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High-dose lormetazepam dependence: strange case of Dr. Jekyll and Mr. Hyde
Abstract
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.
... While all benzodiazepines are associated with a risk of tolerance and dependence, data from animal studies suggest that the potential for dependence is lower with lormetazepam than with nitrazepam or lorazepam (Horowski, 2020). The oral solution of lormetazepam has been associated with a high incidence of abuse in studies from Italy (Faccini et al., 2012;Cosci et al., 2016;Faccini et al., 2019). However, the same studies reported a low incidence of abuse with lormetazepam tablets; for example, in the largest cohort, only 13 of the 1112 patients with benzodiazepine dependence (1.2%) were using lormetazepam tablets (Faccini et al., 2019). ...
... The oral solution of lormetazepam has been associated with a high incidence of abuse in studies from Italy (Faccini et al., 2012;Cosci et al., 2016;Faccini et al., 2019). However, the same studies reported a low incidence of abuse with lormetazepam tablets; for example, in the largest cohort, only 13 of the 1112 patients with benzodiazepine dependence (1.2%) were using lormetazepam tablets (Faccini et al., 2019). Various authors have speculated on the reasons for the high rate of abuse with lormetazepam oral solution, suggesting that this is related to the drip rate, excipients, α 1 -receptor selectivity or a combination of these factors, but the exact reason is not clear (Faccini et al., 2019;Horowski, 2020;Costa et al., 2021). ...
... However, the same studies reported a low incidence of abuse with lormetazepam tablets; for example, in the largest cohort, only 13 of the 1112 patients with benzodiazepine dependence (1.2%) were using lormetazepam tablets (Faccini et al., 2019). Various authors have speculated on the reasons for the high rate of abuse with lormetazepam oral solution, suggesting that this is related to the drip rate, excipients, α 1 -receptor selectivity or a combination of these factors, but the exact reason is not clear (Faccini et al., 2019;Horowski, 2020;Costa et al., 2021). Until there is more clarity about the exact cause of any relationship between lormetazepam oral solution and the risk of abuse, and the extent to which any relationship may be related to the formulation or patient characteristics, clinicians would be advised to preferentially prescribe the tablet formulation. ...
This review aimed to examine the place of benzodiazepines, specifically lormetazepam, in the treatment of insomnia, including during pregnancy or in patients with psychodermatoses. PubMed was searched for the term “lormetazepam” in association with MeSH terms encompassing anxiety, insomnia/sleep disorders, pregnancy/gestation, and psychodermatoses/skin disorders. English-language articles up to 31 July 2022 were identified. Ad hoc searches for relevant literature were performed at later stages of review development. Multiple randomized, placebo-controlled studies have demonstrated that lormetazepam dose-dependently increases total sleep time, decreases wakefulness over a dosing range of 0.5–2.0 mg, and improves subjective assessments of sleep quality. Lormetazepam is as effective as other benzodiazepines in improving sleep duration and quality, but is better tolerated than the long-acting agents with minimal next-day effects. Benzodiazepines can be used as short-term monotherapy at the lowest effective dose during the second or third trimesters of pregnancy; lormetazepam is also a reasonable choice due to its limited transplacental passage. Insomnia associated with skin disorders or pregnancy can be managed by effective symptom control (especially itching), sleep hygiene, treatment of anxiety/depression, and a short course of hypnotics.
... 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.
... and for the intermediate-acting BZD (i.e., half-life 6-24 h) lorazepam (ROR 1.36, 95% CI 1.15-1.61) in the overall population; (c) significantly higher risk of hospitalization for lorazepam (ROR 1.58, 95% CI 1.19-2.11) in the elderly population [1]. a tertiary national referral center for detoxification from high-dose BZD/ZD dependence, where lormetazepam (57% of cases), lorazepam (11%), alprazolam (10%), and zolpidem (9%) were the most common BZD/ZD of high-dose abuse in a middle-aged population (mean age 44.9 ± 10.9 years; interquartile range 37-52) [2]. ...
... Women and elderly people were more represented in the group of patients, who were hospitalized [1], while our sample of high-dose BZD/ZD abusers was very well balanced between genders (men 51.1%; women 48.9%) and mainly composed of middle-aged people [2]. We have reviewed our dataset and found only 56 out of 1112 patients (5.0% of the whole sample) to be ≥65 years old, being again well balanced between genders (men 46.4%; women 53.6%). ...
... Not surprisingly, depression, anxiety, and psychiatric diseases were common both in our sample [2] and in that of Lombardi and coworkers [1], because these conditions increase the likelihood of BZD/ZD prescription. ...
... Lormetazepam was the main active principle used in the ADHD− group, while the number of ADHD+ patients who mainly used zolpidem and alprazolam was approximately twice that of ADHD− ones. We have previously reported lormetazepam to represent the main BZD of high-dose use in the Italian population [37], and from this perspective, data from ADHD− patients appear to be in line with the overall sample of highdose BZD users. Our data suggest that zolpidem and alprazolam, which are among the most widely used hypnotic drugs [37], should be prescribed with care in people with ADHD symptoms. ...
... We have previously reported lormetazepam to represent the main BZD of high-dose use in the Italian population [37], and from this perspective, data from ADHD− patients appear to be in line with the overall sample of highdose BZD users. Our data suggest that zolpidem and alprazolam, which are among the most widely used hypnotic drugs [37], should be prescribed with care in people with ADHD symptoms. Drops and pills were more commonly reported in ADHD− and ADHD+ patients, respectively. ...
... We have previously hypothesized impulsivity of ADHD patients to result in pill preference, because droppers may require long time for the administration of the required high doses of BZD/Z-drugs [27]. However, since nearly all high-dose lormetazepam users prefer the drop formulation [37], the higher prevalence of lormetazepam in ADHD− patients might represent a bias factor for this finding. In accordance with previous reports, poly-drug use [38] and major psychiatric disorders were more common in ADHD+ patients [18], indicating higher SUD complexity in this population. ...
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.
... Fiammetta Cosci 1,2 · Antonio Egidio Nardi 3 · Vladan Starcevic 4 · Guy Chouinard 5 Faccini et al. [1] studied the prevalence of high-dose use of benzodiazepines (BZDs), in particular lormetazepam (LMZ), among patients admitted for detoxification during a period of 15 years at an Italian tertiary center. They analyzed a sample of 882 patients, 79% of whom abused one BZD and 21% abused more than one BZD. ...
... Faccini et al. [1] reported a history of substance-use disorder (SUD) in 52.8% of the sample, with similar prevalence among LMZ abusers and those who abused other BZDs. Thus, findings from the literature suggesting that BZDs are commonly abused by polysubstance abusers is confirmed. ...
... Thus, findings from the literature suggesting that BZDs are commonly abused by polysubstance abusers is confirmed. It should be noted that Faccini et al. [1] analyzed a heterogenous sample which included subjects with poly-drug abuse, subjects with one-drug abuse, as well as subjects with one single BZD abuse. It would be interesting to examine larger and more homogeneous samples with regards to substance abuse patterns. ...
Faccini et al. studied the prevalence of high-dose use of benzodiazepines (BZDs), in particular lormetazepam (LMZ), among patients admitted for detoxifcation during a period of 15 years at an Italian tertiary center. They analyzed a sample of 882 patients, 79% of whom abused one BZD and 21% abused more than one BZD. The numbers of subjects abusing BZDs seem rather low for a tertiary center of a country of about 60 million people, considering that these
data were collected over a period of 15 years, which means
about 74 patients a year on average. This result seems to confirm that the potential for abuse has been dramatically portrayed in the scientific literature and by the media, despite the fact that recreational BZD abuse is uncommon and that rate of abuse of BZDs is low in relation to the number of people using them. The reinforcing effects of benzodiazepines vary and are considerably weaker than those of other
drugs of abuse such as other sedative hypnotics, stimulants
and opiates. On the other hand, the reinforcing effects of
BZDs are stronger than those of drugs recognized as having
little abuse potential, such as chlorpromazine.
... Faccini et al. [1] studied the prevalence of high-dose use of benzodiazepines (BZDs), in particular lormetazepam (LMZ), among patients admitted for detoxification during a period of 15 years at an Italian tertiary center. They analyzed a sample of 882 patients, 79% of whom abused one BZD and 21% abused more than one BZD. ...
... Faccini et al. [1] reported a history of substance-use disorder (SUD) in 52.8% of the sample, with similar prevalence among LMZ abusers and those who abused other BZDs. Thus, findings from the literature suggesting that BZDs are commonly abused by polysubstance abusers is confirmed. ...
... Thus, findings from the literature suggesting that BZDs are commonly abused by polysubstance abusers is confirmed. It should be noted that Faccini et al. [1] analyzed a heterogenous sample which included subjects with poly-drug abuse, subjects with one-drug abuse, as well as subjects with one single BZD abuse. It would be interesting to examine larger and more homogeneous samples with regards to substance abuse patterns. ...
The purpose of this study was to examine several conceptual and cross-cultural issues in neurasthenia, particularly in terms of their relationship to chronic fatigue syndrome. A review of this relationship led to the conclusion that these conditions are much more alike in Western countries than in countries such as China, where neurasthenia could almost be regarded as a "culture-bound syndrome." This may be a consequence of factors such as the heterogeneous nature of neurasthenia and different diagnostic practices in different countries, despite the ICD-10 definition of neurasthenia, intended for worldwide use. Likewise, there is no consensus on what the "core" characteristics of neurasthenia are, because its clinical presentation and key features in different countries are very different. Despite the finding of relatively low comorbidity rates between neurasthenia and other mental disorders, clinical experience suggests that features of neurasthenia frequently overlap with those of depression, chronic anxiety, and somatoform disorders. There is no convincing evidence that in cases of overlap or comorbidity, other diagnoses should automatically have "primacy" over neurasthenia nor should the diagnosis of neurasthenia thereby be excluded. Although some aspects of its validity have improved recently, especially its descriptive validity, the overall validity of the diagnosis of neurasthenia is still not satisfactory. Suggestions for further research, aimed at improving the diagnostic validity of neurasthenia, are offered in this paper.
... Faccini et al. [1] studied the prevalence of high-dose use of benzodiazepines (BZDs), in particular lormetazepam (LMZ), among patients admitted for detoxification during a period of 15 years at an Italian tertiary center. They analyzed a sample of 882 patients, 79% of whom abused one BZD and 21% abused more than one BZD. ...
... Faccini et al. [1] reported a history of substance-use disorder (SUD) in 52.8% of the sample, with similar prevalence among LMZ abusers and those who abused other BZDs. Thus, findings from the literature suggesting that BZDs are commonly abused by polysubstance abusers is confirmed. ...
... Thus, findings from the literature suggesting that BZDs are commonly abused by polysubstance abusers is confirmed. It should be noted that Faccini et al. [1] analyzed a heterogenous sample which included subjects with poly-drug abuse, subjects with one-drug abuse, as well as subjects with one single BZD abuse. It would be interesting to examine larger and more homogeneous samples with regards to substance abuse patterns. ...
Psychotropic agents are increasingly being prescribed by different specialty clinicians for a variety of psychiatric illnesses, making it necessary to improve understanding of the etiology, diagnosis, and management of drug-induced movement disorders (D-IMD) across medical specialties. Early descriptions of movement disorders were based on identifiable disease states such as parkinsonism, dystonia deformans, and Huntington's chorea, which introduced complicated and often overlapping nomenclature. This has hindered communication about, description of, and diagnosis of these drug-induced disorders. Research criteria for tardive dyskinesia, a specific, purposeless, involuntary, hyperkinetic, potentially persistent D-IMD, have varied, with relatively few data-driven conclusions available to support clinical decision-making. The differences in research criteria among published reports on rates of tardive dyskinesia with atypical antipsychotics make it difficult to find meaningful comparisons and conclusions between atypicals. A novel system for classifying D-IMD according to whether they are reversible or persistent, hypokinetic or hyperkinetic, and dystonic or nondystonic is proposed. This new classification system will provide clinicians and researchers across specialties a more precise language, which will hopefully improve the diagnosis of and research criteria for D-IMD.
... Among BZD users, an estimated 6-76% may become long-term users (Kurko et al., 2015), 15-30% may develop moderate-to-severe withdrawal symptoms and rebound symptoms, especially if abrupt cessation of use occurs after 4 weeks of regular intake (Lader and Morton, 1991), and 3-4% may develop misuse or dependence (Faccini et al., 2019;Lader, 2011). Many risk factors for BZD or Z-drug dependence have been suggested, including comorbid neuropsychiatric disorders, ineffective treatments, other substance use, and social factors (Dell'osso and Lader, 2013;Guerlais et al., 2015;Kurko et al., 2015;Manthey et al., 2012). ...
... This study was conducted at the Addiction Medicine Unit, Department of Medicine, of the Integrated University Hospital of Verona, a nationwide tertiary referral inpatient facility specifically devoted to the detoxification from high-dose BZD and Z-drugs dependence by slow flumazenil infusion (Faccini et al., 2016;Faccini et al., 2019) in people aged > 18 years. All consecutive admissions to the inpatient service over the period November 2019 to March 2020 (recruitment was interrupted due to global Covid-19 pandemic) were included into the study. ...
Background: Long-term benzodiazepine (BDZ)/Z-drug use, which is a risk factor for dependence, is frequent in neuropsychiatric conditions, especially emotional disorders. Also, BDZ/Z-drug misuse is associated with increased emotion dysregulation symptoms. This study aimed to investigate neuropsychiatric distress in patients with BZD/Z-drug use disorder, with particular attention to emotional symptoms.
Methods: Forty-two patients hospitalized for BZD/Z-drug use disorder (males/females= 20/22) were enrolled and dichotomized into a high-dose and a low-dose BZD/Z-drug user group. Neuropsychiatric distress was measured using standardized measures. The relationship between symptom profiles and BZD/Z-drug use disorder severity was explored using t-tests and negative binomial regression analyses.
Results: Twenty-seven patients (61.9%) presented with one or more psychiatric disorders, mostly an emotional disorder. Ten patients had a lifetime history of suicide attempt(s) (23.8%), while 11 presented recent suicidal ideation (26.2%), which resulted in suicidal behavior in 2 cases. High rates of depression, anxiety, and emotion dysregulation were reported. The high-dose BZD/Z-drug user group presented with higher depressive symptoms (p = 0.016) and emotion dysregulation (p = 0.044) than the low-dose BZD/Z-drug user group. Further, the higher the depressive symptomatology, the more severe was the BZD/Z-drug abuse (p = 0.028).
Limitations: Long-term patterns of BDZ/Z-drug use disorder among patients with emotional disorders and the role of other potential risk factors, such as gender, other substance use disorder, and personality disorders, need further investigation in larger samples.
Conclusions: This study showed high emotional symptoms among patients with BZD/Z-drug use disorder, with severe depression being associated with a more severe BZD/Z-drug dependence.
... 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. ...
... 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.
... A recent retrospective analysis carried out in a referral addiction centre in Italy on 1112 admissions for detoxification from high-dose benzodiazepines (BDZ) over 15 years (2013-2018) revealed how lormetazepam (LMZ) was the main substance of abuse for patients (57%), whilst lorazepam was the second one (11%) [1]. Since these findings do not match the trend of sales of BDZ on the Italian retail market-where LMZ and lorazepam accounted, respectively, for 26.8% and 20.9% of DDD purchased [2]-the cause needed to be sought elsewhere. ...
... Since these findings do not match the trend of sales of BDZ on the Italian retail market-where LMZ and lorazepam accounted, respectively, for 26.8% and 20.9% of DDD purchased [2]-the cause needed to be sought elsewhere. Remarkably, 96.7% of patients on LMZ abused the oral solution, whereas tablets were more commonly used by other BZD abusers (65.4%) [1]. Differences in pharmacological parameters of BDZ and z-drugsa more recent class which has shown similar hypnotic effects and risks of developing dependency [3]-do not unequivocally reveal what could improve the risk of dependency and tolerance [4]. ...
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.
... Among BZD active principles, lormetazepam was significantly overrepresented in men. Lormetazepam, which is the most popular BZD in Italy, and whose oral formulation has high bioavailability and shorter time-to-peak leading to high plasma concentration [51,52], should be used with care in this specific population of patients, especially in men. Intravenous misuse of flunitrazepam was reported by 8.2% of patients. ...
... Intravenous misuse of flunitrazepam was reported by 8.2% of patients. Flunitrazepam was very popular in the 80 and 90s decades of the last century, and then some restrictions consistently reduced its use [52]. Our patients likely obtained flunitrazepam through black market or other alternative sources. ...
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.
... patients), followed by lorazepam with 11% (125), alprazolam 10% (111), zolpidem 9% (102), clonazepam 3% (37) (Cosci et al., 2015;Faccini et al., 2012Faccini et al., , 2016Faccini et al., , 2019. ...
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 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.
... As for midazolam, the lower risk of hospitalisation associated with this medication is likely to be related to its pharmacological properties, as it has a very short plasma half-life and is available on the Italian market mostly as parenteral formulation, making abuse/misuse more difficult [10]. Indeed, oral formulations of BZD, especially drop formulations, are known to be associated with a greater risk of abuse [30]. Regarding opioids, an increased risk of hospitalisation was found for strong opioids (particularly morphine) as compared to weak opioids or fixed associations (particularly tramadol/dexketoprofen). ...
Purpose
Benzodiazepines (BZD), Z-drugs (ZD), and opioids share a high risk of abuse. This study assessed and characterised adverse events (AEs) related to BDZ, ZD, and opioids leading to emergency department (ED) visits in the Italian setting.
Methods
ED accesses related to BDZ, ZD, and/or opioids were analysed from the MEREAFaPS database. Information on AEs, suspected and concomitant medications was retrieved. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation according to the different treatments.
Results
A total of 5,970 pharmacovigilance reports involving BZD/ZD (n = 3,106), opioids (n = 2,767), or their combination (n = 97) were analysed. Compared to opioids, patients with BZD/ZD-related AEs were often younger (51 vs 64 years), more frequently presented 2+ suspected medications (13 vs 3%), and often had a history of abuse (4%). Twenty-three percent of BZD/ZD-related AEs were related to drug abuse (vs 2% of opioid-related ones) and frequently required patient hospitalisation (52% vs 24%), despite the significantly lower clinical complexity of these patients as compared to those on opioids. An increased risk of hospitalisation was found for flurazepam (ROR 1.62; 95% CI, 1.18–2.22), prazepam (2.66; 1.05–6.70), lorazepam (1.26; 1.07–1.49), and morphine (1.76; 1.11–2.79).
Conclusions
These results indicate that, in Italy, the inappropriate use of BZD/ZD is a relevant heath issue, often leading to serious AEs requiring patients’ ED visits and hospitalisation, especially in young women and patients with a history of substance abuse.
... It is in this area of HDUs that the use of flumazenil (FLU), used worldwide to treat the overdose of BZD, has been demonstrated as effective (9,(11)(12)(13). Experimental findings have shown that FLU acts as a BZD partial agonist with a weak intrinsic activity, when administered by slow intravenous infusion. ...
... It is in this area of HDUs that the use of flumazenil (FLU), used worldwide to treat the overdose of BZD, has been demonstrated as effective (9,(11)(12)(13). Experimental findings have shown that FLU acts as a BZD partial agonist with a weak intrinsic activity, when administered by slow intravenous infusion. ...
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.
... In contrast, the strict concomitance of seizures with classic benzodiazepine abstinence symptoms such as insomnia, restlessness, rigidity, and muscular pain clearly indicated the primary precipitating role of lormetazepam withdrawal. A previous report remarked that lormetazepam is the benzodiazepine that is most frequently associated with abuse and dependence [16], particularly when it is used in the form of an oral solution [17]. The presence of ethanol in the oral solution of lormetazepam has been specifically suspected to increase the risks for abuse and dependence. ...
We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of a severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline (800 mg in an oral solution) before the onset of seizures. Typical signs of amitriptyline intoxication such as sedation and anticholinergic effects were not observed. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously when withdrawal symptomatology subsided eight days after onset. Nonepileptic seizures (NES) were considered in the differential diagnosis because of the patient's psychiatric history including preserved awareness during the bilateral convulsions, the absence of postictal confusion, and normal EEG. The present case indicates that FBMS may occur during benzodiazepine withdrawal in patients who overdosed on amitriptyline. The diagnosis may be challenging as FBMS may mimic NES in the absence of abnormal neurophysiologic findings. This may be especially challenging in patients with an underlying psychiatric disease.
... Athletes might be driven to abuse substances also to achieve good quality sleep, with the aim of recovering from intense effort faster, even jeopardizing their health. In the last years, in the Unit of Addiction Medicine, Department of Internal Medicine, Hospital Trust of Verona, Italy, we treated two patients, both elite athletes, for high-dose lormetazepam [2] detoxification with flumazenil therapy (1 mg/24 hours). The first case was a 38-year-old professional cyclist who developed his addiction to lormetazepam in order to handle insomnia due to a high-dose caffeine use, taken to improve exercise performance [3]. ...
... The big size difference between etizolam and other BZDs/Z-drugs high-dose users hampered a reasonable statistical comparison. However, when compared to high-dose users of lormetazepam, i.e., the most common BZD of high-dose use in Italy (22), etizolam high-dose users appear to be more frequently women, younger, more frequently employed, with lower DDDE, shorter BZD/Z-drug use duration, smaller age of first BZD/Zdrug intake and more frequent poly-drug use. These findings suggest that some populations of patients might be more prone to non-medical use and dependence 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.
... In contrast, the strict concomitance of seizures with classic benzodiazepine abstinence symptoms such as insomnia, restlessness, rigidity, and muscular pain clearly indicated the primary precipitating role of lormetazepam withdrawal. A previous report remarked that lormetazepam is the benzodiazepine that is most frequently associated with abuse and dependence [16], particularly when it is used in the form of an oral solution [17]. The presence of ethanol in the oral solution of lormetazepam has been specifically suspected to increase the risks for abuse and dependence. ...
We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline before the onset of seizures, but there was no clinical evidence of amitriptyline toxicity. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously with overall withdrawal symptomatology eight days after onset. Nonepileptic seizures (NES) were considered in differential diagnosis because of the patient’s psychiatric history, her preserved awareness during the bilateral convulsions, the absence of postictal confusion and the normal EEG findings. The present case indicates that FBMS may occur as the major symptom of benzodiazepine withdrawal syndrome. Diagnosis might be challenging as FBMS may mimic NES in the event of normal neurophysiologic findings, particularly in patients with an underlying psychiatric disease.
... This evidence is further confirmed by the fact that in our sample all suspected agents, when administered parenterally, are associated with a lower relative risk of hospitalisation. It is already demonstrated that oral formulations of BZD, particularly oral solutions, are at higher risk of abuse by the patients [31]. Worldwide, BZD and ZD are generally divided into three groups based on their time of duration: long-(≥ 24 h), intermediate- (6-24 h), and short-acting agents (≤ 6 h) [32]. ...
Benzodiazepines (BZD) and z-drugs (ZD) are a widely prescribed group of medicines. They are often used inappropriately, and this is associated with adverse events (AEs), which may cause emergency department (ED) visits. The present study aimed to describe the characteristics of BZD and ZD related AEs leading to emergency department (ED) visit and hospitalisation in Italy, considering their plasma half-life. Ninety-two Italian EDs were monitored between 2007 and 2018. Rates of ED visit and hospitalisation were calculated. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation. Univariate linear regression was performed to evaluate the ROR of hospitalisation according the plasma half-life of the suspected agents. A total of 3203 AE reports were collected. Overall, multivariate logistic regression showed that the risk of hospitalisation was higher for prazepam (3.26 [1.31–8.11]), flurazepam (1.62 [1.15–2.27]), and lorazepam (1.36 [1.15–1.61]). In the elderly, this risk was higher for prazepam (3.98 [1.03–15.3]), and lorazepam (1.58 [1.19–2.11]). Parenteral and rectal formulations were associated with a lower risk of hospitalisation compared to oral formulations. Our findings underlined the dangers in the use of BZD and ZD in Italy, particularly in women and older adults. ED clinicians must always take into account that the higher risk in terms of hospitalisation related to the use of BZD and ZD can be observed in patients treated with oral formulations, in those exposed to more than one sedative-hypnotics, and in patients exposed to compounds with intermediate or long plasma half-life.
Misuse and dependence from sedatives and hypnotics are frequent, especially with benzodiazepines (BZDs) and non-benzodiazepine hypnotics, the so-called Z-drugs (Zolpidem, Zopiclone, Eszopiclone). They are far less toxic than older sedatives and hypnotics and have replaced other drugs such as barbiturates, meprobamate, chloralhydrat, clomethiazole or others. Beside these prescription drugs there also are a number of over-the-counter sedatives with no or very small abuse potential such as various phytotherapeutics, tryptophane, antihistaminergic drugs like diphenhydramine, among others. This chapter will focus on BZDs and Z-drug abuse (harmful use) and dependence.
BZDs and Z-drugs act via inhibitory GABA-receptors in the brain and can induce tolerance, resulting in dose increase, physical and psychological dependence, craving, loss of control and withdrawal symptoms. Predisposing conditions are psychiatric and psychosomatic disorders (especially anxiety, sleep disorders), other substance use disorders, or chronic pain. Many patients with long-term BZD use are women, and elderly.
In case of sudden or even slow discontinuation of long-term medication a broad range of rebound or withdrawal symptoms can emerge including tremor, sweating, inner restlessness, sleep disorders, depression, anxiety, agitation and many others. In case of high dose dependence and more or less abrupt withdrawal more severe symptoms like seizures, psychosis, suicidality or delirium may emerge. A gradual tapering off the medication following long term use is strongly advocated, and the adjunctive pharmacotherapy is symptomatic with no gold standard being established. Psychotherapy depends on the underlying psychiatric or neurological disorder and may include primary care based brief interventions and counselling for the less severe cases and psychoeducation, cognitive behavioral therapy and contingency management for the more severe dependent patients. Although misuse and dependence of BZDs are frequent these patients are less seen in substance use treatment facilities than in primary care or psychiatric and psychosomatic facilities. Possible strategies for prevention and therapy of misuse and dependence of sedatives and hypnotics are discussed.
Introduction
Insomnia is a stress-related sleep disorder, may favor a state of allostatic overload impairing brain neuroplasticity, stress immune and endocrine pathways, and may contribute to mental and physical disorders. In this framework, assessing and targeting insomnia is of importance.
Aim
Since maladaptive neuroplasticity and allostatic overload are hypothesized to be related to GABAergic alterations, compounds targeting GABA may play a key role. Accordingly, the aim of this review was to discuss the effect of GABAA receptor agonists, short-medium acting hypnotic benzodiazepines and the so called Z-drugs, at a molecular level.
Method
Literature searches were done according to PRISMA guidelines. Several combinations of terms were used such as “hypnotic benzodiazepines” or “brotizolam,” or “lormetazepam” or “temazepam” or “triazolam” or “zolpidem” or “zopiclone” or “zaleplon” or “eszopiclone” and “insomnia” and “effects on sleep” and “effect on brain plasticity” and “effect on stress system”. Given the complexity and heterogeneity of existing literature, we ended up with a narrative review.
Results
Among short-medium acting compounds, triazolam has been the most studied and may regulate the stress system at central and peripheral levels. Among Z-drugs eszopiclone may regulate the stress system. Some compounds may produce more “physiological” sleep such as brotizolam, triazolam, and eszopiclone and probably may not impair sleep processes and related neural plasticity. In particular, triazolam, eszopiclone, and zaleplon studied in vivo in animal models did not alter neuroplasticity.
Conclusion
Current models of insomnia may lead us to revise the way in which we use hypnotic compounds in clinical practice. Specifically, compounds should target sleep processes, the stress system, and sustain neural plasticity. In this framework, among the short/medium acting hypnotic benzodiazepines, triazolam has been the most studied compound while among the Z-drugs eszopiclone has demonstrated interesting effects. Both offer potential new insight for treating insomnia.
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.
The use of zolpidem has been driven by the still-widespread false belief among doctors that, since zolpidem is chemically not a benzodiazepine, it cannot lead to addiction and tolerance. We would like to contribute to better highlight certain characteristics of zolpidem and its potential as a substance of abuse due to the fact that our operating unit, which is entirely dedicated to medication abuse, has described among the most numerous cases of addiction to high doses of benzodiazepines and related hypnotics. - Zolpidem was in fourth place among the 29 molecules present on the Italian market; - We believe it’s now time to drop the term “Z-drugs”: zolpidem, zopiclone e zaneplon all have different chemical structures, they bind to different receptors and have completely different abuse potentials3. In our case history, both zopiclon and zaneplon were virtually absent, albeit being commonly used in Italy; - Istvan & colleagues highlight the fact that addiciton and abuse are prevalent in samples suffering from mental illness. In our case history this hasn’t been confirmed: about half of our patients had no history of psychiatric illnesses, nor a history of addiction to illicit substances or alcohol; - Lastly, regarding zolpidem’s hazardousness, we would like to report the fact that the drug was significantly preferred by addicts with a positive ADHD test result. In conclusion, the 2000s saw solid confirmation of the effectiveness of partial agonists in the treatment of some common addictions, such as buprenorphine, varenicline, cytisine. This didn’t happen for BZs
There are contradictory publications and reports regarding the dependence liability of the 3-hydroxy-benzo-1,4-diazepine derivative lormetazepam, one of the most often prescribed hypnotic benzodiazepines which is now also available as an intravenous (i.v.) product for anesthetists. The author was involved in the preclinical and subsequently in the clinical development and post-marketing surveillance of lormetazepam. Here, he reviews the published and unpublished data about lormetazepam dependence and proposes explanations for contradictory views from other authors. On this basis and in contrast to class labeling from regulatory bodies and WHO, the author comes to the conclusion that use of lormetazepam definitely carries a lower risk of inducing dependence and causing abuse than most other benzodiazepines. This applies as well to Sedalam®, the new i.v. application form of lormetazepam, which is much better tolerated than propofol. Because of its pharmacokinetic properties and because all its effects can be fully antagonized with the benzodiazepine antagonist flumazenil, this innovative intravenous application form of lormetazepam provides an excellent method for premedication, symptomatic treatment of excitation and anxiety in the context of surgical or diagnostic procedures including outpatient interventions and for basic sedation during anesthesia.
Benzodiazepines are one of the most prescribed medications as first-line treatment of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the neuropharmacological understanding of gamma aminobutyric acid (GABA)A receptors revealed distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α1 containing GABAA receptors in the mechanisms of addiction and tolerance in benzodiazepine treatments. This has shown promise in the development of tranquilizers with minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like drug without its side effects, as repeatedly demonstrated in animals, is achievable.
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.
Despite the first reports concerning benzodiazepine dependence being published in the early 1960s literature, the risk of benzodiazepine addiction is still greatly debated. The severe discomfort and life threatening complications usually experienced by long-term benzodiazepine users who suddenly interrupt benzodiazepine intake have led to the development of several detoxification protocols. A successful strategy used by our Addiction Unit is abrupt benzodiazepine cessation by administering flumazenil slow subcutaneous infusion (FLU-SSI) with an elastomeric pump. Although some studies proved the efficacy of flumazenil infusion more than 20 years ago, only a few centres in the world offer this method to their patients. This paper reports the data related to 214 subjects addicted to high doses of benzodiazepine and treated with the FLU-SSI method between 2012 and 2014. This technique is less invasive and requires less nursing intervention than intravenous infusion. Our data support FLU-SSI as a possible efficient strategy for the treatment of patients with long-term, high-dose benzodiazepine addiction, and could become a routine therapy as long as the necessary further studies on dose, duration of infusion and safety issues are carried out.
Background:
High-dose benzodiazepine (BZD) dependence is associated with a wide variety of negative health consequences. Affected individuals are reported to suffer from severe mental disorders and are often unable to achieve long-term abstinence via recommended discontinuation strategies. Although it is increasingly understood that treatment interventions should take subjective experiences and beliefs into account, the perceptions of this group of individuals remain under-investigated.
Methods:
We conducted an exploratory qualitative study with 41 adult subjects meeting criteria for (high-dose) BZD-dependence, as defined by ICD-10. One-on-one in-depth interviews allowed for an exploration of this group's views on the reasons behind their initial and then continued use of BZDs, as well as their procurement strategies. Mayring's qualitative content analysis was used to evaluate our data.
Results:
In this sample, all participants had developed explanatory models for why they began using BZDs. We identified a multitude of reasons that we grouped into four broad categories, as explaining continued BZD use: (1) to cope with symptoms of psychological distress or mental disorder other than substance use, (2) to manage symptoms of physical or psychological discomfort associated with somatic disorder, (3) to alleviate symptoms of substance-related disorders, and (4) for recreational purposes, that is, sensation-seeking and other social reasons. Subjects often considered BZDs less dangerous than other substances and associated their use more often with harm reduction than as recreational. Specific obtainment strategies varied widely: the majority of participants oscillated between legal and illegal methods, often relying on the black market when faced with treatment termination.
Conclusions:
Irrespective of comorbidity, participants expressed a clear preference for medically related explanatory models for their BZD use. We therefore suggest that clinicians consider patients' motives for long-term, high-dose BZD use when formulating treatment plans for this patient group, especially since it is known that individuals are more compliant with approaches they perceive to be manageable, tolerable, and effective.
Objective: To explore the pattern of prescription of benzodiazepines in internal medicine outpatients at a tertiary care hospital. The study included the types of benzodiazepines used, gender and age preference, indication of prescription, past history of use, dosage and length of prescription. Methodology: This cross sectional study was undertaken from 1st of Januaryto 1stof March 2011 at Internal medicine outpatients during this time were indentified through the hospital database. Relevant data from charts of patients was recorded on a preformed questionnaire. All data collected was analyzed in SPSS 17.0. Results: Out of 1706 patients attending the outpatient clinics, 11.1% patients were prescribed benzodiazepines. Female gender and older age was associated with higher rate of prescription. Intermediate acting benzodiazepines prescribed to 98.4% patients, were the most commonly prescribed drugs. Most common indication for prescription of benzodiazepine was anxiety and depression. The length of prescription was mentioned in only 19% of cases. Only24.3%patients had previously been prescribed the drug. Conclusion: The pattern of benzodiazepine prescription in tertiary care hospital is comparable to that of developed countries. Due to the grave potential for abuse, regulation regarding the use of this class of drugs is extremely important. Data from this study and other studies from the country seem to suggest that awareness on this topic is in place. However, further widespread studies need to be carried out at the community level.
In 1977, at a time when psychiatric epidemiology was not as fashionable as it is today, Francis Whitlock outlined its aims and limitations [1]. He criticized a narrow view of psychiatric epidemiology as concerned with the incidence, prevalence and distribution of mental disorders in the general population. He found “the pursuit of investigations of this kind a singularly sterile activity, largely because it is difficult to see what possible purpose such enterprises have […]. Head counting to establish prevalence norms is tedious and rarely can be carried out in any comprehensive fashion by those trained to recognize and treat mental disorders” [1, p.11]. Studies concerned with prevalence rates, however, achieved a prominent role in the subsequent decades [2]. Even though such studies were not driven by financial conflicts of interest, they served an important commercial purpose.
Benzodiazepines are not all the same concerning their risk of high-dose use.
We studied benzodiazepine use from the Luxembourg national records of all insured. We calculated the 12-year prevalence from 1995 to 2007. Benzodiazepine users were divided into 3 groups, short-term with no longer than 3-month intake, intermediate with multiple administration with at least a 1-year interruption, and continuous who never stopped. A high-dose user (HDU) was defined as a patient who received a higher dose than the yearly maximum usual therapeutic dose.
An average of 16.0% of the adult insured population received at least 1 benzodiazepine annually, 42.9% were older than 50, 55.9% were women, and 5.4% were HDUs. We found that 32.6% were short-term users, 49.0% intermediate and 18.4% continuous. Compared to diazepam, hypnotics had higher risks for high-dose use in at least 1 age group at first-benzodiazepine intake, the risks being greater in elderly subjects and women, the highest risks being with triazolam (adjusted odds ratio = 215.85; 95% confidence interval = 133.75-348.35) in the 69- to 105-year-old group at first-benzodiazepine intake. Anxiolytics had a low risk except for alprazolam and prazepam in the 69- to 105-year-old group at first-benzodiazepine intake, clonazepam and clobazam had the lowest risk in 18- to 43-year-olds at first-benzodiazepine intake. Alprazolam had dispensed volumes increased by threefold over the 12-year period.
All hypnotics had higher risks for high-dose use compared to diazepam in continuous users. Two anxiolytics, clonazepam and clobazam, had the lowest risks. Hypnotics and the triazolobenzodiazepines alprazolam and triazolam were most problematic. Elderly subjects and women are at greater risks. © 2015 S. Karger AG, Basel.
Benzodiazepine abuse and dependence have been recognized and widely discussed for more than 40 years. With more than 230 million daily doses prescribed in Germany per year, the burden of reimbursement on the statutory health insurance carriers is high, albeit with a slight decline from year to year. At present, about 50% of all prescriptions in Germany are issued privately, even for patients who have statutory health insurance.
We selectively review the literature on the epidemiology and treatment of benzodiazepine dependence and abuse in Germany.
Estimates of the number of benzodiazepine-dependent persons in Germany range from 128 000 to 1.6 million. Most estimates take no account of the large number of private prescriptions (i.e., those that are not reimbursed by the statutory health insurance scheme), while many exclude prescriptions for elderly persons, for whom these drugs are frequently prescribed. For the outpatient treatment of benzodiazepine withdrawal, it is recommended that the drug should first be switched to an equivalent dose of another benzodiazepine with an intermediate or long-acting effect; the dose should then, in general, be reduced weekly. In case of consumption of a high dose (≥ 20 mg diazepam equivalent), hospitalization and the additional administration of carbamazepine or valproic acid are recommended. Flumazenil treatment can improve with - drawal symptoms and leads to higher abstinence rates. Antidepressants should be given only if the patient is depressed. The dependence potential of nonbenzodiazepine drugs such as zolpidem and zopiclon must also be borne in mind.
Benzodiazepines are generally highly effective when first given, but they should generally be given only for strict indications and for a limited time. If these drugs still need to be given beyond the short term, timely referral to a specialist is indicated, and possibly also contact with the addiction aid system.
Although concern exists regarding the rate of benzodiazepine use, especially long-term use by older adults, little information is available concerning patterns of benzodiazepine use in the United States.
To describe benzodiazepine prescription patterns in the United States focusing on patient age and duration of use.
A retrospective descriptive analysis of benzodiazepine prescriptions was performed with the 2008 LifeLink LRx Longitudinal Prescription database (IMS Health Inc), which includes approximately 60% of all retail pharmacies in the United States. Denominators were adjusted to generalize estimates to the US population.
The percentage of adults filling 1 or more benzodiazepine prescriptions during the study year by sex and age group (18-35 years, 36-50 years, 51-64 years, and 65-80 years) and among individuals receiving benzodiazepines, the corresponding percentages with long-term (≥120 days) benzodiazepine use, prescription of a long-acting benzodiazepine, and benzodiazepine prescriptions from a psychiatrist.
In 2008, approximately 5.2% of US adults aged 18 to 80 years used benzodiazepines. The percentage who used benzodiazepines increased with age from 2.6% (18-35 years) to 5.4% (36-50 years) to 7.4% (51-64 years) to 8.7% (65-80 years). Benzodiazepine use was nearly twice as prevalent in women as men. The proportion of benzodiazepine use that was long term increased with age from 14.7% (18-35 years) to 31.4% (65-80 years), while the proportion that received a benzodiazepine prescription from a psychiatrist decreased with age from 15.0% (18-35 years) to 5.7% (65-80 years). In all age groups, roughly one-quarter of individuals receiving benzodiazepine involved long-acting benzodiazepine use.
Despite cautions concerning risks associated with long-term benzodiazepine use, especially in older patients, long-term benzodiazepine use remains common in this age group. More vigorous clinical interventions supporting judicious benzodiazepine use may be needed to decrease rates of long-term benzodiazepine use in older adults.
Over the last decade there have been further developments in our knowledge of the risks and benefits of benzodiazepines, and of the risks and benefits of alternatives to benzodiazepines. Representatives drawn from the Psychopharmacology Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology together examined these developments, and have provided this joint statement with recommendations
for clinical practice. The working group was mindful of widespread concerns about benzodiazepines and related anxiolytic and hypnotic drugs. The group believes that whenever benzodiazepines are prescribed, the potential for dependence or other harmful effects must be considered. However, the group also believes that the risks of dependence associated with long-term use should be balanced against the benefits that in many cases follow from the short or intermittent use of benzodiazepines and the risk of the underlying conditions for which treatment is being provided.
Objective: Newer non-benzodiazepines zolpidem and zopiclone (“Z-drugs”) are often prescribed instead of benzodiazepine hypnotics, although there is no evidence of differences in effectiveness and safety. Aim was to compare perceptions on benefits and harms of benzodiazepines and Z-drugs between general practitioners (GPs) and community pharmacists (CPs).
Methods: A questionnaire was mailed to a random sample of 1,350 GPs and 600 CPs in 2012. They were asked to rate perceptions on a five-point Likert scale used for both benzodiazepines and Z-drugs. Wilcoxon signed rank test was performed for the comparison of perceptions between GPs and CPs. Due to multiple testing, only p-values ≤0.01 were considered statistically significant.
Results: 458 GPs and 202 CPs returned questionnaires (response 33.9% and 33.7%). Mean age of GPs was 53.3 years (40.6% female) and 48.8 years for CPs (59.2% females). Perceptions on benefits of benzodiazepines (and Z-drugs) between GPs and CPs were not different for 3 (and 2) of 5 items. Concerning side effects of benzodiazepines, there were no statistically significant differences for 3 of 5 comparisons. CPs perceived that 4 of 5 studied side effects of Z-drugs occur significantly more often than GPs (p=0.003 or less). For instance, whereas 45.2% of CPs answered that withdrawal effects on stopping happen often or very often/always on Z-drugs, these were only 28.3% of the GPs.
Conclusions: Although it is difficult to draw unambiguous conclusions from these findings, pharmacists might have a somewhat more critical view on Z-drugs, especially concerning side effects.
Background: For years, anxiolytics and hypnotics have been one of the most prescribed drug classes in most developed countries. The main aim of this study is to explore the pattern of use of anxiolytic and hypnotic drugs during the period 2000-2011, comparing their growth with that of five european countries. Method: We performed an ecological and descriptive study of anxiolytics and hypnotics consumption in Spain. Consumption data were obtained from the databases of medications dispensed in community pharmacies and charged through official prescriptions to the totality of the Spanish National Health System. Annual and total-period consumptions were expressed in defined daily doses (DDD) per 1000 inhabitants per day (DDD/1000 person/day) by each treatment subgroup, active substance and attending the plasma half-life of the medication. Approximate comparisons were also made with some European countries. Results: The use of anxiolytics and hypnotics drugs was 56.7 DDD/1000 person/day in 2000 and 82.9 DDD/1000 person/day in 2011 (a +46.1% increase across the period). Lorazepam and alprazolam were the most used anxiolytics (20.5 and 15.6 DDD/1000 person/day in 2011, respectively), whereas lormetazepam was among the hypnotics (18.3 DDD/1000 person/day in 2011). In relative terms, hypnotics´ lormetazepam and zolpidem increased their use by 103.3% and 85.1%, respectively; while anxiolytics´ lorazepam and hydroxyzine increased 75.1% and 72.8%, respectively. In Spain (period 2003-2010), the total increase in the consumption of anxiolytics and hypnotics was +34.3%, with 24.0% for Portugal, 4.0% for Italy, but a reduction of -6.1% for France. Conclusions: A considerable increase in anxiolytics and hypnotics´ consumption has occurred in Spain during the last decade, being the growth higher than that reported in other European countries.
The purpose of this study was to determine, in the context of a hospital addiction unit, which benzodiazepines were abused and to look for correlations with the characteristics of detoxified patients.
A retrospective study was carried out using the database of hospital admissions to the addiction unit for detoxification from 2003 to 2010.
Of 879 admissions to the addiction unit during the seven-year period, 281 were for benzodiazepines. The percentage of patients addicted only to benzodiazepines was higher among females than males. Benzodiazepine consumption had started as a drug addiction behavior in only 10% of cases. The main sources of prescription identified were general practitioners (52% of cases) or compliant pharmacists (25%). Overall, 15 different benzodiazepines were abused, with lormetazepam being the most commonly used (by 123 patients, 43.8% of the total).
Our data show that, outside the population of multidrug addicts, there is an underestimated group of chronic benzodiazepine consumers who are often not referred to medical institutions for treatment. Even in the group of patients addicted to one substance only, we observed an abnormal number of requests for detoxification from lormetazepam, which appears to be more "popular" than other benzodiazepines. This drug should be prescribed according to stricter criteria and submitted to closer control.
Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.
To analyse sex differences among recipients of benzodiazepines in Dutch general practice.
Study of consultations and associated interventions as recorded in the Dutch national survey of general practice.
Practices of 45 general practitioners monitored during 1 April to 30 June 1987.
61,249 patients (29,035 (47.4%) men in the age groups 19-44, 45-64, and 65 years and over.
Symptoms among recipients of repeat as well as new benzodiazepine prescriptions stratified by sex and age.
Prescriptions for benzodiazepines were found to be significantly more common among women than among men, (a) after correcting for the sex distribution of the total patient population, and (b) in the two oldest age groups after correcting for the number of consultations. Of all prescriptions for benzodiazepines, 89% (6055/6777) were repeats and 70% (4759/6777) requests. Only 9% (439/4759) of these were authorized by the general practitioner, the rest being issued by the general practitioner's assistant after he or she had referred to the diagnosis in the patient's record. In contrast, only three (1%) of the 492 first time recipients of benzodiazepines had requested a prescription and were not seen by the general practitioner. Women (43/96; 45%) aged 45-64 years received their first prescription for benzodiazepines almost twice as often as men (15/63; 24%) without symptoms or a diagnosis being an indication (female to male relative risk 1.88 (95% confidence interval 1.15 to 3.08)).
The sex difference among first time recipients of benzodiazepines seems to be due to general practitioners being less stringent when prescribing this drug for women. The difference continues in repeat prescriptions, physicians failing to check adequately the need for these.
In Norway there has in later years been much discussion of misuse of flunitrazepam. From 1 January 2003 the drug was moved up one level in the schedule of controlled substances. On 1 August 2004 the manufacturer of the Rohypnol brand withdrew it from the Norwegian market. How did these two events influence the sales and use of drugs containing flunitrazepam?
Sales figures for drugs containing flunitrazepam from the statistics database at the Norwegian Institute of Public Health were studied. The Norwegian prescription database was used to describe new (incident) users of flunitrazepam and the two brands of this drug sold in Norway in 2004.
Restrictions on the prescription status of flunitrazepam lead to a decrease in sales from 7.2 defined daily doses (DDD) per 1000 inhabitants per day in 2002 to 3.0 DDD per 1000 inhabitants per day in 2003. This decrease was only partly compensated for by an increase in the sales of nitrazepam (from 5.0 to 6.0 DDD per 1000 inhabitants per day). During the years 1999 to 2004 there was a steady increase in the sales of benzodiazepine-related hypnotics (zopiclone and zolpidem). This shift could mean a change from flunitrazepam to zopiclone. The withdrawal of Rohypnol in August 2004 had only minor effects on the total sales of flunitrazepam. The decline in sales of Rohypnol was almost compensated for by the increase in the overall sales of Flunipam. This was reflected in the fact that in the later months of 2004 there were many new (incident) users of Flunipam, but few new users of flunitrazepam-containing drugs in total. It could be concluded that the restrictions on prescription status of flunitrazepam had a much higher impact than the withdrawal of the Rohypnol brand.
Background
Benzodiazepines are recommended for short-term use due to risk of dependence. This study examined characteristics associated with benzodiazepine and opioid dispensing of 7+ days in a Medicaid population with substance use disorder (SUD).
Methods
Using 2014 MarketScan® data, we performed zero-inflated negative binomial regression to ascertain characteristics associated with longer-term use of these medications.
Results
Nearly 14% of those with SUDs received 1+ fills of benzodiazepines of 7+ days. The highest rates were among those aged 45-64 (IRR = 2.38, p < .0001) and with non-alcohol SUDs (IRR = 1.12, p < .0001). Individuals with co-occurring psychiatric disorders, particularly anxiety and depression (IRR = 1.41, p < .0001), had high rates of benzodiazepine fills. Receiving a 7+ day oral opioid fill (IRR = 1.30, p < .0001) coincided with increased benzodiazepine dispensing. Similar results occurred for longer-term prescribing of opioids, with higher rates among those with non-alcohol SUDs (IRR = 1.23, p < .0001).
Conclusions
For many people with SUDs, receiving a benzodiazepine or opioid prescription of 7+ days is not a single occurrence; patients in our sample were more likely to receive 2+ fills than to receive one. Longer-term prescribing is most pronounced among those with co-occurring anxiety disorders. This suggests that anxiety in those with SUD should preferentially not be treated using benzodiazepines. Longer-term polypharmacy with benzodiazepines and opioids coincided. Overdoses among those using both drugs are growing and this study provides evidence that attention to the opioid epidemic should include attention to polypharmacy that includes benzodiazepines.
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.
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;XX:1-5).
Long-term use of benzodiazepines can lead to dependence. Symptoms of withdrawal include anxiety, irritability, confusion, seizures, and sleep disorders. Withdrawal management relies on the use of a single agent (diazepam) and gradual dose reduction.
Benzodiazepines (BZDs) are the most widely prescribed drug class in developed countries, but they have high potential for tolerance, dependence and abuse. Cognitive deficits in long-term BZD users have long been known, but previous results might have been biased by patients’ old age, coexisting neurological or psychiatric conditions or concurrent alcohol or psychotropic drug dependence. The study was aimed to explore the neuropsychological effect of high-dose BZD dependence, which represents an emerging addiction phenomenon. We recruited a group of high-dose BZD users with neither neurological or psychiatric comorbidity except anxiety or depression nor concurrent alcohol or psychotropic drug dependence. They underwent a battery of cognitive tests to explore verbal, visuospatial memory, working memory, attention, and executive functions. All the neuropsychological measures were significantly worse in patients than controls, and some of them were influenced by the BZD cumulative dose. The severity of depression and anxiety had a minimal influence on cognitive tests. Patients with high-dose BZD intake show profound changes in cognitive function. The impact of cognition should be considered in this population of patients, who may be involved in risky activities or have high work responsibilities.
The use of benzodiazepines (BDZs) represents a critical issue since a long-term treatment may lead to dependence. This study aimed at evaluating socio-demographic and clinical characteristics of BZD long-term users who followed a detoxification programme at a tertiary care centre.
Two hundred-five inpatients were evaluated. Socio-demographic (e.g., gender, age, education) and clinical information (e.g., BZD used, dose, reason of prescription) were collected. BZDs dose was standardized as diazepam dose equivalents and was compared via the Defined Daily Dose (DDD). Chi-square, Fisher test, ANOVA and Bonferroni analyses were performed.
Females were more frequently BDZ long-term users than males. Hypnotics BZDs were frequently prescribed for problems different from sleep disturbances. Lorazepam, alprazolam, and lormetazepam were the most prescribed drugs. Lorazepam was more frequently used by males, consumed for a long period, in pills, and prescribed for anxiety. Lormetazepam was more frequently consumed by females with a high school education, having a psychiatric disorder, taken in drops and prescribed for insomnia. Lormetazepam had the highest DDD.
A specific profile of BZD long-term user seems to exist and presents different socio-demographic and clinical characteristics according to the benzodiazepine taken into account.
The sudden interruption of the increase of the concentration of the gamma-aminobutyric acid (GABA), determines an increase in neuronal activity. GABA withdrawal (GW) is a heuristic analogy, with withdrawal symptoms developed by other GABA receptor-agonists such as alcohol, benzodiazepines, and neurosteroids. GW comprises a model of neuronal excitability validated by electroencephalogram (EEG) in which high-frequency and high-amplitude spike–wave complexes appear. In brain slices, GW was identified by increased firing synchronization of pyramidal neurons and by changes in the active properties of the neuronal membrane. GW induces pre- and postsynaptic changes: a decrease in GABA synthesis/release, and the decrease in the expression and composition of GABAA receptors associated with increased calcium entry into the cell.
GW is an excellent bioassay for studying partial epilepsy, epilepsy refractory to drug treatment, and a model to reverse or prevent the generation of abstinences from different drugs.
Background:
Numerous treatment guidelines recommend that long-term use of benzodiazepines (BZD) should be avoided primarily due to development of tolerance and a risk for BZD dependence. Despite this, long-term BZD use remains a controversial subject in clinical patient care with "for and against" debates. However, there is no explicit understanding of what is meant by long-term BZD use in real world. The aim of this study was to assess different definitions, usage patterns, prevalence and other characteristics of long-term BZD use based on published register-based studies. Synthesis of these characteristics is essential to derive a meaningful definition of long-term BZD.
Methods:
Systematic review of register-based studies on long-term BZD use published in 1994-2014.
Results:
Fourty-one studies met our predetermined inclusion criteria. The length of BZD use defined as "long-term" varied in these studies ranging from one month to several years. The most common definition was six months or longer during a year. The prevalence of long-term BZD use in the general population was estimated to be about 3%. The relative proportion of long-term BZD users (all definitions) in adult BZD users ranged from 6% to 76% (mean 24%; 95% CL 13-36%). The estimates were higher in studies only on the elderly (47%; 95% CL 31-64%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found.
Conclusions:
Long-term BZD use is common and a clinical reality. Uniform definitions for "long-term", which is in line with population-based evidence, is needed to have more comparable results between studies. Our systematic review suggests that duration of BZD treatment over six months, the most common definition for long-term BZD use in the included studies. As also recommended previously, it is a useful starting point for further analyses on disadvantages but also potential advantages associated with long-term BZD use.
benzodiazepine(BZ)系睡眠導入薬lormetazepamのBZ受容体サブタイプ(ω1型，ω2型，ω3型)への作用を明らかにする目的で，マウスhexobarbital睡眠試験と懸垂法筋弛緩試験，並びにラットBZ受容体結合試験を行い，他のBZ系薬物の結果と比較した．lormetazepamは他のBZ系薬物同様hexobarbital誘発正向反射消失時間を用量依存的に延長し，その最小作用量(1mg/kg，p.o.)はtriazolamやbrotizolamと同じで，diazepam(3．2mg，/kg，p.o.)やzopiclone(100mg/kg，p.o.)よりも低かった．lormetazepamは高用量では筋弛緩作用を示したが，その最小作用量(10mg/kg，p.o.)は正向反射消失増強作用の最小作用量よりも10倍高かった．他方，flunitrazepam，diazepam，triazolam，brotizolamの筋弛緩最小作用量は正向反射消失増強作用の最小作用量の各々0.3倍，1倍，1倍，3倍であった．〔3H〕flumazenilを用いた結合置換実験において，lormetazepamは小脳膜標品のω1型受容体に強く結合し(Ki=10nM)，その結合親和性はflunitrazepamに比べ約3倍，diazepamに比べ約11倍高かった．lormetazepamは脊髄膜標品のω2型受容体へも結合し，その結合親和性(Ki=29nM)は小脳膜標品への親和性の約1/3であった．他方，flunitrazepamやdiazepamは小脳膜ω1型受容体および脊髄膜ω2型受容体いずれにもほぼ等しい親和性で結合した．lormetazepamのGABA比(GABA存在と非存在下での結合阻害値IC50の比;GABA受容体への影響度の指標)は小脳膜ω1型受容体では3．9であり，diazepam(3．3)やflunitrazepam(2．6)よりも高く，一方脊髄膜ω2型受容体では4．0であり，diazepam(4．4)やnunitrazepam(5．1)よりも低かった．〔3H〕Ro5-4864を用いた腎臓膜ω3型受容体結合置換実験においてlormetazepamの結合親和性(Ki=213nM)はdiazepam(Ki=362nM)やflunitrazepam(Ki=137nM)と同様に弱かった．以上の結果から，lormetazepamはBZ系睡眠導入薬の中でもとりわけその睡眠増強作用に比して筋弛緩作用が弱い薬物であること，並びにこの薬理学的な性質はlormetazepamがω2型やω3型受容体よりもω1型受容体に対して，より強い結合親和性とアゴニスト活性を有していることに起因すると推察された．
Objective
The aim of this study was to demonstrate a faster absorption and disposition rate for a solution formulation of lormetazepam, comparing the bio-availability of two different oral formulations (tablets and solution), in healthy volunteers.
Study design, methods and participants
24 healthy volunteers (12 male, 12 female) were included in the study. Venous blood samples were taken prior to each administration and at 20 different times within 72 hours after the dose. Plasma concentrations of lormetazepam were determined in a blinded fashion by means of high-resolution gas chromatography. Clinical adverse events were recorded after open-ended questioning. For the purpose of statistical analysis, area under the concentration-time curve (AUC), early exposure AUC (AUCearly), maximum plasma concentration (Cmax) and time to Cmax(tmax) of lormetazepam were considered as the primary variables, and half-life and clearance as secondary ones. Both Cmax and tmax were obtained directly from plasma data, the slope of least-square regression of the terminal elimination phase was estimated by log-linear regression, and the AUC and AUCearly were calculated by the trapezoidal rule.
Results
The standard 90% CI for the log-transformed data was 0.86–1.05 for AUC from time zero to infinity. The relative bioavailability of the solution was 97% compared with that of the tablets. The Cmax standard 90% CI was 1.25–1.72, and the relative Cmax ratio of the lormetazepam solution was 138.1%. The median lormetazepam tmax was 30 minutes for the solution and 1.5 hours for the tablet formulation, the median difference for tmax was —1.17h. The early exposure 90% CI was 1.64–2.48. Comparing both formulations, in terms of early exposure AUC, relative bioavailability was 173% in favour of the solution formulation of lormetazepam.
Conclusions
The pharmacokinetic profile of the solution formulation showed a faster and higher disposition rate than the tablet formulation, and we can thus assume a more rapid onset of hypnotic effect for the solution. This can be useful for patients who have difficulty in falling asleep.
Abstract Purpose. The use of benzodiazepines remains a source of controversy. Some prescribers believe that they are beneficial and espouse their use; others regard their risk:benefit ratio as too adverse for any but occasional use. This review considers these viewpoints based on the appropriate literature. Survey. The recent English-language literature relating to this topic was surveyed. The publications proved too heterogeneous for a formal meta-analysis, so a descriptive review is provided. Overview. Surveys of benzodiazepine use provide data mainly from the UK, Europe and North America. Prescribing patterns varied widely but long-term usage is common and sometimes the norm. Conclusions. Long-term prescription of benzodiazepines still takes place despite general warnings from the medical and other professions and drug regulatory bodies that long-term use is unjustified both from the lack of a systemic database establishing such efficacy and a large literature documenting the risks of long-term usage, such as dependence. The young and the old are particularly at risk. Continued monitoring is essential, but the regulatory authorities may need to take a more active role in curbing such undesirable practice.
To re-examine various aspects of the benzodiazepines (BZDs), widely prescribed for 50 years, mainly to treat anxiety and insomnia. It is a descriptive review based on the Okey Lecture delivered at the Institute of Psychiatry, King's College London, in November 2010.
A search of the literature was carried out in the Medline, Embase and Cochrane Collaboration databases, using the codeword 'benzodiazepine(s)', alone and in conjunction with various terms such as 'dependence', 'abuse', etc. Further hand-searches were made based on the reference lists of key papers. As 60,000 references were found, this review is not exhaustive. It concentrates on the adverse effects, dependence and abuse.
Almost from their introduction the BZDs have been controversial, with polarized opinions, advocates pointing out their efficacy, tolerability and patient acceptability, opponents deprecating their adverse effects, dependence and abuse liability. More recently, the advent of alternative and usually safer medications has opened up the debate. The review noted a series of adverse effects that continued to cause concern, such as cognitive and psychomotor impairment. In addition, dependence and abuse remain as serious problems. Despite warnings and guidelines, usage of these drugs remains at a high level. The limitations in their use both as choice of therapy and with respect to conservative dosage and duration of use are highlighted. The distinction between low-dose 'iatrogenic' dependence and high-dose abuse/misuse is emphasized.
The practical problems with the benzodiazepines have persisted for 50 years, but have been ignored by many practitioners and almost all official bodies. The risk-benefit ratio of the benzodiazepines remains positive in most patients in the short term (2-4 weeks) but is unestablished beyond that time, due mainly to the difficulty in preventing short-term use from extending indefinitely with the risk of dependence. Other research issues include the possibility of long-term brain changes and evaluating the role of the benzodiazepine antagonist, flumazenil, in aiding withdrawal.
Benzodiazepines are widely used clinically to treat anxiety and insomnia. They also induce muscle relaxation, control epileptic seizures, and can produce amnesia. Moreover, benzodiazepines are often abused after chronic clinical treatment and also for recreational purposes. Within weeks, tolerance to the pharmacological effects can develop as a sign of dependence. In vulnerable individuals with compulsive drug use, addiction will be diagnosed. Here we review recent observations from animal models regarding the cellular and molecular basis that might underlie the addictive properties of benzodiazepines. These data reveal how benzodiazepines, acting through specific GABA(A) receptor subtypes, activate midbrain dopamine neurons, and how this could hijack the mesolimbic reward system. Such findings have important implications for the future design of benzodiazepines with reduced or even absent addiction liability.
Long-term use of benzodiazepines (BZDs) has been linked with an array of negative health consequences and increased medical costs and social burden. In this study, we sought to investigate the factors accounting for differential risks in the process from incident BZD use to long-term use and discontinuation in the general population. On the basis of a random sample of 187,413 people enrolled in Taiwan's National Health Insurance program on January 1, 2000, data of 2000-2002 healthcare and pharmacological services utilization were retrieved. Long-term use (LTU) was defined by having received BZD prescriptions for 180 or more days within any given calendar year. Multivariate logistic regression analyses were carried out to assess the strength of associations while adjusting for the effects of individual sociodemographics, service providers, and pharmacological agents simultaneously. Results indicated that males, elderly, and those with physical or mental disorders were more likely to become long-term users of BZDs. Having received BZD prescriptions in multiple pharmacological agents, short-acting or mixed-type agents, and hypnotic indication were associated with a roughly 2- to 5-fold increased risk of BZD LTU soon after prescription initiation. With respect to discontinuation, the effects of pharmacological characteristics seem more salient as compared to those of individual and service-provider factors. Future strategies targeting individual factors and modifying service-provider prescription behaviors may be considered to reduce possible negative consequences of BZD LTU.
To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on [3H]flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to omega 1 receptor (Ki = 10 nM) than to omega 2 receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to omega 1 and omega 2 receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to omega 1 and omega 2 receptors, respectively. In the displacement study on [3H] Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the omega 3 receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central omega 1 receptors.
A study was carried out to estimate the relative bioavailability of 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1, 3-dihydro-1H-1,4-benzodiazepine-2-one (lormetazepam, Minias) in humans after administration of oral tablets and solutions. Plasma concentration of the drug was measured by gaschromatography with electron capture detector. Six healthy males were each given both formulations. With the oral solution higher plasma peak concentration and a shorter peak time were observed than with tablets. Also the elimination half-life was shorter with the oral solution, while no difference was found with the AUC.
This study was conducted to determine the prevalence and profile of use of benzodiazepines in the Italian population and risk factors for use. Between November 1992 and February 1993, 62 general practitioners submitted a validated self-administered questionnaire on health status and drug use to a randomised sample of 3100 subjects ( > or = 18 years of age, stratified by sex and age), of whom 2803 responded (response, rate 90.4%). Main outcome measures were point estimate (past-week) of all the drugs taken by each individual, dosage and length of use and source of the prescription. The overall past-week prevalence of use of benzodiazepines was 8.6% (5.0% males and 11.8% females). In the elderly ( > or = 65 years) 18.8% reported current use (9.0% males and 24.7% females). Fifty-six per cent of the persons exposed to a benzodiazepine were chronic users (daily, for more than 6 months), and 70.1% in subjects > or = 65 years. The average daily dose taken was relatively low: 61% of short-term users and 51% of chronic users used less than half a defined daily dose (DDD). Female sex, older age, unemployment and retirement were independently associated with the use of benzodiazepines. Benzodiazepine use in Italy appeared to be relatively high (about 9% of subjects reported current use 57% of whom were chronic users). Women were prescribed a benzodiazepine twice as often as men and one out of four elderly women was on treatment. Although the average dosage used was rather low, the high prevalence and the elevated proportion of chronic users should encourage drug information campaigns and educational interventions to promote a more conservative use of these drugs especially in the elderly.
This study explored the relative impact of general medical conditions and psychopathology on the current and lifetime use of anxiolytic and/or hypnotic drugs by general hospital inpatients. One hundred and five consecutive patients, admitted to an internal medicine department, were assessed by a structured interview about current and lifetime use of anxiolytic and/or hypnotic drugs, and with somatic and psychopathology scales. Eighty percent of patients reported using anxiolytics and/or hypnotics at least once in a lifetime, 62.9% in the last year, 55.2% in the last 3 months, and 42.9% in the last week. Correlations were found between drug use and current levels of anxiety and depression, but not somatic pathology. Psychological suffering appeared to be a major determinant for anxiolytic and/or hypnotic use by patients with general medical conditions. Consumption rates were higher than in the general population, but there was no direct link between somatic morbidity and drug use.
The extended amygdala, a morphological and functional entity within the basal forebrain, is a neuronal substrate for emotional states like fear and anxiety. Anxiety disorders are commonly treated by benzodiazepines that mediate their action via GABA(A) receptors. The binding properties and action of benzodiazepines depend on the alpha-subunit profile of the hetero-pentameric receptors: whereas the alpha1 subunit is associated with benzodiazepine type I pharmacology and reportedly mediates sedative as well as amnesic actions of benzodiazepines, the alpha2 subunit confers benzodiazepine type II pharmacology and mediates the anxiolytic actions of benzodiazepines. We determined the localization of alpha1 and alpha2 subunits within the extended amygdala, identified by secretoneurin immunostaining, to define the morphological substrates for the diverse benzodiazepine actions. A moderate expression of the alpha1 subunit could be detected in compartments of the medial subdivision and a strong expression of the alpha2 subunit throughout the central subdivision. It is concluded that the alpha1 and alpha2 subunits are differentially expressed within the extended amygdala, indicating that this structure is compartmentalized with respect to function and benzodiazepine action.
Lormetazepam is a short-acting benzodiazepine hypnotic which is beneficial in shortening the time to onset of sleep. The aim of the study was to assess a new formulation of lormetazepam (oral solution) in comparison with lormetazepam tablets in out-patients with insomnia. This trial was an open randomized parallel group study conducted by 30 general practitioners. One hundred and eight patients took 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg (for oral solution) and 0.5 mg (for tablets), respectively, each day and every 2 days. The patients assessed the efficacy, acceptability and tolerance of lormetazepam using a diary card and a set of visual analogue scales assessing their sleep. Over 14 days of treatment, the mean daily dose of lormetazepam was lower in the oral solution group than in the tablets group (0.78 mg versus 0.97 mg). The cumulated dose of lormetazepam was lower with the oral solution (18% reduction). No significant difference between the two groups was found in the assessment of sleep characteristics. The occurrence of side effects did not differ between the two groups. These results suggest that a unitary dose as achieved by an oral solution of lormetazepam allows easier determination of the minimal individual effective dose.
The purpose of the study was to assess prevalence of benzodiazepine use in the Swiss adult population and to assess on benzodiazepine prescription patterns of physicians in domiciliary practice.
A retrospective, population-based cross-sectional study with 520 000 patients covering a 6-month period.
We estimated the prevalence, amount and duration of benzodiazepine use using a pharmacy dispensing database.
Of all patients, 9.1% (n=45 309) received at least one benzodiazepine prescription in the 6-month period. Most persons receiving benzodiazepine prescriptions were women (67%), and half of all patients were aged 65 or older. Of 45 309 patients with benzodiazepine prescriptions, 44% (n=19 954) had one single prescription, mostly for a short period (<90 days) and in lower than the recommended dose range. Fifty-six percent (n=25 354) had repeated benzodiazepine prescriptions, mostly for a long time period (>90 days), and in lower than the recommended or within the recommended dose range. In patients with long-term use (n=25 354), however, 1.6% had benzodiazepine prescriptions in extremely high doses. The sample of patients with repeated prescriptions allowed an estimation of a benzodiazepine use of 43.3 daily defined doses per 1000 inhabitants in Switzerland.
Benzodiazepine prescriptions were appropriate for most patients and thus were prescribed in therapeutic doses, as indicated in the treatment guidelines. On the other hand, our survey showed that 1.6% of the patients had prescriptions for long time periods at very high doses, indicating an abuse or dependence on benzodiazepines in this subgroup.
Databases from the New England Veterans Integrated Service Network were analyzed to determine factors associated with long-term, high-dose anxiolytic benzodiazepine prescriptions dispensed to patients with posttraumatic stress disorder (PTSD) and existing alcoholism and/or drug abuse diagnoses. Among 2,183 PTSD patients, 234 received the highest 10% average daily doses for alprazolam, clonazepam, diazepam, or lorazepam, doses above those typically recommended. Highest doses were more commonly prescribed to patients with existing drug abuse diagnoses. Among patients with PTSD and alcoholism, younger age, drug abuse, and concurrent prescriptions for another benzodiazepine and oxycodone/acetaminophen independently predicted high doses. Results indicate that for veteran patients with PTSD, alcoholism alone is not associated with high-dose benzodiazepines, but existing drug abuse diagnoses do increase that risk.
The availability of medicines on the illicit drug market is currently high on the international policy agenda, linked to adverse health consequences including addiction, drug related overdoses and injection related problems. Continuous surveillance of illicit use of medicines allows for earlier identification and reporting of emerging trends and increased possibilities for earlier intervention to prevent spread of use and drug related harm. This paper aims to identify data sources capable of monitoring the illicit use of medicines; present trend findings for Rohypnol and Subutex using a multi-indicator monitoring approach; and consider the relevance of such models for policy makers.
Data collection and analysis were undertaken in Bergen, Norway, using the Bergen Earlier Warning System (BEWS), a multi-indicator drug monitoring system. Data were gathered at six monthly intervals from April 2002 to September 2006. Drug indicator data from seizures, treatment, pharmacy sales, helplines, key informants and media monitoring were triangulated and an aggregated differential was used to plot trends.
Results for the 4-year period showed a decline in the illicit use of Rohypnol and an increase in the illicit use of Subutex.
Multi-indicator surveillance models can play a strategic role in the earlier identification and reporting of emerging trends in illicit use of medicines.
Hooked on benzodiazepines: GABAA receptor subtypes and addiction
- K R Tan
- U Rudolph
- C Luscher
- KR Tan
Tan KR, Rudolph U, Luscher C (2011) Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci
34:188-197
Alcohol: guide to use. Rome: Italian Ministry of Health
- Italian Ministry
- Health
Italian Ministry of Health (2017) Alcohol: guide to use. Rome:
Italian Ministry of Health. https ://www.salut e.gov.it/porta le/salut
e/p1_5.jsp?lingu a=itali ano&id=81&area=Vivi_sano. Accessed
27 Sep 2018
The American psychiatric publishing textbook of substance abuse treatment, 4th edn
- M Galanter
- H D Kleber
Galanter M, Kleber HD (2008) The American psychiatric publishing textbook of substance abuse treatment, 4th edn. American
Psychiatric Publishers, Arlington
The diagnostic interview for DSM-IV personality disorders (DIPD-IV)
- M Zanarini
- F Frankenburg
- A Sickel
- L Yong