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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...
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Citations
... Failure to adhere to recommendations and contraindications in the product label can occur in patients at risk of drug-drug interactions, patients with certain pre-existing medical conditions, or patients who are at a high risk for treatment-related adverse events (74,75). For instance, high-dose use of BZDs and ZDs were found to be associated with attention deficit hyperactivity disorder (ADHD) (103), and use of high dose levels of long-acting BZDs, short-acting BZDs and Z-drugs were all found to significantly increase the risk of fall-related injuries requiring hospitalization in people aged 65 years and older (104). Due to the increased risk of falls, care is recommended when using BZDs in elderly subjects (27). ...
Chronic insomnia occurs in ~10% of the general population and has numerous negative health effects. The recommended first line treatment of cognitive behavior therapy for insomnia is not widely available for patients in Europe, so pharmacotherapies such as benzodiazepine receptor agonist agents (benzodiazepines and Z-drugs) are commonly used. However, their use is only recommended for ≤4 weeks due to unproven long-term efficacy in treatment of chronic insomnia, and the risk of tolerance, and the potential for dependence and misuse. In Europe, recommendations limiting the use of benzodiazepines (lowest dose and shortest duration) in chronic insomnia are not always followed, likely due to the lack of approved effective alternative therapies. Here we present a recent pilot survey of the pharmacological treatment landscape in chronic insomnia in five European countries (France, Germany, Italy, Spain, and the United Kingdom) and physicians’ attitude toward treatment. The results suggest that benzodiazepines and Z-drugs are the most widely used treatments in chronic insomnia and are being used for longer than their recommended duration. Country variations in prescription rates were observed. Due to the known association between long-term benzodiazepine use and potential for developing dependence, further analysis of the literature was performed on the use and misuse of benzodiazepines. The results show that long-term use of benzodiazepines is associated with multiple consequences of treatment, including dependence, but also that previous use of benzodiazepines may increase the risk of opioid use disorder.
... There were many studies among patients with alcohol use disorder over the years, showing similar results with a high ADHD prevalence (about 20%) [25,[29][30][31][32][33]. Recent studies in patients with benzodiazepine use disorder show even higher ADHD prevalence rates, which lie between 31% [34] and 39% [35,36], but there are also studies in populations of patients with cocaine use disorder showing high ADHD prevalence between 14% [37] and 20% [38]. Thus, people with adult ADHD might adjust their substance abuse to their most disruptive ADHD symptoms. ...
(1) Background: Attention deficit hyperactivity disorder (ADHD) is a common comorbid condition in opioid use disorder (OUD) and is associated with a more severe course of substance use. Patients with severe OUD who have not responded to oral opioid maintenance treatment can be treated with intravenous diamorphine up to three times per day. Here, we investigated the prevalence of ADHD among patients undergoing either daily diamorphine maintenance treatment or daily oral opioid maintenance treatment. (2) Methods: We assessed all participants with the WURS-k and the ADHD-SR. The Diagnostic Interview for ADHD in Adults (DIVA) was performed with all participants who met the cut-off in the WURS-k and/or ADHD-SR. (3) Results: The overall prevalence of ADHD was 17.9%. Prevalence of ADHD among patients undergoing daily diamorphine maintenance treatment was 14.3%. Prevalence of ADHD among patients undergoing daily oral opioid maintenance treatment was 20.3%. The combined presentation of ADHD was the most prevalent condition. In urine samples of participants with comorbid ADHD, heroin was detected the most and cocaine the least frequently. (4) Conclusions: Almost one out of five patients with OUD suffered from comorbid ADHD. In 83.3%, ADHD had not been diagnosed prior to participation in this study. Thus, patients with SUD could benefit from being routinely screened for ADHD.
... Then, among all patients prescribed any benzodiazepines, the aim was to report the dose, the percentage of patients prescribed long-term benzodiazepines, the percentage with a benzodiazepine dose reduction, and the percentage switched to longacting benzodiazepines. Although patients taking higher dosages of benzodiazepines may tolerate larger reductions better than patients taking lower dosages (15), definitions of high dose range from .10 mg to .50 mg diazepam-equivalent daily dose (EDD) (16)(17)(18)(19). Dose reduction and switch to long-acting benzodiazepines are important because clinical guidelines recommend that patients discontinue long-term benzodiazepine use by gradual tapering combined with this switch (20). ...
Objective:
Although long-term benzodiazepine use is not recommended, patients are often prescribed benzodiazepines for >30 days (long-term use). Data from the Veterans Health Administration (VHA) may inform efforts to discontinue such use. This study sought to describe benzodiazepine use and discontinuation among VHA patients and compared patients who continued and discontinued use.
Methods:
The study used nationwide electronic health record data for all VHA-enrolled patients (age ≥18) from fiscal year (FY) 2019 (N=6,032,613). The primary outcome, benzodiazepine discontinuation, was defined as no prescription refill for 120 days.
Results:
In FY2019, 3.5% of VHA enrollees were prescribed benzodiazepines for >30 days, which was 72.0% of those prescribed benzodiazepines. One-third of veterans prescribed long-term benzodiazepines discontinued use. Continuation was more likely among patients who were older, not Black, taking benzodiazepines longer, and taking higher doses. When demographic factors were controlled, patients who continued long-term use were more likely to have a diagnosis of anxiety, posttraumatic stress disorder (PTSD), bipolar disorder, or psychosis and less likely to have depression or an alcohol or drug use disorder. Continuation was associated with a lower likelihood of sleep and cardiopulmonary disorders and of dementia.
Conclusions:
Higher discontinuation prevalence among patients with substance use disorders, dementia, or cardiopulmonary disorders is encouraging. However, the challenge remains of discontinuing long-term use among patients who are White, older, or diagnosed as having anxiety, PTSD, bipolar disorder, or psychosis. There is a need to identify provider, patient, and contextual factors driving long-term benzodiazepine use in these patient groups to effectively apply evidence-based discontinuation strategies.
... Our vision, as a natural consequence of several decades of experience in the study and treatment of smoking and SUDs, which in recent years has increasingly involved the evaluation of the impact of adult ADHD on all behaviors of abuse [28,46,47], leads us to summarize the problem of the relationship between ADHD, smoking, and SUDs, in the following key points: ...
Attention-deficit hyperactivity disorder (ADHD) is a widespread neurodevelopmental disorder in children and adolescents, persisting into adulthood in a majority of them. The discovery of the persistence of ADHD into adolescence and adulthood has progressively oriented the interest of researchers towards the study of its implications for the development of different forms of psychological distress. Comorbidity between ADHD and other disorders is particularly frequent, especially for internalizing and externalizing disorders. Also, ADHD and substance use disorders (SUDs) commonly co-occur in adult population. It has not yet been clarified to what extent ADHD pharmacological treatment contributes to the development of SUDs. On the contrary, treating ADHD patients with methylphenidate may reduce their risk for SUD. Adolescents exhibit greater sensitivity than adults to nicotine reinforcement, and ADHD increases the risk for early-onset smoking. ADHD, especially when comorbid with tobacco abuse, is an important condition to monitor, because an early nicotine exposure could be the gateway to other addictive behaviors. Early-onset SUD is associated with elevated rates of risk behaviors and poor outcomes, including, but not limited to, suicidal behavior, academic failure, and job failure. Neuropsychiatrists dealing with ADHD should carefully monitor the possible copresence of ADHD and nicotine, in an attempt to prevent the development of SUD and other behavioral problems in these high-risk young patients.
... The association was especially notable for major depression and anxiety disorders in a recent systematic review and metaanalysis. 7 The preference for zolpidem in patients who screened positive for adult attention-deficit/hyperactivity disorder (ADHD) in the study of Lugoboni et al. 8 could be explained, at least in part, by its paradoxical effects (stimulants) in the context of self-medication, as ADHD is treated by amphetaminic drugs and cocaine is known to relieve ADHD symptoms. 9 Even if benzodiazepines and related benzodiazepines include different medications, we can assume that the abuse and dependence of these substances are similar to "communicating vessels." ...
... Country of the study Asia and Australia (n = 7) Harnod et al., 2015;Hata et al., 2018;Kim et al., 2017;Rintoul et al., 2013;Takeshima et al., 2016;Tien et al., 2020;Wen et al., 2014 Canada (n = 3) Egan et al., 2001;Sketris et al., 1985;Sullivan & Sellers, 1992 France (n = 2) Etchepare et al., 2016;Imbert et al., 2016 Germany (n = 4) Brinkers et al., 2016;Holzbach et al., 2010;Janhsen et al., 2015;Kaendler et al., 1996 BeNeLux (n = 2) Cloos et al., 2015;Voshaar et al., 2003 Mediterranean Europe (n = 12) Faccini et al., 2016Faccini et al., , 2019Federico et al., 2020Federico et al., , 2017Lekka et al., 1997Lekka et al., , 2002Lugoboni et al., 2020Lugoboni et al., , 2014Lugoboni et al., , 2018Martinez-Cano et al., 1996;Quaglio et al., 2012;Tamburin et al., 2017 Scandinavia (n = 12) Andenaes et al., 2016;Bajwah et al., 2018;Bjerrum et al., 1994;Fredheim et al., 2019Fredheim et al., , 2020Fride Tvete et al., 2015;Johansson et al., 2003;Neutel et al., 2012;Nordfjaern et al., 2014Nordfjaern et al., , 2013Sidorchuk et al., 2018;Vorma et al., 2003 South America (n = 1) Moreno-Gutíerrez et al., 2020 ...
... Switzerland (n = 4) Liebrenz, Schneider et al., 2015;Liebrenz et al., 2016aLiebrenz et al., , 2016b UK (n = 2) Perera & Jenner, 1987;Seivewright & Dougal, 1993 USA (n = 7) Conry et al., 2009;Ellinwood et al., 1990;Hanlon et al., 2009;Hermos et al., 2007Hermos et al., , 2005Kroll et al., 2016;Soumerai et al., 2003 Not applicable (n = 2) Alexander & Perry, 1991;Teboul & Chouinard, 1991 Type of study Systematic review (n = 5) Alexander & Perry, 1991;Brinkers et al., 2016;Janhsen et al., 2015;Kim et al., 2017;Teboul & Chouinard, 1991 Randomized controlled trial (n = 2) Conry et al., 2009;Ellinwood et al., 1990 Epidemiological study (n = 13) Andenaes et al., 2016;Bajwah et al., 2018;Egan et al., 2001;Etchepare et al., 2016;Federico et al., 2017;Hanlon et al., 2009;Harnod et al., 2015;Holzbach et al., 2010;Johansson et al., 2003;Nordfjaern et al., 2014Nordfjaern et al., , 2013Rintoul et al., 2013;Soumerai et al., 2003 National or large registry (n = 9) Cloos et al., 2015;Fredheim et al., 2019Fredheim et al., , 2020Fride Tvete et al., 2015;Moreno-Gutíerrez et al., 2020;Neutel et al., 2012;Sidorchuk et al., 2018;Takeshima et al., 2016;Wen et al., 2014 Local register (n = 8) Bjerrum et al., 1994;Faccini et al., 2016;Federico et al., 2020;Hata et al., 2018;Hermos et al., 2007;Lugoboni et al., 2020Lugoboni et al., , 2014Tamburin et al., 2017; Selected patients (n = 20) Faccini et al., 2019;Hermos et al., 2005;Imbert et al., 2016;Kaendler et al., 1996;Kroll et al., 2016;Lekka et al., 1997Lekka et al., , 2002Liebrenz, Schneider et al., 2015;Liebrenz et al., 2016aLiebrenz et al., , 2016bLugoboni et al., 2018;Martinez-Cano et al., 1996;Perera & Jenner, 1987;Quaglio et al., 2012;Seivewright & Dougal, 1993;Sullivan & Sellers, 1992;Tien et al., 2020;Vorma et al., 2003;Voshaar et al., 2003 Selected physicians (n = 1) Sketris et al., 1985 Length of follow-up Less than 3 months (n = 4) Andenaes et al., 2016;Bjerrum et al., 1994;Ellinwood et al., 1990;Etchepare et al., 2016 3 months to 1 year (n = 16) Conry et al., 2009;Egan et al., 2001;Faccini et al., 2016;Federico et al., 2017;Holzbach et al., 2010;Johansson et al., 2003;Quaglio et al., 2012;Seivewright & Dougal, 1993;Lekka et al., 1997;Lugoboni et al., 2014, Neutel et al., 2012Perera & Jenner, 1987;Sketris et al., 1985;Tamburin et al., 2017;Vorma et al., 2003;Wen et al., 2014 (Continues) CLOOS ET AL. ...
... More than 1 year (n = 30) Bajwah et al., 2018;Cloos et al., 2015;Faccini et al., 2019;Fredheim et al., 2019Fredheim et al., , 2020Fride Tvete et al., 2015;Hanlon et al., 2009;Harnod et al., 2015;Hata et al., 2018;Hermos et al., 2007Hermos et al., , 2005Imbert et al., 2016;Janhsen et al., 2015;Kaendler et al., 1996;Kroll et al., 2016;Lekka et al., 2002;Liebrenz, Schneider et al., 2015;Liebrenz et al., 2016aLiebrenz et al., , 2016bMoreno-Gutíerrez et al., 2020;Nordfjaern et al., 2014Nordfjaern et al., , 2013Rintoul et al., 2013;Sidorchuk et al., 2018;Soumerai et al., 2003;Sullivan & Sellers, 1992;Takeshima et al., 2016;Tien et al., 2020;Voshaar et al., 2003 Not applicable (n = 8) Alexander & Perry, 1991;Brinkers et al., 2016;Federico et al., 2020;Kim et al., 2017;Lugoboni et al., 2020Lugoboni et al., , 2018Martinez-Cano et al., 1996;Teboul & Chouinard, 1991 Characteristics of study population References ...
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.
... A validated screening tool for adult ADHD with good accuracy and short application time might be used in the clinical setting (van de Glind et al. 2013). We have previously documented that a screening test for adult ADHD may be positive in approximately one-third of high-dose BZD and Z-drug users (Tamburin et al. 2017c), and that adult ADHD is associated with worse QoL in this population (Lugoboni et al. 2020b). ...
... Adult ADHD, neuropsychological Z-scores, and variables (i.e., sex, age, education, BZD/Z-drug active principle, and DDDE) that we found to significantly influence QoL in highdose BZD/Z-drug users in previous studies (Tamburin et al. 2017b;Lugoboni et al. 2020b) were entered as covariates in the multivariate analysis with QoL measures as dependent variables. ...
... The present study confirmed that (a) screening for adult ADHD was frequently positive, (b) QoL (SF-36) was worse than the general population (Tamburin et al. 2017b), and (c) worse in ADHD + than ADHD− patients (Lugoboni et al. 2020b) in high-dose BZD/Z-drug users. This report yielded these new findings: (d) executive function was significantly worse in ADHD + than ADHD− patients, (e) some SF-36 dimensions were negatively influenced by executive function Z-score, and (f) multivariate analysis showed a complex interplay of adult ADHD and cognitive dysfunction in negatively influencing QoL measures (SF-36 and GHQ-12). ...
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 dysfunc-tion 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.
... 4 In Italy, lormetazepam has also shown to be the most abused intravenous drug for heroin addicts. 5 Istvan and colleagues also highlight the fact that addiction and abuse are prevalent in populations suffering from mental illnesses. In our experience, this has not been confirmed: about half of our patients had no history of psychiatric illnesses, nor a history of addiction to illicit substances or alcohol. ...
... 2,6 Lastly, regarding zolpidem's hazardousness, we would like to report the fact that zolpidem was significantly preferred by addicts with a positive ADHD test result. 5 These data should be kept in mind by institutions and services that study and handle neurodevelopmental issues. ...
We have read the article by Istvan and colleagues, which recently appeared on your Journal, 1 with great interest. Among doctors, the use of zolpidem has been driven by the still-widespread false belief that, since zolpidem is not chemically a benzodiazepine, it cannot lead to addiction and tolerance. Indeed, it took almost 30 years from when the drug was introduced on the market for pharmacovigilance authorities of various countries to start taking action in regulating its use, as described by Istvan and colleagues. However, due to the fact that our operating unit, which is entirely dedicated to the abuse of medications, has treated an extremely high number of cases of addiction to high doses of benzodiazepines and related hypnotics, we would like to contribute to better highlighting certain characteristics of zolpidem and its potential as a substance of abuse. In their paper, Istvan and colleagues hint at the similarities between the regulation policies of flunitrazepam and zolpidem to draw conclusions about zolpidem's use. Italy has enacted the most restrictive regulations in the world on flunitrazepam, although this did not avoid that its use and abuse would overflow towards other molecules, starting from lormetazepam. Indeed, of the about 1400 cases of hospitalization for addiction to high doses of benzodiazepines and the like in our institution, none were due to flunitrazepam, while more than half of them were due to lormetazepam. Zolpidem was in fourth place among the 29 molecules present on the Italian market. 2 Furthermore, we believe the term "Z-drugs" to be inappropriate: zolpidem, zopiclone, and zaneplon all have different chemical structures, they bind to different receptors, and they have completely different abuse potentials. 3 Indeed, both zopiclon and zaneplon were virtually absent from the cases that were brought to the attention of our institution, albeit both molecules being commonly used in Italy. Lormetazepam, which is vastly prescribed by French doctors, deserves a separate discussion. Reports about its peculiar addictiveness are quite scarce in literature and virtually only come from Italy and Spain, which to our knowledge are the only countries in which the drug is sold in the form of drops. Of the cases we treated, 99% of the abusers that were hospitalized for addiction to lormetazepam were addicted to its soluble formula, unlike all other molecules for which tablets were found to be the most addictive. 3 This phenomenon is still unclear, but it is so evident in Italy that other countries should beware of introducing such a formula. 4 In Italy, lormetazepam has also shown to be the most abused intravenous drug for heroin addicts. 5 Istvan and colleagues also highlight the fact that addiction and abuse are prevalent in populations suffering from mental illnesses. In our experience, this has not been confirmed: about half of our patients had no history of psychiatric illnesses, nor a history of addiction to illicit substances or alcohol. 2,6 Lastly, regarding zolpidem's hazardousness, we would like to report the fact that zolpidem was significantly preferred by addicts with a positive ADHD test result. 5 These data should be kept in mind by institutions and services that study and handle neu-rodevelopmental issues. We would like to conclude with an appeal regarding drug regulation policies.
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.
