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.

Case Report: High doses of Zolpidem and QT interval lengthening: Is there a relationship? A case series.

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.

A virtual reality craving study in tobacco addiction: The role of non-pharmacological support in tobacco detox therapy.

Nicotine addiction is a widespread, worldwide epidemic, causing six million deaths per year. A large variety of treatments for smoking cessation are currently available, including Cytisine, which is a promising drug due to its low cost and high safety levels. Notwithstanding the important amount of research on tobacco addiction treatments, smoking remains one of the most difficult substance use disorders to treat, probably also due to the fact that pharmacological treatment often overlooks other maintaining factors in this addiction, such as sensory impact and cue reactivity. To address this gap in both treatment protocols and scientific literature, we propose a study protocol in which we will compare the effects of combining Cytisine with Nirdosh, a herbal tobacco substitute, to Cytisine only in two groups of patients (C + N and C) who will also undergo exposure to four different virtual reality settings that will assess the importance of environmental cues. We will further assess mood and craving in the two samples, and include a control group taken from the general population. We expect the C + N group to report a more positive mood and a lower sensitivity to tobacco-related environmental cues.

Cytisine induced urticaria : a case report during a smoking cessation treatment.

Cytisine is considered to be the oldest medication for smoking cessation and has been used for this purpose in some Eastern/Central European and Central Asian countries for over 50 years. Several sources points towards cytisine's efficacy and effectiveness; it's well tolerated when taken at the recommended dose, and adverse events reported in trials are typically non-serious and self-limiting gastrointestinal and sleep disturbances. We report a suspect case of urticaria during treatment for smoking cessation with cytisine in a woman of 48 years treated for smoking at the Unit of Addiction Medicine, Department of Internal Medicine, Hospital Trust of Verona, Italy.  The therapeutic protocol of cytisine that was used is of the "inductive" type; it consists in gradually increasing the daily capsules taken, with a parallel reduction in the number of cigarettes smoked until complete cessation between the fifth and ninth day of therapy (quit day) The number of capsules taken is then gradually reduced. She was treated for the firsts three days with betamethasone 1 mg/die, on the advice of her general practitioner, and suspended Cytisine. A week later the patient showed signs of recovery.

Addiction of High Dose of Benzodiazepine: Verona Detox Approach With Flumazenil.

Introduction: Since the 1990s there has been evidence of the significant role Flumazenil (FLU) has in benzodiazepines (BZD) detoxes. The Verona Detox approach has been developed for high dose BZD and Z-drug detoxification via continuous subcutaneous infusion of FLU, a selective BZD receptor antagonist acting on the BZD subunit of the GABA-A receptor. Flumazenil is licensed in the United Kingdom and other countries to treat only BZD overdose although numerous studies have demonstrated its effectiveness in rapidly resetting GABA-A receptors, quickly reducing tolerance and dependence from BZD, and providing a safe and rapid detox from benzodiazepines. Objective: The aim of this article is to provide all healthcare professional who are interested in BZD detoxification with an approach and clear practical information on how to administer FLU. Method: In this article we outline the approach in detail, describing all medical and nursing procedures day by day. This detox treatment is indicated for patients abusing from at least 5 Defined Daily Dose (DDD) of BZDs or Z-drugs. The process lasts 7 days, and is conducted under medical supervision (daily reviews) and continuous nursing (24/7). During this period, 7mg of FLU is administered (1 mg/24) through an elastomeric pump, via continuous subcutaneous infusion. Conclusion: To this day, the largest database of FLU detoxification was published by our group, showing how this treatment is safe, with very little side effects even in patients with significant medical comorbidities.

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.

Mono- and poly-therapy with benzodiazepines or Z-drugs: Results from a tertiary-care Addiction Unit study.

BACKGROUND: Using benzodiazepines (BZDs) or Z-drugs in poly-therapy is a critical issue. OBJECTIVE: Identifying factors influencing the use of BZDs/Z-drugs in poly- vs mono-therapy in patients with or without substance use disorders (SUDs). METHODS: 986 inpatients were analysed. Socio-demographic and clinical variables were collected. BZD/Z-drug doses were compared via the Defined Daily Dose (DDD) and standardized as diazepam dose equivalents. Mann-Whitney, Chi-square, Fisher test, hierarchical multivariate regression analyses were run referring to the whole sample and to subjects with current SUDs, lifetime SUDs, current and lifetime SUDs, non-SUDs. RESULTS: In the whole sample the variance of being mono- vs poly-therapy users was explained by BZD/Z-drug formulation, DDD, duration of treatment, age of first BZDs/Z-drugs use (ΔR2 = 0.141, p < 0.001). Among those with current SUDs (ΔR2 = 0.278, p = 0.332) or current and lifetime SUDs (ΔR2 = 0.154, p = 0.419), no variables explained the variance of being mono-vs poly-therapy users. Among lifetime SUDs subjects, the variance of being mono- vs poly-therapy users was explained by BZD/Z-drug formulation and age of first BZD/Z-drug use (ΔR2 = 0.275, p < 0.001). Among non-SUDs subjects, the variance of being mono- vs poly-therapy users was explained by DDD and duration of treatment (ΔR2 = 0.162, p = 0.001). CONCLUSIONS: Tablets, high drug doses, long duration of treatment, and early age of first use were more likely associated to poly- than mono-therapy. This suggests that patients have different clinical features and a pharmacological prescription should be tailored to them also based on the variables here analysed.

Adult attention-deficit/hyperactivity disorder symptoms, cognitive dysfunction and quality of life in high-dose use of benzodiazepine and Z-drug.

High-dose use of benzodiazepines (BZDs) and Z-drugs was found to be associated with adult attention deficit/hyperactivity disorder (ADHD) and multidomain cognitive deficits, but the interplay between these factors and its effect on quality of life (QoL) is unclear. We explored (a) whether cognitive dysfunction differs in high-dose BZD/Z-drug users with and without adult ADHD and (b) the impact of cognitive deficits and adult ADHD on QoL in this substance-use disorder (SUD). From January 2015 to December 2019, we recruited 207 high-dose BZD/Z-drug users seeking treatment. We assessed the presence of adult ADHD with a screening tool, which was validated in SUD patients, and collected demographic, clinical and QoL data from the 76 included patients. A neuropsychological battery explored five cognitive domains. We found that: (a) screening for adult ADHD was frequently positive; (b) Short Form-36 (SF-36), a self-administered QoL questionnaire, was worse than the general population and worse in patients positive (ADHD+) vs. those negative (ADHD-) to ADHD screening tool; (c) executive function was significantly worse in ADHD+ than ADHD- patients; (d) some SF-36 dimensions were negatively influenced by executive dysfunction; (e) multivariate analysis showed an interplay between adult ADHD and cognitive dysfunction in worsening QoL. We documented a complex interplay between adult ADHD, cognitive dysfunction and QoL in high-dose BZD/Z-drug users. Assessing adult ADHD, neuropsychological measures and QoL may offer a full scenario of these patients, who are frequently impaired in everyday activities. Future research should explore whether pharmacological treatment might improve cognitive dysfunction and QoL in this SUD.

Can oral formulation increase the risk of lormetazepam abuse?

The slowness of dripping and the presence of alcohol have been offered/suggested as possible causes for the increased risk of developing dependence to the oral formulation of lormetazepam rather than to other anxiolytic and hypnotic drugs. We hence assessed the time of dripping of the most used benzodiazepines and z-drugs oral solution products under experimental conditions and the different employed excipients through a comparative analysis of the Summaries of Product Characteristics. A wide range of the median overall dispensing time was found across the eight products included in the analysis. Among the products containing LMZ, Minias® ranked in the fourth position, while LMZ Mylan Generics® and Noctamid® in the sixth and third, respectively. Our data suggest that the pace of dripping and the presence of alcohol cannot be considered themselves the cause that triggered the abuse of lormetazepam. More precisely, the quantity of alcohol per bottle has been found negligible at therapeutic doses; however, when these are exceeded, they may have clinical implications for patients. Further studies are needed to assess them. Meanwhile, the public-health problem remains and some improvements should be carried out at different levels, to guarantee the appropriate prescription and use of lormetazepam oral solution.

High-Dose Dependence and Cognitive Side Effects to Medical Prescription of Etizolam.

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.

Detoxification Improves Multidomain Cognitive Dysfunction in High-Dose Benzodiazepine Abusers.

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 Medicine, Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZD dependence. After selection for inclusion and exclusion criteria, 50 patients (23 men, 27 women; age 42.7 ± 10.3 years) were included. They underwent a comprehensive neuropsychological battery to explore verbal memory, visuospatial memory, working memory, attention, and executive functions 28-30 days prior to admission for detoxification (T0) and at the end of detoxification, i.e., 7 days after admission (T1). A group of 50 healthy adults (24 men, 26 women; mean age 44.5 ± 12.8 years) matched for age, sex, and education served as controls. RESULTS: At T0, patients scored significantly worse than healthy controls in all the neuropsychological tests. Depression and anxiety scores were associated with impaired verbal memory at T0 in patients. T1-T0 comparison showed improved performances in all neuropsychological tests after the end of detoxification in patients. CONCLUSION: We confirmed that all neuropsychological domains were significantly and profoundly impaired by high-dose BZD abuse and documented that cognitive abnormalities improved after detoxification with slow subcutaneous infusion of flumazenil.

Adult Attention-Deficit/Hyperactivity Disorder and Quality of Life in High-Dose Benzodiazepine and Related Z-Drug Users.

BACKGROUND: Problematic high-dose benzodiazepine (BZD) and related Z-drug use for a long period is a substance use disorder previously found to be associated with adult attention-deficit/hyperactivity disorder (ADHD) and worse quality of life (QoL). Whether adult ADHD impacts QoL in high-dose BZD/Z-drug users has not been explored. AIM: The aim of the study was to explore the impact of adult ADHD on QoL in high-dose BZD and related Z-drug users. METHODS: We recruited 393 patients (205 men and 188 women) consecutively admitted to the Department of Medicine, Addiction Medicine Unit, Verona University Hospital, Italy, from July 2016 to July 2019 for detoxification from high-dose BZD or Z-drug dependence. Demographic and clinical variables and QoL measures were recorded. The World Health Organization ADHD Self-Report Scale version 1.1 Symptom Checklist Part A was used to detect adult ADHD. RESULTS: In our sample, 39.4% of patients were positive to adult ADHD testing (ADHD+), with some clinical features differing in comparison to patients negative to ADHD testing (ADHD-). QoL was worse in high-dose BZD/Z-drug users than the general population. The ADHD+ group showed significantly worse QoL measures than the ADHD- group. Multivariate analysis, including potential covariates showed adult ADHD and age to have the most robust and consistent positive effect for age (i.e., higher QoL) and negative effect for ADHD (i.e., lower QoL) on QoL measures. CONCLUSIONS: Adult ADHD is associated with worse QoL measures in high-dose BZD/Z-drug users. Future studies should explore whether appropriate BZD/Z-drug detoxification might improve QoL measures and whether the most appropriate detoxification protocol differs in ADHD+ versus ADHD- populations.

Zolpidem high-dose abuse: what about the liver? Results from a series of 107 patients.

Objectives: Z-Drugs (ZDs) have been developed to limit benzodiazepines (BZDs) abuse for sleep disorders. Data on the liver toxicity of zolpidem (ZLM) are lacking or anecdotal. The authors evaluated the presence of drug-induced liver injury (DILI) among a cohort of high-dose ZLM abusers. Methods: Retrospective study analyzing clinical records of 1112 consecutive patients admitted for BZDs detoxification from 2003 to 2018. Inclusion criteria: age >18 y.o.; ZLM abuse/dependence; high-dose ZDs abuse. Exclusion criteria: missing lab data; lack of informed consent. Main outcome was the presence of DILI measured as elevation of ALT/AST levels >250 U/l. Results: A total of 107 patients met the eligibility criteria. Liver enzymes alterations were present in 9.3% (95% CI 4.6-16.5%); one patient (0.9%, 95% CI 0.0-2.8%) showed DILI criteria. BMI significantly influenced transaminases levels. No correlations between duration nor doses of ZLM abuse and transaminases levels were found. Conclusion: The present study shows a very low prevalence of DILI among high-dose ZLM abusers. The prevalence of hypertransaminasemia was in line with general population. On one hand ZLM has a substantially safe liver profile but on the other hand ZLM abuse and dependence, especially at very high doses, represents an emerging problem.

High-dose lormetazepam dependence: strange case of Dr. Jekyll and Mr. Hyde.

High-dose benzodiazepine (BZD) abuse is emerging as a substance use disorder (SUD). The aim of the study is to explore the impact of high-dose lormetazepam (LMZ) abuse and the characteristics of patients affected by this SUD in a tertiary referral addiction unit. We have retrospectively evaluated 1112 patients admitted to the Addiction Medicine Unit, Verona University Hospital, Italy for detoxification from high-dose BZD dependence. LMZ was the most common BZD, with an increasing prevalence from January 2003 to June 2018. Socio-demographic (more women; higher age and education) and clinical features (higher daily diazepam dosage equivalent, BZD abuse duration, age of first BZD intake; BZD prescribed more frequently for sleep disorders; less frequent history of other SUDs, previous/active alcohol, previous opioids abuse; more frequent overall major psychiatric diseases and major depression; less-frequent bipolar disorders and other psychoses, personality disorders, and more than one psychiatric disease) of LMZ vs. other BZD abusers significantly differed. 96.7% LMZ abusers took oral solution, while two-thirds of other BZD abusers took tablets. Oral solution, BZD abuse duration and prescription of BZD for sleep disorders increased, while history of other SUDs, previous/active alcohol and active cannabinoids SUD reduced the risk of high-dose LMZ vs. other BZDs abuse. The large prevalence of high-dose LMZ abusers in Italy may be strongly related to the availability and characteristics of oral formulation that may transform the innocuous Dr. Jekyll tablets into an evil Mr. Hyde. Restriction to the market of LMZ oral formulation might reduce the risk of high-dose abuse.

Does high-dose benzodiazepine abuse really produce liver toxicity? Results from a series of 201 benzodiazepine monoabusers.

BACKGROUND: Several side-effects related to prolonged benzodiazepines (BZD) use have been reported. Given the primary role of liver in BZD metabolism, toxicity related to prolonged high-dose BZD use could be conceivable. No data are available on the long-term impact of high-dose BZD use on liver. RESEARCH DESIGN AND METHODS: A total of 201 BZD mono-abusers admitted to an Addiction Unit for detoxification were evaluated. Liver enzymes were evaluated at admission, before starting any treatment. An elevation of more than five times the upper limit of normal range (ULN) in serum ALT or conjugated bilirubin, or a combined elevation of AST, alkaline phosphatase and total bilirubin, one of which exceeding >2 the ULN, was considered diagnostic for drug-induced liver injury. RESULTS: None of the evaluated subjects showed significant alterations of liver enzymes. Those with the highest transaminase levels were showing high body mass index. Twenty patients (10%) showed elevated gamma-glutamyl-transferase. No alteration of alkaline phosphatase, nor bilirubin was found in any patient. The average dosage of BZD was 307 mg of diazepam-equivalents for 7 years. CONCLUSIONS: Present data suggest that prolonged use of high-dose BZD, although very dangerous for several reasons, does not seem to produce a significant drug-induced liver injury.

Screening for adult attention deficit/hyperactivity disorder in high-dose benzodiazepine dependent patients.

BACKGROUND AND OBJECTIVES: Adult attention-deficit/hyperactivity disorder (ADHD) is frequent in patients with substance use disorders (SUD), but information on its prevalence in high-dose benzodiazepine (BZD) dependence is lacking. We estimated the prevalence of adult ADHD in a group of treatment-seeking high-dose BZD dependent patients according to a valid screening tool, and explored the demographic and clinical characteristics of patients that screened positive for ADHD (ADHD+) in comparison to those that screened negative (ADHD-). METHODS: We prospectively recruited 167 consecutive patients with high-dose BZD dependence and screened them for adult ADHD with the World Health Organization Adult ADHD Self-Report Scale version 1.1 (ASRS-v1.1) Symptom Checklist Part A. We compared demographic and clinical characteristics in ADHD+ and ADHD- groups. RESULTS: Fifty-three patients (31.7% of the sample) were positive to adult ADHD screening. ADHD+ patients showed a significantly larger prevalence of poly-drug abuse than ADHD- ones. BZD formulation and active principle significantly differed between the two groups. The other clinical variables, including psychiatric comorbidity, as well as the demographic ones, did not differ in ADHD+ versus ADHD- comparison. DISCUSSION AND CONCLUSIONS: Adult ADHD may be common in treatment-seeking high-dose BZD dependent patients according to ASRS-v1.1 Symptom Checklist Part A. SCIENTIFIC SIGNIFICANCE: Screening for ADHD in this type of SUD with this questionnaire is quick and may offer useful information for prognosis and treatment. (Am J Addict 2017;26:610-614).

Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence.

High-dose benzodiazepine (BZD) dependence represents an emerging and under-reported addiction phenomenon and is associated with reduced quality of life. To date there are no guidelines for the treatment of high-dose BZD withdrawal. Low-dose slow flumazenil infusion was reported to be effective for high-dose BZD detoxification, but there is concern about the risk of convulsions during this treatment. We evaluated the occurrence of seizures in 450 consecutive high-dose BZD dependence patients admitted to our unit from April 2012 to April 2016 for detoxification with low-dose slow subcutaneous infusion of flumazenil associated with routine anticonvulsant prophylaxis. In our sample, 22 patients (4.9%) reported history of convulsions when previously attempting BZD withdrawal. Only four patients (0.9%) had seizures during ( n = 2) or immediately after ( n = 2) flumazenil infusion. The two patients with seizures during flumazenil infusion were poly-drug misusers. The most common antiepileptic drugs (AEDs) used for anticonvulsant prophylaxis were either valproate 1000 mg or levetiracetam 1000 mg. Our data indicate that, when routinely associated with AEDs prophylaxis, low-dose slow subcutaneous flumazenil infusion represents a safe procedure, with low risk of seizure occurrence.

Determinants of Quality of Life in High-Dose Benzodiazepine Misusers.

Benzodiazepines (BZDs) are among the most widely prescribed drugs in developed countries, but they have a high potential for tolerance, dependence and misuse. High-dose BZD misuse represents an emerging addiction phenomenon, but data on quality of life (QoL) in high-dose BZD misusers are scant. This study aimed to explore QoL in high-dose BZD misuse. We recruited 267 high-dose BZD misusers, compared the QoL scores in those who took BZD only to poly-drug misusers, and explored the role of demographic and clinical covariates through multivariable analysis. Our data confirmed worse QoL in high-dose BZD misusers and showed that (a) QoL scores were not negatively influenced by the misuse of alcohol or other drugs, or by coexisting psychiatric disorders; (b) demographic variables turned out to be the most significant predictors of QoL scores; (c) BZD intake significantly and negatively influenced QoL. Physical and psychological dimensions of QoL are significantly lower in high-dose BZD misusers with no significant effect of comorbidities. Our data suggest that the main reason for poor QoL in these patients is high-dose BZD intake per se. QoL should be considered among outcome measures in these patients.