Figure - uploaded by Elisa Mantovani
Content may be subject to copyright.
Source publication
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...
Context in source publication
Citations
... 1,2 Etizolam-associated adverse effects include drowsiness, sedation, and slurred speech. 3 Toxicities observed have included CNS depression, ataxia, dysarthria, and respiratory depression. 4 Withdrawal symptoms include palpitations, poor sleep, agitation, and tremors. 2 Etizolam is most commonly ingested as an oral tablet, although powder, sublingual, liquid, blotting paper, and insufflated formulations have been reported. ...
... 5 Therapeutic doses range from 0.25 to 2 mg daily with a maximum of 3 mg daily. 2, 3 Etizolam is approximately 6 to 10 times more potent than diazepam for most pharmacologic effects. Clinical studies 1,2,6 suggest that etizolam is about 10 times more potent Q 2022 AAPP. ...
Background
The availability of nonapproved psychoactive substances with addiction potential from internet sources poses a significant threat to public health. Polysubstance abuse or inadvertent contamination of preparations may result in clinically challenging intoxication and withdrawal syndromes.
Case Report
We report a case of a 32-year-old male with an approximate 2-year history of taking internet-obtained etizolam and tianeptine who presented to the hospital following an overdose. He experienced subsequent withdrawal symptoms consistent with benzodiazepine and opioid withdrawal. Initial attempts at managing symptoms with chlordiazepoxide 25 mg every 6 hours did not relieve his symptoms. On day 3 of admission, addiction medicine was consulted and his regimen was changed to diazepam 80 mg daily with additional as-needed diazepam based on etizolam equivalence. He also received a 5-day methadone taper with plans to transition to buprenorphine in the outpatient setting. Upon discharge he was referred to an addiction medicine specialist who was willing to continue a slow diazepam taper and initiate medications for opioid use disorder to manage both substance use disorders.
Discussion
This case report demonstrates the effectiveness of diazepam in managing benzodiazepine withdrawal from etizolam while concurrently using methadone to manage opioid withdrawal symptoms from tianeptine in a hospitalized patient following overdose. We highlight the importance of a warm handoff in considering the outpatient discharge plan.
... However, data concerning side effects outside these therapeutic dose ranges remain poorly investigated. Only one study conducted in order to document the cognitive changes to etizolam high-dose use has been published [18]. In this one, Tamburin et al. offered preliminary evidence on the cognitive side effects of high-dose etizolam use reporting deficits of working memory, visuospatial memory, and executive function in a 27-year-old woman who has used 15 mg of etizolam daily [18]. ...
... Only one study conducted in order to document the cognitive changes to etizolam high-dose use has been published [18]. In this one, Tamburin et al. offered preliminary evidence on the cognitive side effects of high-dose etizolam use reporting deficits of working memory, visuospatial memory, and executive function in a 27-year-old woman who has used 15 mg of etizolam daily [18]. Moreover, there is also very little data on clinical features observed in etizolam overdose cases. ...
During the last decade, only few cases of acute etizolam intoxication have been detailed. Little is known about the toxic effects of etizolam overdose. Here, the authors report the case of a 42-year-old man who was admitted to the emergency department for intense agitation following etizolam and cocaine consumption. Detection and determination of etizolam and cocaine (including metabolites) were achieved using liquid chromatography tandem mass spectrometry. Etizolam and benzoyecgonine (BZE) were detected in plasma at 64 and 10 ng/mL, respectively. The level of cocaine was below the limit of quantification (< 5 ng/mL). To the authors’ knowledge, the only report detailing an etizolam overdose was provided by O’Connell et al. and was characterized by the presence of central nervous system (CNS) depression signs. Interestingly, here, there were no signs of CNS depression but only signs of CNS excitation. With regard to cocaine and BZE plasma concentrations, the clinical presentation cannot be only explained by the co-consumption of cocaine. It may be hypothesized that the clinical presentation was related to a paradoxical reaction to etizolam overdose. To date, no case of paradoxical excitation related to etizolam use has been reported in adults. The case presented here appears particularly interesting, given the limited data relating to high-dose etizolam toxicity.
... In two placebo-controlled studies in which therapeutic doses of etizolam were administered, no significant differences were found in tests of attention, shortterm and working memory, psychomotor coordination or speed in decision-making (4,5). The effects of etizolam following high-dose administration have not been published; however, some concern has been raised with regard to highdose dependence (6). For example, in a retrospective review of patients admitted to an addiction medicine unit in Italy for benzodiazepine dependence, 11 patients were taking daily dosages of etizolam ranging from 5 to 100 mg (median: 15 mg) (6). ...
... The effects of etizolam following high-dose administration have not been published; however, some concern has been raised with regard to highdose dependence (6). For example, in a retrospective review of patients admitted to an addiction medicine unit in Italy for benzodiazepine dependence, 11 patients were taking daily dosages of etizolam ranging from 5 to 100 mg (median: 15 mg) (6). These patients were prescribed the drug for either anxiety and/or a sleep disorder; however, these dosages far exceed the recommended maximum daily dose. ...
... These patients were prescribed the drug for either anxiety and/or a sleep disorder; however, these dosages far exceed the recommended maximum daily dose. One patient, taking 15 mg/day etizolam, underwent a neuropsychological evaluation, and decrements were reported in both memory and executive functioning (6). ...
Although not used clinically in North America, etizolam has been identified in forensic samples as an illicit, “designer” benzodiazepine. Having central nervous system (CNS) depressant effects, analysis for etizolam has probative value in both death investigations and in forensic cases where incapacitation or human psychomotor performance are relevant. This report examines toxicological findings and demographic data in a series of authentic forensic cases analyzed between November 2019 and December 2020 in which etizolam was quantified by LC-MS/MS analysis. Blood concentrations were determined in 191 individuals aged 1 to 75 years. In living individuals (i.e., impaired driving, sexual assaults), etizolam concentrations ranged from < 5 ng/mL to 767 ng/mL which overlapped with the range of < 5 ng/mL to 260 ng/mL reported in death investigations. In all but one case, other drugs were detected in combination with etizolam. Fentanyl was the most common co-occurring drug and was present in 164 cases (86%). Additional case details are provided for cases of forensic interest: two deaths involving children under three years of age, two deaths involving body-packing, and an individual arrested for drug-impaired driving with, to our knowledge, the highest reported etizolam concentration to date.
... Experimental findings have shown that FLU acts as a BZD partial agonist with a weak intrinsic activity, when administered by slow intravenous infusion. While withdrawal symptoms may be brought on by the use of FLU, BZD-tolerant patients only reported mild symptoms (14,15). ...
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.
... Experimental findings have shown that FLU acts as a BZD partial agonist with a weak intrinsic activity, when administered by slow intravenous infusion. While withdrawal symptoms may be brought on by the use of FLU, BZD-tolerant patients only reported mild symptoms (14,15). ...
For the past 60 years, benzodiazepines such as chlordiazepoxide, diazepam, and alprazolam have been used as pharmaceutical medications for the treatment of myriad conditions including anxiety, seizures, and insomnia. In more recent years, novel benzodiazepine derivatives have emerged as illicit substances in powders and counterfeit tablets on the illicit drug market. In 2016, bromazolam, a brominated derivative of alprazolam, emerged on the illicit drug market in Europe, but the substance was not reported in the USA until 2019-2020. In this study, we report the emergence and subsequent prevalence of bromazolam in postmortem blood in the state of Indiana during 2023. Analysis was completed by a solvent protein precipitation extraction with acetonitrile and detection by liquid chromatography with quadrupole time of flight mass spectrometry. During 2023, bromazolam was detected in 94 cases across 25 counties in Indiana. It was never the sole substance detected and was commonly detected alongside fentanyl (83 cases), norfentanyl (77 cases), 4-anilino-N-phenethylpiperidine (76 cases), acetylfentanyl (49 cases), methamphetamine (32 cases), naloxone (25 cases), 11-nor-9-carboxy-tetrahydrocannabinol (24 cases), and benzoylecgonine (20 cases). After official query with the Indiana Department of Health, it was found that bromazolam was specifically included in the cause of death certification in 31 fatalities (32.9%). Due to the scarcity of information regarding this novel benzodiazepine derivative in postmortem toxicology and its involvement in fatalities, it is important that forensic toxicology laboratories consider adding bromazolam to their comprehensive scope of analysis.
Background:
The standard approach for benzodiazepine detection often includes immunoassay followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The illicit use of non-prescribed benzodiazepines has been trending up nationally.
Methods:
We developed and validated an improved LC-MS/MS assay for benzodiazepine detection in urine. We expanded the testing panel by adding five drugs to the previous panel of ten. We determined the prevalence of individual benzodiazepines in our patient population. Immunoassay results were compared with LC-MS/MS to evaluate assay performance.
Results:
Clonazepam and alprazolam were the most common benzodiazepines present. Etizolam and flualprazolam were also prevalent in Washington State. Compared with the LC-MS/MS assay, the immunoassay had variable cross-reactivity, which explained false negative and false positive immunoassay results. The inclusion of new drugs in the LC-MS/MS panel significantly reduced the incidence of immunoassay results interpreted as falsely positive.
Conclusion:
New illicit benzodiazepines have emerged regionally and nationally. The inclusion of novel drugs in LC-MS/MS assay was helpful in properly characterizing the epidemiology of benzodiazepine use in our patient population. This information will lead to better assay result interpretations and patient care, and our experiences provide a roadmap for other clinical laboratories looking to expand their testing menu or transition to new instrumentation.
Neuroinflammation occurs in the acute phase of spinal cord injury (SCI) and inhibits neural regeneration. In mouse models, etizolam (ETZ) is a strong anxiolytic with unclear effects on SCI. This study investigated the effects of short-term administration of ETZ on neuroinflammation and behavior in mice after SCI. We administrated an ETZ (0.5 mg/kg) daily intraperitoneal injection from the day after SCI for 7 days. Mice were randomly divided into three groups (sham group: only laminectomy, saline group, and ETZ group). Inflammatory cytokine concentrations in the injured spinal cord epicenter were measured using an enzyme-linked immunosorbent assay on day 7 after SCI to evaluate spinal cord inflammation in the acute phase. Behavior analysis was performed the day before surgery and on days 7, 14, 28, and 42 after surgery. The behavioral analysis included anxiety-like behavior using the open field test, locomotor function using the Basso Mouse Scale, and sensory function using the mechanical and heat test. Inflammatory cytokine concentrations were significantly lower in the ETZ group than in the saline group in the acute phase after spinal surgery. After SCI, anxiety-like behaviors and sensory functions were comparable between the ETZ and saline groups. ETZ administration reduced neuroinflammation in the spinal cord and improved locomotor function. Gamma-amino butyric acid type A receptor stimulants may be effective therapeutic agents for patients with SCI.
Sedative hypnotics are medications that cause suppression of the central nervous system by primarily working through GABA agonism. The classes of medications that constitute this category are benzodiazepines and non-benzodiazepine receptor agonists. These medications are utilized for their potential treatments for a variety of conditions including anxiety, fear, insomnia, panic attacks, seizures, restless leg syndrome, sedation and alcohol withdrawal. These classes of medications have considerable side effects that need to be taken into account upon administration and require careful monitoring, specifically in regard to diverse patient characteristics such as baseline renal and hepatic function and also when used concomitantly with other medications that produce sedation through similar and synergistic mechanisms. This adverse event (AE) profile is generally well understood but continued use offers further insights for careful administration. A review of the 2020 publications provides further insight to contribute to the currently available literature. Additional review can be found in previous SEDA publications (Haghparast et al., 2020) [R].
