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Sleep Oct 2018The present study investigated the function of Hypocretin (Hcrt or Orexin/OX) receptor antagonists in sleep modulation and memory function with optical methods in...
STUDY OBJECTIVES
The present study investigated the function of Hypocretin (Hcrt or Orexin/OX) receptor antagonists in sleep modulation and memory function with optical methods in transgenic mice.
METHODS
We used Hcrt-IRES-Cre knock-in mice and AAV vectors expressing channelrhodopsin-2 (ChR2) to render Hcrt neurons sensitive to blue light stimulation. We optogenetically stimulated Hcrt neurons and measured latencies to wakefulness in the presence or absence of OX1/2R antagonists and Zolpidem. We also examined endogenous Hcrt neuronal activity with fiber photometry. Changes in memory after optogenetic sleep disruption were evaluated by the novel object recognition test (NOR) and compared for groups treated with vehicle, OX1/2R antagonists, or Zolpidem. We also analyzed electroencephalogram (EEG) power spectra of wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep following the injections of vehicle, OX1/2R antagonists, and Zolpidem in young adult mice.
RESULTS
Acute optogenetic stimulation of Hcrt neurons at different frequencies resulted in wakefulness. Treatment with dual OX1/2R antagonists (DORAs) DORA12 and MK6096, as well as selective OX2R antagonist MK1064 and Zolpidem, but not selective OX1R antagonist 1SORA1, significantly reduced the bout length of optogenetic stimulation-evoked wakefulness episode. Fiber photometry recordings of GCaMP6f signals showed that Hcrt neurons are active during wakefulness, even in the presence of OXR antagonists. Treatment with dual OX1/2R antagonists improved memory function despite optogenetic sleep fragmentation caused impaired memory function in a NOR test.
CONCLUSIONS
Our results show DORAs and selective OX2R antagonists stabilize sleep and improve sleep-dependent cognitive processes even when challenged by optogenetic stimulation mimicking highly arousing stimuli.
Topics: Animals; Electroencephalography; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Orexin Receptor Antagonists; Photic Stimulation; Sleep; Wakefulness; Zolpidem
PubMed: 30060151
DOI: 10.1093/sleep/zsy141 -
Sleep Medicine: X Dec 2020Zolpidem is associated with sleep-related eating disorder (SRED). We compiled case reports and performed a descriptive study to identify etiology and aggravating factors. (Review)
Review
OBJECTIVE
Zolpidem is associated with sleep-related eating disorder (SRED). We compiled case reports and performed a descriptive study to identify etiology and aggravating factors.
METHODS
A literature search on PubMed's MeSH search feature, CINAHL, and SciFinder was performed using search terms "Zolpidem," "Feeding and Eating Disorders/chemically induced," "Dyssomnias," "sleep eating disorder," and "sleep-related eating disorder." Three reviewers examined all English and Spanish citations and extracted pertinent information. A narrative synthesis of the evidence was prepared.
RESULTS
We identified 40 case reports of which 65% were female, and the mean age was 53 years. SRED onset was most commonly seen with daily zolpidem doses of 10 mg or higher (95% of patients). Prior medical history included obstructive sleep apnea (OSA) (35%), depression (32.5%), and restless leg syndrome (RLS) (25%). Even with controlled RLS and OSA, SRED developed in some patients. All patients had either partial or full amnesia with compulsive eating. Onset of SRED occurred as early as the first dose to after 9 years of use. SRED symptoms occurred nightly in 57.5% of patients. Discontinuation of zolpidem resolved SRED in all patients (n = 36).
CONCLUSION
SRED associated with zolpidem can occur with any dose, but was most common with higher doses of zolpidem. Therefore, prescribers should initiate lower doses of zolpidem. Interestingly, many patients had underlying disorders known to affect sleep (RLS, OSA, depression). Although it is recommended to control these underlying disorders prior to initiating zolpidem, SRED may still occur. Zolpidem discontinuation resolved all cases of SRED.
PubMed: 33870172
DOI: 10.1016/j.sleepx.2020.100019 -
Journal of Medical Toxicology :... Jun 2013Despite their improved pharmacokinetic profile, the Z-drugs, zolpidem, zopiclone, and zaleplon, have a spectrum of adverse effects comparable to benzodiazepines. This... (Review)
Review
Despite their improved pharmacokinetic profile, the Z-drugs, zolpidem, zopiclone, and zaleplon, have a spectrum of adverse effects comparable to benzodiazepines. This review focuses on the impairment from Z-drugs on cognition, behavior, psychomotor performance, and driving ability. Z-drugs are short-acting GABA agonists that reduce sleep latency without disturbing sleep architecture. Bizarre behavioral effects have prompted warnings on the prescription, dispensation, and use of Z-drugs. Psychomotor impairment, falls, and hip fractures are more likely to occur with Z-drugs that have longer half-lives, that are taken at higher-than-recommended doses and when mixed with other psychoactive substances including alcohol. Zopiclone and higher doses of zolpidem are more likely to cause anterograde amnesia than zaleplon. Z-drugs, especially zolpidem, are associated with complex behaviors such as sleepwalking, sleep-driving, and hallucinations. Patients taking zopiclone and zolpidem have an increased risk of motor vehicle collisions, over double that of unexposed drivers. Driving impairment occurs with zopiclone and higher doses of zolpidem but is unlikely to occur after 4 h post-zaleplon administration. The residual effect of Z-drugs on next-day cognitive and psychomotor performance has significant impact on lifestyle, safety, and occupational considerations, including motor vehicle and machine operation. The risk-benefit analysis of Z-drugs in the treatment of insomnia, particularly in the elderly, may not favor treatment due to the increased risks of falls and motor vehicle collisions. Prescribers should warn patients taking Z-drugs of minimum time thresholds before they operate machinery or drive motor vehicles.
Topics: Acetamides; Automobile Driving; Azabicyclo Compounds; GABA-A Receptor Agonists; Humans; Hypnotics and Sedatives; Piperazines; Psychomotor Disorders; Psychomotor Performance; Pyridines; Pyrimidines; Zolpidem
PubMed: 23456542
DOI: 10.1007/s13181-013-0294-y -
Scientific Reports Sep 2021To investigate pharmacokinetic and pharmacodynamic differences of zolpidem between males and females and their causes, including CYP3A4 activity. A single oral dose of...
To investigate pharmacokinetic and pharmacodynamic differences of zolpidem between males and females and their causes, including CYP3A4 activity. A single oral dose of zolpidem (10 mg) was administered to 15 male and 15 female healthy subjects. Blood samples were collected up to 12 h post-dose to determine plasma zolpidem concentrations. Pharmacokinetic parameters were obtained using non-compartmental analysis. Digit symbol substitution test, choice reaction time, and visual analog scale of sleepiness were used to evaluate pharmacodynamics. We measured CYP3A4 activity using 4β-hydroxycholesterol, an endogenous metabolite. Mean maximum plasma concentration and area under the plasma concentration-time curve were higher for females than for males (9.9% and 32.5%, respectively); other pharmacokinetic parameters showed no significant differences. Pharmacodynamic scores for females showed delayed recovery compared with that for males. CYP3A4 activity was higher in females than in males (p = 0.030). There was no serious adverse event, and adverse event incidence was not different between the sexes. Zolpidem exposure was about 30% higher in females than in males. Delayed pharmacodynamic score recovery in females could be related to higher zolpidem concentrations. Although apparent clearance was lower in females, systemic clearance might not be the cause of the different exposures to zolpidem.
Topics: Administration, Oral; Adult; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A; Female; Healthy Volunteers; Humans; Hypnotics and Sedatives; Male; Metabolic Clearance Rate; Sex Factors; Young Adult; Zolpidem
PubMed: 34580385
DOI: 10.1038/s41598-021-98689-z -
CNS Neuroscience & Therapeutics Oct 2011Insomnia is a common condition that affects one's ability to sleep comfortably and consequently to work effectively. Its etiology is multifactorial and involves plethora... (Review)
Review
Insomnia is a common condition that affects one's ability to sleep comfortably and consequently to work effectively. Its etiology is multifactorial and involves plethora of risk factors. Consequences can vary from mild sleepiness to more sever psychiatric disturbances and ischemic stroke. Despite several diagnostic criteria it is poorly diagnosed and less often treated. Benzodiazepines formed the mainline therapy for many years till the advent of newer nonbenzodiazepine group of drugs including zolpidem. Zolpidem is an imidazo-pyridine compound that enhances the GABA(A) receptor function by interaction with Omega-1 receptor subtype. Its pharmacokinetic profile allows the patients to use it later in the night when having trouble falling asleep without any residual cognitive impairment the next morning. It has rapid onset of action, improves total sleep duration, and reduces night-time awakenings. Its adverse effect profile is satisfactory as it appears to have low addiction potential. This review will focus on the current role of zolpidem in the management of insomnia.
Topics: Animals; Disease Management; Humans; Hypnotics and Sedatives; Pyridines; Sleep Initiation and Maintenance Disorders; Sleep Stages; Zolpidem
PubMed: 20553305
DOI: 10.1111/j.1755-5949.2010.00158.x -
Neuropsychopharmacology : Official... Apr 2012Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind,... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
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 GABA(A) 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.
Topics: Adolescent; Adult; Analysis of Variance; Benzofurans; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Electroencephalography; GABA-A Receptor Agonists; Humans; Male; Middle Aged; Neuropsychological Tests; Orexin Receptors; Polysomnography; Psychomotor Performance; Pyridines; Reaction Time; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep Initiation and Maintenance Disorders; Sleep, REM; Surveys and Questionnaires; Thiazoles; Wakefulness; Young Adult; Zolpidem
PubMed: 22237311
DOI: 10.1038/npp.2011.310 -
JAMA Network Open Dec 2023Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Daytime functional impairments are the primary reasons for patients with insomnia to seek treatment, yet little is known about what the optimal treatment is for improving daytime functions and how best to proceed with treatment for patients whose insomnia has not remitted.
OBJECTIVES
To compare the efficacy of behavioral therapy (BT) and zolpidem as initial therapies for improving daytime functions among patients with insomnia and evaluate the added value of a second treatment for patients whose insomnia has not remitted.
DESIGN, SETTING, AND PARTICIPANTS
In this sequential multiple-assignment randomized clinical trial conducted at institutions in Canada and the US, 211 adults with chronic insomnia disorder were enrolled between May 1, 2012, and December 31, 2015, and followed up for 12 months. Statistical analyses were performed on an intention-to-treat basis in April and October 2023.
INTERVENTIONS
Participants were randomly assigned to either BT or zolpidem as first-stage therapy, and those whose insomnia had not remitted received a second-stage psychological therapy (BT or cognitive therapy) or medication therapy (zolpidem or trazodone).
MAIN OUTCOMES AND MEASURES
Study outcomes were daytime symptoms of insomnia, including mood disturbances, fatigue, functional impairments of insomnia, and scores on the 36-item Short-Form Health Survey (SF-36) physical and mental health components.
RESULTS
Among 211 adults with insomnia (132 women [63%]; mean [SD] age, 45.6 [14.9] years), 104 were allocated to BT and 107 to zolpidem at the first stage. First-stage treatment with BT or zolpidem yielded significant and equivalent benefits for most of the daytime outcomes, including depressive symptoms (Beck Depression Inventory-II mean score change, -3.5 [95% CI, -4.7 to -2.3] vs -4.3 [95% CI, -5.7 to -2.9]), fatigue (Multidimensional Fatigue Inventory mean score change, -4.7 [95% CI, -7.3 to -2.2] vs -5.2 [95% CI, -7.9 to -2.5]), functional impairments (Work and Social Adjustment Scale mean score change, -5.0 [95% CI, -6.7 to -3.3] vs -5.1 [95% CI, -7.2 to -2.9]), and mental health (SF-36 mental health subscale mean score change, 3.5 [95% CI, 1.9-5.1] vs 2.5 [95% CI, 0.4-4.5]), while BT produced larger improvements for anxiety symptoms relative to zolpidem (State-Trait Anxiety Inventory mean score change, -4.1 [95% CI, -5.8 to -2.4] vs -1.2 [95% CI, -3.0 to 0.5]; P = .02; Cohen d = 0.55). Second-stage therapy produced additional improvements for the 2 conditions starting with zolpidem at posttreatment in fatigue (Multidimensional Fatigue Inventory mean score change: zolpidem plus BT, -3.8 [95% CI, -7.1 to -0.4]; zolpidem plus trazodone, -3.7 [95% CI, -6.3 to -1.1]), functional impairments (Work and Social Adjustment Scale mean score change: zolpidem plus BT, -3.7 [95% CI, -6.4 to -1.0]; zolpidem plus trazodone, -3.3 [95% CI, -5.9 to -0.7]) and mental health (SF-36 mental health subscale mean score change: zolpidem plus BT, 5.3 [95% CI, 2.7-7.9]; zolpidem plus trazodone, 2.0 [95% CI, 0.1-4.0]). Treatment benefits achieved at posttreatment were well maintained throughout the 12-month follow-up, and additional improvements were noted for patients receiving the BT treatment sequences.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of adults with insomnia disorder, BT and zolpidem produced improvements for various daytime symptoms of insomnia that were no different between treatments. Adding a second treatment offered an added value with further improvements of daytime functions.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01651442.
Topics: Adult; Female; Humans; Middle Aged; Behavior Therapy; Fatigue; Sleep Initiation and Maintenance Disorders; Trazodone; Zolpidem; Male
PubMed: 38153735
DOI: 10.1001/jamanetworkopen.2023.49638 -
Sleep Medicine Apr 2016Prescription sleep medication use is most prevalent among women and older adults. Morning drowsiness and impaired coordination are side effects of sleep medications that...
OBJECTIVE
Prescription sleep medication use is most prevalent among women and older adults. Morning drowsiness and impaired coordination are side effects of sleep medications that may affect driving safety. The association between current use of zolpidem-containing medications and motor vehicle collisions (MVCs) was evaluated among drivers of advanced age.
METHODS
Participants were current drivers aged ≥70 years residing in north-central Alabama, spoke English, had a valid driver's license, and had driven within the past three months (n = 2000). Current zolpidem use was determined by pill bottle review. The participant's five-year MVC history was determined from Alabama Department of Public Safety accident reports. The five-year MVC and at-fault MVC rate ratios (RR) were estimated comparing zolpidem users with nonusers in the overall sample and a priori-defined age and sex subgroups.
RESULTS
The unadjusted RR (95% confidence interval [CI]) of MVCs comparing zolpidem users with nonusers was attenuated after adjustment (1.46 [1.02-2.08] and 1.38 [0.97-1.98], respectively). Among women, the unadjusted and adjusted RRs (95% CI) were 1.65 (1.03-2.66) and 1.61 (1.00-2.60), respectively. The unadjusted and adjusted RRs (95% CI) among those aged 80 years or more were 2.24 (1.19-4.57) and 2.35 (1.20-4.61), respectively. There were no statistically significant associations among men or participants less than 80 years old. Similar patterns were present for at-fault MVCs.
CONCLUSION
Current zolpidem users, specifically women and individuals aged 80 years or more, had higher MVC rates than nonusers. Practitioners should consider behavioral treatment before initiating low doses of zolpidem and increasing it as needed to achieve restorative sleep in women and individuals aged 80 years or more to reduce the risk of zolpidem-associated MVCs.
Topics: Accidents, Traffic; Age Factors; Aged; Aged, 80 and over; Alabama; Automobile Driving; Female; Humans; Hypnotics and Sedatives; Male; Pyridines; Risk Factors; Sex Factors; Zolpidem
PubMed: 27318232
DOI: 10.1016/j.sleep.2015.12.004 -
European Journal of Public Health Apr 2023Since the appearance of zolpidem on the market, the occurrence of serious cases of abuse, misuse and dependence have come to the attention of authorities. In view of the...
BACKGROUND
Since the appearance of zolpidem on the market, the occurrence of serious cases of abuse, misuse and dependence have come to the attention of authorities. In view of the increase in the number and severity of cases among zolpidem users and the predominant presence of zolpidem in falsified prescriptions, the French Health Authorities implemented part of the narcotics regulation for zolpidem in April 2017. The objective of this article was to describe the evolution of the abuse, dependence and misuse of zolpidem.
METHODS
We used three data sources: (i) zolpidem is a reimbursable and strictly prescription drug in France. Medic'AM is a public database that indicates the number of tablets reimbursed each month in France for each reimbursable drug. This database has been analyzed as a proxy of the exposure of the French population to zolpidem; (ii) all French cases of drug dependence or abuse reported by health professionals (regulatory obligation) and (iii) an epidemiological tool based on the surveillance of falsified prescriptions over two periods: the 3-year period before the regulatory measure (2014-16) and the 3-year period after the regulatory measure (2018-20).
RESULTS
This regulatory change had two immediate consequences: a sharp decline in falsified prescriptions and a decrease of ∼57% between the two study periods in the zolpidem reimbursement data. Markers of problematic consumption remained after the regulatory change with worsening cases, particularly for people who were genuinely dependent and/or had comorbidities or misusers for whom zolpidem was the substance of interest, whose proportion increased significantly in the addictovigilance notification system, from 43.6% (N = 107) to 59.3% (N = 127) (P < 0.01).
CONCLUSIONS
Further monitoring is needed in light of these persistent markers of problematic consumption.
Topics: Humans; Zolpidem; Follow-Up Studies; Substance-Related Disorders; Prescriptions; France; Hypnotics and Sedatives
PubMed: 36749030
DOI: 10.1093/eurpub/ckad003 -
PloS One 2018Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of...
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 of zolpidem and poor health outcomes.
Topics: Adult; Afghan Campaign 2001-; Dose-Response Relationship, Drug; Female; Humans; Hypnotics and Sedatives; Iraq War, 2003-2011; Male; Middle Aged; Pyridines; Retrospective Studies; Veterans; Zolpidem
PubMed: 29360821
DOI: 10.1371/journal.pone.0190022