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Croatian Medical Journal Apr 2024To review the literature data on the prevalence of benzodiazepines abuse and poisoning in older adults; the prevalence of polypharmacy with benzodiazepines in this... (Review)
Review
AIM
To review the literature data on the prevalence of benzodiazepines abuse and poisoning in older adults; the prevalence of polypharmacy with benzodiazepines in this demographic; and determine whether benzodiazepine anxiolytics or hypnotics were more frequently implicated in the cases of abuse and poisoning.
METHODS
We searched PubMed and Scopus for relevant studies published from January 1, 2013, to May 1, 2023. Twelve studies were included in the final selection.
RESULTS
The review highlights the diverse prevalence rates of benzodiazepine abuse and poisoning in the older adult population. Benzodiazepine anxiolytics were more frequently associated with negative outcomes than benzodiazepine hypnotics. Concurrent use of benzodiazepines, benzodiazepine-related medications, and opioids was reported, although these medications were not the only ones commonly used by the elderly.
CONCLUSION
It is essential to increase awareness about adhering to prescribed pharmacological therapies to mitigate issues related to drug abuse and poisoning among older adults.
Topics: Humans; Benzodiazepines; Sleep Initiation and Maintenance Disorders; Aged; Hypnotics and Sedatives; Substance-Related Disorders; Polypharmacy; Prevalence; Aged, 80 and over; Anti-Anxiety Agents
PubMed: 38706240
DOI: 10.3325/cmj.2024.65.146 -
MMWR. Morbidity and Mortality Weekly... Aug 2021Nonfatal and fatal drug overdoses increased overall from 2019 to 2020 (1).* Illicit benzodiazepines (e.g., etizolam, flualprazolam, and flubromazolam) were increasingly...
Nonfatal and fatal drug overdoses increased overall from 2019 to 2020 (1).* Illicit benzodiazepines (e.g., etizolam, flualprazolam, and flubromazolam) were increasingly detected among postmortem and clinical samples in 2020, often with opioids, and might have contributed to overall increases in drug overdoses. Availability of recent multistate trend data on nonfatal benzodiazepine-involved overdoses and involvement of illicit benzodiazepines in overdoses is limited. This data gap was addressed by analyzing annual and quarterly trends in suspected benzodiazepine-involved nonfatal overdoses treated in emergency departments (EDs) (benzodiazepine overdose ED visits) during January 2019-December 2020 (32 states and the District of Columbia [DC]) and benzodiazepine-involved overdose deaths (benzodiazepine deaths), which include both illicit and prescription benzodiazepines, during January 2019-June 2020 (23 states) from CDC's Overdose Data to Action (OD2A) program. From 2019 to 2020, benzodiazepine overdose ED visits per 100,000 ED visits increased (23.7%), both with opioid involvement (34.4%) and without (21.0%). From April-June 2019 to April-June 2020, overall benzodiazepine deaths increased 42.9% (from 1,004 to 1,435), prescription benzodiazepine deaths increased 21.8% (from 921 to 1,122), and illicit benzodiazepine deaths increased 519.6% (from 51 to 316). During January-June 2020, most (92.7%) benzodiazepine deaths also involved opioids, mainly illicitly manufactured fentanyls (IMFs) (66.7%). Improving naloxone availability and enhancing treatment access for persons using benzodiazepines and opioids and calling emergency services for overdoses involving benzodiazepines and opioids, coupled with primary prevention of drug use and misuse, could reduce morbidity and mortality.
Topics: Adolescent; Adult; Aged; Benzodiazepines; District of Columbia; Drug Overdose; Female; Humans; Male; Middle Aged; United States; Young Adult
PubMed: 34437522
DOI: 10.15585/mmwr.mm7034a2 -
International Journal of Methods in... Dec 2021A 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... (Review)
Review
OBJECTIVES
A 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.
METHODS
A 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.
RESULTS
Multiples 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.
CONCLUSION
High-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.
Topics: Benzodiazepines; Humans; Prevalence
PubMed: 34331787
DOI: 10.1002/mpr.1888 -
Ugeskrift For Laeger Jun 2022In this case report we describe a life-threatening episode of delirium in a 51-year-old man. The condition was triggered by an abrupt withdrawal of benzodiazepines. The...
In this case report we describe a life-threatening episode of delirium in a 51-year-old man. The condition was triggered by an abrupt withdrawal of benzodiazepines. The patient had been taking multiple sedatives for several years but a large proportion of the drugs were not available in Denmark. His general practitioner substituted and prescribed oxazepam and zolpidem for ten days. Afterwards the patient did not have access to benzodiazepines and developed a severe benzodiazepine withdrawal delirium. He was treated with diazepam and olanzapine with gradual dose reduction.
Topics: Alcohol Withdrawal Delirium; Benzodiazepines; Delirium; Diazepam; Humans; Male; Middle Aged; Oxazepam; Substance Withdrawal Syndrome
PubMed: 35703059
DOI: No ID Found -
Research in Social & Administrative... Apr 2022Deprescribing of medications such as benzodiazepines and benzodiazepine receptor agonists (z-drugs) can be a complex process that varies across practices, specialties,...
Deprescribing of medications such as benzodiazepines and benzodiazepine receptor agonists (z-drugs) can be a complex process that varies across practices, specialties, and health care systems. Care coordination among healthcare providers, patients, families, and other healthcare system components is critical to achieving high levels of deprescribing and person-centered care. We present a framework for promoting care coordination in the context of benzodiazepine/z-drug deprescribing. Future efforts are needed to study the impact of better care coordination on benzodiazepines/z-drug discontinuation and other outcomes that are important to stakeholders.
Topics: Benzodiazepines; Deprescriptions; Humans; Receptors, GABA-A
PubMed: 34229951
DOI: 10.1016/j.sapharm.2021.06.025 -
Basic & Clinical Pharmacology &... Jan 2023Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare...
Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000-2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55-78% of BZ use in 2020, followed by BZ sedatives at 20-44%, BZ-hypnotics at <1-5%, and clonazepam at <1-2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups-despite warnings against their use in this population.
Topics: Adult; Humans; Aged, 80 and over; Benzodiazepines; Clonazepam; Scandinavian and Nordic Countries; Hypnotics and Sedatives; Sweden
PubMed: 36314353
DOI: 10.1111/bcpt.13811 -
Journal of Natural Products May 2022An EtOAc extract of leaves led to an allosteric potentiation of the GABA signal in a fluorometric imaging plate reader (FLIPR) assay on Chinese hamster ovary (CHO)... (Review)
Review
An EtOAc extract of leaves led to an allosteric potentiation of the GABA signal in a fluorometric imaging plate reader (FLIPR) assay on Chinese hamster ovary (CHO) cells stably expressing GABA receptors with an αβγ subunit composition. The activity was tracked by HPLC-based activity profiling, and four known (, , , and ) and five new clerodane-type diterpenoids (, -, and ) were isolated. Compounds - were obtained from the active time window. The absolute configuration of all compounds was established by ECD. Compounds , , and exhibited EC values of 0.5, 4.6, and 1.4 μM, respectively. To explore possible binding sites at the receptor, the most abundant diterpenoid was tested in combination with diazepam, etazolate, and allopregnanolone. An additive potentiation of the GABA signal was observed with these compounds, while the effect of was not inhibited by flumazenil, a negative allosteric modulator at the benzodiazepine binding site. Finally, the activity was validated in voltage clamp studies on oocytes transiently expressing GABA receptors of the αβγS and αβ subtypes. Compound potentiated GABA-induced currents with both receptor subunit compositions [EC (αβγS) = 43.6 μM; = 809% and EC (αβ) = 57.6 μM; = 534%]. The positive modulation of GABA-induced currents was not inhibited by flumazenil, thereby confirming an allosteric modulation independent of the benzodiazepine binding site.
Topics: Animals; Benzodiazepines; CHO Cells; Casearia; Cricetinae; Cricetulus; Diterpenes, Clerodane; Flumazenil; GABA Modulators; Oocytes; Receptors, GABA-A; Xenopus laevis; gamma-Aminobutyric Acid
PubMed: 35475609
DOI: 10.1021/acs.jnatprod.1c00840 -
British Journal of Anaesthesia Mar 2022Buprenorphine is a partial agonist at the mu opioid receptor. Due to its relatively low maximum effect on respiratory depression it is considered by some to be a safe...
Buprenorphine is a partial agonist at the mu opioid receptor. Due to its relatively low maximum effect on respiratory depression it is considered by some to be a safe opioid. But it can produce serious respiratory depression, particularly when combined with sedatives such as benzodiazepines.
Topics: Analgesics, Opioid; Benzodiazepines; Buprenorphine; Humans; Receptors, Opioid, mu; Respiratory Insufficiency
PubMed: 34996591
DOI: 10.1016/j.bja.2021.12.001 -
Clinical Journal of the American... Jun 2020Mortality from benzodiazepine/opioid interactions is a growing concern in light of the opioid epidemic. Patients on hemodialysis suffer from a high burden of...
BACKGROUND AND OBJECTIVES
Mortality from benzodiazepine/opioid interactions is a growing concern in light of the opioid epidemic. Patients on hemodialysis suffer from a high burden of physical/psychiatric conditions, which are treated with benzodiazepines, and they are three times more likely to be prescribed opioids than the general population. Therefore, we studied mortality risk associated with short- and long-acting benzodiazepines and their interaction with opioids among adults initiating hemodialysis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
The cohort of 69,368 adults initiating hemodialysis (January 2013 to December 2014) was assembled by linking US Renal Data System records to Medicare claims. Medicare claims were used to identify dispensed benzodiazepines and opioids. Using adjusted Cox proportional hazards models, we estimated the mortality risk associated with benzodiazepines (time varying) and tested whether the benzodiazepine-related mortality risk differed by opioid codispensing.
RESULTS
Within 1 year of hemodialysis initiation, 10,854 (16%) patients were dispensed a short-acting benzodiazepine, and 3262 (5%) patients were dispensed a long-acting benzodiazepine. Among those who were dispensed a benzodiazepine during follow-up, codispensing of opioids and short-acting benzodiazepines occurred among 3819 (26%) patients, and codispensing of opioids and long-acting benzodiazepines occurred among 1238 (8%) patients. Patients with an opioid prescription were more likely to be subsequently dispensed a short-acting benzodiazepine (adjusted hazard ratio, 1.66; 95% confidence interval, 1.59 to 1.74) or a long-acting benzodiazepine (adjusted hazard ratio, 1.11; 95% confidence interval, 1.03 to 1.20). Patients dispensed a short-acting benzodiazepine were at a 1.45-fold (95% confidence interval, 1.35 to 1.56) higher mortality risk compared with those without a short-acting benzodiazepine; among those with opioid codispensing, this risk was 1.90-fold (95% confidence interval, 1.65 to 2.18; <0.001). In contrast, long-acting benzodiazepine dispensing was inversely associated with mortality (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.99) compared with no dispensing of long-acting benzodiazepine; there was no differential risk by opioid dispensing (=0.72).
CONCLUSIONS
Codispensing of opioids and short-acting benzodiazepines is common among patients on dialysis, and it is associated with higher risk of death.
Topics: Age Factors; Aged; Analgesics, Opioid; Benzodiazepines; Delayed-Action Preparations; Drug Interactions; Drug Prescriptions; Female; Humans; Kidney Failure, Chronic; Male; Medicare Part D; Middle Aged; Mortality; Proportional Hazards Models; Renal Dialysis; Sex Factors; Time Factors; United States
PubMed: 32457228
DOI: 10.2215/CJN.13341019 -
Neurobiology of Disease Sep 2023Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical...
Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAR subunit composition, there was a redistribution of extrasynaptic GABARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.
Topics: Mice; Animals; Diazepam; Alcoholism; Substance Withdrawal Syndrome; Receptors, GABA-A; Benzodiazepines; Brain; Synapses; gamma-Aminobutyric Acid; Synaptic Transmission
PubMed: 37536384
DOI: 10.1016/j.nbd.2023.106248