Consumption patterns and factors associated with inappropriate prescribing of benzodiazepines in Primary Health Care settings.

BACKGROUND: Benzodiazepines are frequently prescribed to treat anxiety and insomnia, but long-term use has been associated with the development of dependence, tolerance, and cognitive decline, especially among older adults. This study aimed to investigate the pattern of consumption and factors associated with inappropriate prescribing of benzodiazepines in primary health care. METHODS: This is a cross-sectional analytical study, using dispensing records of diazepam, clonazepam, and nitrazepam from public pharmacies in a Brazilian municipality between 2018 and 2022. Metrics for benzodiazepine consumption were DDD (Defined Daily Dose) and DDD/1000PD (per 1000 population per day). Long-term/prolonged benzodiazepine use was defined as consuming at least 90 DDD and at least 2 dispensations per year. To ascertain associations between long-term use and predictor variables, a multivariate logistic regression model was utilized. FINDINGS: A total of 40402 participants were included, with an average age of 55 years (SD = 0.30), 38.5% were older aged. Diazepam and nitrazepam exceeded the daily dose recommended. There was a reduction in diazepam consumption during the study period, as calculated by DDD/1.000PD, while the consumption of other benzodiazepines remained stable. However, a significant increase in diazepam consumption is noted when considering the last decade. Prolonged use was observed in 29.1% of participants, with a significant prevalence among the older people (34.8% of them were long-term users) and advancing age was identified as a risk factor for long-term use. Higher PDDs were also associated with long-term use and aging. Participants who used different benzodiazepines during the period had a higher risk of prolonged use. CONCLUSIONS: These results provide insights into the prevalence of problematic utilization of benzodiazepines in primary health care. Authorities and health care providers must take steps to encourage gradual cessation of prolonged benzodiazepine prescriptions and the embrace of suitable strategies for addressing anxiety and insomnia within primary health care settings.

Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

BACKGROUND: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment. SUBJECTS AND METHODS: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures. RESULTS: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001). CONCLUSION: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Effectiveness and Safety of Nitrazepam in Children with Resistant West Syndrome.

OBJECTIVES: To study the effectiveness, tolerability, and safety of oral nitrazepam in children with resistant West syndrome (WS). METHODS: This prospective observational study was conducted at a tertiary care hospital in North India from January 2019 to October 2020. Children with WS resistant to standard therapy were enrolled within 7 d of initiation of nitrazepam and prospectively followed-up for cessation of spasms and adverse events. RESULTS: Forty-one children with resistant WS initiated on nitrazepam therapy were evaluated. The median age at onset of spasms was 6 mo (Q1, Q3: 4, 8). There was a preponderance of male gender (71%) and structural causes (78%). More than half of the enrolled children had failed four or more antiseizure medications (ASM) for epileptic spasms. The study participants had a long lead-time-to-treatment (LTTT) for the initial standard therapy (median: 2 mo; Q1, Q3: 1, 5) and nitrazepam (median: 11 mo; Q1, Q3: 8, 16). Nitrazepam was instituted as monotherapy in 7 (17%) children and as an adjunct in the rest. Twenty-one (51%) children achieved persistent cessation of epileptic spasms. However, the electroclinical response was observed in 17 (42%) children. Drowsiness, sialorrhea, and decreased appetite were the most commonly observed adverse events. Most adverse events were mild to moderate in severity and did not require dose reduction or change of medication. There was no significant difference between the responders and nonresponders in terms of LTTT, age at onset, or etiology. CONCLUSIONS: Nitrazepam is a safe and feasible treatment alternative in children with resistant WS resulting in persistent cessation of spasms and electroclinical response in nearly half of patients.

Caracterización de la prescripción de ansiolíticos en adultos mayores institucionalizados en un hogar de ancianos / Characterization of the prescription of anxiolytics in institutionalized older adults in the nursing home

El objetivo de este estudio fue caracterizar la prescripción de los medicamentos ansiolíticos utilizados en población de adultos mayores institucionalizados en el hogar de ancianos de Pinar del Río durante el año 2017.Se realizó un estudio descriptivo transversal, con recogida de datos retrospectiva, sobre prescripción de medicamentos ansiolíticos en la población de adultos mayores institucionalizados en el hogar de ancianos, se analizó la forma de utilización de los medicamentos, su indicación y prescripción con elementos de esquema terapéutico y factores que condicionan los hábitos de prescripción. Se trabajó con el universo (U= 98) de estudio el cual estuvo conformado por el total de pacientes institucionalizados, que estaban consumiendo ansiolíticos. Se revisaron las historias clínicas individuales y se confeccionó un modelo de recolección de datos.El medicamento más consumido por los adultos mayores fue el nitrazepam (41,8 %), siendo este a su vez el más consumido por el sexo masculino, no así para el femenino que resultó ser el clorodiazepóxido (64,6 %), el grupo de edad que más predominó fue el de 60-69 años, asimismo los viudos y el nivel educacional primario, el 79,5 % de los ancianos consume otros medicamentos que poseen interacción farmacocinética. El profesional que más indicó fue el médico de familia, la prescripción e intervalos entre dosis fue adecuada, la prescripción se consideró no racional.La prescripción de ansiolíticos en la población objeto de estudio, disminuye a medida que aumenta la edad, los más consumidores son los del sexo masculino y los institucionalizados por abandono familiar, esto apunta a la necesidad de continuar trabajando desde el nivel primario de atención dado que es de donde proceden estos ancianos.

The objective of this study was to characterize the prescription of anxiolytic medications used in the institutionalized elderly population at the Pinar del Río Nursing Home during 2017.A cross-sectional descriptive study was carried out, with retrospective data collection, on the prescription of anxiolytic medications in the population of institutionalized older adults in the Nursing Home, the form of use of the medications, their indication and prescription with elements of the therapeutic scheme was analyzed and factors that condition prescription habits. We worked with the universe (U = 98) of the study, which was made up of the total number of institutionalized patients who were consuming anxiolytics. Individual medical records were reviewed and a data collection model was created.The drug most consumed by older adults was nitrazepam (41.8%), this in turn being the most consumed by males, not so for females, which turned out to be chlorodiazepoxide (64.6%), the group The most prevalent age group was 60-69 years, likewise widowers and primary educational level, 79.5% of the elderly consume other drugs that have pharmacokinetic interaction. The professional who indicated the most was the family doctor, the prescription and intervals between doses were adequate, the prescription was considered non-rational.The prescription of anxiolytics in the population under study decreases as age increases, the most consumers are those of the male sex and those institutionalized due to family abandonment, this points to the need to continue working from the primary level of care since that is where these elders come from.

Oral S-ketamine effective after deep brain stimulation in severe treatment-resistant depression and extensive comorbidities.

This case report describes successful maintenance treatment with oral S-ketamine in a patient with severe depression, who previously was resistant to electroconvulsive therapy and deep brain stimulation, and who also had comorbid psychotic and obsessive compulsive symptoms.

Health risk appraisal in older people 7: long-acting benzodiazepine use in community-dwelling older adults in London: is it related to physical or psychological factors?

Aim To investigate whether the use of long-acting benzodiazepines, in individuals aged 65 and over is mediated by physical or psychological factors. BACKGROUND: Long-acting benzodiazepine consumption among older people has implications for mortality, morbidity and cost-effective prescribing. Two models explain benzodiazepine use in this age group, one linked to physical illness and disability and one to psychological factors. METHODS: Secondary analysis of baseline data from a study of 1059 community-dwelling non-disabled people aged 65 years and over recruited from three general practices in London. For this analysis, use of long-acting benzodiazepines was defined as any self-reported use of diazepam or nitrazepam in the last four weeks. Associations between demographic factors, health service use, and physical and psychological characteristics and benzodiazepine use were investigated. Findings The prevalence of benzodiazepine use in this sample was 3.3% (35/1059). In univariate analyses, benzodiazepine use was associated with female gender, low income, high consultation rates, physical factors (medication for arthritis or joint pain, polypharmacy, difficulties in instrumental activities of daily living, recent pain) and psychological factors (poor self-perceived health, social isolation, and symptoms of anxiety or agitation). In a multivariate logistic regression analysis only two factors retained statistically significant independent associations with benzodiazepine use: receiving only the state pension (OR=4.0, 95% CI: 1.70, 9.80) and pain in the past four weeks (OR=3.79, 95% CI: 1.36, 10.54).

The effect of nitrazepam on depression and curiosity in behavioral tests in mice: The role of potassium channels.

Evidence show that gamma-aminobutyric acid (GABA) receptors are involved in depression, so the aim of this study was to investigate the effect of nitrazepam as agonist of GABAA receptors on depression and curiosity in male mice and the role of potassium channel in antidepressant-like response. For this purpose, we studied the antidepressant-like properties of fluoxetine, nitrazepam, glibenclamide, and cromakalim by both forced swimming test (FST) and tail suspension test (TST). Animals were injected by various doses of nitrazepam (0.05, 0.1, and 0.5mg/kg). Nitrazepam at dose of 0.5mg/kg significantly decreased the immobility time compared to control group in both FST and TST. Fluoxetine also showed such a response. Co-administration of nitrazepam (0.05mg/kg) with glibenclamide in TST (1mg/kg) and in FST (0.3, 1mg/kg) also showed antidepressant-like response. Beside, cromakalim (0.1mg/kg) could reverse the antidepressant-like effect of nitrazepam (0.5mg/kg) in both FST and TST, while cromakalim and glibenclamide alone could not change the immobility time compared to control group (P>0.05). The hole-board test revealed that nitrazepam at doses of 0.5 and 0.1mg/kg could increase the activity of the animal's head-dipping and boost the curiosity and exploration behavior of mice. The results of this study revealed that nitrazepam may possess antidepressant-like properties and this effect is dependent to potassium channels in both FST and TST.

[Comparative evaluation of the hypnotic drugs under conditions of brain injury].

The effect of hypnotic drugs on the brain stability with respect to complete ischemia posttraumatic convulsive reactions and hypoxia has been studied in animals with model brain injury. It is established that zopiclone exhibits pronounced hypnotic effect during the first and second week after brain injury, while nitrazepam, zolpidem, and melaxen are effective in the first week. The neuroprotective effects of zopiclone and zolpidem are more pronounced than those of melaxen and nitrazepam.

Treatment of infantile spasms with sodium valproate followed by benzodiazepines.

OBJECTIVE: To review the result of the infantile spasms' treatment with sodium valproate followed by nitrazepam or clonazepam. STUDY DESIGN: Descriptive retrospective study. SETTING: Srinagarind Hospital, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. MATERIAL AND METHOD: Twenty-four infantile spasms admitted between January 1994 and December 2003 were analyzed. The inclusion criteria were the patients with infantile spasms clinically diagnosed by the pediatric neurologist, having hypsarrhythmic pattern EEG, and receiving sodium valproate with or without nitrazepam or clonazepam. The patients who had an uncertain diagnosis, incomplete medical record, or that were incompletely followed up were excluded. Data were collected on sex, age at onset of seizure, type of infantile spasms, associated type of seizure, predisposing etiological factor, neuroimaging study, and the result of treatment including cessation of spasms, subsequent development of other seizure types, quantitative reduction of spasms, relapse rates of spasms, psychomotor development, and adverse effects of AEDs. RESULTS: The mean age at onset was 177 days. The male-to-female ratio was 1:1.2. There were 13 cryptogenic (54.2%) and 11 symptomatic (45.8%) infantile spasms. The most common predisposing etiological factors in symptomatic cases were hypoxic ischemic encephalopathy (45.5%) and microcephaly (36.4%), respectively. Ten patients received sodium valproate (41.7%), another 10 received sodium valproate with clonazepam (41.7%), and four received sodium valproate with nitrazepam (16.7%). Both, the complete cessation rate and the 50% reduction of spasms rate were 45.8%. The duration to complete cessation was 70 days. The relapse rate was 18.2%. The rate of delayed psychomotor development was 83.3%. The mean duration of follow-up was 49.6 months. CONCLUSION: The authors propose to use sodium valproate concomitantly with benzodiazepines, especially clonazepam, in situations such as unavailability, intolerability, or adverse effects of ACTH or vigabatrin, or in a patient who does not respond to ACTH or vigabatrin.

The effect of placebo administration on the first-night effect in healthy young volunteers.

The first-night effect is a well-known phenomenon that is considered to result from a subject's lack of adaptation to the unfamiliar environment of a sleep laboratory and to the technical equipment used for polysomnography. The effect has been explored as a laboratory model for transient insomnia. The main characteristics of this effect are short total sleep time (TST) and rapid eye movement (REM) sleep, a lower sleep efficiency index, and longer REM sleep latency. Previous studies have reported that personality traits (such as trait anxiety) are a potential cause of the first-night effect and that the placebo effect is closely related to the anxiety levels of the subjects. To the best of our knowledge, there are no reports regarding the effects of a placebo on first-night sleep. This omission can be explained by the fact that the polysomnographic recordings obtained during the first night of a study are generally excluded from the analysis in order to avoid the inclusion of the first-night effect. In the present study, 8 male university students were subjected to polysomnographic examinations during drug-free, placebo-administration, and benzodiazepine-administration conditions in order to clarify the placebo effect on sleep during consecutive nights, particularly on the first night. The recordings for each condition were conducted for 4 consecutive nights. A placebo or 5 mg nitrazepam was administered at 2230 h using a double-blind crossover design, while no drug was administered during the drug-free condition. There was a 10-day interval between the examination of each condition. Polysomnographic recording was started at 2300 h and continued until the natural awakening of the subjects on the next morning. Subsequently, the subjects were requested to fill in a rating scale that is used to evaluate the subjective perception of sleep. An increase in stage-2 sleep associated with the first-night effect was observed on the first night during the drug-free and placebo-administration conditions. However, REM sleep reduction associated with the first-night effect was detected on the first night during the drug-free condition; this decrease in REM sleep was counteracted by the placebo during the placebo-administration condition. The nitrazepam, but not the placebo, decreased both slow-wave sleep (SWS) and REM sleep. The values for the tendency to fall asleep, feeling refreshed upon awakening in the morning, and the tension upon awakening in the morning were improved to a greater extent by the placebo and nitrazepam administrations than when no drug was administered. These results demonstrate the possibility that placebo administration may have a hypnotic/anxiolytic effect and may improve transient insomnia without causing SWS and REM sleep reductions.

Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society.

OBJECTIVE: To determine the current best practice for treatment of infantile spasms in children. METHODS: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. RESULTS: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. CONCLUSIONS: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.

[Diagnostics and treatment of sleep disorders in elderly people]. / Diagnostika i lechenie narusheniia sna u lits pozhilogo voztasta.

A meta-analysis was done of the published literature concerning the modern status of the issue of sleep disturbances and of findings from the author's investigations. Data are submitted obtained in a clinical examination of 61 elderly patient in a therapeutical hospital. In the above patients, high prevalence has been revealed of different sleep disturbances. Insomnia is often a sequela of psychophysiological derangements, which fact necessitates an exhaustive differential diagnosis and choice of remedies to be used in therapy of the above disorders. An experience is described of employment of zopiclon (Somnol Grindex) to deal with sleep problems in those patients in the involutional period. It is suggested that psychiatrist services be more actively used to give the necessary advice to those patients of the cardiological profile presenting with sleep disturbances.

A population-based case-control teratologic study of nitrazepam, medazepam, tofisopam, alprazolum and clonazepam treatment during pregnancy.

OBJECTIVE: To study the association between nitrazepam, medazepam, tofisopam, alprazolum and clonazepam treatments during pregnancy and prevalence of different congenital abnormalities (CAs). MATERIALS AND METHODS: A matched case-control study using cases with CAs and population controls from the dataset of the nationwide Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996. RESULTS: Of 38,151 pregnant women who had babies without any defects (population control group), 75 (0.20%) were treated with these five benzodiazepines during pregnancy. Of 22,865 pregnant women who delivered offspring with CAs, 57 (0.25%) had benzodiazepine treatment. The occurrence of five benzodiazepine treatments during the second and third months of gestation, i.e. in the critical period for most major CAs did not show significant differences in matched case-control pairs. CONCLUSION: Treatment with five benzodiazepines studied during pregnancy did not present detectable teratogenic risk to the fetus in humans but the amount of information was limited for different CAs.

[West syndrome: clinical and electroencephalographic follow up of 70 patients and response to its treatment with adrenocorticotropic hormone, prednisone, vigabatrin, nitrazepam and valproate]. / Síndrome de West: evolução clínica e eletrencefalográfica de 70 pacientes e resposta ao tratamento com hormônio adrenocorticotrófico, prednisona, vigabatrina, nitrazepam e ácido valpróico.

In a retrospective study we assessed the outcome of the criptogenic and symptomatic forms of West syndrome and evaluated the efficacy of adrenocorticotropic hormone, vigabatrin, prednisone, valproate and nitrazepam in the spasms control. Seventy patients were follwed up by 2 years. Twelve (17%) were criptogenics and 58 (83%) symptomatics. In criptogenic group significantly more patients were in regular school classes and with normal motor development, better control of seizure, less tendency to evoluate to Lennox Gastaut syndrome and 83. 3% had control of spasms (72.4% of patients from symptomatic group had control of spasms). Adrenocorticotropic hormone and vigabatrin were the most efective drugs, with 68.75% and 60% of spasms control, respectivelly, when used as first line of therapy and 75% and 50%, respectivelly, as second line of therapy.

Síndrome de West: evoluçao clínica e eletrencefalográfica de 70 pacientes e resposta ao tratamento com hormônio adrenocorticotrófico, prednisona, vigabatrina, nitrazepam e ácido valpróico / West syndrome: clinical and eletroencephalographic follow up of 70 patients and response to the adrenocorticotropic hormone, prednisone, vigabatrin, nitrazepam and valproate

Em estudo retrospectivo avaliamos a evoluçao clínica e eletrencefalográfica das formas criptogênica e sintomática da síndrome de West e analisamos a eficácia do hormônio adrenocorticotrófico, vigabatrina, prednisona, ácido valpróico e nitrazepam no controle dos espasmos. Participaram do estudo 70 pacientes, acompanhados por período maior que 2 anos. Doze (17 por cento) eram criptogênicos e 58 (83 por cento) sintomáticos. O grupo criptogênico apresentou percentagem significativamente maior de pacientes que frequentavam escola regular e desenvolvimento motor normal, melhor controle das crises epilépticas, tendência menor a evoluir para síndrome de Lennox Gastaut e 83,3 por cento tiveram controle completo dos espasmos (72,4 por cento dos pacientes do grupo sintomático obtiveram controle completo dos espasmos). O hormônio adrenocorticotrófico e a vigabatrina foram as drogas mais eficazes, controlando 68,75 por cento e 60 por cento dos espasmos, respectivamente, quando utilizados como droga de primeira escolha e 75 por cento e 50 por cento, respectivamente, como drogas de segunda escolha