Implementation of an intervention aimed at deprescribing benzodiazepines in a large US healthcare system using patient education materials: a pre/post-observational study with a control group.

OBJECTIVES: Long-term benzodiazepine use is common despite known risks. In the original Eliminating Medications Through Patient Ownership of End Results (EMPOWER) Study set in Canada, patient education led to increased rates of benzodiazepine cessation. We aimed to determine the effectiveness of implementing an adapted EMPOWER quality improvement (QI) initiative in a US-based healthcare system. DESIGN: We used a pre-post design with a non-randomised control group. SETTING: A network of primary care clinics. PARTICIPANTS: Patients with ≥60 days' supply of benzodiazepines in 6 months and ≥1 risk factor (≥65 years of age, a concurrent high-risk medication prescribed or a diazepam equivalent daily dose ≥10) were eligible. INTERVENTION: In March 2022, we engaged 22 primary care physicians (PCPs), and 308 of their patients were mailed an educational brochure, physician letter and flyer detailing benzodiazepine risks; the control group included 4 PCPs and 291 of their patients. PRIMARY AND SECONDARY MEASURES: The primary measure was benzodiazepine cessation by 9 months. We used logistic regression and a generalised estimating equations approach to control for clustering by PCP, adjusting for demographics, frailty, number of risk factors, and diagnoses of arthritis, depression, diabetes, falls, and pain. RESULTS: Patients in the intervention and control groups were comparable across most covariates; however, a greater proportion of intervention patients had pain-related diagnoses and depression. By 9 months, 26% of intervention patients (81 of 308) had discontinued benzodiazepines, compared with 17% (49 of 291) of control patients. Intervention patients had 1.73 greater odds of benzodiazepine discontinuation compared with controls (95% CI: 1.09, 2.75, p=0.02). The unadjusted number needed to treat was 10.5 (95% CI: 6.30, 34.92) and the absolute risk reduction was 0.095 (95% CI: 0.03 to 0.16). CONCLUSIONS: Results from this non-randomised QI initiative indicate that patient education programmes using the EMPOWER brochures have the potential to promote cessation of benzodiazepines in primary care.

[An overview of natural entheogens]. / Un aperçu des enthéogènes naturels.

Entheogens are a group of little-known psychoactive substances which consumption is nevertheless frequently mentioned in outpatient care and which can have harmful effects. This raises the question of appropriate management of their effects, as well as the treatment of any overdose. In this article, we focus on five of these substances, which are rarely described in the medical literature. At present, few studies exist on their long-term effects on health, and this type of niche consumption does not seem problematic from the authorities' point of view. Rapid screening is unavailable because it has not been developed, and the management of overdoses is often limited to non-specific supportive treatment with benzodiazepines.

Les enthéogènes sont un groupe de substances psychoactives méconnues mais dont la consommation apparaît toutefois lors de consultations ambulatoires et qui peuvent engendrer des effets néfastes. Se pose alors la question de la prise en charge adaptée concernant leurs effets mais également le traitement d'un éventuel surdosage. Dans cet article, le focus a été mis sur cinq de ces substances peu décrites dans la littérature médicale. Actuellement, peu d'études existent sur leurs effets à long terme sur la santé et ce type de consommation de niche ne semble pas problématique du point de vue des autorités. Le dépistage rapide n'est pas disponible car pas développé et la prise en charge des surdosages se limite souvent à un traitement de soutien non spécifique par benzodiazépines.

Prescribing Benzodiazepines and Opioids and Clinical Characteristics Associated With 30-Day Hospital Return in Patients Aged ≥75 Years: Secondary Data Analysis.

PURPOSE: The current study compared prevalence of opioid or benzodiazepine (BZD) prescription and co-prescription of opioids and BZD at discharge and return to a community hospital within 30 days, as well as identified clinical characteristics associated with hospital return in patients aged ≥75 years. METHOD: A secondary analysis of a database created during implementation of the Safe Transitions for At Risk Patients program at a 400-bed community teaching hospital in south Florida was conducted. Multivariable logistic regression analyses were performed to identify significant demographic and clinical characteristics associated with return to the hospital within 30 days of discharge. RESULTS: A total of 24,262 participants (52.6% women) with a mean age of 85.3 (SD = 6.42) years were included. More than 20% in each central nervous system prescription group (i.e., opioids only, BZD only, opioids and BZD) returned to the hospital within 30 days of discharge. Demographic and chronic conditions (e.g., congestive heart failure, chronic obstructive pulmonary disease, diabetes) and poly-pharmacy were significant factors of a 30-day return to the hospital. CONCLUSION: Findings highlight the importance of hospital nurses' role in identifying high-risk patients, educating patients and caregivers, monitoring them closely, communicating with primary care physicians and specialists, and conducting intensive follow up via telephone to avoid 30-day rehospitalization. [Journal of Gerontological Nursing, 50(4), 25-33.].

Status epilepticus: what's new for the intensivist.

PURPOSE OF REVIEW: Status epilepticus (SE) is a common neurologic emergency affecting about 36.1/100 000 person-years that frequently requires intensive care unit (ICU) admission. There have been advances in our understanding of epidemiology, pathophysiology, and EEG monitoring of SE, and there have been large-scale treatment trials, discussed in this review. RECENT FINDINGS: Recent changes in the definitions of SE have helped guide management protocols and we have much better predictors of outcome. Observational studies have confirmed the efficacy of benzodiazepines and large treatment trials indicate that all routinely used second line treatments (i.e., levetiracetam, valproate and fosphenytoin) are equally effective. Better understanding of the pathophysiology has indicated that nonanti-seizure medications aimed at underlying pathological processes should perhaps be considered in the treatment of SE; already immunosuppressant treatments are being more widely used in particular for new onset refractory status epilepticus (NORSE) and Febrile infection-related epilepsy syndrome (FIRES) that sometimes revealed autoimmune or paraneoplastic encephalitis. Growing evidence for ICU EEG monitoring and major advances in automated analysis of the EEG could help intensivist to assess the control of electrographic seizures. SUMMARY: Research into the morbi-mortality of SE has highlighted the potential devastating effects of this condition, emphasizing the need for rapid and aggressive treatment, with particular attention to cardiorespiratory and neurological complications. Although we now have a good evidence-base for the initial status epilepticus management, the best treatments for the later stages are still unclear and clinical trials of potentially disease-modifying therapies are long overdue.

Fourteen-year trends in prescribing patterns for patients with bipolar mania discharged from a public psychiatric hospital in Taiwan.

Bipolar disorder is a complex mental illness. Pharmacological therapy, including antipsychotics and mood stabilizers, is the primary treatment approach for manic episode. The study aimed to analyze prescribing patterns over a 14-year period for patients with bipolar mania discharged from a psychiatric hospital in Taiwan. Patients with bipolar mania discharged from the study hospital between 2006 and 2019 (n = 2956) were included in the analysis. Prescribed drugs for the treatment of manic episode, included mood stabilizers (i.e., lithium, valproate, carbamazepine) and any antipsychotics (i.e., second- and first-generation antipsychotics; SGAs & FGAs). Monotherapy, simple polypharmacy, and complex polypharmacy were also examined. Simple polypharmacy was defined as being prescribed 2 different bipolar drugs (lithium, valproate, carbamazepine, and any antipsychotics), while complex polypharmacy at least 3 bipolar drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. The prescription rates of valproate, SGAs, and complex polypharmacy significantly increased over time, whereas the prescription rates of any mood stabilizers, FGAs, and simple polypharmacy significantly decreased. Prescription rates of lithium and monotherapy did not significantly change. The study highlights the shifts in prescribing practices for bipolar mania. SGAs were prescribed more while FGAs declined, likely due to SGAs' favorable properties. Complex polypharmacy increased, reflecting the complexity of treating bipolar disorder. Long-term outcomes of these changes require further research.

[Pharmacotherapies for insomnia]. / Traitements médicamenteux de l'insomnie.

PHARMACOTHERAPIES FOR INSOMNIA. The first line of treatment in adult chronic insomnia is cognitive behavioral therapy (CBT). However, its difficult accessibility limited its use and medications are still often prescribed. Considering the drugs with marketing authorization, Z-drugs (zolpidem and zopiclone) if taken at the right hour and dosage promote sleep initiation and have less deleterious effects than benzodiazepines, especially the long-acting ones which should be avoided. This class of drugs cannot be prescribed longer than 28 days. Some antihistaminic licensed drugs are authorized as hypnotics, with a low proof of efficacy and a risk of adverse event as sedation and somnolence the next day. Their prescription should be avoided in old subjects. Some clinicians used antidepressant sedative medications, at low dosage, as hypnotic drugs but "off label", outside authorization. Now melatonin, an endogenous synchronizer of biologic rhythms, has obtained the authorization for the treatment of insomniac troubles, in subjects of at least 55 years old, in its slow- release formula, replacing the physiological decline of this hormone with aging. Melatonin is not a hypnotic, but has soporific properties, inducing sleep, improving sleep efficacy, sometimes sleep duration and morning alertness. When discontinued, it induced no withdrawal syndrome. It has shown no risk of abuse potential and no deleterious side-effects, if used at the right dose and in the absence of hepatic interaction with other compounds. Finally, a new class of hypnotics, "the orexin antagonists" has its first representative on the French market: daridorexant. The place of these molecules in the therapeutic strategy for chronic insomnia needs to be clarified.

TRAITEMENTS MÉDICAMENTEUX DE L'INSOMNIE. Le traitement de première intention des adultes atteints d'insomnie chronique est la thérapie cognitivo-comportementale. Toutefois, compte tenu des difficultés d'accès à cette thérapeutique, les prescriptions médicamenteuses restent fréquentes. Considérant les médicaments qui ont une autorisation de mise sur le marché (AMM) dans cette indication, les Z-drugs (zolpidem et zopiclone), prises à bon escient, à la bonne posologie et à la bonne heure, favorisent l'initiation du sommeil et ont moins d'effets indésirables que les benzodiapézines, notamment celles à longue durée d'action, dont la prescription doit être évitée. Cette classe de médicaments est soumise à une réglementation particulière de durée de prescription (28 jours au maximum). Certains antihistaminiques peuvent être utiles comme hypnotiques, avec un faible niveau de preuve d'efficacité et des effets indésirables, notamment sur la vigilance du lendemain ; ils sont à éviter chez les sujets âgés. Certains antidépresseurs sédatifs sont prescrits, à faible dose, hors AMM. Plus récemment, la mélatonine, synchroniseur endogène des rythmes biologiques, a obtenu une AMM dans les troubles du sommeil du sujet âgé de 55 ans ou plus, dans sa formulation à longue durée d'action, suppléant la baisse physiologique de cette hormone avec l'âge. Induisant une somnolence, elle favorise l'endormissement, l'efficacité du sommeil, peut améliorer sa durée et assure un réveil de bonne qualité, sans accoutumance, sans syndrome de sevrage, et sans effet délétère majeur si l'on fait attention à la posologie et aux interactions médicamenteuses. Enfin, une nouvelle classe de médicaments, les anti-orexines, compte un premier représentant commercialisé en France : le daridorexant. La place de ces molécules dans la stratégie thérapeutique de l'insomnie chronique devra être précisée.

Impact of ABCB1 genetic polymorphism on carbamazepine dose requirement among Southern Indian persons with epilepsy.

OBJECTIVES: Carbamazepine (CBZ) is one of the oldest, yet first line drugs for treating epilepsy. However, there is a large inter-individual difference in requirement of maintenance dose and one third of persons treated with antiepileptic drugs (AEDs) exhibit drug resistance to therapy. One of the proposed mechanisms for the drug resistance was increased expression of efflux transporter P-glycoprotein. The pharmacogenetic studies of drug transporters (ABCB1) done in combination therapies of AEDs were inconclusive. Hence, we have attempted to study the impact of ABCB1 3435C>T genetic polymorphism and CBZ monotherapy in persons with epilepsy (PWE) from South India, which is a genetically distinct population. With this background, this study was aimed to determine the dose of CBZ in ABCB1 3435C>T genotypes and to determine the distribution of ABCB1 3435C>T genotypes (which codes P-glycoprotein) between responders and non-responders to CBZ therapy. METHODS: A cross sectional study was conducted in 200 persons with epilepsy, who were categorised as responders and non-responders according to ILAE (international league against epilepsy) criteria. Eligible participants were enrolled from the epilepsy clinic of the neurology department and five ml of blood was collected. DNA extraction and genotyping were done by phenol-chloroform method and real time polymerase chain reaction (RT-PCR), respectively. RESULTS: The mean maintenance dose of carbamazepine was statistically significant among different genotypes (p<0.05) of ABCB1 3435C>T (526 vs. 637 mg/day in CC vs. TT genotype). There was no significant association between ABCB1 3435C>T polymorphism (p=0.827) and CBZ resistance in PWE. Duration of disease and age of onset were found to be significant in predicting the response to CBZ therapy. CONCLUSIONS: We report that ABCB1 3435C>T polymorphism is significantly associated with an increase in dose requirement of CBZ in persons with epilepsy from South India.

Treating status epilepticus in adults. / Behandling av status epilepticus hos voksne.

This clinical review examines the treatment of status epilepticus, a condition in which epileptic seizures are prolonged and pose a significant risk of brain damage and death. International guidelines recommend the use of benzodiazepines as first-line treatment, and these should be administered promptly and in appropriate doses. Second-line treatment involves the use of high-dose anti-seizure medications to stop and prevent seizures. If seizure activity persists, general anaesthesia should be administered as soon as possible. All neurological hospital departments should have established and rehearsed protocols for treating status epilepticus.

Benzodiazepine use in medical cannabis authorization adult patients from 2013 to 2021: Alberta, Canada.

BACKGROUND: Benzodiazepines are a class of medications that are being frequently prescribed in Canada but carry significant risk of harm. There has been increasing clinical interest on the potential "sparing effects" of medical cannabis as one strategy to reduce benzodiazepine use. The objective of this study as to examine the association of medical cannabis authorization with benzodiazepine usage between 2013 and 2021 in Alberta, Canada. METHODS: A propensity score matched cohort study with patients on regular benzodiazepine treatment authorized to use medical cannabis compared to controls who do not have authorization for medical cannabis. A total of 9690 medically authorized cannabis patients were matched to controls. To assess the effect of medical cannabis use on daily average diazepam equivalence (DDE), interrupted time series (ITS) analysis was used to assess the change in the trend of DDE in the 12 months before and 12 months after the authorization of medical cannabis. RESULTS: Over the follow-up period after medical cannabis authorization, there was no overall change in the DDE use in authorized medical cannabis patients compared to matched controls (- 0.08 DDE, 95% CI: - 0.41 to 0.24). Likewise, the sensitivity analysis showed that, among patients consuming ≤5 mg baseline DDE, there was no change immediately after medical cannabis authorization compared to controls (level change, - 0.04 DDE, 95% CI: - 0.12 to 0.03) per patient as well as in the month-to-month trend change (0.002 DDE, 95% CI: - 0.009 to 0.12) per patient was noted. CONCLUSIONS: This short-term study found that medical cannabis authorization had minimal effects on benzodiazepine use. Our findings may contribute ongoing evidence for clinicians regarding the potential impact of medical cannabis to reduce benzodiazepine use. HIGHLIGHTS: • Medical cannabis authorization had little to no effect on benzodiazepine usage among patients prescribed regular benzodiazepine treatment in Alberta, Canada. • Further clinical research is needed to investigate the potential impact of medical cannabis as an alternative to benzodiazepine medication.

A Retrospective Evaluation of Adjunctive Phenobarbital vs. Benzodiazepine Alone for the Treatment of Moderate Alcohol Withdrawal in the Emergency Department.

BACKGROUND: Phenobarbital has been used in the emergency department (ED) as both a primary and adjunctive medication for alcohol withdrawal, but previous studies evaluating its impact on patient outcomes are limited by heterogenous symptom severity. OBJECTIVES: We compared the clinical outcomes of ED patients with moderate alcohol withdrawal who received phenobarbital, with or without benzodiazepines, with patients who received benzodiazepine treatment alone. METHODS: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of ED patients with moderate alcohol withdrawal between 2015 and 2020. Patient encounters were classified into two treatment categories based on medication treatment: phenobarbital alone or in combination with benzodiazepines vs. benzodiazepines alone. Chi-square test or Fisher's exact was used to analyze categorical variables and the Student's t-test for continuous data. RESULTS: Among the 287 encounters that met inclusion criteria, 100 received phenobarbital, compared with 187 that received benzodiazepines alone. Patients who received phenobarbital were provided significantly more lorazepam equivalents. There was a significant difference in the percentage of patient encounters that required admission to the hospital in the phenobarbital cohort compared with the benzodiazepine cohort (75% vs. 43.3%, p < 0.001). However, there was no difference in admission level of care to the floor (51.2% vs. 52.0%), stepdown (33.8% vs. 28%), or intensive care unit (15% vs. 20%), respectively. CONCLUSIONS: Patients who received phenobarbital for moderate alcohol withdrawal were more likely to be admitted to the hospital, but there was no difference in admission level of care when compared with patients who received benzodiazepines alone. Patients who received phenobarbital were provided greater lorazepam equivalents in the ED.

Clinical and neuroimaging predictors of benzodiazepine response in catatonia: A machine learning approach.

Catatonia is a well characterized psychomotor syndrome combining motor, behavioural and neurovegetative signs. Benzodiazepines are the first-choice treatment, effective in 70 % of cases. Currently, the factors associated with benzodiazepine resistance remain unknown. We aimed to develop machine learning models using clinical and neuroimaging data to predict benzodiazepine response in catatonic patients. This study examined a cohort of catatonic patients who underwent standardized clinical evaluation, 3 T brain MRI, and benzodiazepine trial. Based on clinical response, patients were classified as benzodiazepine responders or non-responders. Cortical thickness and regional brain volumes were measured. Two machine learning models (linear model and gradient boosting tree model) were developed to identify predictors of treatment response using clinical, demographic, and neuroimaging data. The cohort included 65 catatonic patients, comprising 30 benzodiazepine responders and 35 non-responders. Using clinical data alone, the linear model achieved 63% precision, 51% recall, a specificity of 61%, and 58% AUC, while the gradient boosting tree (GBT) model attained 46% precision, 60% recall, a specificity of 62% and 64% AUC. Incorporating neuroimaging data improved model performance, with the linear model achieving 66% precision, 57% recall, a specificity of 67%, and 70% AUC, and the GBT model attaining 50% precision, 50% recall, a specificity of 62% and 70% AUC. The integration of imaging data with demographic and clinical information significantly enhanced the predictive performance of the models. The duration of the catatonic syndrome, along with the presence of mitgehen (passive obedience) and immobility/stupor, and the volume of the right medial orbito-frontal cortex emerged as important factors in predicting non-response to benzodiazepines.

Fentanyl abuse proportion in methadone maintenance treatment, and patients' knowledge about its risks.

INTRODUCTION: Fentanyl is not yet routinely monitored among methadone maintenance treatment (MMT) patients in Israel. We aimed 1. to evaluate urine fentanyl proportion changes over 3 years and characterize patients' characteristics 2. To study patients' self-report on fentanyl usage, and compare knowledge about fentanyl risk, before and following brief educational intervention. METHODS: Fentanyl in the urine of all current MMT patients was tested every 3 months year between 2021 and 2023, and patients with positive urine fentanyl were characterized. Current patients were interviewed using a fentanyl knowledge questionnaire (effects, indications, and risks) before and following an explanation session. RESULTS: Proportion of fentanyl ranged between 9.8 and 15.1%, and patients with urine positive for fentanyl (September 2023) were characterized as having positive urine for pregabalin, cocaine, and benzodiazepine (logistic regression). Of the current 260 patients (87% compliance), 78(30%) self-reported of fentanyl lifetime use ("Ever"), and 182 "never" use. The "Ever" group had higher Knowledge scores than the "Never", both groups improved following the explanatory session (repeated measure). The "Ever" group patients were found with urine positive for cannabis and benzodiazepine on admission to MMT, they were younger, did not manage to gain take-home dose privileges and had a higher fentanyl knowledge score (logistic regression). CONCLUSIONS: In the absence of routine fentanyl tests, a high knowledge score, shorter duration in MMT, benzodiazepine usage on admission, and current cannabis usage, may hint of the possibility of fentanyl abuse.

Unraveling the Influence of Age, IQ, Education, and Negative Symptoms on Neurocognitive Performance in Schizophrenia: A Conditional Inference Tree Analysis.

INTRODUCTION: The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. METHODS: This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. RESULTS: The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). CONCLUSIONS: These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D2 occupancy.

Comparison of Pharmacological Treatments for Agitated Delirium in the Last Days of Life.

CONTEXT: Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited. OBJECTIVES: To explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days. METHODS: A prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3. RESULTS: A total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics. CONCLUSION: Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications.

Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats.

Melatonin exhibits potential for pain relief and long-term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox-proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community-based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30-0.73) during the follow-up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation.

Safety and effectiveness of diazepam nasal spray in male and female patients: Post hoc analysis of data from a phase 3 safety study.

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Sedative drug prescription patterns in Danish adults from 2002 through 2021. A register-based cohort study.

OBJECTIVE: Pharmacological treatment strategies for insomnia seem to vary, and there is lack of knowledge about how sedative drugs are used in a real-world setting. We investigated changes in sedative drug prescription patterns in Danish adults who initiated treatment between 2002 and 2016. METHODS: All adults with a first-time purchase of a sedative drug registered in the Danish National Prescription Register from 2002 through 2016 were followed for five years between 2002 and 2021 for subsequent prescriptions of sedative drugs, death, or emigration. Sedative drugs were classified into anxiolytic benzodiazepines (N05BA), hypnotic benzodiazepines (N05CD), Z-drugs (N05CF), melatonin (N05CH01), promethazine (R06AD), and low-dose quetiapine (N05AH04). Analyses were stratified on time: 2002-2006, 2007-2011, and 2012-2016. RESULTS: A total of 842,880 individuals purchased their first sedative drug between 2002 and 2016. Most of them (40.0%) initiated treatment between 2002 and 2006, whereas 29.2% initiated treatment in 2012-2016. In 2002-2006, anxiolytic benzodiazepines (46.4%), Z-drugs (42.8%), and hypnotic benzodiazepines (5.4%) were the most common first treatment. This pattern changed over time with a gradual increase in the use of melatonin, promethazine, and low-dose quetiapine, which in 2011-2016 accounted for 27% of all first treatments. During the five years from first prescription, around 27% shifted to a different sedative drug. This percentage increased slightly over time, but over time the first shift to another drug class was most often to a Z-drug or anxiolytic benzodiazepine. Few individuals (5.8%) had more than one shift and the third choice seemed randomly distributed across all other drug classes. CONCLUSION: Sedative drug prescriptions are distributed on different drug classes, with Z-drugs and anxiolytic benzodiazepines as the most frequent first treatment, and second choice in case of shift.

Benzodiazepines for pediatric epilepsies and their risks in a cohort within the French health care data.

OBJECTIVE: The management of antiseizure treatment in patients with epilepsy relies on the benefit-risk ratio. Data on antiseizure medication (ASM) use in children are limited. We described antiseizure medication use in children with epilepsy (CwE) in France, with a focus on the chronic use of benzodiazepines and related implications. METHODS: We conducted a 5-year cohort study from January 2012, using data from the French national health care data system (Système National des Données de Santé). We included CwE identified through International Classification of Diseases, 10th Revision codes and medications from January 2012 to December 2015 and followed them until December 2016. We described ASMs and assessed whether the risk of initiating a polytherapy after a bitherapy depends on whether benzodiazepine was included in the bitherapy. RESULTS: We identified 62 885 CwE. Valproate was the most reimbursed ASM (40%), followed by lamotrigine (17.6%), levetiracetam (9.3%), clobazam (6.1%), and carbamazepine (5.8%). Prescriptions were initiated at the hospital in 74.5% of CwE. We observed a decrease in the number of CwE with at least one benzodiazepine reimbursement from 15.3% in 2013 to 10.1% in 2016 (p < .0001). The prevalence of CwE with levetiracetam reimbursements increased, whereas that of CwE with valproate decreased. A switch from a bitherapy to a polytherapy was more likely when the bitherapy included a benzodiazepine (subdistribution hazard ratio [sHR] = 1.20 [1.03-1.39]). SIGNIFICANCE: The prevalence of CwE with at least one benzodiazepine reimbursement decreased during the study period. Benzodiazepines were associated with an increased use of subsequent ASM polytherapy.