Novel neuropharmacological activity of citrus lime (Citrus aurantifolia): A standardized lime peel supplement enhances non-rapid eye movement sleep by activating the GABA type A receptor.

Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABAA receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABAA receptor and directly activated the GABAA receptors. The hypnotic effects and GABAA receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABAA receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABAA receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic.

Insomnia and the effect of zolpidem-extended-release on the sleep items of the Hamilton Rating Scale for Depression in outpatients with depression, insomnia, and suicidal ideation: Relationship to patient age.

BACKGROUND: There are limited data regarding gamma-aminobutyric acid (GABA) allosteric modulator sleep-aid medications in persons with depression, insomnia, and suicidal ideation (SI). AIMS: This secondary analysis examined the relationship of age to insomnia and the impact of age on the treatment of insomnia with zolpidem extended-release (zolpidem-ER) in depressed suicidal patients. A prior report found that the addition of zolpidem-ER promoted significantly superior reductions in global severity of insomnia in depressed outpatients with insomnia and SI over 8 weeks, but here we report the differences among early, middle, and late insomnia. METHODS: This secondary analysis examined the three early, middle, and late insomnia items of the Hamilton Rating Scale for Depression (HRSD) and their relationship to age and responsiveness to treatment with zolpidem-ER. One hundred and three patients with major depression, SI, and insomnia received open-label serotonin reuptake inhibitors and were randomly allocated 1:1 to receive zolpidem-ER or placebo at bedtime. Results: Older age at baseline was associated with worse middle and late insomnia, but not with early insomnia. Subsequent treatment with zolpidem-ER produced superior improvement in early and middle insomnia, but not late insomnia. CONCLUSIONS: These findings are consistent with the known age-related advancement of sleep timing in the general population and depressed outpatients and with the expected effects of a short half-life GABA allosteric modulator sleep aid. By implication, prescribers of pharmacologic treatment of insomnia in depressed patients should consider an alternative to zolpidem-ER when late insomnia is a concern.Trial registration number: ClinicalTrials.gov Identifier: NCT01689909.

Subclinical brain manifestations of repeated mild traumatic brain injury are changed by chronic exposure to sleep loss, caffeine, and sleep aids.

INTRODUCTION: After mild traumatic brain injury (mTBI), the brain is labile for weeks and months and vulnerable to repeated concussions. During this time, patients are exposed to everyday circumstances that, in themselves, affect brain metabolism and blood flow and neural processing. How commonplace activities interact with the injured brain is unknown. The present study in an animal model investigated the extent to which three commonly experienced exposures-daily caffeine usage, chronic sleep loss, and chronic sleep aid medication-affect the injured brain in the chronic phase. METHODS: Subclinical trauma by repeated mTBIs was produced by our head rotational acceleration injury model, which causes brain injury consistent with the mechanism of concussion in humans. Forty-eight hours after a third mTBI, chronic administrations of caffeine, sleep restriction, or zolpidem (sedative hypnotic) began and were continued for 70 days. On Days 30 and 60 post injury, resting state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were performed. RESULTS: Chronic caffeine, sleep restriction, and zolpidem each changed the subclinical brain characteristics of mTBI at both 30 and 60 days post injury, detected by different MRI modalities. Each treatment caused microstructural alterations in DTI metrics in the insular cortex and retrosplenial cortex compared with mTBI, but also uniquely affected other gray and white matter regions. Zolpidem administration affected the largest number of individual structures in mTBI at both 30 and 60 days, and not necessarily toward normalization (sham treatment). Chronic sleep restriction changed local functional connectivity at 30 days in diametrical opposition to chronic caffeine ingestion, and both treatment outcomes were different from sham, mTBI-only and zolpidem comparisons. The results indicate that commonly encountered exposures modify subclinical brain activity and structure long after healing is expected to be complete. CONCLUSIONS: Changes in activity and structure detected by fMRI are widely understood to reflect changes in the functions of the affected region which conceivably underlie mTBI neuropathology and symptomatology in the chronic phase after injury.

Paradoxical cognitive and language function recovery by zolpidem in a patient with traumatic brain injury: A case report.

BACKGROUND: Traumatic brain injury (TBI) is a significant public health issue, often resulting from traffic accidents and falls, leading to a wide spectrum of outcomes from mild concussions to severe brain damage. The neurorehabilitation of TBI focuses on enhancing recovery and improving quality of life. Zolpidem, traditionally used for short-term management of insomnia, has shown potential in improving cognitive functions and language in TBI patients. Advances in neuroimaging techniques, such as functional near-infrared spectroscopy (fNIRS), have facilitated the exploration of the effects of therapeutic interventions on brain activity and functional connectivity in TBI patients. CASE SUMMARY: We present the case of a 34-year-old male who sustained a TBI from a traffic collision. Despite severe impairments in cognitive and language functions, administration of 10 mg of zolpidem resulted in temporary but significant improvements in these areas, as evidenced by increased Mini-Mental State Examination scores and observed behavioral changes. fNIRS assessments before and after zolpidem administration revealed notable changes in cerebral cortex activity, including increased left hemisphere activation and a shift in functional connectivity to the bilateral frontal lobes, corresponding with the patient's improvement. CONCLUSION: This case study highlights the potential of zolpidem, a medication traditionally used for insomnia, in enhancing cognitive and verbal functions in a patient with TBI, suggesting a potential therapeutic role for zolpidem in neurorehabilitation, supported by changes in brain activity and connectivity observed through fNIRS. However, further investigation is warranted to validate these findings and elucidate zolpidem's long-term effects on cognitive and functional outcomes in TBI patients.

Zolpidem-triggered atrial fibrillation in a patient with cardiomyopathy: a case report.

BACKGROUND: Zolpidem is a non-benzodiazepine hypnotic widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before. CASE PRESENTATION: A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril/valsartan 12/13 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no significant change. The night before admission, the patient attempted suicide by overdosing on 40 mg of zolpidem after an argument, which resulted in severe lethargy. Upon admission, his ECG revealed new-onset AF, necessitating immediate cessation of zolpidem. Nine hours into admission, AF spontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that AF was not detected. CONCLUSIONS: This study provides valuable clinical evidence indicating that zolpidem overdose may induce AF in patients with cardiomyopathy. It serves as a critical warning for clinicians when prescribing zolpidem, particularly for patients with existing heart conditions. Further large-scale studies are needed to validate this finding and to explore the mechanisms between zolpidem and AF.

The interactive walkway provides fit-for-purpose fall-risk biomarkers in the elderly: Comparison of zolpidem and suvorexant.

Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug-induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall-risk assessments in early clinical drug development. In this three-way crossover study, 18 healthy elderly (age: 65-80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre-dose and approximately hourly until 9 h post-dose. IWW assessments included an 8-meter walking test, goal-directed stepping, obstacle-avoidance, and tandem-walking. Other pharmacodynamic measurements were the Timed-Up-and-Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post-dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post-dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development.

Identification of post-mortem product of zolpidem degradation by hemoglobin via the Fenton reaction.

Zolpidem, N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide, is a hypnotic agent widely used in clinical practice but is detected in many clinical cases of fatal intoxication and suicide. In forensic toxicology, the precise determination of zolpidem concentration in blood is a must to provide concrete evidence of death by zolpidem poisoning. However, the concentrations of zolpidem in blood at autopsy often differ from those at the estimated time of death. In the present study, we found that zolpidem was degraded by hemoglobin (Hb) via the Fenton reaction at various temperatures. The mechanism underlying zolpidem degradation involved the oxidation of its linker moiety. The MS and MS/MS spectra obtained by liquid chromatography quadrupole-Orbitrap mass spectrometry (LC-Q-Orbitrap-MS) showed the formation of 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide (2-OH ZOL) in Hb/H2O2 solution incubated with zolpidem and in the blood of several individuals who died from ingestion of zolpidem. These results suggest that 2-OH ZOL is the post-mortem product of zolpidem degradation by Hb via the Fenton reaction.

Development and Validation of a Sonication-Assisted Dispersive Liquid-Liquid Microextraction Procedure and an HPLC-PDA Method for Quantitative Determination of Zolpidem in Human Plasma and Its Application to Forensic Samples.

The use of z-drugs has increased worldwide since its introduction. Although the prescribing patterns of hypnotics differ among countries, zolpidem is the most widely used z-drug in the world. Zolpidem may be involved in poisoning and deaths. A simple and fast HPLC-PDA method was developed and validated. Zolpidem and the internal standard chloramphenicol were extracted from plasma using a sonication-assisted dispersive liquid-liquid microextraction procedure. The method was validated including selectivity, linearity, precision, accuracy, and recovery. The calibration range (0.15-0.6 µg/mL) covers therapeutic and toxic levels of zolpidem in plasma. The limit of quantification was set at 0.15 µg/mL. Intra- and interday accuracy and precision values were lower than 15% at the concentration levels studied. Excellent recovery results were obtained for all concentrations. The proposed method was successfully applied to ten real postmortem plasma samples. In our series, multiple substances (alcohol and/or other drugs) were detected in most cases of death involving zolpidem. Our analytical method is suitable for routine toxicological analysis.

Effect of Lipopolysaccharide on the Duration of Zolpidem-Induced Loss of Righting Reflex in Mice.

Zolpidem, a non-benzodiazepine hypnotic, is primarily used to treat insomnia. In a previous study, pior treatment with non-benzodiazepine receptor agonists was associated with inflammation. The present study aimed to clarify the association between the effects of zolpidem and inflammation in mice treated with lipopolysaccharide (LPS), a known model of inflammation. We assessed the zolpidem-induced loss of righting reflex (LORR) duration 24 h after LPS treatment in mice. Additionally, the expressions of γ-aminobutyric acid (GABA)A receptor subunit and K+-Cl- cotransporter isoform 2 (KCC2) mRNA in the hippocampus and frontal cortex were examined in LPS-treated mice. Pretreatment with LPS was associated with significantly prolonged duration of zolpidem-induced LORR compared to control mice. This effect was significantly attenuated by administering bicuculline, a GABAA receptor antagonist, or flumazenil, a benzodiazepine receptor antagonist, in LPS-treated mice. Compared to controls, LPS-treated mice showed no significant change in the expression of GABAA receptor subunits in the hippocampus or frontal cortex. Bumetanide, an Na+-K+-2Cl- cotransporter isoform 1 blocker, attenuated the extended duration of zolpidem-induced LORR observed in LPS-treated mice. LPS significantly decreased Kcc2 mRNA expression in the hippocampus and the frontal cortex. These findings suggest that inflammation increases zolpidem-induced LORR, possibly through a reduction in KCC2 expression.

Estimation of the time of zolpidem intake and differentiation between consumption and external contamination using MALDI-MSI for investigations on single hair samples.

Estimation of drug ingestion time (event time) and distinguishing between drug ingestion and external contamination are important for interpreting hair analysis results in forensics practice. Here, we present a matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) method for in situ analysis of intact hair. We applied a longitudinal cutting method for a single hair to analysis authentic hair samples from a victim of a drug-facilitated sexual assault (DFSA) case and zolpidem-soaked hair. MALDI-MSI showed that zolpidem-positive segments distributed at 4-6 mm or 6-8 mm from the root in three single hairs of a DFSA victim collected 25 days after the event, at concentrations ranging from 0.1 to 5.7 pg mm-1, in agreement with the results from segmental analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS). The estimation of drug intake time was about 20-30 days before sampling, which was consistent with the known time of drug intake. This MALDI-MS method allows imaging analysis of trace substances in a single hair and can realize the intuitive reflection of drug taking time. In addition, zolpidem applied by soaking was mainly distributed on both sides of the longitudinal hair shaft, whereas ingested zolpidem was found only in the middle of the hair shaft of the DFSA victim. The MALDI-MS images of unwashed and washed hair suggested that the amount of externally applied drug was decreased by washing, it was still present on surface layer (cuticle) sides although. Visualization using MALDI-MSI could therefore distinguish between drug ingestion and contamination by reflecting the distribution and deposition site of the drug in hair.

Zolpidem improves task-specific dystonia: A randomized clinical trial integrating exploratory transcranial magnetic stimulation and [18F] FDG-PET imaging.

BACKGROUND: Task-specific dystonia (TSFD) is a disabling movement disorder. Effective treatment options are currently limited. Zolpidem was reported to improve primary focal and generalized dystonia in a proportion of patients. The mechanisms underlying its therapeutic effects have not yet been investigated. METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover trial of single-dose zolpidem in 24 patients with TSFD. Patients were clinically assessed using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Writers' Cramp Rating Scale (WCRS), and Visual Analogue Scale (VAS), before and after receiving placebo and zolpidem. Transcranial magnetic stimulation was conducted on placebo and zolpidem to compare corticospinal excitability - active and resting motor thresholds (AMT and RMT), resting and active input/output curves and intracortical excitability - cortical silent period (CSP), short-interval intracortical inhibition curve (SICI), long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Eight patients underwent brain FDG-PET imaging on zolpidem and placebo. RESULTS: Zolpidem treatment improved TSFD. Zolpidem compared to placebo flattened rest and active input/output curves, reduced ICF and was associated with hypometabolism in the right cerebellum and hypermetabolism in the left inferior parietal lobule and left cingulum. Correlations were found between changes in dystonia severity on WCRS and changes in active input/output curve and in brain metabolism, respectively. Patients with lower RMT, and higher rest and active input/output curves exhibited better response to zolpidem compared to placebo. CONCLUSIONS: Zolpidem improved TSFD by reducing corticomotor output and influencing crucial nodes in higher-order sensory and motor networks.

Digital cognitive-behavioural therapy application compared with zolpidem for the treatment of insomnia: protocol for an exploratory randomised controlled trial.

INTRODUCTION: Insomnia is a common health problem and cognitive-behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we developed a digital CBT application (IIIP MED: Sleepy Med) as Software as a Medical Device for insomnia. This paper describes the study protocol for an exploratory randomised controlled trial (RCT) to evaluate effectiveness and safety of our developed digital CBT (dCBT) for 5 weeks compared with zolpidem tartrate for patients with insomnia disorder. METHODS AND ANALYSIS: This proposed multicentre exploratory RCT will be conducted at the outpatient clinic of Chiba University Hospital, Akita University Hospital and Yoyogi Sleep Disorder Center, Japan. The study population comprises two parallel groups (dCBT and zolpidem) consisting of 15 participants each (n=30 in total) diagnosed with insomnia disorder who remain symptomatic at 4 weeks after sleep hygiene education. We will evaluate the effectiveness at baseline, week 5 (post-intervention) and week 10 (follow-up). The primary outcome will be the change of subjective sleep onset latency at week 5 from baseline. Secondary outcomes include sleep-related outcomes, such as objective sleep onset latency measured by mobile electroencephalography, functional improvement during the daytime and quality of life. ETHICS AND DISSEMINATION: Ethics approval was granted by the Institutional Review Board of Chiba University Hospital (K2023001). All participants will be required to provide written informed consent. Results will be published in international journals. TRIAL REGISTRATION NUMBER: jRCT2032230353.

Social network analysis for medical narcotics in South Korea: focusing on patients and healthcare organizations.

BACKGROUND: Medical narcotics must be administered under medical supervision because of their potential for misuse and abuse, leading to more dangerous and addictive substances. The control of medical narcotics requires close monitoring to ensure that they remain safe and effective. This study proposes a methodology that can effectively identify the overprescription of medical narcotics in hospitals and patients. METHODS: Social network analysis (SNA) was applied to prescription networks for medical narcotics. Prescription data were obtained from the Narcotics Information Management System in South Korea, which contains all data on narcotic usage nationwide. Two-mode networks comprising hospitals and patients were constructed based on prescription data from 2019 to 2021 for the three most significant narcotics: appetite suppressants, zolpidem, and propofol. Two-mode networks were then converted into one-mode networks for hospitals. Network structures and characteristics were analyzed to identify hospitals suspected of overprescribing. RESULTS: The SNA identified hospitals that overprescribed medical narcotics. Patients suspected of experiencing narcotic addiction seek treatment in such hospitals. The structure of the network was different for the three narcotics. While appetite suppressants and propofol networks had a more centralized structure, zolpidem networks showed a less centralized but more fragmented structure. During the analysis, two types of hospitals caught our attention: one with a high degree, meaning that potential abusers have frequently visited the hospital, and the other with a high weighted degree, meaning that the hospital may overprescribe. For appetite suppressants, these two types of hospitals matched 84.6%, compared with 30.0% for propofol. In all three narcotics, clinics accounted for the largest share of the network. Patients using appetite suppressants were most likely to visit multiple locations, whereas those using zolpidem and propofol tended to form communities around their neighborhoods. CONCLUSIONS: The significance of this study lies in its analysis of nationwide narcotic use reports and the differences observed across different types of narcotics. The social network structure between hospitals and patients varies depending on the composition of the medical narcotics. Therefore, these characteristics should be considered when controlling medication with narcotics. The results of this study provide guidelines for controlling narcotic use in other countries.

Powder bed fusion-laser beam (PBF-LB) three-dimensional (3D) printing: Influence of laser hatching distance on the properties of zolpidem tartrate tablets.

Laser sintering, known as powder bed fusion-laser beam (PBF-LB), offers promising potential for the fabrication of patient-specific drugs. The aim of this study was to provide an insight into the PBF-LB process with regard to the process parameters, in particular the laser hatching distance, and its influence on the properties of zolpidem tartrate (ZT) tablets. PHARMACOAT® 603 was used as the polymer, while Candurin® Gold Sheen and AEROSIL® 200 were added to facilitate 3D printing. The particle size distribution of the powder blend showed that the layer height should be set to 100 µm, while the laser hatching distance was varied in five different steps (50, 100, 150, 200 and 250 µm), keeping the temperature and laser scanning speed constant. Increasing the laser hatching distance and decreasing the laser energy input led to a decrease in the colour intensity, mass, density and hardness of the ZT tablets, while the disintegration and dissolution rate were faster due to the more fragile bonds between the particles. The laser hatching distance also influenced the ZT dosage, indicating the importance of this process parameter in the production of presonalized drugs. The absence of drug-polymer interactions and the amorphization of the ZT were confirmed.

Z-Drug Use and Benzodiazepine Use and Misuse Among LGB Populations: The Role of Psychological Distress.

BACKGROUND: Z-drugs (hypnotics such as zolpidem, zopiclone, and zaleplon) and benzodiazepines (BZDs) are sedative medications with misuse liability. The goals of this study are to report the (1) prevalence of past-year any Z-drug use, any BZD use, and any BZD misuse by sexual identity category and psychological distress; (2) associations among these 3 categories between sexual identity and past-year psychological distress; (3) associations among these 3 categories with sexual identity by past-year psychological distress status. METHODS: Data were collected from the National Survey on Drug Use and Health (years 2015-2019 [n = 210,392]), a yearly representative national household survey of the American population. We report prevalences of any Z-drug use, any BZD use, and any BZD misuse by sexual identity and past-year psychological distress status. We ran logistic regressions with complex survey design with the 3 dichotomous variables described above as the dependent variables, stratified and not-stratified by psychological distress. RESULTS: Prevalence of any Z-drug an BZD use and any BZD misuse were higher among LGB (lesbian/gay/bisexual) populations, especially gay men and bisexual women. Psychological distress was positively associated with any Z-drug and BZD use and any BZD misuse. Women were at higher risk of Z-drug (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.18-1.37) and BZD use (OR, 1.64; 95% CI, 1.55-1.73), but lower risk of BZD misuse (OR, 0.82; 95% CI, 0.76-0.88). When stratifying by psychological distress, differences between LGB and heterosexuals were more pronounced among those without past-year psychological distress, especially gay men and bisexual women. CONCLUSIONS: The presence of psychological distress attenuates the disparities between LGB and heterosexual individuals in Z-drug use and BZD use and misuse.

Successful treatment of cranial dystonia using a Zolpidem+Melatonin combination: A video case-series.

INTRODUCTION: Cranial dystonias (CrD) are challenging to treat. Oral pharmacotherapy is often sub-optimal, while delicate anatomy and limited availability of skilled botulinum toxin injectors makes this approach risky, and often difficult to access; neurosurgical options e.g. deep brain stimulation, are high-risk in the elderly populations most affected. We observed significant improvement in CrD in 2 patients prescribed Zolpidem+Melatonin combination treatment for insomnia, and therefore trialled this treatment in a further 4 patients with CrD. METHODS: Six patients were treated with Zolpidem+Melatonin. Pre- and post-treatment videotaped clinical examinations were blindly rated by an independent assessor (EM) and scored using the 'Facial and Oral Movements' section of the abnormal involuntary movements scale (AIMS), as well as the Jankovic rating scale for blepharospasm. RESULTS: Dystonic features, as measured by the abnormal involuntary movements scale (AIMS) improved by an average of 75% after treatment (6.5±3.1 before treatment to 1.7 +/- 0.8 after treatment). Improvements were also observed in blepharospasm severity scores, and in cervical dystonic features. CONCLUSION: Zolpidem+Melatonin combination treatment represents a safe and effective treatment for CrD. Low cost and wide availability makes it an attractive option, particularly in resource-constrained healthcare settings, or in patients who have failed, or lack access to alternatives.

Treatment Failure and Long-Term Prescription Risk for Guideline-Recommended Hypnotics in Japan.

Importance: Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. Objective: To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment. Design, Setting, and Participants: This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023. Exposures: Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy. Main Outcomes and Measures: The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively. Results: The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone. Conclusions and Relevance: Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.

Zolpidem Stimulant Effect and Dependence: A Case Report on Intranasal Use.

Zolpidem is a widely used hypnotic. Dependence on zolpidem due to the induction of euphoria is a rare condition, while intranasal misuse of zolpidem is a rather new phenomenon. We present the first case of a patient who developed zolpidem dependence, which was associated with the prompt onset of euphoria exclusively following intranasal use. Mr. A was a 51-year-old polydrug abuser with antisocial personality disorder and a physical dependence on zolpidem. Over several years, he consumed 500 mg of the drug daily, usually divided into 30 mg doses, exclusively via the nasal route because unlike the oral administration of the same dose of the drug, intranasal administration induced euphoria. Euphoric effects manifested 3-5 minutes after taking the drug, and pronounced withdrawal symptoms (i.e., profuse sweating, tremors, nausea, vomiting, diarrhea, and inability to drink and eat), present 7-8 hours after the use could disappear within 3-5 minutes upon drug re-administration. The dependence was managed through a slow tapering of the zolpidem use. Clinicians should be aware that intranasal use of zolpidem could be associated with euphoric effects and the development of addiction. The potential for misuse of zolpidem via the nasal route may be of interest for future research.