UNASSIGNED: Because of their similar appearance and inexpensive cost, sulfonylureas can cause hypoglycemia when substituted for benzodiazepines by the illicit drug market. We present a patient who developed hypoglycemia after ingestion of what she thought to be Valium; work-up revealed sulfonylurea exposure.
UNASSIGNED: A 33-year-old patient was brought to the hospital after being found unresponsive by paramedics with a reported venous blood glucose level of 18 mg/dL (reference range, 70-140 mg/dL). This prompted treatment with 12.5 g of dextrose administered intravenously. At the hospital, the venous blood glucose level was 15 mg/dL resulting in intravenous dextrose infusion initiation. Once stable, the patient endorsed a medical history of substance use disorder and anxiety. She reported ingesting 2 blue pills given to her by a friend as Valium for her anxiety. Laboratory values showed an elevated insulin level of 47.4 mIU/mL (2.6-24.9), an elevated C-peptide level of 5.4 ng/mL (1.1-4.4), and a glucose level of 44 mg/dL (>70 mg/dL). The patient underwent a 72-hour fasting test. Blood hypoglycemia agent screening showed positive results for glyburide (>5 ng/mL). The patient was discharged home in stable condition.
UNASSIGNED: There are approximately 2 to 5 case reports of hypoglycemia among persons taking illicit drugs containing sulfonylureas. Laboratory values consistent with the use of a hypoglycemic agent include elevated insulin and C-peptide levels, a low glucose level, and positive results for hypoglycemia agent screening.
UNASSIGNED: Sulfonylurea-induced hypoglycemia may lead to clinical sedation, mimicking the effects of benzodiazepines. Sulfonylurea substitution or drug contamination should be suspected when severe hypoglycemia is diagnosed in unresponsive patients suspected of taking illicit drugs.

This prospective, blinded, randomized crossover study aimed to assess the anesthetic effects of the combination of 30 mg/kg ketamine and 2 mg/kg midazolam via intranasal (IN) or intramuscular (IM) routes in twelve domestic chickens. Physiological parameters (respiratory rate - RR, heart rate - HR, and cloacal temperature -Tºcloacal) were monitored throughout the experiment, along with recovery time and sedation level (S0: awake, no recumbency, responsive to stimuli; S1: blinking eyes, recumbency, relaxed, response to stimulus, mild movement; S2: open eyes, recumbency, relaxed, mild response to stimuli; S3: closed eyes, recumbency, relaxed, no movement). In the IM group, all birds reached S3, while in IN 5/12 reached S3, 4/12 reached at most S1, and 1/12 at most S2. IM administration showed higher sedation at 5, 10, 15, 20, 30, 35, 40, and 45 minutes (p<0.05). IN administration exhibited a shorter total recovery time (26.3±21.4 min vs. 92.9±33.4 min; p<0.001). No time, group, or time-group interaction effects were observed in HR and cloacal Tº, with a trend to a decrease in RR both groups (p<0.001). Increased incidences of vocalization and agitation was observed via IM (4/12 vs. 0/12; p=0.028), with no difference in salivation. Despite faster recovery with less agitation and vocalization, the ketamine and midazolam combination via IN provided less consistent sedation compared to the IM route in chickens.
Este estudo crossover randomizado objetivou avaliar os efeitos anestésicos da associação de 30 mg/kg de cetamina e 2 mg/kg de midazolam via intranasal (IN) ou intramuscular (IM) em doze galinhas. Além dos parâmetros fisiológicos (frequência respiratória – FR e cardíaca – FC e temperatura cloacal – Tºcloacal), registrou-se o tempo de recuperação e o grau de sedação ao longo do experimento (S0: acordada, sem decúbito, responsiva a estímulos; S1: olhos piscando, decúbito, relaxada, resposta a estímulo, movimentação leve; S2: olhos abertos, decúbito, relaxada, resposta leve a estímulos; S3: olhos fechados, decúbito, relaxada, sem movimentação. Pela via IM, todas as aves atingiram o grau S3, enquanto pela via IN 5/12 alcançaram S3, 4/12 atingiram no máximo S1 e 1/12 no máximo S2. A via IM apresentou maior sedação em 5, 10, 15, 20, 30, 35, 40 e 45 min (p<0,05). A via IN apresentou menor tempo total até recuperação (26,3±21,4 min vs. 92,9±33,4 min; p<0,001). Não foram observados efeitos de tempo, grupo e interação tempo-grupo na FC e na Tºcloacal com uma tendência de queda da FR nos dois grupos (p<0,001). Observou-se maior incidência de vocalização e agitação pela via IM (4/12 vs. 0/12; p=0,028), não havendo diferença para sialorreia. Apesar da recuperação mais rápida e com menos agitação e vocalização, a associação cetamina e midazolam via IN levou a uma sedação menos consistente que a via IM em galinhas.

OBJECTIVE: Exposure to critical illness and intensive care may lead to long-term psychologic and physical impairments. To what extent ICU survivors become prolonged users of benzodiazepines after exposure to critical care is not fully explored. This study aimed to describe the extent of onset of prolonged high-potency benzodiazepine use among ICU survivors not using these drugs before admission, identify factors associated with this use, and analyze whether such usage is associated with increased mortality.
METHODS: Retrospective cohort study.
METHODS: Sweden, including all registered ICU admissions between 2010 and 2017.
METHODS: ICU patients surviving for at least 3 months, not using high-potency benzodiazepine before admission, were eligible for inclusion.
METHODS: Admission to intensive care.
RESULTS: A total of 237,904 patients were screened and 137,647 were included. Of these 5338 (3.9%) became prolonged users of high-potency benzodiazepines after ICU discharge. A peak in high-potency benzodiazepine prescriptions was observed during the first 3 months, followed by sustained usage throughout the follow-up period of 18 months. Prolonged usage was associated with older age, female sex, and a history of both somatic and psychiatric comorbidities, including substance abuse. Additionally, a longer ICU stay, a high estimated mortality rate, and prior consumption of low-potency benzodiazepines were associated with prolonged use. The risk of death between 6 and 18 months post-ICU admission was significantly higher among high-potency benzodiazepine users, with an adjusted hazard ratio of 1.8 (95% CI, 1.7-2.0; p < 0.001). No differences were noted in causes of death between users and nonusers.
UNASSIGNED: Despite the lack of evidence supporting long-term treatment, prolonged usage of high-potency benzodiazepines 18 months following ICU care was notable and associated with an increased risk of death. Considering the substantial number of ICU admissions, prevention of benzodiazepine misuse may improve long-term outcomes following critical care.

Background/Objectives: Concurrent opioid (OPI) and benzodiazepine (BZD) use may exacerbate injurious fall risk (e.g., falls and fractures) compared to no use or use alone. Yet, patients may need concurrent OPI-BZD use for co-occurring conditions (e.g., pain and anxiety). Therefore, we examined the association between longitudinal OPI-BZD dosing patterns and subsequent injurious fall risk. Methods: We conducted a retrospective cohort study including non-cancer fee-for-service Medicare beneficiaries initiating OPI and/or BZD in 2016-2018. We identified OPI-BZD use patterns during the 3 months following OPI and/or BZD initiation (i.e., trajectory period) using group-based multi-trajectory models. We estimated the time to first injurious falls within the 3-month post-trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. Results: Among 622,588 beneficiaries (age ≥ 65 = 84.6%, female = 58.1%, White = 82.7%; having injurious falls = 0.45%), we identified 13 distinct OPI-BZD trajectories: Group (A): Very-low OPI-only (early discontinuation) (44.9% of the cohort); (B): Low OPI-only (rapid decline) (15.1%); (C): Very-low OPI-only (late discontinuation) (7.7%); (D): Low OPI-only (gradual decline) (4.0%); (E): Moderate OPI-only (rapid decline) (2.3%); (F): Very-low BZD-only (late discontinuation) (11.5%); (G): Low BZD-only (rapid decline) (4.5%); (H): Low BZD-only (stable) (3.1%); (I): Moderate BZD-only (gradual decline) (2.1%); (J): Very-low OPI (rapid decline)/Very-low BZD (late discontinuation) (2.9%); (K): Very-low OPI (rapid decline)/Very-low BZD (increasing) (0.9%); (L): Very-low OPI (stable)/Low BZD (stable) (0.6%); and (M): Low OPI (gradual decline)/Low BZD (gradual decline) (0.6%). Compared with Group (A), six trajectories had an increased 3-month injurious falls risk: (C): HR = 1.78, 95% CI = 1.58-2.01; (D): HR = 2.24, 95% CI = 1.93-2.59; (E): HR = 2.60, 95% CI = 2.18-3.09; (H): HR = 2.02, 95% CI = 1.70-2.40; (L): HR = 2.73, 95% CI = 1.98-3.76; and (M): HR = 1.96, 95% CI = 1.32-2.91. Conclusions: Our findings suggest that 3-month injurious fall risk varied across OPI-BZD trajectories, highlighting the importance of considering both dose and duration when assessing injurious fall risk of OPI-BZD use among older adults.

Background and Objectives: Remimazolam, a novel benzodiazepine, is used for procedural sedation and general anesthesia due to its rapid onset and short duration of action. However, remimazolam-induced anaphylaxis (RIA) is a rare but severe complication. This study aimed to analyze RIA characteristics, focusing on cardiovascular collapse, and provide guidelines for safe remimazolam use. Methods: This study conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Research articles retrieved from PubMed on 26 May 2023, using the keywords \'remimazolam AND anaphylaxis\' were evaluated based on the inclusion criteria of being written in English and aligning with the World Allergy Organization criteria for anaphylaxis, while studies not meeting these criteria were excluded. All published articles up to the search date were included without any date restrictions. The review analyzed factors such as age, sex, type of anesthesia, remimazolam dose (bolus/continuous), allergic symptoms and sign, epinephrine use, serum tryptase levels, and skin prick tests. Results: Among eleven cases, the mean age was 55.6 ± 19.6 years, with 81.8% male. Hypotension (81.8%) was the most common symptom, followed by bradycardia (54.5%) and desaturation (36.4%). Two patients experienced cardiac arrest. Serum tryptase levels confirmed anaphylaxis in ten cases. Epinephrine was the primary treatment, with intravenous doses ranging from 0.1 mg to 0.3 mg. Conclusions: Vigilance is crucial when administering remimazolam, adhering to recommended dosages, and promptly treating RIA with epinephrine. Further research is needed to understand the risk factors and refine the management strategies. Guidelines for safe remimazolam use are proposed.

Effective treatments for major depressive disorder (MDD) have long been needed. One hypothesis for the mechanism of depression involves a decrease in neuroactive steroids such as allopregnanolone, an endogenous positive allosteric modulator of the γ-aminobutyric acid-gated chloride channel (GABAA) receptor. In our previous study, we discovered that allopregnanolone, not diazepam, exhibited antidepressant-like effects in the social interaction test (SIT) of social defeat stress (SDS) model mice. However, the dynamics of neuronal activity underlying the antidepressant-like effect remain unknown. In the current study, we conducted local field potentials (LFPs) recordings from the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) during the SIT to elucidate the relationship between the antidepressant-like effect and neuronal oscillation. We discovered that allopregnanolone has antidepressant-like effects in the SIT of SDS model mice by decreasing intervals of repetitive social interaction (inter-event intervals), resulting in increase of total social interaction time. We also found that theta and beta oscillation increased in BLA at the onset of social interaction following administration of allopregnanolone, which differed from the effects of diazepam. Theta and beta power in BLA within the social interaction zone exhibited a positive correlation with interaction time. This increase of theta and beta power was negatively correlated with inter-event intervals. Regarding theta-band coordinated activity between the BLA and mPFC, theta power correlation decreased at the onset of social interaction with the administration of allopregnanolone. These findings suggest that theta activity in BLA following social interaction and the reduced theta-band coordinated activity between the BLA and mPFC are implicated in social interaction, which is one of the antidepressant behaviors. These differences in neural activity could elucidate the distinctive mechanism underlying antidepressant-like effects of neuroactive steroids, as opposed to benzodiazepines.

BACKGROUND: It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice.
METHODS: One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = \"unfamiliar\"; 1 = \"familiar\") and how they managed insomnia using a nine-point Likert scale (1 = \"I never prescribe/perform it\"; 9 = \"I often prescribe/perform it\"). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it.
RESULTS: Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8-5.4 points and 4.0-4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5-1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48-74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points.
CONCLUSIONS: This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists.

Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.

UNASSIGNED: Clinicians face difficulties in making treatment decisions for unspecified anxiety disorder due to the absence of any treatment guidelines. The objective of this study was to investigate how familiar and how often primary care physicians use pharmacological and nonpharmacological approaches to manage the disorder.
UNASSIGNED: A survey was conducted among 117 primary care physicians in Japan who were asked to assess the familiarity of using each treatment option for unspecified anxiety disorder on a binary response scale (0 = \"unfamiliar,\" 1 = \"familiar\") and the frequency on a nine-point Likert scale (1 = \"never used,\" 9 = \"frequently used\").
UNASSIGNED: While several benzodiazepine anxiolytics were familiar to primary care physicians, the frequencies of prescribing them, including alprazolam (4.6 ± 2.6), ethyl loflazepate (3.6 ± 2.4), and clotiazepam (3.5 ± 2.3), were low. In contrast, certain nonpharmacological options, including lifestyle changes (5.4 ± 2.3), coping strategies (5.1 ± 2.7), and psychoeducation for anxiety (5.1 ± 2.7), were more commonly utilized, but to a modest extent. When a benzodiazepine anxiolytic drug failed to be effective, primary care physicians selected the following management strategies to a relatively high degree: differential diagnosis (6.4 ± 2.4), referral to a specialist hospital (5.9 ± 2.5), lifestyle changes (5.2 ± 2.5), and switching to selective serotonin reuptake inhibitor (5.1 ± 2.4).
UNASSIGNED: Primary care physicians exercise caution when prescribing benzodiazepine anxiolytics for unspecified anxiety disorder. Nonpharmacological interventions and switching to SSRI are modestly employed as primary treatment options and alternatives to benzodiazepine anxiolytics. To ensure the safe and effective treatment of unspecified anxiety disorder in primary care, more information should be provided from field experts.

UNASSIGNED: Nocturnal eating behavior in patients with sleep-related eating disorder (SRED) is difficult to control and can become chronic, causing weight gain and psychological distress. Here, we report a case of SRED comorbid with major depressive disorder successfully treated by switching from brotizolam to suvorexant, that is, from a benzodiazepine to an orexin receptor antagonist.
UNASSIGNED: A 25-year-old woman complained of night snacking with partial/complete amnesia and sleepwalking for 1 year. She had a diagnosis of major depressive disorder at age 20 and was on paroxetine and brotizolam for depression and insomnia. At 24 years of age, she experienced her second depressive episode, then her amnestic nocturnal eating became prominent. Even after improvement in depressive symptoms, she experienced uncontrollable nocturnal eating episodes every 2 days, resulting in weight gain of over 10 kg. After a partial amnestic eating episode following an awakening from stage N2 sleep was confirmed through video polysomnography, she was diagnosed with SRED. Considering her strong desire to resolve involuntary eating, we instructed her to discontinue brotizolam and start suvorexant. Subsequently, her nocturnal eating completely disappeared. She experienced rebound insomnia, which improved within 1 month. She was then continued on 10 mg of suvorexant and has not experienced nocturnal eating for 2 years.
UNASSIGNED: This case highlights the importance of discontinuing benzodiazepines in the treatment of SRED, but also suggests the potential benefit of orexin receptor antagonists in the treatment of SRED. The efficacy of orexin receptor antagonists in idiopathic SRED should be tested in future studies.