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Purpose
High-dose benzodiazepines (BZDs) abuse has been documented to cause multidomain cognitive dysfunction. We explored whether cognitive abnormalities to high-dose BZD abuse might be reversed by detoxification with slow subcutaneous infusion of flumazenil.
Methods
We recruited 96 patients consecutively admitted to the Department of Internal Me...
Context in source publication
Context 1
... group of 50 age, sex, and education-matched healthy subjects not assuming BZDs served as controls (24 men, 26 women; age 44.5 ± 12.8 years, median 44; education 13.1 ± 3.4 years, median 13; n.s. for all comparisons vs. patients). Baseline demographic variables in patients and controls are shown in Table 1. ...Similar publications
Introduction: The use of novel designer drugs has increased worldwide over the years. Etizolam is a designer benzodiazepine (BZD) that has raised concern because of its growing non-medical use, liability to tolerance and dependence, and related harms. Studies exploring the abuse liability and cognitive effects of etizolam outside the therapeutic do...
Citations
... The variables that can affect the effectiveness of the FLU are: the duration and dose of exposure to BZD: higher is the tolerance and more effective the FLU is. In Italy, for some years now, the Verona unit of Addiction Medicine applies the treatment with slow infusion FLU in cases of chronic abuse of high doses of BZD [17,18]. The treatment allows to suspend quickly (7-8 days) very high doses of BZD (400 mg diazepam-equivalent, the median dose daily abuse of some cases) well tolerated and with little effect collateral [19]. ...
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
... Regarding the effects of flumazenil application after midazolam anesthesia on brain function, we can only speculate. However, it is known that cognitive abnormalities can significantly be ameliorated after benzodiazepine use by slow subcutaneous infusion of flumazenil [38] and that flumazenil administration attenuates cognitive impairment [38]. Therefore, flumazenil use might be effective in reducing POD. ...
... Regarding the effects of flumazenil application after midazolam anesthesia on brain function, we can only speculate. However, it is known that cognitive abnormalities can significantly be ameliorated after benzodiazepine use by slow subcutaneous infusion of flumazenil [38] and that flumazenil administration attenuates cognitive impairment [38]. Therefore, flumazenil use might be effective in reducing POD. ...
Midazolam is a widely used short-acting benzodiazepine. However, midazolam is also criticized for its deliriogenic potential. Since delirium is associated with a malfunction of the neurotransmitter acetylcholine, midazolam appears to interfere with its proper metabolism, which can be triggered by epigenetic modifications. Consequently, we tested the hypothesis that midazolam indeed changes the expression and activity of cholinergic genes by acetylcholinesterase assay and qPCR. Furthermore, we investigated the occurrence of changes in the epigenetic landscape by methylation specific PCR, ChiP-Assay and histone ELISA. In an in-vitro model containing SH-SY5Y neuroblastoma cells, U343 glioblastoma cells, and human peripheral blood mononuclear cells, we found that midazolam altered the activity of acetylcholinesterase /buturylcholinesterase (AChE / BChE). Interestingly, the increased expression of the buturylcholinesterase evoked by midazolam was accompanied by a reduced methylation of the BCHE gene and the di-methylation of histone 3 lysine 4 and came along with an increased expression of the lysine specific demethylase KDM1A. Last, inflammatory cytokines were not induced by midazolam. In conclusion, we found a promising mechanistic link between midazolam treatment and delirium, due to a significant disruption in cholinesterase homeostasis. In addition, midazolam seems to provoke profound changes in the epigenetic landscape. Therefore, our results can contribute to a better understanding of the hitherto poorly understood interactions and risk factors of midazolam on delirium.
... When compared to placebo, bolus infusion of flumazenil (1 mg in 5 min) produced effects similar to BZD withdrawal in BZD users (23,26). Nonetheless, results of studies in chronic BZD users who have discontinued BZD use suggest that multiple slow bolus infusions of flumazenil reduce the symptoms of withdrawal (9,11,21,27). ...
An effective approach in the treatment of benzodiazepine (BZD) overdosing and detoxification is flumazenil (FLU). Studies in chronic users who discontinued BZD in a clinical setting suggested that multiple slow bolus infusions of FLU reduce BZD withdrawal symptoms. The aim of this study was to confirm FLU efficacy for reducing BZD withdrawal syndrome by means of continuous elastomeric infusion, correlated to drugs plasma level and patients' compliance.
Methods: Seven-day FLU 1 mg/day subcutaneously injected through an elastomeric pump and BZDs lormetazepam, clonazepam, and lorazepam were assessed by HPLC-MS/MS in serum of patients before and after 4 and 7 days of FLU continuous infusion treatment. Changes in withdrawal severity were assessed by using the BZD Withdrawal Scale (BWS).
Results: Fourteen patients (mean age ± SD 42.5 ± 8.0 years, 5 male and 9 female), admitted to the hospital for high-dose BZD detoxification, were enrolled in the study. Serum FLU concentrations significantly decreased from 0.54 ± 0.33 ng/ml (mean ± SD) after 4 days of treatment to 0.1 ± 0.2 ng/ml at the end of infusion. Lormetazepam concentrations were 502.5 ± 610.0 ng/ml at hospital admission, 26.2 ± 26.8 ng/ml after 4 days, and 0 at the end of treatment. BWS values decreased during FLU treatment temporal period. FLU was well-tolerated by patients.
Conclusions: Elastomeric FLU infusion for BZD detoxification is a feasible administration device to maintain adequate, constant, and tolerated FLU concentrations for reducing BZD withdrawal symptoms.
... When compared to placebo, bolus infusion of flumazenil (1 mg in 5 min) produced effects similar to BZD withdrawal in BZD users (23,26). Nonetheless, results of studies in chronic BZD users who have discontinued BZD use suggest that multiple slow bolus infusions of flumazenil reduce the symptoms of withdrawal (9,11,21,27). ...
... Etizolam negatively influenced most of the cognitive domains in the patient who underwent neuropsychological testing, in particular working memory, visuospatial memory, and executive function, some of them being <2 SDs worse than normal values. This finding, despite being preliminary since stemming from a single patient, extends the notion that high doses of BZDs have an impact on cognition, even in younger patients (13,24). BZDs cognitive side effects have been suggested to be related to the function of the GABA-A receptor α1 (responsible for anterograde amnesia) and the α5 subunits, which are involved in cognition, learning and memory (25). ...
Introduction: The use of novel designer drugs has increased worldwide over the years. Etizolam is a designer benzodiazepine (BZD) that has raised concern because of its growing non-medical use, liability to tolerance and dependence, and related harms. Studies exploring the abuse liability and cognitive effects of etizolam outside the therapeutic doses are lacking.
Aims: To explore the abuse liability of etizolam and the characteristics of patients affected by etizolam high-dose dependence in a nationwide tertiary referral addiction unit. To document the cognitive changes to etizolam high-dose use.
Design and Methods: Sociodemographic and clinical data on subjects with etizolam high-dose use were retrospectively collected from a database of 1,293 patients consecutively admitted to the Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZDs or Z-drugs dependence. Thorough neuropsychological testing explored the cognitive side effects of high-dose etizolam use.
Results: We found eleven etizolam high-dose users, of which eight used etizolam only, and three used etizolam with other BZDs/zolpidem. All the patients were prescribed etizolam for medical reasons, i.e., anxiety and/or insomnia. Neuropsychological evaluation showed deficits of working memory, visuospatial memory and executive function in a 27-year-old woman who used etizolam 15 mg daily.
Discussion: Our findings suggest that abuse and dependence liability of etizolam should be considered a public health and social problem. They offer preliminary evidence on the cognitive side effects of etizolam high-dose use.
Conclusions: This report offers new information on the potential harms of etizolam in patients who are prescribed this drug for medical reasons.
Zolpidem is indicated in cases of severe insomnia in adults and, as for BDZs, its assumption should be limited to short periods under close medical supervision. Since several drugs cause corrected QT interval (QTc) elongation, the authors investigated whether high daily doses of Zolpidem could cause QTc elongation. The study was conducted in the Addiction Medicine Unit of the G.B. Rossi University Hospital in Verona. The data were collected from hospitalizations carried out between January 2015 and February 2020 and refer to a total of 74 patients, 38 males and 36 females, who were treated for detoxification from high doses of Zolpidem with the “Verona Detox Approach With Flumazenil.” One patient out of 74 had QTc elongation (479 ms). The patient was male and took a daily dose of 50 mg of Zolpidem; he did not take concomitant therapies that could cause QTc lengthening. He had no electrolyte alterations, no contemporary or previous intake of barbiturates, heroin, cocaine, THC, alcohol, NMDA or nicotine which could cause an elongation of the QTc interval. The present study highlights the low risk of QTc elongation due to high dosages of Zolpidem; however, if, on one hand, we can affirm that Zolpidem is a safe drug, on the other, the widespread use of high dosages of this drug for prolonged periods of time is problematic and worrying.
