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CNS Drugs Jul 2023Daridorexant, a dual orexin receptor antagonist approved in early 2022, reduces wake after sleep onset without reducing the number of awakenings in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Daridorexant, a dual orexin receptor antagonist approved in early 2022, reduces wake after sleep onset without reducing the number of awakenings in patients with insomnia. The objective of this post hoc analysis was to explore the effect of daridorexant on the number, duration, and distribution of night-time wake bouts, and their correlation with daytime functioning.
METHODS
Adults with insomnia disorder were randomized 1:1:1:1:1:1 to placebo, zolpidem 10 mg, or daridorexant 5, 10, 25, or 50 mg in a phase II dose-finding study, and 1:1:1 to placebo or daridorexant 25 or 50 mg in a pivotal phase III study. We analyzed polysomnography data for daridorexant 25 and 50 mg, zolpidem 10 mg, and placebo groups. Polysomnography was conducted at baseline, then on Days 1/2, 15/16, and 28/29 in the phase II study, and Months 1 and 3 in the phase III study. The number, duration, and distribution of wake bouts (≥ 0.5 min) were assessed.
RESULTS
Data from 1111 patients (phase II study: daridorexant 50 mg [n = 61], zolpidem 10 mg [n = 60], placebo [n = 60]; phase III study: daridorexant 25 mg [n = 310], daridorexant 50 mg [n = 310], placebo [n = 310]) were analyzed. Long wake bouts were defined as > 6 min. Compared with placebo, daridorexant 50 mg reduced overall wake time (p < 0.05; all time points, both studies), the odds of experiencing long wake bouts (p < 0.001; Months 1 and 3, phase III study), and the cumulative duration of long wake bouts (p < 0.01; all time points, both studies). Reductions in long wake bouts were sustained through the second half of the night and correlated with improvements in daytime functioning. An increase in the cumulative duration of short wake bouts was observed with daridorexant 50 mg (p < 0.01 vs placebo, Months 1 and 3, phase III study); this was uncorrelated with daytime functioning.
CONCLUSION
Daridorexant reduced the number and duration of longer wake bouts throughout the night compared with placebo, corresponding with improved daytime functioning.
CLINICAL TRIALS
Clinicaltrials.gov NCT02839200 (registered July 20, 2016), NCT03545191 (registered June 4, 2018).
Topics: Adult; Humans; Zolpidem; Sleep Initiation and Maintenance Disorders; Pyridines; Double-Blind Method
PubMed: 37477771
DOI: 10.1007/s40263-023-01020-9 -
Frontiers in Psychiatry 2022Mental health problems and impaired sexual function are widely reported among those suffering from drug abuse, particularly among those under methadone maintenance...
BACKGROUND
Mental health problems and impaired sexual function are widely reported among those suffering from drug abuse, particularly among those under methadone maintenance therapy (MMT).
AIMS
The current study aimed to, firstly, investigate the effect of melatonin and zolpidem on mental health and sexual function of those with drug abuse under MMT, and, secondly, to compare the effects of melatonin and zolpidem on the studied outcomes.
METHODS
The current randomized, single-blind, placebo-controlled clinical trial was conducted on 98 participants who were randomly assigned into three groups of melatonin ( = 34), zolpidem ( = 32), and placebo ( = 32). All participants received the intervention once a day for 30 days, without changes in nutrition. Mental health and sexual function were measured before and 30 days after the intervention.
RESULTS
The mean age of participants in the groups of melatonin, zolpidem, and placebo was 35.8 ± 9.6 years (22-58 years of old), 35.9 ± 9.3 years (21-58), and 37.2 ± 7.8 years (26-53), respectively. Sexual function mean score was significantly increased from 38 to 41 in the melatonin group, while it deceased in zolpidem (from 39.1 to 38) and placebo (39.25-38.59) groups. Also, mental health mean scores improved statistically significantly in the melatonin group (from 60.65 to 43.56; = 0.002), and descriptively in the zolpidem group (57.88-51.18; = 0.129). Concerning both outcomes, the observed improvement was considerably higher in the melatonin group. The highest improvement was observed in dimensions of overall satisfaction and depression in the melatonin group (1.18 and -8.4, respectively).
CONCLUSION
Melatonin could significantly improve both mental health and some domains of sexual function of those with drug abuse under MMT, while zolpidem did not show a significant effect.
TRIAL REGISTRATION NUMBER
https://www.irct.ir/trial/53047, identifier: IRCT20201214049718N1.
PubMed: 35295771
DOI: 10.3389/fpsyt.2022.850480 -
SAGE Open Medicine 2017Women 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...
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, and specifically young women, with initial prescriptions for low-dose zolpidem significantly increased as compared to before the labeling change.
PubMed: 28515934
DOI: 10.1177/2050312117707687 -
Annals of Emergency Medicine Mar 2015
Topics: Aged; Aircraft; Confusion; Emergencies; Humans; Hypnotics and Sedatives; Male; Pyridines; Stroke; Zolpidem
PubMed: 25702187
DOI: 10.1016/j.annemergmed.2014.11.003 -
BMJ Case Reports May 2015
Topics: Aged, 80 and over; Antipsychotic Agents; Azabicyclo Compounds; Chorea; Drug Administration Schedule; Female; Humans; Hypnotics and Sedatives; Piperazines; Pyridines; Sleep Wake Disorders; Tiapride Hydrochloride; Treatment Outcome; Zolpidem
PubMed: 25999122
DOI: 10.1136/bcr-2014-208872 -
Forensic Toxicology Jul 2022Zolpidem (ZOL) is a hypnotic sometimes used in drug-facilitated crimes. Understanding ZOL metabolism is important for proving ZOL intake. In this study, we synthesized...
PURPOSE
Zolpidem (ZOL) is a hypnotic sometimes used in drug-facilitated crimes. Understanding ZOL metabolism is important for proving ZOL intake. In this study, we synthesized standards of hydroxyzolpidems with a hydroxy group attached to the pyridine ring and analyzed them to prove their presence in postmortem urine. We also searched for novel ZOL metabolites in the urine sample using liquid chromatography-triple quadrupole mass spectrometry (LC-QqQMS) and liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QqTOFMS).
METHODS
7- and 8-Hydroxyzolpidem (7OHZ and 8OHZ, respectively) were synthesized and analyzed using LC-QqQMS. Retention times were compared between the synthetic standards and extracts of postmortem urine. To search for novel ZOL metabolites, first, the urine extract was analyzed with data-dependent acquisition, and the peaks showing the characteristic fragmentation pattern of ZOL were selected. Second, product ion spectra of these peaks at various collision energies were acquired and fragments that could be used for multiple reaction monitoring (MRM) were chosen. Finally, MRM parameters were optimized using the urine extract. These peaks were also analyzed using LC-QqTOFMS.
RESULTS
The presence of 7OHZ and 8OHZ in urine was confirmed. The highest peak among hydroxyzolpidems was assigned to 7OHZ. The novel metabolites found were zolpidem dihydrodiol and its glucuronides, cysteine adducts of ZOL and dihydro(hydroxy)zolpidem, and glucuronides of hydroxyzolpidems.
CONCLUSIONS
The presence of novel metabolites revealed new metabolic pathways, which involve formation of an epoxide on the pyridine ring as an intermediate.
Topics: Zolpidem; Glucuronides; Tandem Mass Spectrometry; Chromatography, Liquid; Pyridines
PubMed: 36454403
DOI: 10.1007/s11419-021-00611-9 -
The Journal of Clinical Psychiatry Jun 2021To describe lemborexant for the treatment of insomnia () in adults using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or... (Randomized Controlled Trial)
Randomized Controlled Trial
Lemborexant for the Treatment of Insomnia: Direct and Indirect Comparisons With Other Hypnotics Using Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed.
To describe lemborexant for the treatment of insomnia () in adults using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Lemborexant data were obtained from two Phase 3 trials conducted 2016-2018. Efficacy was assessed using different categorical definitions for response, and tolerability was assessed by evaluating rates of adverse events (AEs). Direct comparisons were made with zolpidem extended release (ER), and indirect comparisons were made with other hypnotic agents, including suvorexant, doxepin, ramelteon, zolpidem immediate release, eszopiclone, zaleplon, and selected benzodiazepines, using data from published reports and regulatory documents. Lemborexant had a clinically relevant magnitude of therapeutic effect, as evidenced by NNT values versus placebo as robust as 3 (95% CI, 2-3). In general, NNH values for lemborexant versus placebo were ≥ 10, suggesting that lemborexant is relatively tolerable. Somnolence was the most common AE, with NNH estimates of 28 (95% CI, 18-61) and 15 (95% CI, 11-22) for lemborexant 5 mg and 10 mg, respectively. Rates of discontinuation of lemborexant because of an AE were low, and for lemborexant 5 mg the rate was lower than that for placebo. LHH contrasting the statistically significant endpoint efficacy measures versus discontinuation because of an AE ranged from 13 to 54. NNT values for lemborexant were generally more robust than for zolpidem ER for the polysomnography and sleep diary outcomes. In indirect comparisons, NNT data for the other hypnotics demonstrated effect sizes that were generally similar to those for lemborexant. In Phase 3 trials, the benefit-risk ratio for lemborexant is favorable as measured by NNT, NNH, and LHH. ClinicalTrials.gov identifiers: NCT02783729, NCT02952820.
Topics: Acetamides; Adolescent; Adult; Azepines; Benzodiazepines; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Orexin Receptor Antagonists; Pyridines; Pyrimidines; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; Young Adult; Zolpidem
PubMed: 34077032
DOI: 10.4088/JCP.20m13795 -
Revista Brasileira de Psiquiatria (Sao... Apr 2020To evaluate the safety and efficacy of a 5 mg sublingual dose of zolpidem, compared to a 10 mg oral dose, at bedtime and "as needed" following middle-of-the-night... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
To evaluate the safety and efficacy of a 5 mg sublingual dose of zolpidem, compared to a 10 mg oral dose, at bedtime and "as needed" following middle-of-the-night awakenings.
METHODS
Participants were randomized into an oral group (oral zolpidem 10 mg and sublingual placebo at bedtime and "as-needed") and a sublingual group (oral placebo and sublingual zolpidem 5 mg at bedtime and "as-needed"). Participants underwent medical evaluation, polysomnography, the psychomotor vigilance test, and completed questionnaires.
RESULTS
Of 85 patients, 67 met the criteria for insomnia (48±10 years; 79% women) and were randomized. Of these, 46 completed 92±5 days of treatment. Mild-to-moderate adverse events were reported by 25% of the participants, including headache, sleepiness, and dizziness. Both treatments decreased middle-of-the-night awakenings by an average of -3.1±2.3 days/week and increased total sleep time by 1.5 hours. Changes in sleep quality and insomnia severity scores were also favorable and comparable between groups: variation depended on continuation of treatment. Regarding PSG findings, sleep latency decreased more in the sublingual group than the oral group (-14±42 vs. 10±29 min; p = 0.03). The psychomotor vigilance test showed minor residual effects 30 minutes after awakening, which reversed after 2 hours.
CONCLUSIONS
The safety and efficacy of both zolpidem formulations are comparable. The sublingual 5 mg dose induced sleep more rapidly.
CLINICAL TRIAL REGISTRATION
NCT01896336.
Topics: Administration, Oral; Administration, Sublingual; Adult; Double-Blind Method; Female; Humans; Male; Middle Aged; Polysomnography; Prospective Studies; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Zolpidem
PubMed: 31859791
DOI: 10.1590/1516-4446-2019-0389 -
Journal of Clinical Sleep Medicine :... Aug 2009Recent meta-analyses raising concern about risks of hypnotics suggest a need for more clarification of these risks. (Meta-Analysis)
Meta-Analysis Review
STUDY OBJECTIVES
Recent meta-analyses raising concern about risks of hypnotics suggest a need for more clarification of these risks.
METHODS
Because of preliminary suggestions that eszopiclone causes infections, we studied US Food and Drug Administration files on the 4 most-recently approved hypnotics, combined with published studies, to compile the risk ratios of infections for groups randomly assigned to receive hypnotics versus those assigned to receive placebos in controlled trials. Parallel controlled clinical trials of eszopiclone, ramelteon, zaleplon, and zolpidem were included when data on subjects, duration of exposure, and adverse effects were available. Results of trials were combined by meta-analyses.
RESULTS
Of 8828 participants assigned to the 4 hypnotics and 4383 participants who randomly received placebos, 606 in the hypnotics groups and 200 in the placebo groups were reported to develop some kind of infection (risk ratio = 1.44, 95% confidence interval 1.25-1.64, p < 0.00001). Most infections were apparently mild and did not lead to dropouts. Subanalyses for individual drugs indicated that eszopiclone and zolpidem individually were associated with reported infections. There were insufficient data concerning individual studies of zaleplon and ramelteon for valid secondary meta-analyses of zaleplon or ramelteon by themselves.
CONCLUSIONS
Research is needed to objectively determine whether the use of hypnotics increases the risk of infections. Immune compromise or esophageal reflux and aspiration should be studied as possible mechanisms.
Topics: Acetamides; Azabicyclo Compounds; Eszopiclone; Humans; Hypnotics and Sedatives; Indenes; Infections; Piperazines; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Risk; Zolpidem
PubMed: 19968019
DOI: No ID Found -
The American Journal of Psychiatry Jun 2008Ms. F, a 42-year-old divorced woman, presents for evaluation of chronic insomnia. She complains of difficulty falling asleep, often 30 minutes or longer, and difficulty...
Ms. F, a 42-year-old divorced woman, presents for evaluation of chronic insomnia. She complains of difficulty falling asleep, often 30 minutes or longer, and difficulty maintaining sleep during the night, with frequent awakenings that often last 30 minutes or longer. These symptoms occur nearly every night, with only one or two “good” nights per month. She typically goes to bed around 10:00 p.m. to give herself adequate time for sleep, and she gets out of bed around 7:00 a.m. on work days and as late as 9:00 a.m. on weekends. Her nighttime sleep problems result in daytime irritability and difficulty focusing and organizing her thoughts, which subjectively impair her work as an administrative assistant, although her performance evaluations have been satisfactory. She says that she has “no energy for anything extra,” that her house is a mess, and that she routinely declines invitations to join social and even family activities. Her insomnia began approximately 5 years ago during a period of increased life stress related to a difficult divorce and a job change. At that time she was diagnosed with major depression and was started on a successful trial of escitalopram, which she continues at a dose of 10 mg/day. Her current symptoms are distinct from those that were associated with her episode of major depression. She denies pervasive sadness or loss of interest, but she is very frustrated with her inability to function more effectively, which she attributes to her insomnia. In fact, she believes that her cognitive difficulties and irritability are most noticeable after nights of particularly poor sleep. Her medical history is unremarkable other than a past history of Graves’ disease. She has been treated with levothyroxine for the past 15 years. How should Ms. F be evaluated? What medical testing, if any, would be appropriate? What factors should be considered in formulating a treatment plan? What treatments would be appropriate?
Topics: Adult; Behavior Therapy; Chronic Disease; Combined Modality Therapy; Comorbidity; Depressive Disorder, Major; Diagnosis, Differential; Female; Humans; Hypnotics and Sedatives; Medical History Taking; Patient Education as Topic; Pyridines; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 18519533
DOI: 10.1176/appi.ajp.2008.08010129