Non-benzodiazepine Research Articles

Association Between Hypnotics and Dementia: A Mini Narrative Review

Objective This narrative review aims to provide a comprehensive assessment of the existing literature on the relationship between hypnotics and dementia, considering both potential link and inconclusive or lack of association.Methods Data from studies that investigate the association between hypnotic medications and dementia were reviewed. Studies included both cohort studies and systematic reviews, participants with various type of dementia and hypnotics including benzodiazepines (BZDs) and Z-drugs (ZDs).Results The existing literatures presents conflicting evidence regarding the association between hypnotics, including BZDs and ZDs, and the risk of dementia. Some studies suggest a potential link between prolonged use of hypnotics and an increased risk of dementia. However, other studies indicate inconclusive or lacking evidence regarding this association. Factors such as study design, sample characteristics, and control of confounding variables contribute to the variability in findings.Conclusion The relationship between hypnotics and dementia remains complex and controversial. While some studies suggest a potential association, others find inconclusive or conflicting evidence. Future research should focus on addressing methodological limitations, considering classifying dementia subtypes, and try to adjust medication lag time.

Managing insomnia in Elderly patients: Evidence-based treatment approaches

Elderly patients (EP) often have Chronic Sleep (CS). Although elders are among the categories with the highest need for therapy, these EP are often seen as challenging to treat. This study offers a thorough the studies on the therapy of persistent insomnia in EP with an emphasis on Evidence-Based (EB) therapeutic strategies. Meta-Analyses (MA), EB evaluations of therapy modalities, randomized controlled trials of Non-Pharmacologic (NP) treatment, and the features and treatment of insomnia were all criteria for selecting publications. MA, EB on solid, and studies including pertinent new data were given preference. When NP gets closer, the field is on their side. Among the medications used to treat insomnia include sedating antidepressants, barbiturates, OTC, prescription, and chloral hydrate antihistamines, as well as OTC and OTC nutritional supplements and cognitive behavioral therapy (CBT). SH drugs, including Benzodiazepine (BZD), Non-Benzodiazepine (NB), and melatonin agonists. NP therapies for insomnia in people of all ages have a large body of research supporting their efficacy and durability, yet still need to be addressed. With a few notable exceptions, the bulk of pharmacological trials found was of short length and did not just include EP as participants. The Non-benzodiazepine Sedative Hypnotics (NSH) proved to have minor, if any, substantial therapeutic benefits in effectiveness or tolerability in EP compared to BZD. Melatonin agonists are among the newer medicines with unique mechanisms of accomplishment and better security profiles that show promise for treating Chronic Insomnia (CI) in EP. There is no strong evidence base for the long-term use of sedative hypnotics (SH) to treat insomnia, and this practice has historically been discouraged because of concerns about possible adverse effects such as cognitive impairment, daytime sedation, motor incoordination, and an increased risk of falls and car accidents. The most effective management technique for senior people with CI will need more study to establish the extended-term consequences of therapy.

Prescription of Sedative Hypnotics in Psychiatric and Somatic Inpatients

Abstract: Benzodiazepines (BZD) and Z-drugs (ZD) are often prescribed to treat psychiatric disorders. Despite the risk of dependency and serious adverse events, they are increasingly prescribed to outpatients. Yet little is known about the prescription to inpatients. In this article, we analyze the BZD and ZD prescription patterns in the routine data of 913 psychiatric and somatic inpatients treated in Bochum, Germany. BZD were prescribed more often as regular medication in psychiatry and ZD in somatic hospitals. ZD were more often used on demand, by female patients, and combined with other substances. Both were frequently prescribed to older adults, especially as part of somatic treatment and in combination with opioids. Prescription of sedative hypnotics is frequent in psychiatric and somatic inpatients. Their use seems to be partially independent of recorded psychiatric indications.

Hospitalisations related to benzodiazepine, Z-drug, and opioid treatment in Italy: a claim on the risks associated with inappropriate use

PurposeBenzodiazepines (BZD), Z-drugs (ZD), and opioids share a high risk of abuse. This study assessed and characterised adverse events (AEs) related to BDZ, ZD, and opioids leading to emergency department (ED) visits in the Italian setting.MethodsED accesses related to BDZ, ZD, and/or opioids were analysed from the MEREAFaPS database. Information on AEs, suspected and concomitant medications was retrieved. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation according to the different treatments.ResultsA total of 5,970 pharmacovigilance reports involving BZD/ZD (n = 3,106), opioids (n = 2,767), or their combination (n = 97) were analysed. Compared to opioids, patients with BZD/ZD-related AEs were often younger (51 vs 64 years), more frequently presented 2+ suspected medications (13 vs 3%), and often had a history of abuse (4%). Twenty-three percent of BZD/ZD-related AEs were related to drug abuse (vs 2% of opioid-related ones) and frequently required patient hospitalisation (52% vs 24%), despite the significantly lower clinical complexity of these patients as compared to those on opioids. An increased risk of hospitalisation was found for flurazepam (ROR 1.62; 95% CI, 1.18–2.22), prazepam (2.66; 1.05–6.70), lorazepam (1.26; 1.07–1.49), and morphine (1.76; 1.11–2.79).ConclusionsThese results indicate that, in Italy, the inappropriate use of BZD/ZD is a relevant heath issue, often leading to serious AEs requiring patients’ ED visits and hospitalisation, especially in young women and patients with a history of substance abuse.

Phenobarbital use in benzodiazepine and z-drug detoxification: a single-centre 15-year observational retrospective study in clinical practice

Given the increase in benzodiazepine (BZD) and Z-drug (ZD) use disorder, this study described the use of phenobarbital (PHB) as detoxification in clinical practice. A 15-year observational retrospective study was performed on medical records of BZD-ZD use disorder patients detoxified with PHB at the Toxicology Unit and Poison Centre, Careggi University Hospital, Florence (Italy). A multivariate logistic regression was used to estimate odd ratios (ORs) and related 95% confidence intervals (CI) of “treatment failure” considering demographic and pharmacological characteristics. “Hospitalisation length”, “PHB discharge dose”, and “BZD-ZD free status” at discharge were also calculated. During detoxification, out of 355 patients (57% of men), with a mean age of 42.92 years, only 20 (5.6%) treatment failures were recorded: 19 were discharged against medical advice or due to misbehaviour, and only one for PHB-related non-serious skin rash. Analysis showed a higher probability to be BZD-ZD free at discharge for subjects who reported to be employed (OR 2.29; CI 95% 1.00–5.24), for those who abused oral drops of BZD-ZD (OR 2.16, CI 1.30–3.59), and for those treated with trazodone (OR 2.86, CI 1.14–7.17) during hospital stay. A hospitalisation length of > 7 days was observed for patients with opioid maintenance therapy (OR 2.07, CI 1.20–3.58) for substance use disorder, and for those treated with more than 300 mg/day of PHB equivalents at hospital admission (OR 1.68, CI 1.03–2.72). Our results suggested that PHB can be considered a valuable detoxification option for different types of BZD and ZD use disorder patients.

Benzodiazepine and Z-Drug Use in Switzerland: Prevalence, Prescription Patterns and Association with Adverse Healthcare Outcomes

PurposeThis study aimed to give a nationwide comprehensive picture of the prevalence and prescription patterns of benzodiazepines (BZ) and Z-drugs (ZD) in Switzerland and to analyze the association with adverse health care outcomes.Patients and MethodsA population-based, cross-sectional study was conducted, using a large health insurance database in Switzerland. Records from all adult patients with ≥1 prescription for a benzodiazepine and/or a Z-drug in 2018 were included. We calculated the prevalence of BZ and ZD user (extrapolated to the Swiss general population), the number of prescriptions and the type of provider (among each BZ and ZD only user). Multivariate logistic regression models were performed to estimate the association between drug prescription and the risk of hospitalization in different healthcare settings.ResultsOf a total of 844ʹ692 patients, 95ʹ179 had ≥1 BZ and/or ZD prescription in 2018. The extrapolated one-year prevalence for the general Swiss population was 8.1% for a BZ prescription, 3.5% for a ZD prescription, and 10.5% for a BZ and/or ZD prescription, and continuously increased with age. The majority of the elderly (over 65 years) had ≥1 prescription (BZ: 51.9%; ZD: 56.9%; BZ and/or ZD: 53.5). The proportion of patients with ≥6 prescriptions per year was 23.1% for BZ only user and 35.2% for ZD only user. Most patients had ≥1 prescription from a general practitioner. Regression models showed a higher likelihood to be admitted to acute care, psychiatry, rehabilitation, or nursing home with ≥1 prescription for a benzodiazepine and/or a Z-drug.ConclusionThis study is the first to give a nationwide overview of the current use of benzodiazepines and Z-drugs in Switzerland based on health insurance claims data. The results revealed a remarkably high prevalence among the general Swiss population, especially in older generations. The negative consequences of heavy BZ and ZD use are a crucial public health problem, that should be addressed.

Risk of hospitalisation associated with benzodiazepines and z-drugs in Italy: a nationwide multicentre study in emergency departments.

Benzodiazepines (BZD) and z-drugs (ZD) are a widely prescribed group of medicines. They are often used inappropriately, and this is associated with adverse events (AEs), which may cause emergency department (ED) visits. The present study aimed to describe the characteristics of BZD and ZD related AEs leading to emergency department (ED) visit and hospitalisation in Italy, considering their plasma half-life. Ninety-two Italian EDs were monitored between 2007 and 2018. Rates of ED visit and hospitalisation were calculated. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation. Univariate linear regression was performed to evaluate the ROR of hospitalisation according the plasma half-life of the suspected agents. A total of 3203 AE reports were collected. Overall, multivariate logistic regression showed that the risk of hospitalisation was higher for prazepam (3.26 [1.31-8.11]), flurazepam (1.62 [1.15-2.27]), and lorazepam (1.36 [1.15-1.61]). In the elderly, this risk was higher for prazepam (3.98 [1.03-15.3]), and lorazepam (1.58 [1.19-2.11]). Parenteral and rectal formulations were associated with a lower risk of hospitalisation compared to oral formulations. Our findings underlined the dangers in the use of BZD and ZD in Italy, particularly in women and older adults. ED clinicians must always take into account that the higher risk in terms of hospitalisation related to the use of BZD and ZD can be observed in patients treated with oral formulations, in those exposed to more than one sedative-hypnotics, and in patients exposed to compounds with intermediate or long plasma half-life.

Benzodiazepines, “Z-Drugs,” and Risks for Dementia in Patients with Affective Disorders

Because of the cognitive adverse effects of benzodiazepines, the hypnotic nonbenzodiazepine “Z-drugs,” and other anxiolytics, concerns have grown about

Problematic Medication With Benzodiazepines, "Z-drugs", and Opioid Analgesics.

An estimated 1.4 to 2.6 million people in German suffer from drug dependence. Most of them are long-term users of benzodiazepines (BZD), Z drugs (ZD), or opioid analgesics (OA). This analysis is based on prescription data from patients of the national statutory health insurance system in the German federal states of Schleswig-Holstein, Hamburg, Bremen, and Lower Saxony. Drug-taking trends, duration, dosage, and long-term use of BZD, ZD, and OA in the years 2006 to 2015 are analyzed; prevalences are estimated for the years 2006 to 2016. In 2006, 7.7% of patients received at least one prescription for a BZD, ZD, or OA; in 2016, 7.0% did. Over the period of analysis, a marked drop was seen in prescriptions of BZD and a slight fall in prescriptions of ZD (2006: BZD 3.5%, ZS 1.1%; 2016: BZD 2.0%, ZS 0.8%), but there was also an increase in prescriptions of OA, from 4.2% to 4.9%. The number of defined daily doses (DDD) prescribed per year fell for both BZD and ZD. For OA, the number of DDD prescribed per year rose from 2006 to 2009 and decreased by a small amount in subsequent years. The proportions of BZD and ZD patients who had long-term prescriptions fell over time, while the corresponding percentage of OA patients rose. Nearly one-fifth of all prescriptions for BZD were long-term prescriptions for an entire year, in violation of the relevant guidelines. The rising prevalence of OA use was in the expected range in view of the aging population, but the number of prescriptions rose among younger patients as well. This trend toward more common treatment with opioid analgesics should be critically examined.

Zolpidem high-dose abuse: what about the liver? Results from a series of 107 patients

ABSTRACTObjectives: Z-Drugs (ZDs) have been developed to limit benzodiazepines (BZDs) abuse for sleep disorders. Data on the liver toxicity of zolpidem (ZLM) are lacking or anecdotal. The authors evaluated the presence of drug-induced liver injury (DILI) among a cohort of high-dose ZLM abusers.Methods: Retrospective study analyzing clinical records of 1112 consecutive patients admitted for BZDs detoxification from 2003 to 2018. Inclusion criteria: age >18 y.o.; ZLM abuse/dependence; high-dose ZDs abuse. Exclusion criteria: missing lab data; lack of informed consent. Main outcome was the presence of DILI measured as elevation of ALT/AST levels >250 U/l.Results: A total of 107 patients met the eligibility criteria. Liver enzymes alterations were present in 9.3% (95% CI 4.6–16.5%); one patient (0.9%, 95% CI 0.0–2.8%) showed DILI criteria. BMI significantly influenced transaminases levels. No correlations between duration nor doses of ZLM abuse and transaminases levels were found.Conclusion: The present study shows a very low prevalence of DILI among high-dose ZLM abusers. The prevalence of hypertransaminasemia was in line with general population. On one hand ZLM has a substantially safe liver profile but on the other hand ZLM abuse and dependence, especially at very high doses, represents an emerging problem.

Benzodiazepines and the Z-Drugs in Pregnancy—Reasonably Reassuring for Neurodevelopment But Should We Really Be Using Them?

Benzodiazepines and the Z-Drugs in Pregnancy—Reasonably Reassuring for Neurodevelopment But Should We Really Be Using Them?

Nonbenzodiazepine Muscle Relaxants Do Not Improve Outcomes in Low Back Pain Treated with Naproxen

Investigators previously showed that diazepam does not improve outcomes in patients with low back pain treated with naproxen (NEJM JW Emerg Med Apr

More than 250,000 people in UK taking benzodiazepines and Z-drugs for longer than recommended

More than 250,000 people in UK taking benzodiazepines and Z-drugs for longer than recommended

Anxiolytics and Hypnotics Are Associated with Excess Mortality

Use of anxiolytic and hypnotic drugs such as benzodiazepines and Z-drugs (e.g., zolpidem [Ambien and generics], zaleplon [Sonata and generics]) is

Excess Risk for Hip Fracture Among Nursing Home Residents Who Take Nonbenzodiazepine Hypnotics

The lack of Medicare Part D coverage of benzodiazepines (BZDs) because of hip-fracture concerns effectively has eliminated their use in nursing homes,

Determination of stability indicating assay method for eszopiclone in pharmaceutical drug substances a comparative study by UPLC and HPLC

Eszopiclone is a nonbenzodiazepine hypnotic used as a treatment for insomnia . Eszopiclone is the active dextrorotatory stereoisomer of zopiclone , and belongs to the class of drugs known as cyclopyrrolones . A simple, Isocratic, rapid and selective RP-UPLC method was developed for the quantification of Capecitabine in active pharmaceutical ingredients (API’S) using a simple mobile phase of solution A (5.0g of sodium dodecyl sulfate and 2.0 g of monobasic sodium phosphate were dissolved in one liter of water and adjusted the pH to 3.8 with 10% phosphoric acid) and solution B acetonitrile in the ratio of 65:35 at a flow rate of 0.50 mL/min. The chromatographic separation was achieved on a Poroshell C18 column of dimension 4.6 X 50 mm, 2.7µm. The column and sample compartment temperatures were maintained at ambient. UV detector was monitored at 303nm. The retention time (RT) of Eszopiclone was about 8.4min at an overall runtime of 12min. The developed method was validated as per the requirements of ICH guidelines. Finally a comparison of the method was done against conventional HPLC. The developed method was superior with respect to analysis time , efficiency and sensitivity. The runtime of Eszopiclone in conventional hplc method was about 60.0min. Compare to HPLC method the developed method is cost effective and more rugged. The method can be used for routine analysis of assay in Quality Control laboratory on regular basis.

‘Z-Drugs’ for Imsomnia Come With a Caveat

‘Z-Drugs’ for Imsomnia Come With a Caveat

First-Line ‘Z-Drugs’ for Insomnia Come With a Caveat

First-Line ‘Z-Drugs’ for Insomnia Come With a Caveat

Benzodiazepine receptor agonists cause drug-specific and state-specific alterations in EEG power and acetylcholine release in rat pontine reticular formation.

Benzodiazepine (BDZ) and non-benzodiazepine (NBDZ) hypnotics enhance GABAergic transmission and are widely used for the treatment of insomnia. In the pontine reticular formation (PRF), GABA inhibits rapid eye movement (REM) sleep and acetylcholine (ACh) release. No previous studies have characterized the effects of BDZ and NBDZ hypnotics on ACh release in the PRF. This study tested 2 hypotheses: (1) that microdialysis delivery of zolpidem, eszopiclone, and diazepam to rat PRF alters ACh release in PRF and electroencephalographic (EEG) delta power and (2) that intravenous (i.v.) administration of eszopiclone to non-anesthetized rat alters ACh release in the PRF, sleep, and EEG delta power. A within- and between-groups experimental design. University of Michigan. Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 57). In vivo microdialysis of the PRF in rats anesthetized with isoflurane was used to derive the concentration-response effects of zolpidem, eszopiclone, and diazepam on ACh release. Chronically instrumented rats were used to quantify the effects of eszopiclone (3 mg/kg, i.v.) on ACh release in the PRF, sleep-wake states, and cortical EEG power. ACh release was significantly increased by microdialysis delivery to the PRF of zolpidem and eszopiclone but not diazepam. EEG delta power was increased by zolpidem and diazepam but not by eszopiclone administered to the PRF. Eszopiclone (i.v.) decreased ACh release in the PRF of both anesthetized and non-anesthetized rats. Eszopiclone (i.v.) prevented REM sleep and increased EEG delta power. The concentration-response data provide the first functional evidence that multiple GABA(A) receptor subtypes are present in rat PRF. Intravenously administered eszopiclone prevented REM sleep, decreased ACh release in the PRF, and increased EEG delta power. The effects of eszopiclone are consistent with evidence that ACh release in the PRF is lower during NREM sleep than during REM sleep, and with data showing that cholinergic stimulation of the PRF activates the cortical EEG.

Helping Patients Discontinue Benzodiazepines

Many long-term users of benzodiazepines find it difficult to discontinue their medication. In this double-blind U.S. study, researchers examined whether either the tricyclic antidepressant imipramine or the non-benzodiazepine antianxiety agent buspirone is helpful for patients trying to discontinue benzodiazepine therapy. The researchers …