnambulo' by the Italian composer Michele Carafa is based on a libretto by Felice Romani. Although it shares some features with the Verdi and Bellini operas, it also presents original elements. Our analysis of this forgotten opera supports the contention that studying operas can shed light on medical theories and practices, and on how ideas about mind and body disorders were transmitted to the laity in times past. © 2016 S. Karger AG, Basel.

[Safety profile of zolpidem: two studies of 3805 patients by Swiss practitioners].

PubMed

Ganzoni, E; Gugger, M

1999-06-24

Evaluation and treatment of insomnia are frequent procedures in the physician's everyday practice, since many patients seek medical treatment for this condition. Knowledge of pharmacological therapeutical alternatives is therefore decisive, in order to identify the most efficaceous and safe therapy for the patient among the available hypnotics. The short-acting hypnotic zolpidem has been investigated in Switzerland in two multicenter safety studies in ambulatory practice. In the first study 8.9% (n = 125 of 1,972 treated patients), and in the second 7.2% of the patients (n = 175 of 1,833 treated patients) reported an adverse event. The most frequent events were related to the central nervous system (CNS) (somnolence, headache, confusion, vertigo); gastrointestinal and cutaneous symptoms were the most frequent non CNS-dependent effects. New, unknown or serious adverse events were not found and no specific risk factor or population at risk was identified. The safety profile of zolpidem is consistent with its known pharmacological properties, the results of previous clinical trials and the international experience obtained in large patients groups.

Effects of Alprazolam, Zolpidem and Zopiclone, and of chronic inflammation on peripheral experimental algesia in Wistar rats.

PubMed

Zdrîncă, Mihaela; Muţiu, Gabriela; Bogdan, Maria; Dobjanschi, Luciana; Antonescu, Angela; Moş, Ioana; Mureşan, Mariana; Zdrîncă, M; Antonescu, Andreea

2011-01-01

In the literature, there are some data which indicate that benzodiazepines and other chemical compounds with the same mechanism of action (Diazepam, Chlordiazepoxide, Lorazepam, Zopiclone, etc.) also have other effects. We investigated the effects of experimental chronic inflammation under the administration of some tranquilizers and hypnotics on peripheral algesia induced in rats by "writhing test". Chronic inflammation was induced by "cotton wool granuloma" technique. The "writhing test" consisted in intraperitoneal injection of an irritant agent (acetic acid 0.0025%, 0.4 mL). The animal reacts with a characteristic stretching behavior called writhing. A writhe is indicated by stretching of the abdomen with simultaneous stretching of at least one hind limb. Then, the animals were placed individually into glass beakers and 5 minutes were allowed to elapse. The rats were then observed for a period of 10 minutes and the number of writhes is recorded for each animal. Three drugs were administered by gastric probe: Alprazolam 1 mg/kg, Zolpidem 10 mg/kg and Zopiclone 10 mg/kg. Alprazolam is a triazolobenzodiazepine derivative used as a tranquilizer. Zolpidem is an imidazopyridine with marked sedative-hypnotic effect and it has the same mechanism of action like benzodiazepines. Zopiclone is a cyclopyrrolone with sedative-hypnotic effect used as hypnotic and acts like benzodiazepines. After that, the animals were sacrificed and the weight of cotton wool granuloma was determined. In the same time, the histopatological aspect of granulomatous inflammation was studied. It was found that experimental proliferative inflammation under the action of these drugs was accompanied by a peripheral analgesic activity in "writhing test". The mechanisms of these effects are not fully elucidated. Some explanations are: they act as agonists or antagonists on algesia and inflammation mediators and they have a stimulating effect on peripheral ω3-benzodiazepine receptors ("peripheral

Orexin Plays a Role in Growth Impediment Induced by Obstructive Sleep Breathing in Rats

PubMed Central

Tarasiuk, Ariel; Levi, Avishag; Assadi, Mohammad H.; Troib, Ariel; Segev, Yael

2016-01-01

Study Objectives: The mechanisms linking sleep disordered breathing with impairment of sleep and bone metabolism/architecture are poorly understood. Here, we explored the role of the neuropeptide orexin, a respiratory homeostasis modulator, in growth retardation induced in an upper airway obstructed (AO) rat model. Methods: The tracheae of 22-day-old rats were narrowed; AO and sham-control animals were monitored for 5 to 7 w. Growth parameters, food intake, sleep/wake activity, and serum hormones were measured. After euthanasia, growth plate (GP) histology, morphometry, orexin receptors (OXR), and related mediators were analyzed. The effect of dual orexin receptor antagonist (almorexant 300 mg/kg) on sleep and GP histology were also investigated. Results: The AO group slept 32% less; the time spent in slow wave and paradoxical sleep during light period and slow wave activity was reduced. The AO group gained 46% less body weight compared to the control group, despite elevated food intake; plasma ghrelin increased by 275% and leptin level decreased by 44%. The impediment of bone elongation and bone mass was followed by a 200% increase in OX1R and 38% reduction of local GP ghrelin proteins and growth hormone secretagogue receptor 1a. Sry-related transcription factor nine (Sox9), a molecule mediating cartilage ossification, was downregulated and the level of transcription factor peroxisome proliferator-activated receptor gamma was upregulated, explaining the bone architecture abnormalities. Administration of almorexant restored sleep and improved GP width in AO animals. Conclusions: In AO animals, enhanced expression of orexin and OX1R plays a role in respiratory induced sleep and growth abnormalities. Citation: Tarasiuk A, Levi A, Assadi MH, Troib A, Segev Y. Orexin plays a role in growth impediment induced by obstructive sleep breathing in rats. SLEEP 2016;39(4):887–897. PMID:26943473

[Complex injuries associated with somnambulism].

PubMed

Sillesen, Nanna Hylleholt; Nielsen, Lisa Toft; Bonde, Christian

2010-12-13

Up to 3% of adults walk in their sleep and some perform complex behaviours. Treatment recommendations for sleepwalking are inconsistent. This case report describes a 64-year-old man who climbed out of a 2nd floor toilet window during somnambulism. He fell 6-8 meters and fractured the tibia, fibula, cervical columna, lumbal columna, calcaneus, costae and suffered a pneumothorax. Evidence to support sleepwalking treatment is lacking and besides benzodiazepines, prevention is the preferred treatment choice according to the literature.

Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link

PubMed Central

Velázquez-Moctezuma, J.

2016-01-01

Sleep is a vital phenomenon related to immunomodulation at the central and peripheral level. Sleep deficient in duration and/or quality is a common problem in the modern society and is considered a risk factor to develop neurodegenerative diseases. Sleep loss in rodents induces blood-brain barrier disruption and the underlying mechanism is still unknown. Several reports indicate that sleep loss induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them may promote changes in cellular components of the blood-brain barrier, particularly on brain endothelial cells. In the present review we discuss the role of inflammatory mediators that increase during sleep loss and their association with general disturbances in peripheral endothelium and epithelium and how those inflammatory mediators may alter the blood-brain barrier. Finally, this manuscript proposes a hypothetical mechanism by which sleep loss may induce blood-brain barrier disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins. PMID:27738642

Organization and logistics of drug-induced sleep endoscopy in a training hospital.

PubMed

Benoist, L B L; de Vries, N

2015-09-01

Drug-induced sleep endoscopy (DISE) is a rapidly growing method to evaluate airway collapse in patients receiving non-CPAP therapies for sleep-disordered breathing (SDB). The growing number of DISEs has consequences for the organization of clinical protocols. In this paper we present our recent experiences with DISE, performed by an ENT resident, with sedation given by a nurse anesthetist, in an outpatient endoscopy setting, while the staff member/sleep surgeon discusses the findings and the recommended treatment proposal on the same day.

Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

PubMed

Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

2012-05-02

The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Aging-driven decomposition in zolpidem hemitartrate hemihydrate and the single-crystal structure of its decomposition products.

PubMed

Vega, Daniel R; Baggio, Ricardo; Roca, Mariana; Tombari, Dora

2011-04-01

The "aging-driven" decomposition of zolpidem hemitartrate hemihydrate (form A) has been followed by X-ray powder diffraction (XRPD), and the crystal and molecular structures of the decomposition products studied by single-crystal methods. The process is very similar to the "thermally driven" one, recently described in the literature for form E (Halasz and Dinnebier. 2010. J Pharm Sci 99(2): 871-874), resulting in a two-phase system: the neutral free base (common to both decomposition processes) and, in the present case, a novel zolpidem tartrate monohydrate, unique to the "aging-driven" decomposition. Our room-temperature single-crystal analysis gives for the free base comparable results as the high-temperature XRPD ones already reported by Halasz and Dinnebier: orthorhombic, Pcba, a = 9.6360(10) Å, b = 18.2690(5) Å, c = 18.4980(11) Å, and V = 3256.4(4) Å(3) . The unreported zolpidem tartrate monohydrate instead crystallizes in monoclinic P21 , which, for comparison purposes, we treated in the nonstandard setting P1121 with a = 20.7582(9) Å, b = 15.2331(5) Å, c = 7.2420(2) Å, γ = 90.826(2)°, and V = 2289.73(14) Å(3) . The structure presents two complete moieties in the asymmetric unit (z = 4, z' = 2). The different phases obtained in both decompositions are readily explained, considering the diverse genesis of both processes. Copyright © 2010 Wiley-Liss, Inc.

Evaluation of benzodiazepines and zolpidem in nails and their stability after prolonged exposure to chlorinated water.

PubMed

Moretti, Matteo; Andrello, Luisa; Visonà, Silvia; Vignali, Claudia; Groppi, Angelo; Freni, Francesca; Osculati, Antonio; Tajana, Luca; Morini, Luca

2018-04-15

The study aims the development and validation of a LC-MS/MS method for the identification and quantification of benzodiazepines and zolpidem in nails as alternative keratinized matrix to hair in long-term monitoring of anxiolytic and hypnotic drugs. Both fingernail and toenail samples (1-2 mm) were collected by clipping the excess overhang of the nail from volunteers and from postmortem cases. They were washed twice with organic solvents, dried under nitrogen stream, pulverized, immersed in a methanol solution (internal standard: diazepam-D5) and sonicated up to two hours. The solution was then direct injected in the LC-MS/MS system. Mass spectrometry was set in MRM mode, selecting two transitions for each substance. 32 analytes among benzodiazepines, metabolites and hypnotics were included in the list. The method fulfilled the internationally required criteria for validation. Limits of detection ranged from 0.03 pg/mg (zolpidem) to 13.1 pg/mg (bromazepam). 9 subjects under therapy were positive at 7 different benzodiazepines and/or metabolites (lorazepam, desalkylflurazepam, bromazepam, diazepam, alprazolam, lormetazepam and prazepam), while 5 molecules were measured in 4 postmortem cases (diazepam, desmethyldiazepam, delorazepam, 7-aminoclonazepam and zolpidem). In vitro experiments on eight authentic samples suggested that benzodiazepines in nails are influenced by the prolonged exposure to chlorinated water. Copyright © 2018 Elsevier B.V. All rights reserved.

ERK signaling pathway regulates sleep duration through activity-induced gene expression during wakefulness.

PubMed

Mikhail, Cyril; Vaucher, Angélique; Jimenez, Sonia; Tafti, Mehdi

2017-01-24

Wakefulness is accompanied by experience-dependent synaptic plasticity and an increase in activity-regulated gene transcription. Wake-induced genes are certainly markers of neuronal activity and may also directly regulate the duration of and need for sleep. We stimulated murine cortical cultures with the neuromodulatory signals that are known to control wakefulness in the brain and found that norepinephrine alone or a mixture of these neuromodulators induced activity-regulated gene transcription. Pharmacological inhibition of the various signaling pathways involved in the regulation of gene expression indicated that the extracellular signal-regulated kinase (ERK) pathway is the principal one mediating the effects of waking neuromodulators on gene expression. In mice, ERK phosphorylation in the cortex increased and decreased with wakefulness and sleep. Whole-body or cortical neuron-specific deletion of Erk1 or Erk2 significantly increased the duration of wakefulness in mice, and pharmacological inhibition of ERK phosphorylation decreased sleep duration and increased the duration of wakefulness bouts. Thus, this signaling pathway, which is highly conserved from Drosophila to mammals, is a key pathway that links waking experience-induced neuronal gene expression to sleep duration and quality. Copyright © 2017, American Association for the Advancement of Science.

Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance.

PubMed

Verster, Joris C; Volkerts, Edmund R; Schreuder, Antonia H C M L; Eijken, Erik J E; van Heuckelum, Janet H G; Veldhuijzen, Dieuwke S; Verbaten, Marinus N; Paty, Isabelle; Darwish, Mona; Danjou, Philippe; Patat, Alain

2002-12-01

Thirty healthy volunteers participated in this two-part study. Part 1 was a single-blind, two-period crossover design to determine the effects of a single dose of ethanol (0.03% < BAC < 0.05%) or ethanol-placebo on driving ability, memory, and psychomotor performance. Part 2 was a double-blind, five-period crossover design to measure the effects of a middle-of-the-night administration of zaleplon 10 or 20 mg, zolpidem 10 or 20 mg, or placebo on driving ability 4 hours after administration and memory and psychomotor performance 6 hours after administration. The on-the-road driving test consisted of operating an instrumented automobile over a 100-km highway circuit at a constant speed (95 km/h) while maintaining a steady lateral position between the right lane boundaries. The standard deviation of lateral position (SDLP) was the primary performance parameter of the driving test. The psychomotor and memory test battery consisted of the Word Learning Test, the Critical Tracking Test, the Divided Attention Test, and the Digit Symbol Substitution Test. Data for each part were analyzed separately using ANOVA for crossover designs. Zaleplon 10 and 20 mg did not significantly impair driving ability 4 hours after middle-of-the-night administration. Relative to placebo, after zolpidem 10 mg, SDLP was significantly elevated, but the magnitude of the difference was small and not likely to be of clinical importance. Memory and psychomotor test performance was unaffected after both doses of zaleplon and zolpidem 10 mg. In contrast, zolpidem 20 mg significantly increased SDLP and speed variability. Further, zolpidem 20 mg significantly impaired performance on all psychomotor and memory tests. Finally, driving performance, Digit Symbol Substitution Test, Divided Attention Test, and immediate and delayed free recall of the Word Learning Test were significantly impaired after ethanol. The results show that zaleplon (10 and 20 mg) is a safe hypnotic devoid of next-morning residual

Sleep loss and acute drug abuse can induce DNA damage in multiple organs of mice.

PubMed

Alvarenga, T A; Ribeiro, D A; Araujo, P; Hirotsu, C; Mazaro-Costa, R; Costa, J L; Battisti, M C; Tufik, S; Andersen, M L

2011-09-01

The purpose of the present study was to characterize the genetic damage induced by paradoxical sleep deprivation (PSD) in combination with cocaine or ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in multiple organs of male mice using the single cell gel (comet) assay. C57BL/6J mice were submitted to PSD by the platform technique for 72 hours, followed by drug administration and evaluation of DNA damage in peripheral blood, liver and brain tissues. Cocaine was able to induce genetic damage in the blood, brain and liver cells of sleep-deprived mice at the majority of the doses evaluated. Ecstasy also induced increased DNA migration in peripheral blood cells for all concentrations tested. Analysis of damaged cells by the tail moment data suggests that ecstasy is a genotoxic chemical at the highest concentrations tested, inducing damage in liver or brain cells after sleep deprivation in mice. Taken together, our results suggest that cocaine and ecstasy/MDMA act as potent genotoxins in multiple organs of mice when associated with sleep loss.

Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses.

PubMed

Aho, Vilma; Ollila, Hanna M; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S A; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

2016-04-22

Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases.

Development and pharmacological characterization of a model of sleep disruption-induced hypersensitivity in the rat.

PubMed

Wodarski, R; Schuh-Hofer, S; Yurek, D A; Wafford, K A; Gilmour, G; Treede, R-D; Kennedy, J D

2015-04-01

Sleep disturbance is a commonly reported co-morbidity in chronic pain patients, and conversely, disruption of sleep can cause acute and long-lasting hypersensitivity to painful stimuli. The underlying mechanisms of sleep disruption-induced pain hypersensitivity are poorly understood. Confounding factors of previous studies have been the sleep disruption protocols, such as the 'pedestal over water' or 'inverted flower pot' methods, that can cause large stress responses and therefore may significantly affect pain outcome measures. Sleep disruption was induced by placing rats for 8 h in a slowly rotating cylindrical cage causing arousal via the righting reflex. Mechanical (Von Frey filaments) and thermal (Hargreaves) nociceptive thresholds were assessed, and plasma corticosterone levels were measured (mass spectroscopy). Sleep disruption-induced hypersensitivity was pharmacologically characterized with drugs relevant for pain treatment, including gabapentin (30 mg/kg and 50 mg/kg), Ica-6p (Kv7.2/7.3 potassium channel opener; 10 mg/kg), ibuprofen (30 mg/kg and 100 mg/kg) and amitriptyline (10 mg/kg). Eight hours of sleep disruption caused robust mechanical and heat hypersensitivity in the absence of a measurable change in plasma corticosterone levels. Gabapentin had no effect on reduced nociceptive thresholds. Ibuprofen attenuated mechanical thresholds, while Ica-6p and amitriptyline attenuated only reduced thermal nociceptive thresholds. These results show that acute and low-stress sleep disruption causes mechanical and heat hypersensitivity in rats. Mechanical and heat hypersensitivity exhibited differential sensitivity to pharmacological agents, thus suggesting dissociable mechanisms for those two modalities. Ultimately, this model could help identify underlying mechanisms linking sleep disruption and hypersensitivity. © 2014 European Pain Federation - EFIC®

Simultaneous analysis by Quadrupole-Orbitrap mass spectrometry and UHPLC-MS/MS for the determination of sedative-hypnotics and sleep inducers in adulterated products.

PubMed

Lee, Ji Hyun; Park, Han Na; Choi, Ji Yeon; Kim, Nam Sook; Park, Hyung-Joon; Park, Seong Soo; Baek, Sun Young

2017-12-01

Adulterated products are continuously detected in society and cause problems. In this study, we developed and validated a method for determining synthetic sedative-hypnotics and sleep inducers, including barbital, benzodiazepam, zolpidem, and first-generation antihistamines, in adulterated products using Quadrupole-Orbitrap mass spectrometry and ultrahigh performance liquid chromatography with tandem mass spectrometry. In Quadrupole-Orbitrap mass spectrometry analysis, target compounds were confirmed using a combination of retention time, mass tolerance, mass accuracy, and fragment ions. For quantification, several validation parameters were employed using ultrahigh performance liquid chromatography with tandem mass spectrometry. The limit of detection and limit of quantitation was 0.05-53 and 0.17-177 ng/mL, respectively. The correlation coefficient for linearity was more than 0.995. The intra- and interassay accuracies were 86-110 and 84-111%, respectively. Their precision values were evaluated as within 4.0 (intraday) and 10.7% (interday). Mean recoveries of target compounds in adulterated products ranged from 85 to 116%. The relative standard deviation of stability was less than 10.7% at 4°C for 48 h. The 144 adulterated products obtained over 3 years (2014-2016) from online and in-person vendors were tested using established methods. After rapidly screening with Quadrupole-Orbitrap mass spectrometry, the detected samples were quantified using ultrahigh performance liquid chromatography with tandem mass spectrometry. Two of them were adulterated with phenobarbital. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Review of field studies of aircraft noise-induced sleep disturbance.

PubMed

Michaud, David S; Fidell, Sanford; Pearsons, Karl; Campbell, Kenneth C; Keith, Stephen E

2007-01-01

Aircraft noise-induced sleep disturbance (AN-ISD) is potentially among the more serious effects of aircraft noise on people. This literature review of recent field studies of AN-ISD finds that reliable generalization of findings to population-level effects is complicated by individual differences among subjects, methodological and analytic differences among studies, and predictive relationships that account for only a small fraction of the variance in the relationship between noise exposure and sleep disturbance. It is nonetheless apparent in the studied circumstances of residential exposure that sleep disturbance effects of nighttime aircraft noise intrusions are not dramatic on a per-event basis, and that linkages between outdoor aircraft noise exposure and sleep disturbance are tenuous. It is also apparent that AN-ISD occurs more often during later than earlier parts of the night; that indoor sound levels are more closely associated with sleep disturbance than outdoor measures; and that spontaneous awakenings, or awakenings attributable to nonaircraft indoor noises, occur more often than awakenings attributed to aircraft noise. Predictions of sleep disturbance due to aircraft noise should not be based on over-simplifications of the findings of the reviewed studies, and these reports should be treated with caution in developing regulatory policy for aircraft noise.

Trigeminal induced arousals during human sleep.

PubMed

Heiser, Clemens; Baja, Jan; Lenz, Franziska; Sommer, J Ulrich; Hörmann, Karl; Herr, Raphael M; Stuck, Boris A

2015-05-01

Arousals caused by external stimuli during human sleep have been studied for most of the sensorial systems. It could be shown that a pure nasal trigeminal stimulus leads to arousals during sleep. The frequency of arousals increases dependent on the stimulus concentration. The aim of the study was to evaluate the influence of different stimulus durations on arousal frequency during different sleep stages. Ten young healthy volunteers with 20 nights of polysomnography were included in the study. Pure trigeminal stimulation with both different concentrations of CO2 (0, 10, 20, 40% v/v) and different stimulus durations (1, 3, 5, and 10 s) were applied during different sleep stages to the volunteers using an olfactometer. The application was performed during different sleep stages (light sleep, deep sleep, REM sleep). The number of arousals increased with rising stimulus duration and stimulus concentration during each sleep stage. Trigeminal stimuli during sleep led to arousals in dose- and time-dependent manner.

Effects of one night of induced night-wakings versus sleep restriction on sustained attention and mood: a pilot study.

PubMed

Kahn, Michal; Fridenson, Shimrit; Lerer, Reut; Bar-Haim, Yair; Sadeh, Avi

2014-07-01

Despite their high prevalence in daily life, repeated night-wakings and their cognitive and emotional consequences have received less research attention compared to other types of sleep disturbances. Our aim was to experimentally compare the effects of one night of induced infrequent night-wakings (of ∼15 min, each requiring a purposeful response) and sleep restriction on sustained attention and mood in young adults. In a within-between subjects counterbalanced design, 61 healthy adults (40 females; aged 20-29 years) underwent home assessments of sustained attention and self-reported mood at two times: after a normal (control) sleep night, and after a night of either sleep restriction (4h in bed) or induced night-wakings (four prolonged awakenings across 8h in bed). Sleep was monitored using actigraphy and sleep diaries. Sustained attention was assessed using an online continuous performance test (OCPT), and mood was reported online using the Profile of Mood States (POMS). Actigraphic data revealed good compliance with experimental sleep requirements. Induced night-wakings and sleep restriction both resulted in more OCPT omission and commission errors, and in increased depression, fatigue and confusion levels and reduced vigor compared to the normal sleep night. Moreover, there were no significant differences between the consequences of induced awakenings and sleep restriction. Our pilot study indicates that, similar to sleep restriction, one night of life-like repeated night-wakings negatively affects mood and sustained attention. Copyright © 2014 Elsevier B.V. All rights reserved.

Vitamin C Prevents Sleep Deprivation-induced Elevation in Cortisol and Lipid Peroxidation in the Rat Plasma.

PubMed

Olayaki, L A; Sulaiman, S O; Anoba, N B

2015-12-20

Sleep deprivation (SD) is biological stressor that alters metabolic parameters, induced oxidative stress and lipid peroxidation. Previous studies have shown that antioxidants substances such as melatonin, tryptophan, vitamin E and vitamin C improved stress tolerance in laboratory animals. In this study, we examined the potential protective effects of administration of vitamin C on acute and chronic sleep deprivation-induced metabolic derangement. In addition, possible processes involved in vitamin C effects on acute and chronic sleep deprivation-induced metabolic derangement were determined. Thirty-five rats (120-250g) were used. The rats were divided into 7 groups of 5 rats each as Control (CTRL), Acute sleep deprived untreated with vitamin C (AC), Acute sleep deprived treated with vitamin C (AWC), Chronic sleep deprived untreated with vitamin C (CC), Chronic sleep deprived treated with vitamin C (CWC), Chronic sleep deprived + Recovery untreated with vitamin C (RC), and Chronic sleep deprived + Recovery treated with vitamin C (RWC). The SD was carried out for 20h for 1 day on the acute groups, and for 20h/day for 5 days on the chronic group, using the Multiple Modified Platforms (MMP) after oral administration of 300mg/kg of vitamin C to all vitamin C-treated groups. The recovery groups were further observed for five days after SD. The control group were treated with vitamin C and without stress in their home cages. At the end of the experiment, the animals were sacrificed and blood was collected for estimation of plasma glucose, insulin, cortisol and malondialdehyde (MDA). The results showed that acute and chronic SDs significantly  increased MDA and cortisol levels, while significantly reduced the levels of insulin. Treatment with vitamin C reversed the changes in the MDA, cortisol and plasma insulin levels. Additionally, allowing the rats to recover for 5 days after sleep deprivation corrected the observed changes. Plasma glucose was significantly

Sleep Deprivation Aggravates Median Nerve Injury-Induced Neuropathic Pain and Enhances Microglial Activation by Suppressing Melatonin Secretion

PubMed Central

Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-01-01

Study Objectives: Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Design: Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Participants: Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Measurements: Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. Results: In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Conclusions: Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. Citation: Huang CT, Chiang RP, Chen CL, Tsai YJ. Sleep

Dynamic upper airway changes during sleep in patients with obstructive sleep apnea syndrome.

PubMed

Chuang, Li-Pang; Chen, Ning-Hung; Li, Hsueh-Yu; Lin, Shih-Wei; Chou, Yu-Ting; Wang, Chao-Jan; Liao, Yu-Fang; Tsai, Ying-Huang

2009-12-01

The narrowing pattern of the upper airway in obstructive sleep apnea patients may be different in sleep as compared with awake. Three different types of obstruction were observed in these subjects during drug-induced sleep. The different obstruction pattern during drug-induced sleep suggests that different strategies should be selected in upper airway management. To identify the sites of narrowing and evaluate dynamic upper airway movement in patients with obstructive sleep apnea syndrome (OSAS) while awake and asleep. This study included 10 patients treated for OSAS between August 2003 and June 2004. Overnight polysomnography was performed on all patients. Parameters including gender, age, neck circumference, and body mass index were recorded. Ultra-fast MRI during awake and drug-induced sleep was arranged to evaluate the dynamic motion of the upper airway. The narrowing pattern of the upper airway during awake differed from the narrowing pattern during drug-induced sleep in 3 of 10 subjects. Three different types, palatal obstruction, combined upper and lower pharyngeal obstruction, and circumferential obstruction of the upper airway, were observed in these patients during drug-induced sleep.

A Rodent Model of Night-Shift Work Induces Short-Term and Enduring Sleep and Electroencephalographic Disturbances.

PubMed

Grønli, Janne; Meerlo, Peter; Pedersen, Torhild T; Pallesen, Ståle; Skrede, Silje; Marti, Andrea R; Wisor, Jonathan P; Murison, Robert; Henriksen, Tone E G; Rempe, Michael J; Mrdalj, Jelena

2017-02-01

Millions of people worldwide are working at times that overlap with the normal time for sleep. Sleep problems related to the work schedule may mediate the well-established relationship between shift work and increased risk for disease, occupational errors and accidents. Yet, our understanding of causality and the underlying mechanisms that explain this relationship is limited. We aimed to assess the consequences of night-shift work for sleep and to examine whether night-shift work-induced sleep disturbances may yield electrophysiological markers of impaired maintenance of the waking brain state. An experimental model developed in rats simulated a 4-day protocol of night-work in humans. Two groups of rats underwent 8-h sessions of enforced ambulation, either at the circadian time when the animal was physiologically primed for wakefulness (active-workers, mimicking day-shift) or for sleep (rest-workers, mimicking night-shift). The 4-day rest-work schedule induced a pronounced redistribution of sleep to the endogenous active phase. Rest-work also led to higher electroencephalogram (EEG) slow-wave (1-4 Hz) energy in quiet wakefulness during work-sessions, suggesting a degraded waking state. After the daily work-sessions, being in their endogenous active phase, rest-workers slept less and had higher gamma (80-90 Hz) activity during wake than active-workers. Finally, rest-work induced an enduring shift in the main sleep period and attenuated the accumulation of slow-wave energy during NREM sleep. A comparison of recovery data from 12:12 LD and constant dark conditions suggests that reduced time in NREM sleep throughout the recorded 7-day recovery phase induced by rest-work may be modulated by circadian factors. Our data in rats show that enforced night-work-like activity during the normal resting phase has pronounced acute and persistent effects on sleep and waking behavior. The study also underscores the potential importance of animal models for future studies on the

Social Media Impact of the Food and Drug Administration's Drug Safety Communication Messaging About Zolpidem: Mixed-Methods Analysis

PubMed Central

Sinha, Michael S; Freifeld, Clark C; Brownstein, John S; Donneyong, Macarius M; Rausch, Paula; Lappin, Brian M; Zhou, Esther H; Dal Pan, Gerald J; Pawar, Ajinkya M; Hwang, Thomas J; Avorn, Jerry

2018-01-01

Background The Food and Drug Administration (FDA) issues drug safety communications (DSCs) to health care professionals, patients, and the public when safety issues emerge related to FDA-approved drug products. These safety messages are disseminated through social media to ensure broad uptake. Objective The objective of this study was to assess the social media dissemination of 2 DSCs released in 2013 for the sleep aid zolpidem. Methods We used the MedWatcher Social program and the DataSift historic query tool to aggregate Twitter and Facebook posts from October 1, 2012 through August 31, 2013, a period beginning approximately 3 months before the first DSC and ending 3 months after the second. Posts were categorized as (1) junk, (2) mention, and (3) adverse event (AE) based on a score between –0.2 (completely unrelated) to 1 (perfectly related). We also looked at Google Trends data and Wikipedia edits for the same time period. Google Trends search volume is scaled on a range of 0 to 100 and includes “Related queries” during the relevant time periods. An interrupted time series (ITS) analysis assessed the impact of DSCs on the counts of posts with specific mention of zolpidem-containing products. Chow tests for known structural breaks were conducted on data from Twitter, Facebook, and Google Trends. Finally, Wikipedia edits were pulled from the website’s editorial history, which lists all revisions to a given page and the editor’s identity. Results In total, 174,286 Twitter posts and 59,641 Facebook posts met entry criteria. Of those, 16.63% (28,989/174,286) of Twitter posts and 25.91% (15,453/59,641) of Facebook posts were labeled as junk and excluded. AEs and mentions represented 9.21% (16,051/174,286) and 74.16% (129,246/174,286) of Twitter posts and 5.11% (3,050/59,641) and 68.98% (41,138/59,641) of Facebook posts, respectively. Total daily counts of posts about zolpidem-containing products increased on Twitter and Facebook on the day of the first DSC

Durability of treatment response to zolpidem with three different maintenance regimens: a preliminary study

PubMed Central

Perlis, Michael; Grandner, Michael; Zee, Jarcy; Bremer, Erin; Whinnery, Julia; Barilla, Holly; Andalia, Priscilla; Gehrman, Phil; Morales, Knashawn; Thase, Michael; Bootzin, Richard; Ader, Robert

2015-01-01

Background and aim At present, there is no consensus regarding how to medically manage chronic insomnia in the long term. The unstated standard of practice is for patients to use hypnotics intermittently. The present study aimed to compare a partial reinforcement strategy with nightly and intermittent dosing strategies for its potential as a maintenance therapy. Methods A mixed model was used in the study. One between-subjects factor: group (n = 4). One repeated-measures factor: time (12 weekly assessments). A total of 74 subjects with chronic Insomnia were treated with 10 mg zolpidem for 4 weeks. Treatment respondents were randomized to nightly dosing with 10 mg or 5 mg (QHS-10 and QHS-5), intermittent dosing with 10 mg (IDS-10 [3–5 days weekly]), or partial reinforcement dosing with 10 mg (PRS-10 [nightly pill use with 50% active medication and 50% placebos]) for 12 weeks. Results It was found, in compliant subjects (n = 55), that all four strategies evaluated maintained treatment response over time (ie, prevented or delayed relapse). For the subjects that remained in remission, the subjects in the intermittent dosing group (IDS-10) group exhibited poorer sleep continuity. Conclusions While best considered a preliminary study, the present findings suggest that the partial reinforcement strategy may be a viable means toward maintaining treatment gains over time with less active medication. PMID:26298795

Noise-Induced Sleep Disturbance in Residences Near Two Civil Airports

NASA Technical Reports Server (NTRS)

Fidell, Sanford; Howe, Richard R.; Tabachnick, Barbara G.; Pearsons, Karl S.; Sneddon, Matthew D.

1995-01-01

A large-scale field study of noise-induced sleep disturbance was conducted in the vicinities of Stapleton International Airport (DEN) and Denver International Airport (DIA) in anticipation of the closure of the former and opening of the latter. Both indoor and outdoor measurements of aircraft and other nighttime noises were made during four time periods. Measurements were made in 57 homes located as close as feasible to the runway ends of the two airports. Sleep disturbance was measured by several indices of behaviorally confirmed awakening (button pushes upon awakening) and body movement (as measured with wrist-worn actimeters). A total of 2717 subject-nights of observations were made over the course of the study. Although average noise event levels measured outdoors decreased markedly at DEN after closure of the airport and increased slightly at DIA after its opening, indoor noise event levels varied much less in homes near both airports. No large differences were observed in noise-induced sleep disturbance at either airport. Indoor sound exposure levels of noise events were, however, closely related to and good predictors of actimetrically defined motility and arousal.

AMPA receptors mediate passive avoidance deficits induced by sleep deprivation.

PubMed

Dubiela, Francisco Paulino; Queiroz, Claudio Marcos; Moreira, Karin Di Monteiro; Nobrega, Jose N; Sita, Luciane Valéria; Tufik, Sergio; Hipolide, Debora Cristina

2013-11-15

The present study addressed the effects of sleep deprivation (SD) on AMPA receptor (AMPAR) binding in brain regions associated with learning and memory, and investigated whether treatment with drugs acting on AMPAR could prevent passive avoidance deficits in sleep deprived animals. [(3)H]AMPA binding and GluR1 in situ hybridization signals were quantified in different brain regions of male Wistar rats either immediately after 96 h of sleep deprivation or after 24h of sleep recovery following 96 h of sleep deprivation. Another group of animals were sleep deprived and then treated with either the AMPAR potentiator, aniracetam (25, 50 and 100mg/kg, acute administration) or the AMPAR antagonist GYKI-52466 (5 and 10mg/kg, acute and chronic administration) before passive avoidance training. Task performance was evaluated 2h and 24h after training. A significant reduction in [(3)H]AMPA binding was found in the hippocampal formation of SD animals, while no alterations were observed in GluR1 mRNA levels. The highest dose of aniracetam (100mg/kg) reverted SD-induced impairment of passive avoidance performance in both retention tests, whereas GYKI-52466 treatment had no effect. Pharmacological enhancement of AMPAR function may revert hippocampal-dependent learning impairments produced after SD. We argue that such effects might be associated with reduced AMPAR binding in the hippocampus of sleep deprived animals. Copyright © 2013 Elsevier B.V. All rights reserved.

Analysis of slow-wave activity and slow-wave oscillations prior to somnambulism.

PubMed

Jaar, Olivier; Pilon, Mathieu; Carrier, Julie; Montplaisir, Jacques; Zadra, Antonio

2010-11-01

STUDY OBJECTIVIES: several studies have investigated slow wave sleep EEG parameters, including slow-wave activity (SWA) in relation to somnambulism, but results have been both inconsistent and contradictory. The first goal of the present study was to conduct a quantitative analysis of sleepwalkers' sleep EEG by studying fluctuations in spectral power for delta (1-4 Hz) and slow delta (0.5-1 Hz) before the onset of somnambulistic episodes. A secondary aim was to detect slow-wave oscillations to examine changes in their amplitude and density prior to behavioral episodes. twenty-two adult sleepwalkers were investigated polysomnographically following 25 h of sleep deprivation. analysis of patients' sleep EEG over the 200 sec prior to the episodes' onset revealed that the episodes were not preceded by a gradual increase in spectral power for either delta or slow delta over frontal, central, or parietal leads. However, time course comparisons revealed significant changes in the density of slow-wave oscillations as well as in very slow oscillations with significant increases occurring during the final 20 sec immediately preceding episode onset. the specificity of these sleep EEG parameters for the occurrence and diagnosis of NREM parasomnias remains to be determined.

Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study.

PubMed

Murillo-Rodriguez, Eric; Blanco-Centurion, Carlos; Sanchez, Cristina; Piomelli, Daniele; Shiromani, Priyattam J

2003-12-15

The principal component of marijuana, delta-9-tetrahydrocannabinol increases sleep in humans. Endogenous cannabinoids, such as N-arachidonoylethanolamine (anandamide), also increase sleep. However, the mechanism by which these molecules promote sleep is not known but might involve a sleep-inducing molecule such as adenosine. Microdialysis samples were collected from the basal forebrain in order to detect levels of adenosine before and after injection of anandamide. Rats were implanted for sleep studies, and a cannula was placed in the basal forebrain to collect microdialysis samples. Samples were analyzed using high-performance liquid chromatography. Basic neuroscience research laboratory. Three-month-old male F344 rats. At the start of the lights-on period, animals received systemic injections of dimethyl sulfoxide (vehicle), anandamide, SR141716A (cannabinoid receptor 1 [CB1] antagonist), or SR141716A and anandamide. One hour after injections, microdialysis samples were collected (5 microL) from the basal forebrain every hour over a 20-minute period for 5 hours. The samples were immediately analyzed via high-performance liquid chromatography for adenosine levels. Sleep was also recorded continuously over the same period. Anandamide increased adenosine levels compared to vehicle controls with the peak levels being reached during the third hour after drug injection. There was a significant increase in slow-wave sleep during the third hour. The induction in sleep and the rise in adenosine were blocked by the CB1-receptor antagonist, SR141716A. Anandamide increased adenosine levels in the basal forebrain and also increased sleep. The soporific effects of anandamide were mediated by the CB1 receptor, since the effects were blocked by the CB1-receptor antagonist. These findings identify a potential therapeutic use of endocannabinoids to induce sleep in conditions where sleep may be severely attenuated.

Linalool Ameliorates Memory Loss and Behavioral Impairment Induced by REM-Sleep Deprivation through the Serotonergic Pathway.

PubMed

Lee, Bo Kyung; Jung, An Na; Jung, Yi-Sook

2018-07-01

Rapid eye movement (REM) sleep has an essential role in the process of learning and memory in the hippocampus. It has been reported that linalool, a major component of Lavandula angustifolia , has antioxidant, anti-inflammatory, and neuroprotective effects, along with other effects. However, the effect of linalool on the cognitive impairment and behavioral alterations that are induced by REM-sleep deprivation has not yet been elucidated. Several studies have reported that REM-sleep deprivation-induced memory deficits provide a well-known model of behavioral alterations. In the present study, we examined whether linalool elicited an anti-stress effect, reversing the behavioral alterations observed following REM-sleep deprivation in mice. Furthermore, we investigated the underlying mechanism of the effect of linalool. Spatial memory and learning memory were assessed through Y maze and passive avoidance tests, respectively, and the forced swimming test was used to evaluate anti-stress activity. The mechanisms through which linalool improves memory loss and behavioral alterations in sleep-deprived mice appeared to be through an increase in the serotonin levels. Linalool significantly ameliorated the spatial and learning memory deficits, and stress activity observed in sleep-deprived animals. Moreover, linalool led to serotonin release, and cortisol level reduction. Our findings suggest that linalool has beneficial effects on the memory loss and behavioral alterations induced by REM-sleep deprivation through the regulation of serotonin levels.

Therapy for sleep hypoventilation and central apnea syndromes.

PubMed

Selim, Bernardo J; Junna, Mithri R; Morgenthaler, Timothy I

2012-10-01

• Primary Central Sleep Apnea (CSA): We would recommend a trial of Positive Airway Pressure (PAP), acetazolamide, or zolpidem based on thorough consideration of risks and benefits and incorporation of patient preferences.• Central Sleep Apnea Due to Cheyne-Stokes Breathing Pattern in Congestive Heart Failure (CSR-CHF): We would recommend PAP devices such as continuous positive airway pressure (CPAP) or adaptive servo-ventilation (ASV) to normalize sleep-disordered breathing after optimizing treatment of heart failure. Oxygen may also be an effective therapy. Acetazolamide and theophylline may be considered if PAP or oxygen is not effective.• Central Sleep Apnea due to High-Altitude Periodic Breathing: We would recommend descent from altitude or supplemental oxygen. Acetazolamide may be used when descent or oxygen are not feasible, or in preparation for ascent to high altitude. Slow ascent may be preventative.• Central Sleep Apnea due to Drug or Substance: If discontinuation or reduction of opiate dose is not feasible or effective, we would recommend a trial of CPAP, and if not successful, treatment with ASV. If ASV is ineffective or if nocturnal hypercapnia develops, bilevel positive airway pressure-spontaneous timed mode (BPAP-ST) is recommended.• Obesity hypoventilation syndrome: We would recommend an initial CPAP trial. If hypoxia or hypercapnia persists on CPAP, BPAP, BPAP-ST or average volume assured pressure support (AVAPS™) is recommended. Tracheostomy with nocturnal ventilation should be considered when the above measures are not effective. Weight loss may be curative.• Neuromuscular or chest wall disease: We would recommend early implementation of BPAP-ST based on thorough consideration of risks and benefits and patient preferences. AVAPS™ may also be considered. We recommend close follow up due to disease progression.

Delta sleep-inducing peptide (DSIP): a still unresolved riddle.

PubMed

Kovalzon, Vladimir M; Strekalova, Tatyana V

2006-04-01

Delta sleep-inducing peptide (DSIP) was isolated from rabbit cerebral venous blood by Schoenenberger-Monnier group from Basel in 1977 and initially regarded as a candidate sleep-promoting factor. However, the link between DSIP and sleep has never been further characterized, in part because of the lack of isolation of the DSIP gene, protein and possible related receptor. Thus the hypothesis regarding DSIP as a sleep factor is extremely poorly documented and still weak. Although DSIP itself presented a focus of study for a number of researchers, its natural occurrence and biological activity still remains obscure. DSIP structure is different from any other known representative of the various peptide families. In this mini-review we hypothesize the existence of a DSIP-like peptide(s) that is responsible (at least partly) for DSIP-like immunoreactivity and DSIP biological activity. This assumption is based on: (i) a highly specific distribution of DSIP-like immunoreactivity in the neurosecretory hypothalamic nuclei of various vertebrate species that are not particularly relevant for sleep regulation, as revealed by the histochemical studies of the Geneva group (Charnay et al.); (ii) a large spectrum of DSIP biological activity revealed by biochemical and physiological studies in vitro; (iii) significant slow-wave sleep (SWS) promoting activity of certain artificial DSIP structural analogues (but not DSIP itself!) in rabbits and rats revealed by our early studies; and (iv) significant SWS-promoting activity of a naturally occurring dermorphin-decapeptide that is structurally similar to DSIP (in five of the nine positions) and the sleep-suppressing effect of its optical isomer, as revealed in rabbits. Potential future studies are outlined, including natural synthesis and release of this DSIP-like peptide and its role in neuroendocrine regulation.

Intermittent hypercapnic hypoxia during sleep does not induce ventilatory long-term facilitation in healthy males.

PubMed

Deacon, Naomi L; McEvoy, R Doug; Stadler, Daniel L; Catcheside, Peter G

2017-09-01

Intermittent hypoxia-induced ventilatory neuroplasticity is likely important in obstructive sleep apnea pathophysiology. Although concomitant CO 2 levels and arousal state critically influence neuroplastic effects of intermittent hypoxia, no studies have investigated intermittent hypercapnic hypoxia effects during sleep in humans. Thus the purpose of this study was to investigate if intermittent hypercapnic hypoxia during sleep induces neuroplasticity (ventilatory long-term facilitation and increased chemoreflex responsiveness) in humans. Twelve healthy males were exposed to intermittent hypercapnic hypoxia (24 × 30 s episodes of 3% CO 2 and 3.0 ± 0.2% O 2 ) and intermittent medical air during sleep after 2 wk washout period in a randomized crossover study design. Minute ventilation, end-tidal CO 2 , O 2 saturation, breath timing, upper airway resistance, and genioglossal and diaphragm electromyograms were examined during 10 min of stable stage 2 sleep preceding gas exposure, during gas and intervening room air periods, and throughout 1 h of room air recovery. There were no significant differences between conditions across time to indicate long-term facilitation of ventilation, genioglossal or diaphragm electromyogram activity, and no change in ventilatory response from the first to last gas exposure to suggest any change in chemoreflex responsiveness. These findings contrast with previous intermittent hypoxia studies without intermittent hypercapnia and suggest that the more relevant gas disturbance stimulus of concomitant intermittent hypercapnia frequently occurring in sleep apnea influences acute neuroplastic effects of intermittent hypoxia. These findings highlight the need for further studies of intermittent hypercapnic hypoxia during sleep to clarify the role of ventilatory neuroplasticity in the pathophysiology of sleep apnea. NEW & NOTEWORTHY Both arousal state and concomitant CO 2 levels are known modulators of the effects of intermittent hypoxia on