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.

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.

COVID-19 vaccination and drug users: Past, present, and future.

Vaccination against COVID-19 is crucial in the attempt of containing the virus' spread, but facing a viral pathogen with such a high prevalence means that vaccination strategies are facing an unprecedented situation. People that use illicit drugs may have elevated risk of adverse outcomes from COVID-19 given their high prevalence of underlying medical conditions, including respiratory and pulmonary disease, chronic liver disease, cardiovascular and cerebrovascular conditions, diabetes, and compromised immune systems. Despite a widespread distribution on the Italian territory, a large presence of health personnel and a long-standing experience in vaccinations, addiction clinics have yet to be involved in the vaccination campaign against COVID-19. The aim of this study was to investigate the beliefs of drug users attending some Italian addiction clinics, in order to envisage any vaccine administration strategies involving the services themselves. A questionnaire used for the Italian general population to investigate the relative importance of some factors in influencing the propensity to vaccinate against COVID-19, was administrated to drug users in a multicenter survey. The majority of respondents expressed general confidence in vaccines and a good willingness to undergo vaccination. Given strong peer networks, high coverage of treatment and harm reduction interventions, Italian public addiction clinics could play a strategic role in administering the vaccine in this hard-to-reach population, usefully aiding the global campaign against the virus.

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.

Alter Game: A Study Protocol on a Virtual "Serious Game" for Relapse Prevention in Patients With Gambling Disorder.

Cognitive behavioral therapy (CBT) is the most successful protocol in gambling disorder (GD) treatment. However, it presents some weaknesses, especially concerning relapse prevention (RP). RP is one of the most important therapeutic steps, aiming at managing cravings and to avoid future relapse increasing perceived self-efficacy. Encouraging results come from the blending of psychotherapy and virtual reality (VR), containing gambling cues. The goal of Alter Game (approved by the Ethical Commission, Prot. No. 69346) is verifying the efficacy of an innovative psychological treatment for GD based on the integration of traditional CBT therapy and an immersive VR cue exposure therapy using a serious virtual game, which is a game designed for purposes other than entertainment. RP in virtual cue-exposure therapy allows pathological gamblers to manage the urge to gamble and to avoid relapse by becoming aware of which internal and external triggers are related to craving. We hypothesize that the integrated intervention will be more effective than simple CBT with regard to self-efficacy, craving, and gambling-related distortions. Four virtual ecological environments were developed, and a virtual app, Exludo, interfaced with a computerized multiparametric acquisition system for biofeedback, was created. A sample of about 60 patients aged between 18 and 65 with GD referring to the Addiction Medicine Unit of Verona (Rossi Hospital) will be recruited. Patients will be randomly assigned to the CBT group (16 CBT sessions) or the CBT + VR group (8 CBT sessions + 8 VR cue-exposure therapy sessions). The MCMI-III, the BIS-11, and the SOGS will be used to evaluate inclusion and exclusion criteria, while the Gambling Related Cognitions Scale and the Multidimensional Gambling Self-Efficacy Scale will be used to verify changes as a function of the treatment. Craving will be evaluated through VAS, and psychophysiological variables will be assessed through biofeedback. A pre-test/post-test experimental design with a 1-month follow-up will be conducted. This study will examine an innovative psychotherapeutic protocol for GD treatment, and it will help in identifying new virtual tools to increase the efficacy of traditional therapeutic approaches that could also be applied to treat other addictions.

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.

Benzodiazepines in sport, an underestimated problem: Recommendations for sports medicine physicians' practice.

In the last years, only few studies in literature have focused on the use and abuse of benzodiazepines (BZDs) in sport. Benzodiazepine-related problems include misuse, addiction, driving impairments, and morbidity and mortality related to overdose and withdrawal. Two clinical cases regarding elite endurance athletes evidenced that they had started to use BZDs to counteract insomnia, to recover faster from training sessions and to manage muscle pain. One of the important points that emerged from their stories was that their sports doctors did not recognize the drugs' addictive properties, and did not intervene to gradually reduce the dosage. Experts have previously provided recommendations for BZD therapy management in clinical practice. In this article, we would like to address sports medicine physicians specifically and provide guidelines to help them manage situations involving BZD prescription, the recognition of addiction, and intervention strategies.

The effect of benzodiazepines on exercise in healthy adult participants: A systematic review.

The use of benzodiazepines among athletes is a new and growing phenomenon according to the recent case reports published. Therefore, there is an urgent need to identify if there is rationale for the use of benzodiazepines and its effects on exercise. This review aims to provide an overview of the effects of benzodiazepine in exercise among healthy adult participants and if they might have an additional ergogenic or ergolytic effect. Electronic searches were conducted in Pubmed, Scopus and Web of Science databases up to December 2020. Search terms covered all active substance names of benzodiazepine class and search terms about sport, exercise performance and athletes. We used the Physiotherapy Evidence Database (PEDro) to assess the methodological quality of the studies included in the qualitative synthesis. The methods and planned analyses of this systematic review were pre-registered at Open Science Framework (OSF: https://osf.io/uq6j8). A total of thirty-one full articles were assessed for eligibility and ten of them were included in the qualitative analysis. We found 7 studies which investigated benzodiazepine effects after an acute dose administered, whereas only 3 studies studied long-term effects after several doses used. According to our findings it does not seem that benzodiazepines might have an ergogenic or ergolytic effect on exercise performance. The small number of articles included (n = 10) with a relatively low sample of participants (N = 16, range = 6-58) does invite us to take our results with caution. This review evidences valuable insights into the use of benzodiazepines from a physical performance point of view. Our findings highlight the unclear effects benzodiazepines might have on exercise performance and its possible mechanisms of actions. Hence, the need to conduct new studies to understand its possible effects becomes essential to protect the health of athletes of all levels.

The Effectiveness of Cognitive Behavioral Therapy Techniques for the Treatment of Substance Use Disorders: A Narrative Review of Evidence.

ABSTRACT: Substance use disorders (SUDs) are characterized by a recurrent and maladaptive use of drugs and/or alcohol. Cognitive behavioral therapies (CBTs) comprise different types of interventions: traditional CBT and the more recent "third wave" behavior therapies, such as acceptance and commitment therapy (ACT), dialectical behavior therapy (DBT), mindfulness-based cognitive therapy (MBCT), and schema therapy (ST). We searched English-language articles published between 2014 and present. This review includes randomized controlled trials (RCTs), quasi-RCTs, pilot studies, and reviews of CBTs for SUDs available on PubMed. Results seem to indicate that CBT and MBCT are effective interventions for SUDs; however, the studies showed a high degree of heterogeneity, so no exhaustive conclusions could be outlined at this time. ACT and DBT in SUD management are limited to few studies and results are therefore inconclusive.

Continuous Infusion of Flumazenil in the Management of Benzodiazepines Detoxification.

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.

ASRS Questionnaire and Tobacco Use: Not Just a Cigarette. A Screening Study in an Italian Young Adult Sample.

Young adults exhibit greater sensitivity than adults to nicotine reinforcement, and Attention Deficit Hyperactivity Disorder (ADHD) increases the risk for early-onset smoking. We investigated the correlation between ADHD Self-Report Scale (ASRS) scores and smoking, evaluated the prevalence of ADHD symptomatology (not diagnoses) in smokers and non-smokers and its comorbidity with benzodiazepine and gambling addictions. A total of 389 young adults from 14 schools in Northern Italy fill out a survey and the Adult ADHD Self-Report Scale (ASRS). A total of 15.2% of subjects tested positive at the ASRS, which correlated with smoking; moreover, smokers had twice the probability of testing positive at the ASRS. ADHD symptomatology, especially when comorbid with tobacco abuse, is an important condition to monitor because early nicotine exposure could be a gateway for other addictive behaviors.

COVID-19 lockdown: Impact on online gambling, online shopping, web navigation and online pornography.

Background: The COVID-19 pandemic and control measures may have had an impact on unpleasant emotions experimented during the lockdown (LD). This may have increased the number of hours spent online and could have impacted the quality of the enacted behavior, in terms of loss of control of Internet use. In this online survey, we were interested in measure how much loss of control was perceived regarding online gambling, online shopping, the fruition of online pornographic content and web navigation. Design and methods: The online survey was carried out during the COVID-19 pandemic in the post-lockdown and 1232 subjects participated in the survey. In the participating sample, healthcare workers (HW) were 43.1% of the sample, of which 18.7% were directly involved in the Coronavirus emergency, and 52.3% of the sample is not a HW. Only 0.6% of the sample gambled online and 37.5% of those reported losing control of their gambling mode. Most of the sample shopped online during the LD (70.1%), but only 7.2% of those lost control by buying and/or spending more than what they had set themselves. Results: Significant data emerged showing that those who lost control while online shopping also lost control regarding the amount of time spent online (p<0.001); 21.6% of the sample, reported making use of online pornographic material during LD, 4.7% of them stated that the frequency increased and 5.1% reported losing control by having spent more money or more time than what was intended. Finally, 44.7% of the sample have experienced loss of control during the web navigation. Furthermore, during the LD 67.8% of the sample reports having experienced unpleasant emotions. Of these, 8.4% state that they enacted behaviors such as online gambling, online shopping, online pornographic material viewing and web navigation to counter their negative emotions. Interestingly, we found a correlation between loss of control during web navigation and online shopping and the emotional states "upset", "scared" and "restless" (p<0.05). Conclusion: To conclude, there was no significant increase in potentially addictive behaviors, nor an increase in loss of control of these behaviors when enacted online. However, the loss of control in online shopping and web navigation was significantly correlated to the unpleasant emotional states of nervousness, fear and restlessness, whereas those who reported feeling strong and able to handle the situation experienced a lower loss of control in their web navigation. These correlations may suggest that these online behaviors may act as modulators of unpleasant emotional states.

Internet Addiction and Related Clinical Problems: A Study on Italian Young Adults.

The considerable prominence of internet addiction (IA) in adolescence is at least partly explained by the limited knowledge thus far available on this complex phenomenon. In discussing IA, it is necessary to be aware that this is a construct for which there is still no clear definition in the literature. Nonetheless, its important clinical implications, as emerging in recent years, justify the lively interest of researchers in this new form of behavioral addiction. Over the years, studies have associated IA with numerous clinical problems. However, fewer studies have investigated what factors might mediate the relationship between IA and the different problems associated with it. Ours is one such study. The Italian version of the SCL-90 and the IAT were administered to a sample of almost 800 adolescents aged between 16 and 22 years. We found the presence of a significant association between IA and two variables: somatization (ß = 7.80; p < 0.001) and obsessive-compulsive symptoms (ß = 2.18; p < 0.05). In line with our hypothesis, the results showed that somatization predicted the relationship between obsessive-compulsive symptoms and IA (ß = -2.75; t = -3.55; p < 0.001), explaining 24.5% of its variance (ΔR 2 = 1.2%; F = 12.78; p < 0.01). In addition, simple slopes analyses revealed that, on reaching clinical significance (+1 SD), somatization showed higher moderation effects in the relationship between obsessive-compulsive symptoms and IA (ß = 6.13; t = 7.83; p < 0.001). These results appear to be of great interest due to the absence of similar evidence in the literature, and may open the way for further research in the IA field. Although the absence of studies in the literature does not allow us to offer an exhaustive explanation of these results, our study supports current addiction theories which emphasize the important function performed by the enteroceptive system, alongside the more cited reflexive and impulsive systems.

Association between Adult Attention Deficit/Hyperactivity Disorder and Intravenous Misuse of Opioid and Benzodiazepine in Patients under Opioid Maintenance Treatment: A Cross-Sectional Multicentre Study.

BACKGROUND: Intravenous misuse and attention-deficit/hyperactivity disorder (ADHD) are common in patients under opioid maintenance treatment (OMT), who often misuse benzodiazepine (BZD). OBJECTIVES: To explore the rate of adult ADHD among patients under OMT in Italy and whether screening positive for adult ADHD is associated with OMT and BZD misuse and emergency room (ER) admission because of misuse. METHODS: We recruited 1,649 patients from 27 addiction units (AUs) in Italy and collected data on the self-reported rate of OMT intravenous misuse (prevalence, repeated misuse, main reason, temporal pattern in relation to AU access, experience), concurrent intravenous and intranasal BZD misuse (prevalence, type of misused BZD), ADHD and ER admissions because of misuse complications. RESULTS: Screening positive for adult ADHD was found in 11.2% patients (ADHD+), with a significant gender difference (women: 15.3%, men: 10.3%). OMT misuse was reported by 24.4 and 18.5% patients during lifetime and in the previous 6 months respectively. BZD misuse was reported by 20.0 and 8.6% patients for intravenous and intranasal route respectively. Misuse was significantly more common in ADHD+ (OMT 27.4-33.1%, BZD 14.5-31.5%) than ADHD- group (OMT 17.4-23.3%, BZD 7.9-18.3%). The multivariate logistic regression model showed positive screening for ADHD to be significantly associated with intravenous OMT misuse in the previous 6 months, and intravenous/intranasal BZD misuse, independently of age, gender and route of previous heroin administration. CONCLUSIONS: Screening positive for adult ADHD was associated with OMT and BZD misuse. AU physicians and medical personnel should focus on OMT patient's features that are associated with a higher likelihood of misuse, in particular ADHD.