Investigating the potential of highly porous zopiclone-loaded 3D electrospun nanofibers for brain targeting via the intranasal route.

Nanofibers (NFs) have proven to be very attractive tool as drug delivery plateform among the different plethora of nanosystems, owing to their unique features. They exhibit two- and three-dimensional structures some of which mimic structural environment of the body tissues, in addition to being safe, efficacious, and biocompatible drug delivery platform. Thus, this study embarked on fabricating polyvinyl alcohol/chitosan (PVA/CS) electrospun NFs encapsulating zopiclone (ZP) drug for intranasal brain targeted drug delivery. Electrospun NFs were optimized by adopting a three factor-two level full factorial design. The independent variables were: PVA/CS ratio (X1), flow rate (X2), and applied voltage (X3). The measured responses were: fiber diameter (Y1,nm), pore size (Y2,nm) and ultimate tensile strength (UTS,Y3,MPa). The selected optimum formula had resulted in NFs diameter of 215.90 ± 15.46 nm, pore size 7.12 ± 0.27 nm, and tensile strength around 6.64 ± 0.95 MPa. In-vitro biodegradability testing confirmed proper degradation of the NFs within 8 h. Moreover, swellability and breathability assessment revealed good hydrophilicity and permeability of the prepared NFs. Ex-vivo permeability study declared boosted ex-vivo permeation with an enhancement factor of 2.73 compared to ZP suspension. In addition, optimized NFs formula significantly reduced sleep latency and prolonged sleep duration in rats compared to IV ZP drug solution. These findings demonstrate the feasibility of employing the designed NFs as an effective safe platform for intranasal delivery of ZP for insomnia management.

Zopiclone-Induced Methemoglobinemia: A Case Report Highlighting How the Treatment Differs in Patients on Serotonergic Medication.

Zopiclone is a sedative-hypnotic that is increasingly being used for insomnia, especially among patients with depression. The side effects of zopiclone include nausea, vomiting, headache, giddiness, sedation, altered mental status, and coma. Here, we describe a rare case of a patient with underlying depression who overdosed on zopiclone, resulting in a presentation of drowsiness and dyspnea. A diagnosis of methemoglobinemia was made only through astute observation of the presence of a saturation gap, poor oxygen saturation despite high flow oxygen supplementation, and the arterial blood gas sample appearing chocolate brown in color. Treatment of such patients usually includes the gold standard of methylene blue. However, in our case, there was a risk of serotonin syndrome as the patient was on a serotonergic antidepressant prior. As such, an alternative treatment with ascorbic acid was utilized instead. Methemoglobinemia, while uncommon, should always be suspected in patients who present with zopiclone overdose as it can be life-threatening and is easily treatable.

Developing, validating, and comparing an analytical method to simultaneously detect z-drugs in urine samples using the QuEChERS approach with both liquid chromatography and gas chromatography-tandem mass spectrometry.

Detecting z-drugs, a sedative-hypnotic medication, is also misused for criminal activities. Therefore, the analysis of urine samples is crucial for clinical and forensic purposes. We conducted a study where we developed, validated, and compared an analytical method for simultaneously detecting z-drugs in urine samples. Our approach uses the QuEChERS method for sample preparation, combined with liquid chromatography (LC) and gas chromatography (GC) coupled with tandem mass spectrometry (MS/MS). We optimized the QuEChERS method to effectively extract z-drugs from urine samples while minimizing matrix effects and achieving high recovery rates. After extraction, we split the samples into two parts for analysis using LC-MS/MS and GC-MS/MS. We validated our methods, and the results showed good linearity over a broad concentration range (1-200 ng/mL) for each z-drug. The limits of detection and quantification were within clinically relevant ranges, ensuring sensitivity for detecting z-drugs in urine samples. We compared the two chromatographic techniques by analyzing a set of urine samples spiked with known concentrations of z-drugs using both LC-MS/MS and GC-MS/MS methods and then applied to the real samples. The results were statistically analyzed to assess any significant differences in accuracy and precision above 95 %, and both methods offered reliable and consistent results with the samples as well. In conclusion, our analytical method coupled with both LC-MS/MS and GC-MS/MS using the QuEChERS approach provides a comprehensive and robust solution for the simultaneous detection of z-drugs in urine samples. The choice between the two chromatographic techniques can be based on the specific z-drugs of interest and the required analytical performance. This method holds promise for applications in clinical toxicology, forensic analysis, and monitoring z-drug usage.

Treatment of insomnia in myasthenia gravis-A prospective study on non-benzodiazepine hypnotics in the treatment of myasthenia gravis patients with insomnia.

Objectives: This study aimed to evaluate the efficacy and safety of non-benzodiazepine hypnotics in the treatment of myasthenia gravis (MG) patients with insomnia. Methods: This is a prospective longitudinal study. Outpatients who met the criteria for stable MG and insomnia diagnosis according to the International Classification of Sleep Disorders (third edition) were included in the study. They took a regular dose of non-benzodiazepine hypnotics (zolpidem 10 mg per night or zopiclone 7.5 mg per night) based on their own preferences. Patients received psychotherapy (including sleep health education) and were followed up for 4-5 weeks. Cases with lung diseases, respiratory disorders, or inappropriate use of hypnotic medications were excluded. The primary outcome is the difference in total Pittsburgh Sleep Quality Index (PSQI) score between baseline and the end of follow-up period. Secondary outcomes include the difference in Myasthenia Gravis Activities of Daily Living (MG-ADL) score, 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), and the Patient Health Questionnaire-9 (PHQ-9) between baseline and the end of follow-up period and the safety of medication. Results: A total of 75 MG patients with insomnia were included in this study. After 4-5 weeks of treatment, the total PSQI score and MG-ADL score were lower than baseline (p < 0.01). No patients had an increased MG-ADL score. The incidence rate of adverse events was 16.0% (12 cases), including dizziness (6 cases, 8.0%), drowsiness (3 cases, 4.0%), fatigue (2 cases, 2.7%), and nausea (1 case, 1.3%), all of which were mild. No patients had new onset breathing disorders. Conclusion: Non-benzodiazepine hypnotics are safe and effective for stable MG patients who need insomnia treatment.

Development and validation of presumptive spot test for the identification of z-drugs used in drug-facilitated crimes.

The significance and desire for preliminary testing approaches that are straightforward, quick, selective, affordable, and practical for use in the field are highlighted by the increasing enormous amounts of potentially illegal samples being seized worldwide. The "z-drugs," which include zolpidem, zopiclone, and eszopiclone, are non-benzodiazepine medications used to treat insomnia. z-drugs are short-term solutions for sleeplessness and anxiety but have a long history of abuse and misuse. The extensive list is primarily utilized for drug-facilitated crimes and drug dependence. The presumptive color spot test for z-drugs, such as zolpidem, zopiclone, and eszopiclone, has been created and validated in this study. In the preliminary identification of zolpidem, zopiclone, and eszopiclone, no color spot test has been documented as per the literature. The color spot test is the most essential and routinely used technique for identifying any unknown sample substance. The color test method was proven to provide high-quality, dependable presumptive test findings and satisfy standards for preliminary screening usage. Validation experiments demonstrate that, at room temperature, the color change is specific to the zolpidem, zopiclone, and eszopiclone classes and unaffected by the common cutting agent's presence. It was discovered that 5, 10, and 6 ppm were the operational limit of detection of the sample present against the reagents 0.1% diphenyl carbazone, aqueous potassium iodoplatinate, and modified cobalt thiocyanate reagent, respectively. The color test is immediate and validated with other substances of a similar category and 10 ppm was the operational limit of detection.

Factors affecting clinical pharmacist decision-making when reviewing and prescribing z-drugs in primary care: a qualitative interview study.

BACKGROUND: Z-drugs (zopiclone, zolpidem and zaleplon) are drugs with dependence forming characteristics licensed for the short-term management of insomnia. Patients regularly prescribed z-drugs are candidates for 'structured medication reviews', routinely delivered by pharmacists employed in general practice or primary care networks in England. AIM: To understand the factors that affect pharmacist decision-making when reviewing and prescribing z-drugs in primary care. METHOD: Qualitative semi-structured interviews with general practice based pharmacists were conducted using MS Teams®. Clinical vignettes to simulate real-world practice were sent to participants and then discussed at interview, followed by structured interview questions. Interview transcripts were thematically analysed to identify themes and sub-themes expressed by participants. RESULTS: Three over-arching themes emerged over the course of qualitative interviews with 10 clinical pharmacists: the perceived role of the pharmacist in deprescribing, the decision-making process, and perceptions of best practice. Pharmacists highlighted that relationships with patients were an important foundation for medication reviews regarding z-drugs and that at times they felt pressure to continue prescribing z-drugs beyond their licensed use. Participants explored rule-based reasoning and compassionate care when rationalising their decision-making for reviewing and prescribing z-drugs. CONCLUSION: Patient factors, time pressures, 'rule-based' beliefs and pharmacist self-efficacy were key practice aspects which can influence the pharmacist decision-making process when reviewing or prescribing z-drugs. Pharmacists believed z-drugs should be short-term interventions for insomnia, with non-pharmacological, holistic treatment being more appropriate for long term management.

Driving under the influence of zopiclone: Elimination between two consecutive blood samples.

AIM: Zopiclone is a widely used hypnotic drug which is frequently detected in apprehended drivers. For assessments in forensic cases, the elimination half-life (t1/2) of a drug is sometimes important. A t1/2 of 3.5-6.5 h for zopiclone is previously reported in healthy individuals, but different factors like age and drug-interactions can affect the t1/2 of zopiclone. The aim of this study was to describe concentrations of zopiclone and co-ingestion of additional drugs in apprehended drivers, and to investigate the t1/2 of zopiclone based on two consecutive blood samples. METHODS: Data was collected from apprehended drivers in Norway between 2003 and 2021. All cases where zopiclone was detected were included. In a subset of the material, two consecutive whole blood samples were collected ≥ 20 and < 60 min apart. Concentrations of zopiclone in blood were determined by LC-MS or UHPLC-MS/MS. The elimination and t1/2 of zopiclone was estimated from the concentration change of zopiclone and the time interval between the two consecutive blood samples, under the assumption of first order kinetics. RESULTS: The median concentration among all zopiclone positive cases was 0.044 mg/L (IQR 0.070 mg/L) (n = 2401). The most frequent additional drugs detected were ethanol (36%), diazepam (22%), amphetamine (14%) and THC (14%). In zopiclone-only cases (n = 364), the median concentration of zopiclone was 0.066 mg/L (IQR 0.115 mg/L). In 112 cases, two consecutive blood samples were collected. Of these, 28 cases showed increasing concentrations of zopiclone between the two sampling time points. Among the cases in which the concentration decreased (n = 84), the median C1 was 0.048 mg/L (IQR 0.062 mg/L) and the median C2 was 0.043 mg/L (IQR 0.056 mg/L). A Bayesian statistical model was used to obtain the posterior distribution of t1/2. The posterior median of t1/2 was estimated to 3.1 h (IQR=0.39 h) when including only the cases showing decreasing concentrations, and this increased to 3.8 h (IQR=0.52 h) when also including samples showing non outlying increase in concentrations. There was no statistically significant gender difference in the calculated half-lives (two-sided Mann-Whitney U test, p = .525). CONCLUSIONS: This study showed that zopiclone is frequently detected in apprehended drivers in supra therapeutic concentrations and poly drug cases. The elimination of zopiclone in blood from two consecutive blood samples indicated an apparent t1/2 of between 3.1 and 3.8 h, which is within the lower range of what previous experimental studies on healthy individuals have reported.

Rapid enantiomeric analysis of zopiclone in serum by supercritical fluid chromatography-tandem mass spectrometry.

Zopiclone (ZOP) is a hypnotic drug prescribed to treat insomnia. Due to the chiral nature of ZOP, the psychologically active S-form and inactive R-form need to be determined enantiomerically in a forensic drug analysis. In the present study, a supercritical fluid chromatography (SFC) method was designed with a faster analysis ability than that of previously reported techniques. The SFC-tandem mass spectrometry (SFC-MS/MS) method was optimized using a column with a chiral polysaccharide stationary phase (Trefoil CEL2). ZOP was extracted from pooled human serum using solid-phase extraction (Oasis HLB) and analyzed. The developed SFC-MS/MS method achieved the baseline separation of S-ZOP and R-ZOP within 2 min. The fit-for-purpose method validation indicated that the optimized solid-phase extraction achieved near complete recovery and approximately 70% of the matrix effect. Both the retention time and peak area showed sufficient precision. The lower and upper limits of quantification (LOQ) were 5.7 × 10-2 ng/mL and 25 ng/mL for R-ZOP, and 5.2 × 10-2 ng/mL and 25 ng/mL for S-ZOP. The calibration line was linear in the range from lower LOQ to upper LOQ. The stability test indicated that ZOP in serum stored in a refrigerator (4°C) degraded and about 55% remained in 31 days. The quick analysis of the SFC-MS/MS method makes it a valid option for the enantiomeric analysis of ZOP.

Prescribing Z-drugs in Greece: an analysis of the national prescription database from 2018 to 2021.

BACKGROUND: The Z-drugs are indicated for the short-treatment of insomnia, but they are associated with abuse, dependence and side-effects. There are only sparse data about Z-drug prescribing in Greece. METHODS: We analyzed data from the Greek prescription database, considering prescriptions for the available Z-drugs in Greece, i.e., zolpidem and zopiclone, during the period from 01.10.2018 to 01.10.2021 in order to examine the prevalence, monthly number and characteristics of Z-drug prescriptions in Greece. RESULTS: There were 1,229,842 prescriptions for Z-drugs (zolpidem: 89.7%) during the investigated period from 2018 to 2021, which corresponded to 156,554 patients (73.1% ≥ 65 years, 64.5% female). More than half of the patients (65.8%) had more than one prescription with a median number of 8, interquartile range IQR [3, 17], prescriptions during the three-year study period. Most patients (76.1%) were prescribed by medical specialties other than psychiatrists and neurologists, despite a considerable frequency of psychiatric comorbidities (53.7%). About half of patients with anxiety/depression were not prescribed anxiolytics or antidepressants, a practice more frequently observed among medical specialties other than psychiatrists and neurologists. The average annual prevalence of at least one prescription for Z-drugs in the Greek population during 2019-2020 was approximately 0.9% (higher in females and older adults). The monthly number of prescriptions was relatively stable with a median number of 334.2 IQR [310.4; 351.6] prescriptions per 100,000 persons. CONCLUSIONS: A considerable number of patients are prescribed Z-drugs in Greece, more often older adults, females and patients with psychiatric comorbidities. The prescribing physicians were in the majority (70%) internists and general practitioners, while psychiatrists (10.9%) and neurologists (6.1%) accounted for a smaller proportion. Due to the limitations inherent to medical claims databases, further research is warranted in order to elucidate the potential abuse and misuse of Z-drugs.

Comparative Risk of Harm Associated with Zopiclone or Trazodone Use in Nursing Home Residents: a Retrospective Cohort Study in Alberta, Canada.

Background: There is growing evidence of harm associated with trazodone and nonbenzodiazepine sedative hypnotics (e.g., zopiclone); however, their comparative risk of harm is unknown. Methods: We conducted a retrospective cohort study with linked health administrative data, which enrolled older (≥66 years old) nursing home residents living in Alberta, Canada, between December 1, 2009, and December 31, 2018; the last follow-up date was June 30, 2019. We compared the rate of injurious falls and major osteoporotic fractures (primary outcome) and all-cause mortality (secondary outcome) within 180 days of first prescription of zopiclone or trazodone with cause-specific hazard models and inverse probability of treatment weights to control for confounding; primary analysis was intention-to-treat and secondary analysis was per-protocol (i.e., residents censored if dispensed the other exposure drug). Results: Our cohort included 1,403 residents newly dispensed trazodone and 1,599 residents newly dispensed zopiclone. At cohort entry, the mean resident age was 85.7 (standard deviation [SD] 7.4), 61.6% were female, and 81.2% had dementia. New zopiclone use was associated with similar rates of injurious falls and major osteoporotic fractures (intention-to-treat-weighted hazard ratio 1.15, 95% confidence interval [CI] 0.90-1.48; per-protocol-weighted hazard ratio 0.85, 95% CI 0.60-1.21) and all-cause mortality (intention-to-treat-weighted hazard ratio 0.96, 95% CI 0.79-1.16; per-protocol-weighted hazard ratio 0.90, 95% CI 0.66-1.23) compared to trazodone. Conclusions: Zopiclone was associated with a similar rate of injurious falls, major osteoporotic fractures, and all-cause mortality compared to trazodone-suggesting one medication should not be used in lieu of the other. Appropriate prescribing initiatives should also target zopiclone and trazodone.

[Measurement of benzodiazepine receptor agonists metabolites and their concentration in urine]. / Opredelenie metabolitov agonistov benzodiazepinovykh retseptorov i ustanovlenie ikh protsentnogo soderzhaniya v moche.

The study objective was to detect and measure the ratio of metabolites of benzodiazepine receptor agonists in urine during forensic chemical and chemical and toxicological studies, as well as to characterize the main metabolites to use them to confirm the oral intake of the test substances. Data on the presence of metabolites in the urine will allow us to reliably confirm the intake of zaleplon, zopiclone, clobazam, and phenazepam and determine the routes of administration (intake) into the body of the victim. Benzodiazepine derivatives (clobazam and phenazepam) and non-benzodiazepines (zaleplon and zopiclone) have different chemical structures and similar mechanisms of action resulting in a similar clinical presentation of side effects and the need for forensic chemical study according to poisoning symptoms. Metabolites of benzodiazepine receptor agonists and their ratio in urine after oral administration were measured: zaleplon (parent compound), deethylzaleplon, 5-oxozaleplon, 5-oxodeethylzaleplon, oxozaleplon glucuronide; zopiclone (parent compound), zopiclone-N-oxide, N-desmethylzopiclone; clobazam (parent compound), N-desmethylclobazam, 4-hydroxyclobazam, hydroxydesmethylclobazam; phenazepam (parent compound) and 3-hydroxyphenazepam. It is advisable to determine zaleplon in urine by the presence of 5-oxaleplon (97% of the total amount of metabolites), zopiclone by zopiclone-N-oxide (86% in urine), clobazam by the parent compound (61% in urine), phenazepam by the parent compound (90-100% in urine).

Cod liver oil nano-structured lipid carriers (Cod-NLCs) as a promising platform for nose to brain delivery: Preparation, in vitro optimization, ex vivo cytotoxicity & in vivo biodistribution utilizing radioiodinated zopiclone.

Nano-structured lipid carriers containing zopiclone were prepared as a targeted drug delivery system to convey zopiclone directly to brain via nasal route. Nano-structured lipid carriers were constructed adopting hot emulsification-ultrasonication method using palmitic acid in place of the solid lipid, cod liver oil as liquid lipid, and poloxamer 407 as a surfactant. A three-factor three-level central composite face-centered design was used to optimize the formulated nano-structured lipid carriers. The independent factors were lipid amount (X1), surfactant amount (X2), and sonication time (X3). The examined responses were entrapment efficiency (EE,Y1,%), particle size (PS,Y2,nm), zeta potential(mV), polydispersity index(PDI,Y3), in vitro release(Q8h,Y4,%) and dissolution efficiency (DE,Y5,%). The optimum formula showed high entrapment efficiency of 94.31% ± 2.44, in vitro drug release of 83.89% ± 1.77 with dissolution efficiency equals 88.63% ± 2.01, small particle size of 71.27 nm ± 13.57 and low polydispersity index 0.097 ± 0.15. In vivo biodistribution in mice was evaluated by a radiobiological technique using radioiodinated zopiclone([131I]iodo-ZP). Results revealed the superiority of the intranasal route to deliver zopiclone directly to brain faster and higher brain uptake (6.9 ± 1.02%ID/g at 5 min post-administration). The current study confirmed that intranasal administration of nano-structured lipid carriers had great potential as an effective tool for targeted brain zopiclone delivery for insomnia treatment.

Analgesic efficacy of sleep-promoting pharmacotherapy in patients with chronic pain: a systematic review and meta-analysis.

Dysregulation of sleep heightens pain sensitivity and may contribute to pain chronification. Interventions which consolidate and lengthen sleep have the potential to improve pain control. The main objective of this systematic review was to examine the effects of sleep-promoting pharmacotherapy on pain intensity in patients with chronic pain. Multiple electronic databases were searched from inception to January 2022 to identify relevant randomized controlled trials (RCTs). Two independent reviewers screened titles, abstracts, and full-text articles; extracted data; and assessed risk of bias for each included study. The GRADE approach was used to determine the strength of evidence. The search identified 624 articles. After full-text screening, 10 RCTs (n = 574 randomized participants) involving 3 pharmacologic interventions (melatonin, zopiclone, and eszopiclone) and 7 different chronic pain populations were included. Minimum clinically significant pain reduction ≥30% was reported in 4 studies. There is low-quality evidence (downgraded due to inconsistency and imprecision) that 2 to 8 weeks treatment with a sleep-promoting medication alone or in combination with an analgesic (6 trials, n = 397) decreases pain intensity compared with placebo or the same analgesic treatment alone (SMD -0.58 [95% confidence interval -1.00, -0.17], P = 0.006). Analyses of associations between changes in sleep and pain outcomes were only provided in 2 articles, with inconsistent findings. Notably, pain-relieving effects were most consistent in melatonin trials. Only 3 studies implemented polysomnography to obtain objective sleep measures. Low-quality evidence indicates that pharmacologic sleep promotion may decrease pain intensity in chronic pain populations. More research is needed to fully understand the influence of sleep-targeting interventions on pain control.

Toxicity evaluation of main zopiclone impurities based on quantitative structure-activity relationship models and in vitro tests.

Toxicity evaluation of main zopiclone impurities can provide a basis for safety assessment and quality standards of zopiclone. In this study, the impurity profile of zopiclone was analyzed using forced degradation and related substances of zopiclone tablets using high-performance liquid chromatography (HPLC). Furthermore, various quantitative structure-activity relationship (QSAR) models were used to compare the toxicity, especially genotoxicity of two main zopiclone degradation impurities, namely, impurity B and 2-amino-5-chloropyridine. The predictive genotoxicity results were verified using an in vitro bacterial reverse mutation (Ames) test. Meanwhile, using zebrafish embryos as an animal model, zopiclone and its main impurities were analyzed at different concentrations, and their effects on zebrafish development, including embryonic teratogenesis and lethality, were examined. The results showed that impurity B and 2-amino-5-chloropyridine were the main degradation impurities of zopiclone; the latter's content increased with increase in the solution storage time. QSAR prediction and in vitro test results confirmed that both impurity B and 2-amino-5-chloropyridine were non-mutagenic and classified in the fifth impurity category. According to ICH M7 guidelines, these could be controlled as general non-mutagenic impurities. The relative toxicity to zebrafish embryo development was the highest for 2-amino-5-chloropyridine, followed by impurity B and zopiclone, and the malformation rate and mortality of embryos were concentration dependent. In conclusion, an increase in the control limit of 2-amino-5-chloropyridine is recommended when the quality standards of zopiclone materials and preparations are revised to ensure safety and quality control. The specific limit value of this impurity should be determined through further evaluation and research.

Zopiclone versus placebo for short-term treatment of insomnia in patients with advanced cancer-a double-blind, randomized placebo-controlled clinical multicenter phase IV trial.

PURPOSE: Insomnia is frequent in patients with advanced cancer, and a variety of pharmacological agents is used to treat this condition. Still, few clinical trials have investigated the effectiveness of pharmacological sleep therapies in this patient group. We aimed to study the short-term effectiveness of zopiclone on sleep quality in patients with advanced cancer who report insomnia. METHODS: A randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase IV clinical trial in adult patients with metastatic malignant disease and insomnia. Patients were treated with zopiclone or placebo for six subsequent nights. Primary end point was patient-reported sleep quality during the final study night (NRS 0-10). Secondary end points were patient-reported sleep onset latency (SOL) and total sleep time (TST). RESULTS: Forty-one patients were randomized, with 18 being analyzed in the zopiclone group and 21 in the placebo group. Median age was 66, median Karnofsky performance score was 80, and 56% were male. Mean sleep quality at end of study was 2.9 (CI 2.3 to 3.8) in the zopiclone group and 4.5 (CI 3.6 to 5.4) in the placebo group (p = 0.021). At end of study, SOL was significantly different between the treatment groups: zopiclone 29 min (CI 13 to 51) and placebo 62 min (CI 40 to 87) (p = 0.045). TST was not significantly different across groups: zopiclone 449 min (403 to 496) and placebo 411 min (CI 380 to 440) (p = 0.167). CONCLUSION: Zopiclone improved short-term patient-reported sleep quality in this cohort of patients with advanced cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02807922.

[Potential for the use of cards for sampling and transportation of biological material during forensic chemical and toxicological examinations]. / Vozmozhnost' ispol'zovaniya kart dlya zabora i transportirovki biologicheskogo materiala pri sudebno-khimicheskom i khimiko-toksikologicheskom issledovaniyakh.

The objective of the study is to evaluate the potential for the use of cards for sampling and transportation of biological material during forensic chemical and toxicological examinations by the example of a biological sample, urine containing zopiclone. Two methods of sample preparation were compared. The use of cards for the collection and transportation of biological material, such as urine, followed by high-resolution high-performance liquid chromatography-mass spectrometry (HPLC-MS) for the identification of zopiclone metabolites was shown to be beneficial in forensic chemical and toxicological examination. The validation evaluation of the proposed sample preparation and identification method met the acceptance criteria.

Residual effects of zopiclone on driving performance using a standardized driving simulator among healthy volunteers.

RATIONALE: The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance. OBJECTIVE: To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance. METHODS: In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks-road-tracking, car-following, and harsh-braking-using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone. RESULTS: The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71-5.79) and 4.07 cm (90% CI: 2.02-6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94-6.69) and 24.6 ms (90% CI: 12.7-36.4), respectively. CONCLUSIONS: The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance.

Clonidine is better than zopiclone for insomnia treatment in chronic pain patients.

STUDY OBJECTIVES: Chronic pain is associated with insomnia. The objective of this clinical study was to compare the efficacy and safety of different prescribed doses of zopiclone and clonidine for the management of insomnia in patients with chronic pain. METHODS: This prospective observational crossover study included 160 consenting adult patients receiving pain management treatment. For insomnia treatment, each patient ingested different prescribed doses of zopiclone or clonidine on alternate nights. Each patient used a special validated sleep diary to collect data including pain score, sleep scores, sleep duration, sleep medication dose, and adverse effects. Each patient completed the diary for 3 continuous weeks. Pain was measured using a numeric pain rating scale. Sleep score was measured using the Likert Sleep Scale. A change in the pain or sleep scores by 2 points was considered significant. Of the 160 study participants, 150 (93.8%) completed the study successfully, and their data were analyzed with IBM SPSS Statistics 25 (IBM Corporation, Armonk, NY) using Student's t test, analysis of variance, Pearson chi-square test, and regression analysis. A P value < .05 was considered significant. RESULTS: Pain score was lower with clonidine than zopiclone (P = .025). Time to fall asleep was shorter with clonidine than zopiclone (P = .001). Feeling rested on waking in the morning was better with clonidine than zopiclone (P = .015). Overall sleep quality was better with clonidine than zopiclone (P = .015). Total Likert sleep score was better with clonidine than zopiclone (P = .005). Total sleep duration was better with clonidine than zopiclone (P = .013). Adverse effects were commoner with zopiclone, including collapse, fall, confusion, amnesia, mood disorder, hallucination, nightmare, nocturnal restlessness, locomotor dysfunction, nausea and headache. A minor adverse effect of dry mouth was commoner with clonidine. CONCLUSIONS: Clonidine is significantly better than zopiclone with respect to sleep quality, analgesia, tolerability profile, and patient safety. Further studies comparing clonidine with other insomnia medications will be beneficial. CITATION: Bamgbade OA, Tai-Osagbemi J, Bamgbade DO, et al. Clonidine is better than zopiclone for insomnia treatment in chronic pain patients. J Clin Sleep Med. 2022;18(6):1565-1571.

Retrospective Observational Study of Daytime Add-On Administration of Zopiclone to Difficult-to-Treat Psychiatric Inpatients With Unpredictable Aggressive Behavior, With or Without EEG Dysrhythmia.

Managing violent behavior is a particularly challenging aspect of hospital psychiatric care. Available pharmacological interventions are often unsatisfactory. Aim: To assess the effectiveness and safety of daytime zopiclone add-on administration in violent and difficult-to-treat psychiatric inpatients. Methods: Chart review of inpatients treated with daytime zopiclone, between 2014 and 2018, with up to 12 weeks follow-up. Effectiveness was retrospectively assessed with the Clinical Global Impression rating scale (CGI) and the frequency and severity of aggressive incidents recorded with the Staff Observation Aggression Scale-Revised (SOAS-R). Results: Forty-five (30 male, 15 female) cases, 18-69 years age range, average (SD) baseline CGI-S score of 5.4 (1.0), and a variety of diagnoses. Sixty-nine percent showed CGI-S improvement of any degree. For patients with at least one aggressive incident within 7 days prior to initiation of zopiclone (N = 22), average (SD) SOAS-R-Severity LOCF to baseline change was -3.5 (2.7) P < 0.0001. Most patients reported no side effects; 24% reported one or more side effects, and 11% discontinued zopiclone due to sedation (4), insomnia (1) or slurred speech (1). No SAEs were recorded. Zopiclone maximum daily dose correlated with CGI-S baseline-to-LOCF change (rho = -0.5, P = 0.0003). The ROC AUC of zopiclone maximum daily dose and improvement on CGI-S was 0.84 (95% CI 0.70-0.93, P < 0.0001). The ROC AUC of zopiclone maximum daily dose and SOAS-R-N improvement was 0.80 (95% CI 0.58-0.92; P = 0.0008) and maximum Youden's index value was achieved at a dose of >30 mg. Conclusions: Zopiclone doses >30 mg daily achieved the best anti-aggressive effect.

Zopiclone to treat insomnia in older adults: A systematic review.

Considering the global increase in use of Z-drugs to treat insomnia, the study objective was to conduct a systematic review on the efficacy and safety of zopiclone to treat sleep disorders in older adults compared to other sedative-hypnotics, to placebo or to non-pharmacological interventions. The literature search for original reports - clinical trials, cohort studies and cross-sectional, observational investigations - was done in eleven databases and web search engines followed PRISMA guidelines, and methodological quality was assessed using the Risk of Bias tool in the Cochrane Reviewers' Handbook. The search resulted in 12 randomized, placebo-controlled clinical trials along with 2 open studies and 2 observational reports. Overall, the studies suggest that zopiclone is effective to treat insomnia by reducing sleep latency, nocturnal awakenings and wake time after sleep onset while increasing total sleep time, with probable effects on sleep architecture. Zopiclone was found to be fairly tolerated, to induce a low rate of adverse events with non-severe impact on psychomotor or cognitive performance and to produce no major harm to the overall well-being and daily living abilities. However, the quality of most studies was classified as low or unclear. Though the studies available support benefits from zopiclone use, there is still a need for further evidence on long-term effects, tolerability and safety in the treatment of older adults by means of high-quality trials.