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.

Assessment of Triage DOA®, Status DS10, and DRIVEN-FLOW® M8-Z on-site drug screening kits for postmortem urine.

Based on the screening results of mass analyses using gas chromatography- mass spectrometry (GC-MS) and liquid chromatograph-tandem mass spectrometry (LC-MS/MS), we assessed the performance of Status DS10 (Status) and DRIVEN-FLOW® M8-Z (DF8), and compared the results with those of Triage DOA® (Triage) using 356 autopsy urine samples within one month of death. The sensitivity to benzodiazepines was 0.52 in Triage, 0.59 in Status, and 0.58 in DF8 with few false-positive cases. Triage detected triazolo-derivatives more easily than DF8. DF8 detected diazepam and nitro-benzodiazepines more easily than Status and Triage, with Status performing better than Triage. However, lorazepam detection with Status was difficult. There were 11 false-positive cases for amphetamines in Triage and 12 for Status-AMP at more than one week after death, but there were no false-positive in Status-MET and DF8. Tricyclic antidepressant (TCA) was detected in five cases by mass analysis, while there were 6 false-positive cases in Triage and 10 in both Status and DF8. In the TCA false-positive cases, tricyclic psychotics such as quetiapine, chlorpromazine, and carbamazepine existed. There were 23 true-positive and 6 false-positive cases for zolpidem in DF8 without false-negative cases. The accuracy of Status and DF8 for barbiturates or opiates was almost 1, but Triage was 0.98. There were no samples containing cocaine, THC, phencyclidine, or methadone. Based on the above, we conclude that Status and DF8 are comparable or slightly better than Triage, with fewer false-positive and fewer false-negative cases, except for TCA.

Impact of Secured Prescription Implementation for Zolpidem on Hypnotics Use in France: A Time-Series Analysis on National Data.

We evaluated the impact of the implementation of a requirement that zolpidem prescriptions be obtained via secured forms (April 2017) on zolpidem and other hypnotics use in France. We conducted a time-series analysis on data from the French national health care system, from January 1, 2015 to January 3, 2018, for all reimbursed hypnotics. An important and immediate decrease in zolpidem use (-161,873 defined daily doses [DDD]/month; -215,425 to -108,323) was evidenced, with a concomitant raise in zopiclone use (+64,871; +26,925 to +102,817). These findings suggest that the change in zolpidem prescribing policies was effective, but has resulted in a shift from zolpidem to zopiclone. Further interventions are needed to decrease hypnotics' overuse in France.

Twelve-year trend in the use of zolpidem and physicians' non-compliance with recommended duration: a Korean national health insurance database study.

OBJECTIVES: Abuse of zolpidem has sporadically been reported and little is known regarding nationwide patterns of zolpidem use in Korea. This study investigates the extent of zolpidem usage exceeding the recommended duration and the predictors. METHODS: We conducted a drug utilization study using the national sample cohort database of the Korea National Health Insurance Corporation between 2002 and 2013. The study subjects were patients treated with zolpidem in the outpatient setting. An episode was defined as a period of continuous zolpidem therapy. The provider-based episode allowed for a gap of up to 3 days between two consecutive prescriptions from the same institution. The person-based episode allowed for a gap of up to 3 days, regardless of institution. We calculated the proportion of zolpidem use for periods over 30 days and conducted logistic regression analyses to investigate the relevant predictors. An adjusted odds ratio (aOR) with a 95% confidence interval (CI) was estimated for each predictor. RESULTS: The usage of zolpidem is dramatically increased by approximately 18 times since zolpidem was authorized in the market (1181 in 2002 vs. 21,399 in 2013). The treatment duration in 8.3% of episodes exceeded 30 days out of 75,087 zolpidem users. The odds of zolpidem prescription exceeding 30 days were highest in patients aged 65 years and older (aOR = 2.13, 95% CI 1.78-2.53) and at tertiary hospitals (aOR = 2.14, 95% CI 1.68-2.72). Women were more likely than men to be treated with zolpidem for over 30 days. CONCLUSION: We found dramatic increase of zolpidem use from 2002 to 2013. In 8.3% of the prescribed episodes of zolpidem, the recommended duration was exceeded. Efforts are required to reduce prescriptions that are inconsistent with the recommended guidelines for older patients, women, and in tertiary hospitals.

Evaluation of the effect of different routes of administrating flumazenil against hypnosis / 药学实践杂志

Objective To study the effect of flumazenil on hypnotic mice induced by diazepam and zolpidem ,and to eval-uate the possibility of flumazenil oral administration .Methods First ,Kunming mice were injected intraperitoneally with nor-mal saline and sodium pentobarbital (S + W) ,diazepam and pentobarbital sodium (D + W) ,zolpidem and pentobarbital sodi-um (Z + W) .The hypnotic effect of diazepam and zolpidem on prolonging the sleep time of pentobarbital sodium would be ver-ified by (D + W) group and (Z + W) group .Then the mice were injected intraperitoneally with flumazenil .The sleep time was used as the evaluation index to evaluate the effect of flumazenil against hypnosis . Finally , the oral administration of flumazenil was observed against hypnosis ,which was evaluated by using sleep time as an index .Results Compared with the control group (S+W) ,the diazepam group (D+W) and the zolpidem group (Z+W) significantly prolonged the sleep time in-duced by pentobarbital sodium (P<0 .001 ,P<0 .05);After Intraperitoneal injection of flumazenil ,compared with the diazepam group (D+W) and the zolpidem group (Z+W) ,the sleep time of the diazepam group [F(ip)+D+W] and the zolpidem group [F(ip)+Z+W] were significantly shorter (P<0 .001 ,P<0 .05);After oral administration of flumazenil ,the sleep time of the diazepam group [F(ig)+ D+ W] and the zolpidem group [F(ig)+ Z+ W] were also significantly shorter (P< 0 .001 ,P<0.05) .Conclusion Flumazenil ,whether intraperitoneal injection or intragastric administration ,could antagonize the hypnotic effect of diazepam and zolpidem .It was proved that oral administration of flumazenil had the same effect compared with intrap-eritoneal injection of flumazenil ,which provided the possibility of preparation of oral administration of flumazenil .

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

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

3-Aminomethyl Derivatives of 2-Phenylimidazo[1,2-a]-pyridine as Positive Allosteric Modulators of GABAA Receptor with Potential Antipsychotic Activity.

Schizophrenia is a mental illness characterized by behavioral changes as well as anatomical and neurochemical abnormalities. There has been remarkable progress in the drug discovery for schizophrenia; however, antipsychotics that act through molecular targets, other than monoaminergic receptors, have not been developed. One of the hypotheses of schizophrenia states that GABAergic dysfunction might be implemented in the pathophysiology of this disease. Our recent findings and previous clinical observations have suggested that modulation of GABAergic system through α1-GABAA receptors would represent an original approach for the treatment of schizophrenia. This study presents the synthesis and biological evaluation of a series of fluorinated 3-aminomethyl derivatives of 2-phenylimidazo[1,2-a]-pyridine as potential antipsychotic agents. Compound 7 has a high affinity for GABAA receptor (Ki = 27.2 nM), high in vitro metabolic stability, and antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 10 mg/kg). Compound 7 represents a promising point of entry in the course of development of antipsychotic agents with a nondopaminergic mechanism of action.

Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse.

The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted.

In vitro and in vivo evaluation of nano-based films for buccal delivery of zolpidem

Abstract Insomnia is becoming increasingly prevalent in the world general population. Therapies used by patients include over-the-counter therapies, herbal and dietary supplements, and pharmacological or nonpharmacological treatments. Among these, zolpidem is a pharmacological treatment popularly used for insomnia. Zolpidem is well tolerated and especially efficacious for initiation of sleep, and therefore is effective for the treatment of sleep-onset insomnia. The purpose of the present study was to design and evaluate zolpidem nanoparticle-impregnated buccal films to prolong the duration of its action. Zolpidem nanospheres were prepared by double emulsion solvent evaporation and then loaded into buccoadhesive films (Z1-Z4) comprised of different concentrations of HPMC K100, Eudragit® RL 100, and carbopol 974P. The prepared films were characterized for physicomechanical properties, mucoadhesion, percent hydration, in vitro drug release, ex vivo permeation, and in vivo studies. In vitro drug release was found to depend upon film composition. Ex vivo studies showed that film Z4 had the highest flux. In vivo studies revealed that administration of zolpidem nanosphere-impregnated film enhanced absorption of the drug (p < 0.0001), with a higher peak plasma concentration (52.54 ± 8.22 ng/mL) and area under the curve from time 0 to α (236.00 ± 39.51 ng.h/mL) than oral administration. The increase in time taken to reach the maximum drug concentration (1.5 h) further signifies the potential of these films to provide prolonged drug release. Given these promising results, we concluded that these buccal films could be an alternative route for effective zolpidem delivery.

Prescription patterns of Chinese herbal products for patients with sleep disorder and major depressive disorder in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal products (CHPs) are commonly prescribed for sleep disorder and major depressive disorder (MDD). The aim of this study was to investigate the prescription patterns of CHPs and Western medicine for patients with these disorders in Taiwan, and analyze the frequency of using single herbs (SHs) and herbal formulas (HFs). MATERIALS AND METHODS: In this retrospective population-based study secondary data analysis was performed using data from Taiwan's Longitudinal Health Insurance Database (LHID) between January 2007 and December 2011. In total, 1000,000 beneficiaries from the LHID were randomly selected from the 2010 registry for beneficiaries of the National Health Insurance Research Database. Patients with sleep disorder and MDD according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes 307.40 and 311, respectively. RESULTS: Among a total of 11,030 patients with sleep disorder, 9619 used Western medicine, 1334 used CHPs, and 77 used both, Among a total of 11,571 patients with MDD, 11,389 used Western medicine, 131 used CHPs, and 51 used both. Regardless of disorder type, women were predominant The majority of the patients were aged 22-44 years, had a monthly income of NT$17,281-NT$22,800, and lived in an area with Level 1 and Level 2 urbanization. Of the patients with sleep disorder, 1411 had used CHPs and visited a clinic 5298 times on average. Of the patients with MDD, 182 had used CHPs and visited a clinic 755 times on average. The three most commonly used SHs and HFs were Ziziphi Spinosae Semen, Polygoni Multiflori Caulis, and Polygalae Radix, and Jia-Wei-Xiao-Yao-San, Suan-Zao-Ren-Tang, and Chai-Hu-Chia-Lung-Ku-Mu-Li-Tang, respectively. CONCLUSION: Chinese herbal products including SHs and HFs are prescribed for patients with sleep disorder and MDD. However, the efficacy and safety of CHPs for sleep disorder and MDD need to be further evaluated.

Zolpidem and the risk of Parkinson's disease: a nationwide population-based study.

BACKGROUND: This nationwide population-based study investigated the risk of Parkinson's disease (PD) after zolpidem use in patients with sleep disturbance using the National Health Insurance Research Database (NHIRD) in Taiwan. MATERIAL AND METHODS: In total, 59,548 adult patients newly diagnosed with sleep disturbance and who used zolpidem were recruited as the study cohort, along with 42,171 subjects who did not use zolpidem as a comparison cohort from 2002 to 2009. Each patient was monitored for 5 years, and those who subsequently had PD were identified. A Cox proportional hazards model was used to compare the risk of PD between the study and comparison cohorts after adjusting for possible confounding risk factors. RESULTS: The patients who received zolpidem had a higher cumulative rate of PD than those who did not receive zolpidem during the 5-year follow-up period (1.2% vs. 0.5%, P < 0.001). The adjusted hazard ratios were 1.10 (95% CI, 0.88-1.37), 1.41 (95% CI, 1.17-1.72), and 1.27 (95% CI, 1.05-1.55) for zolpidem use with 28-90, 91-365, and more than 365 cumulative defined daily doses (cDDDs), respectively, compared to those who did not use zolpidem. CONCLUSIONS: Among the patients with sleep disturbance, zolpidem use increased the risk of PD after 5 years of follow-up. Further mechanistic research of zolpidem effect in PD is needed.

The association between zolpidem and infection in patients with sleep disturbance.

OBJECTIVE: Recent case reports suggest that zolpidem usage may be associated with infection events. The aim of this study was to determine the risk of infection events in patients with sleep disturbance taking zolpidem in a full 3-year follow-up study. METHODS: A total of 17474 subjects with a diagnosis of sleep disturbance in 2002 and 2003 were identified, of whom 5882 had used zolpidem after recruitment. A Cox proportional hazard model was used to estimate the 3-year infection event-free rates for the patients using zolpidem and those not using zolpidem after adjusting for confounding factors. To maximize case ascertainment, only patients hospitalized for infection events were included. RESULTS: A total of 646 patients had had infection events, 331 (5.63%) of whom had been taking zolpidem and 315 (2.71%) had not. Zolpidem usage increased the risk of infection events. After adjustments for gender, age, co-morbidities, and other medications, patients using zolpidem with cDDD 1-28, 29-84, and >84 had hazard ratios of 1.67 (95% CI, 1.32-2.11), 1.91 (95% CI, 1.47-2.49) and 1.62 (95% CI, 1.32-1.98) respectively, compared with patients who did not use zolpidem. CONCLUSIONS: Zolpidem increased the risk of infection events in sleep disturbance patients. This increased risk of infection should be explained to sleep disturbance patients, and prescriptions of zolpidem to chronic insomnia patients should be restricted.

The effect of GABAmimetics on the duration of immobility in the forced swim test in albino mice.

OBJECTIVES: Studies regarding the role of gamma aminobutyric acid (GABA) in depression are conflicting. Therefore, it was decided to examine the effect of different drugs that enhance the GABA system on the time of immobility induced by the forced swim test (FST). MATERIALS AND METHODS: Adult albino mice were divided into several groups of six animals. Each group received an intraperitoneal injection of either imipramine (10, 20, or 30 mg/kg), diazepam (0.5, 1, or 2 mg/kg), vigabatrin (100, 200, or 300 mg/kg), zolpidem (2.5, 5, or 10 mg/kg), or alprazolam (1, 2.5, or 5 mg/kg). Control groups received the appropriate vehicle. One hour after injection, the duration of immobility was measured for 5 min in the FST. The percentage change in the duration of immobility from the control was calculated for each group. The statistical test of the difference between the treated and the control groups was calculated using unpaired Student's t-test. RESULTS: Imipramine produced a significant dose-dependent decrease in the duration of immobility (78, 74, and 56%, respectively). Different doses of diazepam, vigabatrin, and zolpidem produced a significant increase in the duration of immobility (119, 126, and 128%), (116, 124, and 128%), and (108, 109, and 119%), respectively. The two low doses of alprazolam produced a significant increase (115 and 120%), while the high dose produced a significant decrease in the duration of immobility (74%). CONCLUSION: Increasing central GABAergic activity by different mechanisms has resulted in a depressant-like activity measured as an increase in the duration of immobility in the FST model of depression.

A mouse model mimicking human first night effect for the evaluation of hypnotics.

In humans, a first night effect (FNE) is characterized by increased sleep latency and decreased total sleep time in an unfamiliar environment, but the mechanism and treatment options for this universally experienced acute insomnia are unclear. We continuously recorded electroencephalography (EEG) and electromyogram (EMG) and measured plasma corticosterone levels to develop a mouse FNE model by inducing acute insomnia in mice that have been placed in unfamiliar cage environments. The sleep latency of mice 'moved to clean cages' (MCC) was longer than that for mice 'moved to dirty ones' (MDC). As compared to MDC mice, MCC mice showed stronger decreases in the amount of non-rapid eye movement (non-REM, NREM) and REM sleep, with a lower power density of NREM sleep, increased fragmentation and decreased stage transitions from NREM sleep to wake, and higher variation in plasma corticosterone levels. Treatment of MCC mice with zolpidem, diazepam, raclopride, pyrilamine, except SCH23390 shortened NREM sleep latency. In addition, zolpidem significantly increased NREM and REM sleep with the increase in slow wave activity (1.00-2.75 Hz), while raclopride significantly increased NREM and REM sleep without changing the EEG power density in MCC mice, whereas diazepam increased sleep with a drastic decrease in power density of the frequency band between 1.00 and 4.00 Hz, diazepam also increased the frequency band between 9.75 and 24.75 Hz during NREM sleep. These results indicate that a MCC mouse can mimic a FNE phenotype of humans and that zolpidem and raclopride may be useful drugs to prevent acute insomnia, including FNE.

Efficacy and safety of a polyherbal sedative-hypnotic formulation NSF-3 in primary insomnia in comparison to zolpidem: a randomized controlled trial.

OBJECTIVES: To assess the efficacy and safety of NSF-3, a polyherbal sedative-hypnotic (containing standardized extracts of Valeriana officinalis, Passiflora incarnate and Humulus lupulus), in comparison to zolpidem in primary insomnia. MATERIALS AND METHODS: The present study was designed as a parallel group, double- blind, randomized, controlled trial and registered with Clinical Trials Registry-India (CTRI/2011/12/002197). Patients diagnosed with primary insomnia with a perceived total sleep time of <6 hours per night and insomnia severity index >7 were included. They were treated with either NSF-3 (one tablet) or zolpidem (one 10 mg tablet) at bedtime for two weeks. Total sleep time, sleep latency and number of awakenings per night were assessed using a sleep diary. Quality of life and daytime sleepiness were evaluated by insomnia severity index and Epworth sleepiness score respectively. Vital signs, routine blood counts, liver and renal function tests, and treatment emergent adverse events were recorded for safety assessment. RESULTS: A total of 91 subjects were recruited, of which 39 in each group completed the study. There was significant improvement in total sleep time, sleep latency, number of nightly awakenings and insomnia severity index scores in both groups. However, no statistically significant difference was observed between the groups. Epworth sleepiness scores did not change significantly over the study period. Although 12 treatment emergent adverse events were reported with NSF-3 and 16 with zolpidem (commonest was drowsiness in both), most were mild and no serious adverse events were encountered. CONCLUSIONS: NSF-3 is a safe and effective short-term alternative to zolpidem for primary insomnia. It remains to be explored whether the benefits are sustained and whether there is dependence liability with this formulation upon long term use.