Long-acting Benzodiazepines Research Articles

High rate of potentially inappropriate medication use in older people: a case–control study

Annually, 172 million fall events cause temporary or permanent impairment in older adults, and this number is increasing. Contributing factors that increase the risk for falls include age, polypharmacy, and malnutrition. This study evaluated medications mainly included in the EU(7)-PIM (potentially inappropriate medication) list. From March 21, 2022, to July 6, 2022, 945 patients who experienced a fall and visited the Department of Emergency Medicine at the Albert Szent-Györgyi Health Centre of the University of Szeged in Hungary. Data from 886 patients were collected (study group). The control group included 1364 patient data collected from three general practice in Hungary. The use of ≥ 2 EU(7)-PIM drugs was found to be associated with increased risk for falls (adjusted odds ratio [AOR], 1.38; 95% confidence interval [CI] 1.01–1.88). Piracetam (AOR, 1.81; 95% CI, 1.28–2.57) and trimetazidine (AOR, 1.62; 95% CI, 1.17–2.24) were associated with increased risk for falls. Doxazosin was associated with a low risk for falls (AOR, 0.59; 95% CI, 0.41–0.86). Tiapride (AOR, 3.54; 95% CI, 1.75–7.17), gliclazide (AOR, 1.57; 95% CI, 1.02–2.43), and vinpocetine (AOR, 1.95; 95% CI, 1.29–2.95) are not included in the EU(7)-PIM list; however, they are associated with increased risk for falls. Long-acting benzodiazepines (AOR, 1.79; 95% CI, 1.20–2.68), antidepressants (AOR, 1.89; 95% 95% CI, 1.37–2.61), serotonin–norepinephrine reuptake inhibitor (AOR, 2.82; 95% CI, 1.41–5.67; p < 0.01), and selective serotonin reuptake inhibitor (AOR, 1.88; 95% CI, 1.24–2.85) were also associated with increased risk for falls. However, Z-drugs were associated with a low risk for falls (AOR, 0.57; 95% CI, 0.36–0.92). With the help of this tool, trimetazidine and piracetam are filtered as EU(7)-PIM drugs associated with increased risk for falls.

Reliability and validity of the Swedish indicator ‘Drugs that should be avoided in older people’—an appraisal of a set of potentially inappropriate medications

PurposeTo analyse the reliability and validity of the Swedish indicator ‘Drugs that should be avoided in older people’.MethodsFrom a previous study that included consecutive primary care patients ≥ 65 years of age, all patients ≥ 75 years of age were analysed. Two physicians independently screened their medication lists and medical records, applying the Swedish indicator which includes potentially inappropriate medications (PIMs): long-acting benzodiazepines, drugs with anticholinergic action, tramadol, propiomazine, codeine, and glibenclamide. The clinical relevance of identified PIMs was independently assessed. Thereafter, the physicians determined in consensus whether some medical action related to the drug treatment was medically justified and prioritised before the next regular visit. If so, the drug treatment was considered inadequate, and if not, adequate.ResultsA total of 1,146 drugs were assessed in 149 patients (75‒99 years, 62% female, 0‒20 drugs per patient). In 29 (19%) patients, at least one physician identified ≥ 1 PIM according to the indicator at issue; 24 (16%) patients were concordantly identified with ≥ 1 such PIM (kappa: 0.89). Of 26 PIMs concordantly identified, the physicians concordantly assessed four as clinically relevant and 12 as not clinically relevant (kappa: 0.17). After the consensus discussion, six (4%) patients had ≥ 1 PIM according to the studied indicator that merited action. Using the area under the receiver operating characteristic (ROC) curve, the indicator did not outperform chance in identifying inadequate drug treatment: 0.56 (95% confidence interval: 0.46 to 0.66).ConclusionThe Swedish indicator has strong reliability regarding PIM detection but does not validly reflect the adequacy of drug treatment.

The Rise of Remimazolam: A Review of Pharmacology, Clinical Efficacy, and Safety Profiles.

Anesthesiologists often use benzodiazepines (BZDs) due to their remarkable amnestic and anxiolytic capabilities. Because of this, they are perfect for use during the perioperative phase, when patients' anxiety levels are already high. Remimazolam has replaced certain commonly used intravenous (IV) anesthetics due to its excellent safety profile, rapid onset of action, and short half-life. The four classes of BZDs, 2-keto-benzodiazepines, 3-hydroxy-benzodiazepines, triazolobenzodiazepines, and 7-nitro-benzodiazepines based on chemical structure, provide various levels of drowsiness, forgetfulness, and anxiolysis. Based on their elimination half-life, short-acting BZDs typically have a half-life ranging from one to 12 hours, e.g., oxazepam; intermediate-acting BZDs have an average elimination half-life of 12 to 40 hours, e.g., alprazolam; and long-acting BZDs have an average elimination half-life of more than 40 hours, e.g., diazepam. The chloride ion channel is conformationally shifted by the benzodiazepine molecule resulting in central nervous system (CNS) inhibition and hyperpolarization. Each type of benzodiazepine has a favored use. For example, diazepam is used to treat anxiety. Midazolam is used for its anxiolytic and anterograde amnestic effects during the perioperative phase. Anxiety and epilepsy are two conditions that lorazepam effectively treats. There are now phase II and III clinical studies investigating remimazolam. It is not sensitive to alterations in its surroundings and has a brief half-life so that it may be removed rapidly, even after extensive infusion. Being a soft drug means the body easily breaks it down via metabolism, which explains many features. Remimazolam is hydrolyzed into methanol and its carboxylic acid metabolite CNS 7054 by esterase metabolism. Therefore, remimazolam has a shorter onset time and faster recovery than other BZDs. Remimazolam is metabolized independently of any particular organ. Patients with hepatic and renal problems will not see any changes in metabolism or excretion since the drug's ester moiety makes it a substrate for general tissue esterase enzymes. Like its predecessor, midazolam, it has a high potential for addiction. Some side effects that could occur during infusion include headaches and drowsiness. In clinical trials, hypotension, respiratory depression, and bradycardia were noted in participants. BZDs are helpful when used in conjunction with anesthesia. Remimazolam stands out, thanks to its unique pharmacokinetics, pharmacodynamics, safety profile, and potential medical applications. Its desirable properties make it a potential surgical premedication and sedative in the critical care unit. Anesthesiologists and other doctors could have access to more consistent and safer medication. However, additionalcomprehensive clinical trials are necessary to understand remimazolam's advantages and disadvantages.

Prescribing and deprescribing guidance for benzodiazepine and benzodiazepine receptor agonist use in adults with depression, anxiety, and insomnia: an international scoping review

Clinical practice guidelines and guidance documents routinely offer prescribing clinicians' recommendations and instruction on the use of psychotropic drugs for mental illness. We sought to characterise parameters relevant to prescribing and deprescribing of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA), in clinical practice guidelines and guidance documents internationally, for adult patients with unipolar depression, anxiety disorders and insomnia to understand similarities and discrepancies between evidence-based expert opinion. A Scoping Review was conducted to characterize documents that offered evidence-based and/or consensus pharmacologic guidance on the management of unipolar depression, anxiety disorders, obsessive-compulsive disorders, post-traumatic stress disorders and insomnia. A systematic search was conducted of PubMed, SCOPUS, PsycINFO and CINAHL from inception to October 13, 2023 and supplemented by a gray literature search. Documents were screened in Covidence for eligibility. Subsequent data-charting on eligible documents collected information on aspects of both prescribing and deprescribing. 113 documents offering guidance on BZD/BZRA use were data-charted. Overall, documents gathered were from Asia (n=11), Europe (n=34), North America (n=37), Oceania (n=7), and South America (n=4) with the remainder being "International" (n=20) and not representative to any particular region or country. By condition the documents reviewed covered unipolar depressive disorders (n=28), anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder (n=42) and Insomnia (n=25). Few documents (n=18) were sufficiently specific and complete to consider as de-prescribing focused documents. Documents were in concordance in terms of BZD and BZRA not being used routinely as first-line pharmacologic agents. When used, it is advisable to restrict their duration to "short-term" use with the most commonly recommended duration being less than four weeks. Documents were less consistent in terms of prescriptive recommendations for specific drug, dosing and administration pattern (i.e regular or 'as needed') selection for each condition. Deprescribing documents were unanimously in favor of gradual dose reduction and patient shared decision-making. However, approaches towards dose-tapering differed substantially. Finally, there were inconsistencies and/or insufficiency of detail, among deprescribing documents, in terms of switching to a long-acting BZD, use of adjunctive pharmacotherapies and micro-tapering. The authors received no funding for this work.

Contemporary Management and Outcomes of Veterans Hospitalized With Alcohol Withdrawal: A Multicenter Retrospective Cohort Study.

Few studies describe contemporary alcohol withdrawal management in hospitalized settings or review current practices considering the guidelines by the American Society of Addiction Medicine (ASAM). We conducted a retrospective cohort study of patients hospitalized with alcohol withdrawal on medical or surgical wards in 19 Veteran Health Administration (VHA) hospitals between October 1, 2018, and September 30, 2019. Demographic and comorbidity data were obtained from the Veteran Health Administration Corporate Data Warehouse. Inpatient management and hospital outcomes were obtained by chart review. Factors associated with treatment duration and complicated withdrawal were examined. Of the 594 patients included in this study, 51% were managed with symptom-triggered therapy alone, 26% with fixed dose plus symptom-triggered therapy, 10% with front loading regimens plus symptom-triggered therapy, and 3% with fixed dose alone. The most common medication given was lorazepam (87%) followed by chlordiazepoxide (33%), diazepam (14%), and phenobarbital (6%). Symptom-triggered therapy alone (relative risk [RR], 0.68; 95% confidence interval [CI], 0.57-0.80) and front loading with symptom-triggered therapy (RR, 0.75; 95% CI, 0.62-0.92) were associated with reduced treatment duration. Lorazepam (RR, 1.20; 95% CI, 1.02-1.41) and phenobarbital (RR, 1.28; 95% CI, 1.06-1.54) were associated with increased treatment duration. Lorazepam (adjusted odds ratio, 4.30; 95% CI, 1.05-17.63) and phenobarbital (adjusted odds ratio, 6.51; 95% CI, 2.08-20.40) were also associated with complicated withdrawal. Overall, our results support guidelines by the ASAM to manage patients with long-acting benzodiazepines using symptom-triggered therapy. Health care systems that are using shorter acting benzodiazepines and fixed-dose regimens should consider updating alcohol withdrawal management pathways to follow ASAM recommendations.

Evaluation of a benzodiazepine deprescribing quality improvement initiative for older adults in primary care.

Older adults are commonly prescribed long-term benzodiazepines for anxiety and insomnia despite evidence of risks and limited evidence of long-term benefits. Recent quality measures and guidelines have recommended benzodiazepine deprescribing, yet there is little real-world data on clinic-based deprescribing programs. We developed a benzodiazepine deprescribing quality improvement program for older adults at a large US academic medical center. The program targeted adults aged 65 years and older who were prescribed chronic benzodiazepines by their primary care physician (PCP). PCPs were contacted to opt-out patients not suitable for deprescribing; then eligible patients were mailed a letter discussing patient-specific risks and advising them to discuss deprescribing with their PCP or a pharmacist who was available to support tapering. The primary outcomes were the number of patients who discussed deprescribing and who initiated a taper within 90 days of outreach. Of 504 older adults prescribed benzodiazepines, 133 (26%) were opted out by their PCPs leaving a cohort of 371 (median age 71 years [IQR 68-75], 58% female, 82% White). The median daily diazepam milligram equivalent was 5 mg (IQR 3-6 mg) and 30% were prescribed long-acting benzodiazepines. Three months following patient outreach, 97 patients (26%) had a documented discussion of benzodiazepines with their PCP or clinic pharmacist. Of these patients, 35 (36%) had documentation of a deprescribing discussion and 25 (26%) initiated a taper. At 12 months, 16 patients (64%) were tapered successfully, with nine (36%) patients taking a lower benzodiazepine dose and seven (28%) discontinuing benzodiazepines completely. A low-intensity benzodiazepine deprescribing outreach program led to deprescribing conversations for a minority of patients, but one-quarter of older adults who engaged in a conversation chose to taper and nearly two-thirds sustained reduced use. Incorporating benzodiazepine deprescribing into routine care may require more intensive population-health efforts to engage patients and clinicians.

Treatment of high dose of intravenous midazolam abuse: a case report.

This study reports a rare case of high-dose midazolam abuse and Munchausen Syndrome. A 48-year-old female physician was referred by a psychiatrist to the Toxicology Department of Imam Reza Hospital for abstaining from 300 mg/day of parenteral midazolam. She had mimicked the symptoms of Crohn's disease; therefore, she had undergone 15 colonoscopies and 40 times MRI or CT scan, all of which were normal. Six months earlier, she had switched oral methadone to 30 mg/day of intravenous midazolam. She also had several skin lesions on injection sites that she considered pyoderma gangrenosum. When the total daily dose of intravenous midazolam was switched to oral bioequivalence of clonazepam, she could not tolerate withdrawal (Clinical Institute Withdrawal Assessment Scale-Benzodiazepines = 68). Therefore, she received midazolam again as a continuous intravenous infusion. Within 7 days, the whole dose was replaced by the bioequivalence oral dose of clonazepam. She was also treated with carbamazepine and cognitive behavior therapy. Afterward, she was transferred to the psychiatric ward for further psychiatric treatment. Dependency on a high dose of midazolam could be treated by tapering off the long-acting benzodiazepine.

Another Option for Aggression and Self-Injury, Alternative Benzodiazepines for Catatonia in Profound Autism.

Introduction: Individuals with profound autism often present for inpatient care due to aggression. Diagnostic and treatment options are limited. Agitated catatonia is a treatable comorbidity in autism, which should be considered in cases of aggression. Preliminary data report high clinical response rates of catatonia in autism when treated with electroconvulsive therapy (ECT), with poor response to lorazepam. However, access to ECT is often limited, especially in pediatric populations. Methods: We conducted a retrospective chart review to identify cases of hyperactive catatonia with partial response to lorazepam in profoundly autistic children presenting to the pediatric medical hospital. Five cases were identified, all of whom were followed by the child and adolescent psychiatry consult-liaison service during admission and treated without the use of ECT. Data from the medical record were obtained after institutional review board (IRB) approval including the following: (1) treatment course, (2) Bush-Francis Catatonia Rating Scale (BFCRS) scores, and (3) Kanner Catatonia Rating Scale (KCRS) severity scores. The Clinical Global Impressions-Improvement (CGI-I) Scale was applied retrospectively to each case. Results: All five patients demonstrated clinically significant improvements. The average CGI-I score was 1.2. The average percentage reduction in the BFCRS and KCRS severity scores was 63% and 59%, respectively. Two of five patients were first stabilized with infusions midazolam and dexmedetomidine due to the symptom severity and then transitioned to long-acting oral benzodiazepines. Overall, four of five patients were stabilized with oral clonazepam and one of five with oral diazepam. Notably, four of five patients experienced an acute worsening of aggression, self-injury, and other catatonic symptoms with escalating dosages of antipsychotic treatment, which occurred before inpatient admission. All patients experienced resolution of physical aggression toward self and/or others, experienced improvement in their communicative abilities, and were able to return home or enter residential level of care upon discharge. Conclusions: Given the limited availability of ECT and the unclear utility of lorazepam for hyperactive catatonia in autism, the use of long-acting benzodiazepines and/or midazolam infusion may offer a safe and readily available treatment alternative.

Production of Bi-Compartmental Tablets by FDM 3D Printing for the Withdrawal of Diazepam

Diazepam (DZP) is a long-acting benzodiazepine to treat anxiety or acute alcohol withdrawal. Although this class of drugs should be taken for a short period of time, many patients take them for longer than recommended, which has been linked to an increased risk of dementia and dependence. The present work aimed at using the dual-nozzle system of fused deposition modeling (FDM) 3D printers to prepare tablets with gradual doses of DZP with constant mass and size. Placebo and DZP-loaded filaments were prepared by hot-melt extrusion and used to print the bi-compartmental tablets. Thermal processing allowed the conversion of crystalline DZP to its amorphous counterpart. Tablets with different DZP contents were effectively printed with a mass, thickness and diameter average of 111.6 mg, 3.1 mm, and 6.4 mm, respectively. Microscopic data showed good adhesion between the different layers in the printed tablets. The desired drug contents were successfully achieved and were within the acceptance criteria (European Pharmacopeia). The combination of a placebo and drug-loaded extrudates proved to be beneficial in the production of tablets by FDM for patients in need of drug withdrawal.

Association Between Benzodiazepines and Dementia in South Korea: A Nation-Wide Study

Objective: Benzodiazepines are a widely used class of medications for anxiety, depression, and insomnia. Despite their common use, concerns remain about memory problems with benzodiazepines. Despite the growing financial and social burden of dementia, inconsistent results persist regarding the association between benzodiazepines and dementia. Therefore, we aimed to evaluate the association between benzodiazepines and dementia in Korea. Methods: Diagnostic and prescription information from the Health Insurance Review and Assessment (HIRA) database in South Korea between 2009 and 2014 was utilized. The dementia group included people who were diagnosed with a dementia code and received one or more prescriptions for dementia. A total of 68,241 participants with dementia and 341,205 control participants were matched. Possible confounders, such as major medical and psychiatric disorders, were adjusted, and multivariate logistic regression was conducted to assess the association between benzodiazepines and dementia. Results: The highest odds ratio (OR) for dementia was noted for clonazepam (OR=2.86, 95% confidence interval [CI]=2.77–2.95) followed by those for diazepam (OR=2.60, 95% CI=2.53–2.66), lorazepam (OR=1.34, 95% CI=1.30–1.37), and triazolam (OR=1.26, 95% CI=1.21–1.32). Conclusion: Overall, relatively long-acting benzodiazepines, such as clonazepam, diazepam, and lorazepam, were associated with the incidence of dementia. Triazolam, which is approved for insomnia, was also significantly associated with dementia. Individuals who are prescribed with benzodiazepines should be cautious regarding memory loss and dementia. Further studies are needed to confirm the temporal and biological causality between benzodiazepines and dementia.

The Burden of Postoperative Delirium After Shoulder Arthroplasty and Modifiable Pharmacological Perioperative Risk Factors: A Retrospective Nationwide Cohort Study.

Background: Increasing demand for shoulder arthroplasty and an aging population may increase the rate of complications associated with advanced age such as postoperative delirium, but little is known on its burden in this cohort. Purpose: We sought to answer the following questions: (1) What is the epidemiology of postoperative delirium after shoulder arthroplasty? (2) What modifiable risk factors can be identified for postoperative delirium after shoulder arthroplasty? (3) Do risk factors differ in those younger than and in those older than 70 years of age? Methods: In a retrospective nationwide cohort study, we extracted data from the Premier Healthcare database on inpatient total and reverse shoulder arthroplasties from 2006 to 2016. The primary outcome was postoperative delirium; modifiable risk factors of interest were perioperative opioid use (high, medium, or low), peripheral nerve block use, and perioperative prescription medications. Mixed-effects models assessed associations between risk factors and postoperative delirium. Odds ratios and confidence intervals are reported. We applied a cutoff of 70 years of age because it was the median age of the cohort, as well as the age at which we observed that delirium prevalence increased. Results: A total of 92,429 total and reverse shoulder arthroplasties were identified (age range: 14-89 years). Overall delirium prevalence was 3.1% (n = 2909). Age-specific prevalence of postoperative delirium was lower in patients aged 50 to 70 years and higher in those aged 70 years and older, up to 8% among those older than 88 years. After adjusting for relevant covariates, only long-acting and combined short-acting and long-acting benzodiazepines (compared with no benzodiazepines) were associated with increased odds of postoperative delirium. Corticosteroids were associated with decreased odds of postoperative delirium. Conclusion: Our retrospective cohort study demonstrated that benzodiazepine use and older patient age were significantly associated with postoperative delirium in shoulder arthroplasty patients. The relationship between benzodiazepine use and delirium was particularly notable among those 70 years of age and older. Further investigation is indicated, given the known adverse effects of benzodiazepines in older adults and our findings of higher than expected use of these medications in this surgical cohort.

Potentially inappropriate medications in nursing homes and the community older adults using the French health insurance databases.

Potentially inappropriate medications (PIMs) have become a major issue in improving prescribing practices and reducing the risk of adverse drug events in older people. However, very few studies have compared exposition to PIMs controlling for differences in demographic and health between nursing home residents (NHRs) and community-dwelling older adults (CDOAs). This study aimed to assess the prescribing pattern of PIMs between NHRs and CDOAs. We conducted a cross-sectional study over three months in 2019 using the French Health Insurance databases. The study population included 274 971 NHRs and 4 893 721 CDOAs aged 75 years or over. The prevalence ratio (PR) between NHRs and CDOAs of 17 PIM indicators, based on the Beers and STOPP criteria lists, was assessed using multivariable robust Poisson regression adjusted for age, sex, diseases, and polypharmacy. During the study period, 54% of NHRs and 29% of CDOAs received at least one PIM. After adjustment, the prevalence of PIMs was 33% higher among NHRs compared to CDOAs (aPR=1.33; 95% CI [1.33-1.34]). NHRs received PIMs related to benzodiazepines (aPR=1.43; 95% CI [1.42-1.43]), anticholinergic drugs (aPR=1.29; 95% CI [1.27-1.31]), and at least three central nervous system-active drugs (aPR=1.94; 95% CI [1.92-1.96]) more frequently. Prevalence of PIMs related to non-steroidal anti-inflammatory drugs (aPR=0.50; 95% CI [0.48-0.52]) and long-acting benzodiazepines (aPR=0.84; 95% CI [0.82-0.85]) was lower among NHRs. The NHRs were at greater risk for PIM than CDOAs, although differences exist according to the category of PIMs. As the population is aging, it is essential to promote and evaluate interventions in NHs and the community to enhance medication optimization.

Trends and patterns of benzodiazepines and Z-drugs prescriptions in Australian general practice: A national study (2011-2018).

We aimed to explore trends and sociodemographic patterns in benzodiazepine (BZD) (by half-life) and Z-drugs prescribing in Australian general practice. This open cohort study used de-identified electronic health records of 1.4 million patients (50,812,413 consultations) from 402 Australian practices (MedicineInsight 2011-2018). Annual prescribing frequency and changes over time were estimated according to sex, age, socioeconomic position and rurality. Between 2011 and 2018, the prescribing of very short-acting BZD increased from 0.10 to 0.29 per 1000 consultations (average annual change +17.2% [95% CI 9.6; 25.3]), while it declined for short-intermediate (from 38.5 to 26.6 per 1000 consultations; annual change -5.1% [95% CI -5.6; -4.5]), long-acting BZD (from 24.1 to 21.6 per 1000 consultation; annual change -1.5% [95% CI -2.2; -0.8]) and Z-drugs (from 4.6 to 4.0 per 1000 consultations; annual change -1.9% [95% CI -3.0; -0.7]). Short-intermediate-acting BZD prescribing was three times more frequent among women aged 65+ years than younger women, and long-acting BZD three-to-four times more likely among younger than older men. Z-drugs prescribing was higher among women aged 45-64 years than younger or older females. Short-intermediate- and long-acting BZD were more likely prescribed for patients from more disadvantaged areas, and Z-drugs in more advantaged areas. There were no disparities by rurality. Although most BZD and Z-drugs prescriptions declined over time, short-intermediate BZD prescriptions remained higher among older women and long-acting BZD more frequent among younger men, especially for those living in more disadvantaged areas. Targeted interventions could reduce the prescribing of BZD and Z-drugs in these groups.

Use of a long-acting substitute in detoxification from benzodiazepines: safety (accumulation) problems and proposed mitigation procedure

ObjectiveIn the majority of approaches, detoxification of patients with benzodiazepine (BZD) addiction is preceded by conversion to long-acting BZDs. Resulting BZD accumulation, however, is neither monitored nor prevented. An unrecognized shift of the key low-concentration phase beyond the nominal treatment period may underlie delayed unassisted crises and treatment failures. This open, single-arm, semi-naturalistic study examines the anti-accumulation paradigm to minimize the high-concentration treatment phase and to regain time for medical assistance during the low-concentration phase.MethodsIn 133 of 165 patients with BZD dependency, after conversion to diazepam by titration up to the satiation state, the loading dose and satiating concentration were recorded. The subsequent anti-accumulation procedure consisted of aggressive daily dose reductions under laboratory feedback (serum BZD concentration, radioimmunoassay) until accumulation stopped. The final overaccumulation ratio (OA) and maintenance-dose/loading-dose ratio (MTN) were estimated. The post-conversion peak-concentration/loading-dose ratio was illustratively compared with the concentration/dose ratio in 32 long-term diazepam users demonstrating the natural plateau.ResultsDespite gender- and age-related differences in loading and maintenance doses and in satiating and peak concentrations (higher in younger and male patients), their quotients remained similar. The MTN ratio had an average value of 0.29 and a median value of 0.25, with OA ratios of 1.54 and 1.39, respectively. The concentration/dose ratio was approximately 3 times lower than that in regular diazepam users. With effective elimination starting (on average) from the 6th day, the treatment, including post-elimination recovery, lasted on average 52 days.ConclusionsThe MTN values show how harmfully popular tapering schedules intensify and extend the high-concentration stage during alleged detoxification, leading to unrecognized delays in elimination, and delayed withdrawal crises. The common errors are discussed. An individual MTN, estimated from laboratory feedback (the anti-accumulation paradigm), expeditiously moves patients to the onset of actual detoxification. This action regains time to maintain medical assistance until treatment is properly completed.

Risk of Falls Associated with Long-Acting Benzodiazepines or Tricyclic Antidepressants Use in Community-Dwelling Older Adults: A Nationwide Population-Based Case-Crossover Study.

Background: Falls are common in older adults and increase in recent years. This study aimed to examine the risk of falls associated with long-acting benzodiazepines (BZDs) or tricyclic antidepressants (TCAs) use in community-dwelling older adults. Methods: A nationwide population-based case–crossover design was used. We screened information on 6,370,275 fall or fall fracture cases among community-dwelling elderly patients from the database of the national health insurance data warehouse in South Korea. We extracted the data of elderly patients who visited the hospital for a fall and were diagnosed with the first fall or fall fracture after prescription of long-acting BZDs (n = 1805) or TCAs (n = 554). The study used conditional logistic regression analysis to analyze the associations and stratified analysis by gender and age group to control for their confounding effects. Results: Risk of falls or fall fractures increased by more than two times after taking long-acting BZDs (odds ratio [OR] = 2.16; 95% confidence interval [CI] = 1.85–2.52) or TCAs (OR = 2.13; 95% CI = 1.62–2.83). The longer the prescription period of both, the higher the risk of falls or fall fractures was (≥49 days for long-acting BZDs vs. ≥ 56 days for TCAs). Conclusions: Long-acting BZDs or TCAs should be avoided or prescribed for a shorter duration based on these adverse effects. Health care providers should focus on fall prevention practices in older adults who take such drugs.

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis

Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. UK National Institute for Health Research Oxford Health Biomedical Research Centre.

A Retrospective Study of the Adjunctive Use of Gabapentin With Benzodiazepines for the Treatment of Benzodiazepine Withdrawal.

Benzodiazepine withdrawal is a widespread problem with potentially severe and deadly consequences. Currently, the only medications available for treating benzodiazepine withdrawal are short-acting and long-acting benzodiazepines. Identifying other drugs to help in treating benzodiazepine withdrawal is necessary. Gabapentin, an anxiolytic drug that is also used off-label to treat alcohol withdrawal, is a potential candidate for modulating benzodiazepine withdrawal. Using electronic records from a large inpatient psychiatric facility, a retrospective study of 172 patients presenting with benzodiazepine withdrawal was conducted to determine if the coincidental use of gabapentin for other medical conditions was associated with better outcomes of benzodiazepine withdrawal (N=57 gabapentin, N=115 no gabapentin). The primary outcomes were hospital length of stay and total amount of benzodiazepines given (lorazepam milligram equivalent). In this retrospective analysis of electronic medical record data, the patients experiencing benzodiazepine withdrawal who received gabapentin as an adjunct to the use of benzodiazepines were administered a smaller amount of benzodiazepines and had a shorter length of hospital stay relative to the comparison group who did not receive adjunctive gabapentin. These results suggest the potential use of gabapentin as an adjunct to the use of benzodiazepines for treating benzodiazepine withdrawal. The limitations of this study included a small sample size and variability in medication management strategies across the sample.

Reversible Dementia With Rapid Recovery to Normal Cognition: A Case Report

We report the case of a 54-year-old female who was diagnosed with clinical dementia and recovered to normal cognition in only 11 days through appropriate intervention. The patient was on a complicated regimen of psychiatric medications for underlying depression and panic disorder. The patient noted increased deterioration in executive function gradual memory impairment starting in early 2020. As a result of the neuroimaging, prominent neurodegeneration and in vivo brain pathology were not observed. During outpatient clinic follow-up, severe obstructive sleep apnea (OSA) was confirmed. Based on the diagnostic results, a clinical impression was made for reversible dementia due to psychiatric drugs and OSA. During hospitalization for 10 days, the patient’s regimen of psychiatric medications with anticholinergic effects was changed, and long-acting benzodiazepines were reduced. The patient also underwent continuous positive airway pressure titration to ameliorate OSA. The patient reported subjective cognitive improvement and a comprehensive neuropsychiatric test performed at discharge later showed a normal range in all cognitive domains, and the patient s activity of daily living evaluated at the outpatient clinic after discharge had recovered.

Anesthesia and breastfeeding

The importance of breastfeeding with its positive impact on the wellbeing of the mother-infant pair is well established. Anesthesiologists should encourage the promotion of lactation by being willing to give reassurance during the preoperative period and preparing a plan that does not interfere with safe breastfeeding. There is concern regarding the transfer of drugs into breast milk, which may lead to inconsistent advice from many health professionals and to early discontinuation. However, evidence shows that most anesthetic drugs are safe in terms of transfer into breast milk, and hence, compatible with breastfeeding, which should be resumed after anesthesia as soon as the mother is alert and feels well enough to hold her infant, without the need to “pump and dump”. This review provides pharmacokinetic information on commonly used anesthesia drugs and their passage into breast milk, to help practitioners discuss risks and benefits with the mother, emphasizing that anesthesia should not interfere with the benefits of breastfeeding. Four practical clinical scenarios are presented: pregnant women concerned about the effect of epidural analgesia on subsequent breastfeeding, spinal anesthesia for c-section and lactation, patients who will receive general anesthesia during cesarean section, and finally women who are breastfeeding and require anesthesia for elective or urgent surgery. Neuraxial anesthesia allows for better pain control and immediate skin-to-skin contact at the time of childbirth. Also, it interferes the least with the woman’s ability to care for her infant. Regional techniques, opioid-sparing techniques and outpatient surgery are preferred. Drugs such as opioids and longer-acting benzodiazepines should be administered cautiously, particularly in repeat doses.

The Perioperative Use of Benzodiazepines for Major Orthopedic Surgery in the United States.

Despite numerous indications for perioperative benzodiazepine use, associated risks may be exacerbated in elderly and comorbid patients. In the absence of national utilization data, we aimed to describe utilization patterns using national claims data from total hip/knee arthroplasty patients (THA/TKA), an increasingly older and vulnerable surgical population. We included data on 1,863,996 TKAs and 985,471 THAs (Premier Healthcare claims data, 2006-2019). Benzodiazepine utilization (stratified by long- and short-acting agents) was assessed by patient- and health care characteristics, and analgesic regimens. Given the large sample size, standardized differences instead of P values were utilized to signify meaningful differences between groups (defined by value >0.1). Among 1,863,996 TKA and 985,471 THA patients, the utilization rate of benzodiazepines was 80.5% and 76.1%, respectively. In TKA, 72.6% received short-acting benzodiazepines, while 7.9% received long-acting benzodiazepines, utilization rates 68.4% and 7.7% in THA, respectively. Benzodiazepine use was particularly more frequent among younger patients (median age [interquartile range {IQR}]: 66 [60-73]/64 [57-71] among short/long-acting compared to 69 [61-76] among nonusers), White patients (80.6%/85.4% short/long-acting versus 75.7% among nonusers), commercial insurance (36.5%/34.0% short/long-acting versus 29.1% among nonusers), patients receiving neuraxial anesthesia (56.9%/56.5% short/long-acting versus 51.5% among nonusers), small- and medium-sized (≤500 beds) hospitals (68.5% in nonusers, and 74% and 76.7% in short- and long-acting benzodiazepines), and those in the Midwest (24.6%/25.4% short/long-acting versus 16% among nonusers) in TKA; all standardized differences ≥0.1. Similar patterns were observed in THA except for race and comorbidity burden. Notably, among patients with benzodiazepine use, in-hospital postoperative opioid administration (measured in oral morphine equivalents [OMEs]) was substantially higher. This was even more pronounced in patients who received long-acting agents (median OME with no benzodiazepines utilization 192 [IQR, 83-345] vs 256 [IQR, 153-431] with short-acting, and 329 [IQR, 195-540] with long-acting benzodiazepine administration). Benzodiazepine use was also more frequent in patients receiving multimodal analgesia (concurrently 2 or more analgesic modes) and regional anesthesia. Trend analysis showed a persistent high utilization rate of benzodiazepines over the last 14 years. Based on a representative sample, 4 of 5 patients undergoing major orthopedic surgery in the United States receive benzodiazepines perioperatively, despite concerns for delirium and delayed postoperative neurocognitive recovery. Notably, benzodiazepine utilization was coupled with substantially increased opioid use, which may project implications for perioperative pain management.