High-dose Benzodiazepine Research Articles

Characteristics of high-dose benzodiazepine use: nationwide cohort study on new benzodiazepine users with 5-year follow-up.

A nationwide register-based cohort study from Finland including 48 124 incident benzodiazepines and related drug (BZDR) users aged 18-65 years who initiated use in 2006 and were not dispensed BZDRs during 2004-2005. The follow-up was 5 years or until death, whichever occurred first. To investigate sociodemographic and clinical factors associated with high-dose use of BZDRs (i.e. Z-drugs) among new BZDR users. The temporal BZDR dose was calculated as a point estimate every 6 months after initiation as defined daily doses (DDDs) per day, based on the PRE2DUP method (an approach based on mathematical modelling of personal drug purchasing behaviours). Sociodemographic and clinical factors associated with dose categories were studied using multinomial logistic regression. During the 5-year follow-up, very high-dose BZDR use was observed in 7.4% (n = 3557) and medium high-dose use in 25.5% (n = 12 266) of the users (corresponding to ≥30 mg and 10-29 mg in diazepam equivalents, respectively). Very high-dose use was more common among men compared with women (10.9% versus 4.6%). Very high-dose use patterns were especially observed in younger age groups (18- to 25-year-olds). Compared with oxazepam, initiating BZDR use with clonazepam (adjusted odds ratio 3.86, 95% CI 3.24-4.60), diazepam (2.05, 1.78-2.36) or alprazolam (1.76, 1.52-2.03) was associated with increased odds for very high-dose use. Both medium high-dose and very high-dose BZDR use were associated with a lower level of education. In all, 58% of very high-dose use occurred in BZDR users who received their first prescription from general practitioners. Clinicians should be aware of the dose escalation risk especially when prescribing diazepam, alprazolam or clonazepam for psychiatric indications. If BZDRs are needed, our findings suggest favouring oxazepam.

Successful Electroconvulsive Therapy in a Patient With Catatonia and Maternal Duplication 15q11-13 Syndrome.

The 15q11-q13 chromosomal region contains genes encoding for GABA-A receptor subunits and is a known region of epigenetic modification associated with the development of neurodevelopmental disorders. The presence of at least one additional copy of the maternal 15q11-q13 results in a syndrome (maternal dup15q) characterized by intellectual disability, autism spectrum disorder, mood disorders, and epilepsy. Catatonia is a serious syndrome of behavioral and motor dysfunction, which occurs across a variety of psychiatric, neurologic, and general medical conditions, which has successfully been treated with benzodiazepines and electroconvulsive therapy. In this case report, we describe the treatment course of a patient with established maternal dup 15q with comorbid intellectual disability, autism spectrum disorder, bipolar mood disorder, and juvenile epilepsy who developed hypokinetic catatonia refractory to high-dose benzodiazepine therapy. In contrast with benzodiazepine treatment, electroconvulsive therapy resulted in rapid improvement in catatonic symptoms and return to premorbid baseline. This case suggests that electroconvulsive therapy can be safely delivered for some patients with maternal dup 15q and may be rapidly effective when benzodiazepine treatment results in inadequate symptom improvement.

Morbidity Associated with Deviation from Pediatric Status Epilepticus Guidelines

Treatment guidelines for the management of pediatric status epilepticus (PSE) are often institution-specific. We aim to characterize deviation from our hospital-based PSE treatment guidelines, the total dosage of benzodiazepines administered, and the need for intubation. The study population included all patients with an ICD −10 code for PSE who required admission to the Pediatric Intensive Care Unit (PICU) from April 2019 to April 2022. There were 66 PICU admissions. All patients with concern for PSE and altered mental status are admitted to the PICU. The cohort was divided between those treated according to the PSE protocol (benzodiazepine dose (0.05 mg/kg- 0.2 mg/kg) versus those who had low dose (≤0.05 mg/kg) and high-dose benzodiazepine (> 0.2 mg/kg) totals. The dosage was calculated as the total dose of benzodiazepines received pre-hospital and in the ED before intubation or transport. Forty-one (62 %) of patients received high-dose benzodiazepines (median 0.34 mg/kg [IQR 0.29–0.56], 19 (29 %) received recommended-dose benzodiazepines (median 0.13 mg/kg [IQR 0.09,0.15] and 6 (9 %) received low-dose (median 0.05 mg/kg [IQR 0.03,0.05]. The high-dose group was 15.9 (95 % CI = 3.7, 99.9) times more likely to be intubated controlling for the location of care (tertiary versus community hospital), and the age of the patient. The recommended-dose and low-dose groups required intubation with much less frequency.

1224 Management of Dopaminergic Augmentation of Restless Legs Syndrome with Concurrent High Dose Benzodiazepine Therapy

Abstract Introduction Restless Legs Syndrome (RLS) or Willis-Ekbom disease, is sleep related movement disorder characterized by an irresistible urge to move the legs, often accompanied by uncomfortable and unpleasant sensations. Over the years, dopaminergic agonists (DAs) have served as the primary treatment for RLS. However, the emergence of dose-dependent augmentation has prompted a shift in the management approach. This change is marked by a growing emphasis on prioritizing alpha2-delta calcium channel ligands (A2D) as alternative therapeutic agents Report of case(s) We report a case of a 70-year-old woman with a 15-year history of RLS, with crawling and unpleasant sensation of her legs preventing from falling asleep, successfully managed initially with pramipexole 0.5mg at night and eventually started on clonazepam. With escalating symptoms, Pramipexole and Clonazepam gradually increased. Despite dose escalation of pramipexole to 0.75mg and clonazepam to 4mg nightly, symptoms persisted and even intensified. Abruptly discontinuing Pramipexole and transitioning to ropinirole at 1mg and continuing Clonazepam 4mg nightly failed to yield improvement. Patient presented for consultation at this time highlighting the severity of RLS augmentation as moderate. Recommendation in this situation is to introduce A2D or possible opiate medication to ameliorate symptoms before tapering DA. The patient's high-dose benzodiazepine regimen increases respiratory depression and fall risk, hindering the standard approach of introducing alternative agents. In response, a tailored strategy was implemented, gradually tapering clonazepam while initiating gabapentin therapy, RLS symptoms began to improve. Subsequent cautious tapering of ropinirole contributed to sustained relief. This case demonstrates the need for individualized approaches in managing dopaminergic augmentation in RLS, especially when high-dose benzodiazepines are involved. Conclusion In navigating the intricacies of RLS treatment, our case highlights the effectiveness of a nuanced approach when confronted with dopaminergic augmentation alongside concurrent high-dose benzodiazepine therapy. Tapering benzodiazepines and introducing gabapentin proved successful, emphasizing the importance of tailored interventions. This case contributes to the understanding of RLS management in complex scenarios. Support (if any)

High-dose benzodiazepine use and QTc interval prolongation, a latent class analysis study

Benzodiazepine (BDZ) addiction is a widespread and multifaceted phenomenon. For many patients, especially females, the concomitant use of other drugs also increases their risk of QTc prolongation, possibly leading to complications such as seizures and even sudden death. However, the relationship between BDZ use and QTc prolongation is currently unclear. The present study aims to examine patterns of polysubstance use among a sample of Italian adults with BDZ dependence in relation with their QTc prolongation risk. We used Latent Class Analysis (LCA) on data collected from 251 inpatients of the Addiction Medicine Unit in Verona to group patients into three classes according to their substance use and their QTc prolongation risk. Results showed no significant relationship between QTc prolongation and BDZ use in any of the classes considered. We conclude that BDZs, even if used long-term and at high dosages, can be considered safe in terms of cardiovascular complications for patients.

Severe alcohol withdrawal in an adolescent male

Ethanol remains one of the most frequently abused agents by adolescents, exceeding all others except for vaping nicotine, and use is rising. With increased ethanol use comes a greater risk for dependence and potential for alcohol withdrawal syndromes (AWS). Pediatric AWS is extremely rare and poorly characterized in the literature. Pediatric acute care practitioners may have limited exposure to AWS. We report the case of a 16-year-old male with a history of polysubstance abuse who presented with mild AWS and progressed rapidly to delirium tremens. His withdrawal was initially refractory to high dose benzodiazepine therapy but responded well to phenobarbital. This case highlights how rapidly and dangerously AWS can progress if not aggressively treated. Given the rise in adolescent alcohol use and potential for life threatening symptoms, practitioners, especially in acute care specialties such as emergency medicine, critical care, and hospital medicine, would benefit from additional familiarity with AWS diagnoses and management strategies.

Use of Flumazenil in Detoxification of High-Dose Benzodiazepine Users: A Mini Review of Pharmacological Basis and Clinical Studies

Introduction: The use of benzodiazepines (BDZ) is notoriously associated with significant long-term problems and it is estimated that the long-term users (LTU) in Italy are over 3 million people, including many elderly people. Unfortunately, 40 to 80% of the LTUs develop dependence and many also have tolerance, with the need for a progressive increase in the daily dosage up to the point of tolerating daily megadoses. In recent years, the off-label use of continuous infusion subcutaneous flumazenil has established itself as a viable approach for rapid hospital detoxification of these sometimes very complex clinical cases. The purpose of the article is, starting from the pharmacological and biochemical bases, to describe the mechanism of action, the areas of applicability and the possible criticalities by analyzing the Italian data. Materials and Methods: A computerized research was carried out for the articles to be inserted through use of international databases PUBMED and RESEARCHGATE by typing in keywords such as “flumazenil, high dose benzodiazepine users, use of flumazenil for benzo detoxification” and related articles. We also used the PUBCHEM database to describe some chemical and pharmacological characteristics of flumazenil. Both Italian and international research articles have been selected, starting from 1980 to today. Discussion and Conclusions: The use of flumazenil in slow infusion remains off-label but, for almost 20 years, it has been in use (in Italy and beyond) to detoxify, in about a week of hospitalization, patients with equivalent daily doses of diazepam greater than 50 mg / day for more than 6 months (with a description of cases up to 350 mg / day of diazepam-equivalent). This would allow the GABA-Argic receptor resensitization in a short time and with minimal or absent withdrawal symptoms, being able to suspend megadoses of BDZ in a very short time. In Italy this approach is still used to a limited extent and it cannot be said that it is absolutely the best method but the analysis of various endpoints in published studies, such as acute withdrawal discomfort, discharge without prescription of benzodiazepines and relapses in the first 6-12 months of discharge, certainly makes us reflect on the possibility of extending this approach to various territorial hospitals.

Study protocol-Evoked craving in high-dose benzodiazepine users.

Benzodiazepine (BDZ) abuse, especially concerning high doses of BDZs, is an impairing substance use disorder (SUD) that is often difficult to treat. Craving and cue reactivity (CR) are two important phenomena that have a prominent role in maintaining addiction and triggering relapses in BDZ abuse; nevertheless, they have rarely been addressed in scientific literature. The present study aims to fill these gaps by implementing a highly innovative virtual reality (VR) design to assess the impact of substance-related environmental cues on BDZ craving, as well as their influence on patients’ affective states. Therefore, on one hand, this research will contribute to the assessment of VR feasibility in the study of these phenomena, and, on the other, it will help disentangle the role that CR and craving have on mood and attention, which are equally important factors to consider when treating SUDs. We will recruit a healthy control group and a patient group comprising people seeking treatment for BDZ detoxification. The experimental design will consist of the presentation of three VR scenarios, one neutral, one BDZ-related but without BDZ cues, and another with BDZ cues. The craving will be measured through a virtual analog scale (VAS); the Profile of Mood States (POMS) and Alcohol Attention Scale (AAS) questionnaires in a modified version will also be administered. We will additionally control for VR-induced feelings of sickness by administering the Simulator Sickness Questionnaire (SSQ), and the Presence Questionnaire (PQ) will be used to investigate participants’ sense of presence in virtual environments. We expect patients to exhibit higher levels of craving, and that the craving will be higher after exposure to a cue-related virtual environment as compared to a neutral scenario.

2.60 How Much Is Too Much?: A Review of Current Treatments for Catatonia

Catatonia is very rare in children and adolescents, seen in only 0.6% of the inpatient population. High-dose benzodiazepines are the first-line therapy for catatonia. However, there is limited research on alternative therapies for patients who fail to respond to high-dose benzodiazepines. The objective of this study is to review the available literature on the treatment of catatonia in children and adolescents and explore potential augmentation strategies.

Use of a Novel Standardized Administration Protocol Reduces Agitation Pro Re Nata (PRN) Medication Requirements: The Birmingham Agitation Management (BAM) Initiative.

Agitation management is a principal challenge on inpatient psychiatric units. Overreliance on common prescribing strategies of pro re nata (PRN) medication administration is problematic, given the tendencies to have overlapping or unclear indications. Piloted project to determine whether a standardized protocol for agitation intervention may reduce PRN medication administration. The Birmingham Agitation Management (BAM) interdisciplinary team uniquely connected the Brøset Violence Checklist (BVC) for assessment of agitation severity to a standardized PRN medication order set. Nurses on the piloted unit were trained on how to score the BVC and administer medications. Patients were assessed by the BVC every 4 hours and, based on their score, would receive no medication, low-dose benzodiazepine, high-dose benzodiazepine, or high-dose benzodiazepine plus antipsychotic. The primary end point compared the number of PRNs administered after novel protocol implementation with a retrospective cohort. Secondary measures included analysis of medication-related effects, seclusion, and physical restraint rates. 377 patients were included in the final analyses (184 pre-BAM, 193 BAM intervention group). No significant differences were seen in patient characteristics between groups. The total number of PRNs administered decreased by 42.5%, with both the mean and median number of administrations decreasing significantly (95% confidence interval [CI] = [1.68-5.75]; P < 0.001). A trend was noted between the number of PRNs administered and seclusion rates, but did not reach statistical significance (95% CI = [-7.28 to 60.31]; P = 0.124). In seemingly the first initiative of its kind, we found that a standardized agitation management protocol can help decrease the total number of PRN administrations for agitation without worsening of restraint rates and may possibly reduce the risk of adverse effects. These results require validation in specific, larger populations.

Outcomes of patients treated with low-dose flumazenil for benzodiazepine detoxification: A description of 26 participants

IntroductionBenzodiazepines are commonly prescribed for a variety of indications and can be employed in the short- and long-term. While they are efficacious, issues arise from long-term use with the emergence of dependence and tolerance to doses within the therapeutic range and beyond. Discontinuation from benzodiazepines can be problematic for patients and may result in a withdrawal syndrome, which can be protracted and last months to years. Methods26 participants received low-dose subcutaneous flumazenil infusions (4 mg/24 h for approximately eight days) as part of a randomised control crossover trial. Return to benzodiazepine use was assessed monthly for three months based on the benzodiazepine use in the previous week. Where data was not available, the treating psychiatrist examined patient files and clinical documents to determine benzodiazepine use. Withdrawal and craving scores were also measured. ResultsAbstinence rates from benzodiazepines at one-, two-, and three-month follow ups were 65.4 %, 50.0 %, and 46.2 % respectively. When considering patient files and clinical documents for those lost to follow-up, abstinence rates were higher at 73.1 %, 65.4 % and 61.5 % at the one-, two-, and three-month follow ups respectively. Withdrawal and craving scores were higher in those that had returned to any benzodiazepine use. ConclusionSelf-reported rates of abstinence from benzodiazepines at three months was between 46.2 % and 61.5 %. Flumazenil may yield greater success than benzodiazepine tapering from high dose benzodiazepine use (≥30 mg diazepam equivalent). Further research should compare abstinence rates after treatment with flumazenil compared to benzodiazepine tapering in high dose benzodiazepine users.

Dosing profiles of concurrent opioid and benzodiazepine use associated with overdose risk among US Medicare beneficiaries: group-based multi-trajectory models.

One-third of opioid (OPI) overdose deaths involve concurrent benzodiazepine (BZD) use. Little is known about concurrent opioid and benzodiazepine use (OPI-BZD) most associated with overdose risk. We aimed to examine associations between OPI-BZD dose and duration trajectories, and subsequent OPI or BZD overdose in US Medicare. Retrospective cohort study. US Medicare. Using a 5% national Medicare data sample (2013-16) of fee-for-service beneficiaries without cancer initiating OPI prescriptions, we identified 37 879 beneficiaries (age ≥ 65 = 59.3%, female = 71.9%, white = 87.6%, having OPI overdose = 0.3%). During the 6 months following OPI initiation (i.e. trajectory period), we identified OPI-BZD dose and duration patterns using group-based multi-trajectory models, based on average daily morphine milligram equivalents (MME) for OPIs and diazepam milligram equivalents (DME) for BZDs. To label dose levels in each trajectory, we defined OPI use as very low (< 25 MME), low (25-50 MME), moderate (51-90 MME), high (91-150 MME) and very high (>150 MME) dose. Similarly, we defined BZD use as very low (< 10 DME), low (10-20 DME), moderate (21-40 DME), high (41-60 DME) and very high (> 60 DME) dose. Our primary analysis was to estimate the risk of time to first hospital or emergency department visit for OPI overdose within 6 months following the trajectory period using inverse probability of treatment-weighted Cox proportional hazards models. We identified nine distinct OPI-BZD trajectories: group A: very low OPI (early discontinuation)-very low declining BZD (n = 10 598; 28.0% of the cohort); B: very low OPI (early discontinuation)-very low stable BZD (n = 4923; 13.0%); C: very low OPI (early discontinuation)-medium BZD (n = 4997; 13.2%); D: low OPI-low BZD (n = 5083; 13.4%); E: low OPI-high BZD (n = 3906; 10.3%); F: medium OPI-low BZD (n = 3948; 10.4%); G: very high OPI-high BZD (n = 1371; 3.6%); H: very high OPI-very high BZD (n = 957; 2.5%); and I: very high OPI-low BZD (n = 2096; 5.5%). Compared with group A, five trajectories (32.3% of the study cohort) were associated with increased 6-month OPI overdose risks: E: low OPI-high BZD [hazard ratio (HR) = 3.27, 95% confidence interval (CI) = 1.61-6.63]; F: medium OPI-low BZD (HR = 4.04, 95% CI = 2.06-7.95); G: very high OPI-high BZD (HR = 6.98, 95% CI = 3.11-15.64); H: very high OPI-very high BZD (HR = 4.41, 95% CI = 1.51-12.85); and I: very high OPI-low BZD (HR = 6.50, 95% CI = 3.15-13.42). Patterns of concurrent opioid and benzodiazepine use most associated with overdose risk among fee-for-service US Medicare beneficiaries initiating opioid prescriptions include very high-dose opioid use (MME > 150), high-dose benzodiazepine use (DME > 40) or medium-dose opioid with low-dose benzodiazepine use.

Polysubstance Use Patterns Among High Dose Benzodiazepine Users: A Latent Class Analysis and Differences Between Male and Female Use.

Benzodiazepines (BZDs) represent one of the most widely used groups of pharmaceuticals, but if used for long periods of time they are associated with dependence and an increased risk of harmful effects. High-dose (HD) BZD dependence is a specific substance use disorder associated with a poor quality of life. It is especially important to pinpoint differences in HD BZD addict subgroups in order to tailor treatment to the individual's specific needs, also considering possible comorbidities with other substance use disorders. We conducted a study to evaluate HD BZD dependence (converted doses to diazepam equivalents, mg) in an Italian sample of 1,354 participants. We also investigated if and to which extent participants co-used other substances (alcohol, tobacco, cannabis/cannabinoids, cocaine, and heroin). We then performed latent class analysis (LCA) to identify the use patterns of these substances, finding three classes: participants in Class 1 (4.3% of the sample) had the highest probability of also using cocaine and alcohol (Polysubstance BZD users); Class 2 comprised subjects with the highest probability of being former heroin, cocaine, THC, and alcohol users (Former polysubstance BZD users); Class 3 represented mono-dependence BZD users (78.5% of the sample) and was the most prevalent among women, while young men were most prevalent in Class 1.The present study underlines different characteristics in HD BZD users both concerning other addictions and sex, and also highlights the need for a stricter control of BZD use, ranging from prescriptions to sales.

Comparison of Clinical Manifestations of Patients Poisoned with Tricyclic Antidepressants Alone or with Benzodiazepine Intoxication According to the Dose of Benzodiazepines.

Tricyclic antidepressants poisoning (TCA) is associated with cardiovascular complications, electrocardiographic abnormalities, and central nervous system toxicity. This study aimed to compare the clinical manifestations of poisoned patients with tricyclic antidepressants alone or with benzodiazepine (BZD) intoxication according to the dose of BZDs. In this case-control study, 120 patients with TCA poisoning were divided into four groups: the first group of TCA poisoning alone, the second group of TCA and BZD poisoning of <7.75 mg, the third group of TCA and B poisoning of 7.75 to 80 mg, and the fourth group of more than 80 mg of TCA and BZD poisoning. Patients' demographic, clinical, and cardiac information was extracted from their records at admission and 6 h after admission. Cardiac complications 6 h after referral and total cardiac complications between TCA and TCA low-dose BZD groups were significantly reduced in the low-dose BZD poisoning group. Comparison of TCA and TCA groups with a moderate dose of BZD showed a significant reduction in time six and total cardiac complications. However, due to the significant difference in TCA values between the two groups, the results are not significant. Comparing the two groups of TCA and TCA with a high dose of BZD, both 6-hour cardiac complications and total cardiac complications in the high-dose BZD group, it was significantly reduced. However, the loss of consciousness was also considerably greater in the high-dose BZD group than in the TCA group. Concomitant BZDs with TCA can reduce cardiovascular complications from TCA poisoning. However, with high doses of BZDs, there is a greater loss of consciousness.

Gamma-hydroxybutyric acid-induced organic delirium complicated by polydrug use successfully treated with electroconvulsive therapy: a case report

BackgroundPatients with gamma-hydroxybutyric acid withdrawal symptoms are at high risk of developing organic delirium, which can be fatal. The recommended first-line treatment is benzodiazepines, but treatment-resistant cases are frequent. Here we describe a case of successful bilateral electroconvulsive therapy in a patient with severe and highly agitated acute organic delirium induced by gamma-hydroxybutyric acid withdrawal and complicated by polydrug use resistant to first-line treatment. To our knowledge, this is the first report on the effect of electroconvulsive therapy on treatment-resistant delirium caused by gamma-hydroxybutyric acid withdrawal.Case presentationA 21-year-old Danish man diagnosed with untreated attention deficit hyperactivity disorder developed severely agitated acute organic delirium caused by gamma-hydroxybutyric acid withdrawal in a Danish psychiatric ward. The patient was subjected to physical restraints and transferred to the intensive care unit for treatment. During the next 10 days, the patient showed no clinical improvement despite first-line, high-dose benzodiazepines along with intense supportive treatment with propofol, phenobarbital, and antipsychotics. On day 11, bilateral frontotemporal electroconvulsive therapy treatment was initiated and full clinical recovery was obtained after four sessions.DiscussionThe full clinical remission after four electroconvulsive therapy sessions, strongly supports that electroconvulsive therapy may be an effective treatment when severe delirium induced by gamma-hydroxybutyric acid withdrawal is resistant to conventional first-line treatment with benzodiazepines. Moreover, this case illustrates that clinically effective seizures were achieved despite intensive concurrent exposure to anticonvulsive drugs. Therefore, this case report encourages consideration of electroconvulsive therapy in patients with gamma-hydroxybutyric acid delirium who are resistant to psychopharmacological treatment.

Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.

Benzodiazepine high-doses: The need for an accurate definition.

ObjectivesA clear definition of what we understand of high‐dose misuse or of a ‘markedly increased dose’ (as stated by the DSM‐5) is important and past definitions may be inadequate. The aim of this review is to describe the different definitions used and to test these definitions for their accuracy.MethodsA narrative PubMed literature review was conducted based on articles published between 1 January 1990 and 31 December 2020 describing benzodiazepines (in MeSH Terms or MeSH Major Topic) and high‐dose (or high‐dosage). Specific definitions were applied to a population sample to show how definitions affect high‐dose benzodiazepine prevalence.ResultsMultiples of an equivalent‐diazepam dose or of the World Health Organization ‘defined daily dosage’ were used more frequently than the overstep of the recommended maximum therapeutic dosage as a cut‐off point.ConclusionHigh‐dose use is rare but the prevalence in the general population varies among studies, mainly due to different definitions, making both clinical and epidemiological comparisons between studies difficult. Defining a high‐dose user as a person who takes at least a higher dose than the maximum usual therapeutic dose over a defined period of time therefore appears to be clinically more consistent.

Sociodemographic and clinical correlates of gabapentin receipt with and without opioids among a national cohort of patients with HIV

ABSTRACT Gabapentin is commonly prescribed for chronic pain, including to patients with HIV (PWH). There is growing concern regarding gabapentin's potential for harm, particularly in combination with opioids. Among PWH, we examined factors associated with higher doses of gabapentin receipt and determined if receipt varied by opioid use. We examined data from the Veterans Aging Cohort Study, a national prospective cohort including PWH, from 2002 through 2017. Covariates included prescribed opioid dose, self-reported past year opioid use, and other sociodemographic and clinical variables. We used multinomial logistic regression to determine independent predictors of gabapentin receipt. Among 3,702 PWH, 902 (24%) received any gabapentin during the study period at a mean daily dose of 1,469 mg. In the multinomial model, high-dose gabapentin receipt was associated with high-dose benzodiazepine receipt (adjusted odds ratio [aOR], 95% confidence interval [CI]= 1.53, [1.03–2.27]), pain interference (1.65 [1.39–1.95]), and hand or foot pain (1.81, [1.45–2.26]). High-dose gabapentin receipt was associated with prescribed high-dose opioids receipt (2.66 [1.95–3.62]) but not self-reported opioid use (1.03 [0.89–1.21]). PWH prescribed gabapentin at higher doses are more likely to receive high-dose opioids and high-dose benzodiazepines, raising safety concerns.

Impact of benzodiazepines on time to awakening in post cardiac arrest patients

AimAlthough guidelines recommend use of short acting sedation after cardiac arrest, there is significant practice variation. We examined whether benzodiazepine use is associated with delayed awakening in this population. MethodsWe performed a retrospective single center study including comatose patients treated after in- or out-of-hospital cardiac arrest from January 2010 to September 2019. We excluded patients who awakened within 6 h of arrest, those who arrested due to trauma or neurological event, those with nonsurvivable primary brain injury and those with refractory shock. Our primary exposure of interest was high-dose benzodiazepine (>10 mg of midazolam equivalents per day) administration in the first 72-h post arrest. Our primary outcome was time to awakening. We used Cox regression to test for an independent association between exposure and outcome after controlling for biologically plausible covariates. ResultsOverall, 2778 patients presented during the study period, 621 met inclusion criteria and 209 (34%) awakened after a median of 4 [IQR 3–7] days. Patients who received high-dose benzodiazepines awakened later than those who did not (5 [IQR 3–11] vs. 3 [IQR 3–6] days, P = 0.004). In adjusted regression, high-dose benzodiazepine exposure was independently associated with delayed awakening (adjusted hazard ratio 0.63 (95% CI 0.43–0.92)). Length of stay, awakening to discharge, and duration of mechanical ventilation were similar across groups. ConclusionHigh-dose benzodiazepine exposure is independently associated with delayed awakening in comatose survivors of cardiac arrest.

Effect of medication on risk of traumatic brain injury in patients with bipolar disorder: A nationwide population-based cohort study.

Increased traumatic brain injury (TBI) risk was found in patients with bipolar disorder (BPD). Whether the medications for BPD and dosage moderate the risk of TBI is not clear. This study aimed to determine whether an association exists between BPD and TBI and whether the prescription of psychotropics moderates TBI risk. A total of 5606 individuals who had received diagnoses of BPD between January 1, 1997 and December 31, 2013 and 56,060 matched controls without BPD were identified from Taiwan's National Health Insurance Research Database. Cases and controls were followed until the date of TBI diagnosis. BPD was associated with a high risk of TBI (adjusted hazard ratio (aHR): 1.85; 95% CI: 1.62-2.11). Patients with BPD, with or without a history of psychiatric hospitalization, had increased risks of TBI (aHR: 1.94, 95% CI: 1.57-2.4 and aHR: 1.82, 95% CI: 1.55-2.1, respectively). The prescription of typical antipsychotics (0 < defined daily dose (DDD) < 28: hazard ratio (HR) = 1.52, 95% CI: 1.19-1.94; ⩾28 DDD: HR = 1.54, 95% CI: 1.15-2.06) and tricyclic antidepressants (TCAs) (0 < DDD < 28: HR = 1.73, 95% CI: 1.26-2.39; ⩾28 DDD: HR = 1.52, 95% CI: 1.02-2.25) was associated with higher TBI risk. Patients receiving higher doses of benzodiazepines (BZDs) (cumulative dose ⩾28 DDD) had a higher TBI risk (HR = 1.53, 95% CI: 1.13-2.06). Patients with BPD have a higher risk of TBI. The use of typical antipsychotics, TCAs, or high-dose BZDs increases the risk of TBI in BPD.