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Mono- and poly-therapy with benzodiazepines or Z-drugs: Results from a tertiary-care Addiction Unit study
Abstract
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.
... Third, the cross-sectional data limited the ability to test causality formally and limited the generalizability of our results, so longitudinal studies are suggested in future research. Forth, some control variables that may impact distress intolerance, psychological flexibility and psychological distress are not investigated: for example, data on past of current pharmacological treatments (e.g., using or not BZDs, z drugs, SSRI/SNRI; using psychotropic drugs in poly-therapy or mono-therapy) and data on past or current psychological treatments (Bright et al., 2020;Cosci et al., 2016;Hausken et al., 2007;Mansueto, Lugoboni, et al., 2021;Swartz, 2020). Considering and assessing these variables is an important direction for future research. ...
The global COVID-19 outbreak has put the human race's distress tolerance abilities to the test. And, the distress experienced getting worse with each pandemic wave; however, the more flexible the person, the greater the chance of surviving. Thus, the current study aimed to examine the mediating role of personalized psychological flexibility (PPF) in the link between distress intolerance to psychological distress during the fourth wave of the pandemic in Iran. A total of 576 individuals (Meanage 34.80, ±10.9, females 55.6 %) took part in the online survey. In this national sample, PPF partially played a role in mediating the association mentioned above. Interestingly, this mediation was independent of demographic factors (age, gender, marital status, and educational level) and fear of COVID-19, mindfulness, and satisfaction with life. So, despite the mentioned variables, accepting and using unpleasant emotions as fuel to achieve valued goals rather than avoiding them would mitigate the psychological distress during the pandemic. Consequently, public health services can aim to provide psychological flexibility enhancing interventions to decay COVID-19-related mental distress.
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.
Purpose: To evaluate whether the concurrent use of benzodiazepines,
antidepressants, and opioid analgesics with zolpidem increases the risk of suicide or triggers suicide compared with the use of zolpidem alone.
Methods: We conducted a case-control and case-crossover study using the Korean National Health Insurance Service-National Sample Cohort database. Cases were older than 20 years with a suicide record (International Codes of Disease 10th Revision codes: X-60-X84 and Y87.0 intentional self-harm) between January 1, 2004, and December 31, 2013. For case-control design, 10 controls were matched to each
case by age, sex, index year, region, income, and health insurance type. For casecrossover analysis, we set hazard period to 60 days and assigned 5 corresponding sets of control periods of equal length. Exposure was assessed during 60-days before suicide for combinations of benzodiazepines, antidepressants, opioid analgesics with zolpidem against zolpidem alone. We conducted a conditional logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs).
Results: In the case-control study, the risk of suicide was 2.80-fold higher in cases taking benzodiazepines, antidepressants with zolpidem than in those taking zolpidem alone (adjusted OR [aOR], 2.80; 95% CI, 1.38–5.70). However, in the case-crossover
study, suicide risk showed no significant difference (crude OR [cOR], 0.92; 95% CI, 0.55–1.52) and was underpowered.
Conclusions: The results of the traditional case-control study confirmed that the concurrent use of benzodiazepines and antidepressants with zolpidem was associated with an increased risk of suicide compared with the use of zolpidem alone. However,
there was no significant difference in the magnitude of risk in the within-person comparison design.
Abstract
Background
Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone (‘Z-drugs’) clinical concerns relating to their potential of abuse, dependence and withdrawal have been reported overtime. We aimed here at assessing these issues analysing datasets of Adverse Drug Reactions (ADR) provided by the European Medicines Agency (EMA) through the EudraVigilance (EV) system.
Methods
Analysing the ADR databases of each Z-drug, descriptive analyses have been performed on cases, and Proportional Reporting Ratios (PRRs) computed.
Results
An overall number of 33,240 (e.g. 23,420 zolpidem; 9,283 zopiclone; and 537 zaleplon) misuse/abuse/dependence/withdrawal-related ADRs, corresponding to some 6,246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data, such as concomitant drugs, doses, routes of administration, and outcomes of the reactions, being fatalities recorded. Considering PRR values, and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was the most involved in overdose ADRs. If compared with zaleplon, zopiclone presented higher dependence and overdose-related issues, but slightly lower misuse/abuse and withdrawal PRR values.
Conclusion
Current data may only represent a gross underestimate of the Z-drugs’ misusing issues’ real prevalence. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand and prevent any possible misusing potential of prescribed medications.
Purpose:
1) To evaluate trends for benzodiazepines (BZD) and Z-Drugs over 15-years in a general Canadian adult population measured by: a) consumption b) pharmacologic exposure c) dose intensity and d) prevalence of use. 2) To demonstrate the utility of Diazepam Milligram Equivalence (DME) based measurements when used in conjunction with traditional standard measurements of drug utilization such as the Defined Daily Dose (DDD) system.
Methods:
Administrative data covering all prescriptions from April 2001-March 2016 for BZD and Z-Drugs for patients ≥18 years was used. Consumption was calculated as DDD/1000-person days. Dose intensity (DI) was determined by conversion of individual daily doses to Diazepam Milligram Equivalents (DME). Pharmacologic exposure (PE) was calculated as DME-DDD/1000-person days. Prevalence was determined as the proportion of the adult population with receipt of ≥1 prescription in a given year. Changes were assessed using either Poisson or simple linear regression at an alpha of 0.05.
Results:
Z-Drug usage (~99% zopiclone) statistically increased on every measure over the course of the study period; consumption (8.2 to 28.6 DDD/1000-person days), PE (4.1 to 14.3 DME-DDD/1000-person days), DI (5.0 to 5.43 DME/day) and prevalence (2.0% to 4.8%). For BZD the only statistically significant changes were in DI (17.1 to 20.1 DME/day) and prevalence (9.3% to 8.1%). Consumption and PE gradually increased from 2001 to 2011 for BZD before declining thus producing a non-significant trend for BZD.
Conclusion:
1) Z-Drug usage increased markedly from 2001 to 2016 whereas BZD use only increased in terms of DI. 2) DME-based measurements enable further interpretation of BZD utilization compared to sole reliance on DDD.
Benzodiazepine-like drugs (z-hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z-hypnotics are recommended for short-term treatment not exceeding 4 weeks. We aimed to study the use of z-hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co-medication with benzodiazepines and opioids in long-term users. Data were obtained from the Norwegian Prescription Database. New users in 2009 were followed through 2013. Recurrent z-hypnotic use was defined as new fillings at least once in each of the four 365-day follow-up periods. Age groups 18-39, 40-64 and 65+ were analysed separately for men and women. In 2013, 354,571 (8.9%) of the population filled at least one prescription of z-hypnotics and the prevalence was relatively stable over time. Among the 92,911 new users of z-hypnotics in 2009, 13,996 (16.8%) received z-hypnotics all four 365-day periods of follow-up. In these long-term recurrent users, the treatment intensity was high already the second year, with mean annual amounts of 199 and 169 DDDs per patient in men and women, respectively. The interquartile differences were greatest in the youngest age group. 27.9% of the long-term recurrent users of z-hypnotics used benzodiazepines the fourth year and 33.9% used opioids. The proportions with co-medication increased with level of z-hypnotic treatment intensity. Overall, many z-hypnotics users had medicines dispensed for longer periods than recommended, and co-medications with drugs that may reinforce the central depressing and intoxicating effects were common. This article is protected by copyright. All rights reserved.
Statistical methods involved in carrying out a study include planning, designing, collecting data, analysing, drawing meaningful interpretation and reporting of the research findings. The statistical analysis gives meaning to the meaningless numbers, thereby breathing life into a lifeless data. The results and inferences are precise only if proper statistical tests are used. This article will try to acquaint the reader with the basic research tools that are utilised while conducting various studies. The article covers a brief outline of the variables, an understanding of quantitative and qualitative variables and the measures of central tendency. An idea of the sample size estimation, power analysis and the statistical errors is given. Finally, there is a summary of parametric and non-parametric tests used for data analysis.
Background:
Benzodiazepines are frequently prescribed to patients with drug use disorders. However, it has previously been difficult to distinguish whether this frequent prescribing was due to underlying psychiatric disorders or inappropriate prescribing. In a nationwide cohort study, we investigated the prescribing of benzodiazepines to patients with drug use disorders in connection with treatment admission.
Methods:
Benzodiazepine prescriptions to patients (N = 33203) aged 18 to 67 years admitting for outpatient treatment for drug use disorders in Denmark, 2000 to 2010, were studied by using linked data from nationwide health registries. Factors associated with increasing amounts of benzodiazepine use within the first year after admission were assessed by multinomial logistic regression. Proportions of very long-term benzodiazepine prescription were calculated.
Results:
During the first year after admission to treatment, 26.2 % of patients were prescribed benzodiazepines. Of these, 35.5 % were prescribed benzodiazepines at dose levels that might indicate inappropriate use (>365 Defined Daily Dose per year), and 34.6 % were prescribed more than one type of benzodiazepines. Diazepam was the most commonly prescribed type. Among patients with opioid use, 43.2 % were prescribed benzodiazepines which were three times higher than for patients with cannabis (12.2 %) or central stimulating drugs (13.8 %) as their primary drug use. Admitting to treatment for a drug use disorder did not increase the specialized psychiatric treatment coverage of this patient group, disregarding use of prescribed benzodiazepines. 29.5 % were new users of prescribed benzodiazepines, and of these, 27.5 % continued into very long-term use (≥4 years after admission) during the study period.
Conclusions:
Benzodiazepines were commonly prescribed to patients admitting to treatment for drug use disorders, and included prescription of multiple and non-optimal types, high doses, and very long-term prescriptions. These findings point towards inappropriate prescribing of benzodiazepines in many cases more than treatment for psychiatric disorders.
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.
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.
Many patients with mental illness receive psychotropic medicine in high dosages and from more than one drug. One of the consequences of this practice is obesity, which is a contributing factor to increased physical morbidity and premature death.
Our study was a cluster-randomized intervention study involving 6 facilities and 174 patients diagnosed with severe mental illnesses (73% schizophrenia). The intervention period was 12 months and consisted of teaching sessions with the staff and evaluating the patients' intake of psychotropic medication. At index, 44% met criteria for obesity and 76% met criteria for overweight. Waist circumferences were 108 cm for men and 108 cm for women. Olanzapine, clozapine and quetiapine were the most common prescribed antipsychotics. Mean values of daily doses of antipsychotic were 2.5.
The intervention showed no significant differences between the intervention and control group regarding psychotropic treatment. At follow up, independent of intervention, patients receiving antipsychotic polypharmacy had a larger waist circumference compared with patients receiving antipsychotic monotherapy of 9.8 cm (1.5-18.1) (p = 0.028).
We found both a high prevalence of obesity and that the patients received treatment with antipsychotic polypharmaceutics in high dosages. Active awareness did not change practice and we must think of other ways to restrict treatment with psychotropics in this group of patients.
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.
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.
Lormetazepam (Noctamid®) at a dosage of 1 mg was compared with diazepam (Valium®) at a dosage of 5 mg in a 7-day double-blind study. The study involved fifty patients in the lormetazepam group and fifty patients in the diazepam group. All the patients were suffering from sleep disorders as a concomitant symptom of general diseases.
Lormetazepam was significantly better than diazepam in the:
Reduction of the time taken to fall asleep (p < 0.05) Prolongation of the duration of uninterrupted sleep (p < 0.05) Reduction of the frequency of awakening (p < 0.05)
Lormetazepam displayed no hang-over effects or other side-effects and, in this respect too, was significantly superior to diazepam (p < 0.05).
The objectives of the study were to compare long-acting dihydropyridine calcium channel blockers (CCBs) with angiotensin II receptor blockers (ARBs) according to the ambulatory blood pressure monitoring (ABPM) profile in stage 1 and 2 newly diagnosed hypertensives and also to evaluate the efficacy of high-dose monotherapy vs low-dose combination therapy of the two drug categories among the subjects with inadequate blood pressure (BP) control after conventional low-dose monotherapy. We obtained 24-h ABPM readings from 302 subjects with newly diagnosed stage 1 or 2 essential hypertension. The study protocol consisted of initial drug treatment with a low dose of either CCBs or ARBs. Hypertensives who did not achieve BP control were randomized to high-dose monotherapy of either category of drug or low-dose combination therapy. CCBs and ARBs in low-dose monotherapy achieved BP control in 53.8 and 55.3% of the cases, respectively. However, subjects under treatment with CCBs experienced side effects more often and required that treatment be discontinued. Hypertensives who failed to control their BP with low-dose monotherapy did significantly better with low-dose combination treatment (61.6%) than with high-dose CCBs (42.8%) or ARBs (40.5%) monotherapy (P<0.05). In terms of ABPM, low-dose combination therapy exhibited better 24-h BP profile according to trough-to-peak ratio, hypertensive burden and BP variability. In conclusion, low-dose ARBs and CCBs have a comparable effect in subjects with grade 1 and 2 arterial hypertension. In hypertensives who are not controlled by low-dose monotherapy, low-dose combination therapy proves be more efficacious than high-dose monotherapy.
Objectives: Z-Drugs (ZDs) have been developed to limit benzodiazepines (BZDs) abuse for sleep disorders. Data on the liver toxicity of zolpidem (ZLM) are lacking or anecdotal. The authors evaluated the presence of drug-induced liver injury (DILI) among a cohort of high-dose ZLM abusers.
Methods: Retrospective study analyzing clinical records of 1112 consecutive patients admitted for BZDs detoxification from 2003 to 2018. Inclusion criteria: age >18 yo; ZLM abuse/dependence; high dose ZDs abuse. Exclusion criteria: missing lab data; lack of informed consent. Main outcome was the presence of DILI measured as elevation of ALT/AST levels >250 U/l.
Results: A total of 107 patients met the eligibility criteria. Liver enzymes alterations were present in 9.3% (95% CI 4.6-16.5%); one patient (0.9%, 95% CI 0.0-2.8%) showed DILI criteria. BMI significantly influenced transaminases levels. No correlations between duration nor doses of ZLM abuse and transaminases levels were found.
Conclusion: The present study shows a very low prevalence of DILI among high-dose ZLM abusers. The prevalence of hypertransaminasemia was in line with general population. On one hand ZLM has a substantially safe liver profile but on the other hand ZLM abuse and dependence, especially at very high doses, represents an emerging problem.
High-dose 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.
Background: Benzodiazepine misuse is a growing public health problem, with increases in benzodiazepine-related overdose deaths and emergency room visits in recent years. However, relatively little attention has been paid to this emergent problem. We systematically reviewed epidemiological studies on benzodiazepine misuse to identify key findings, limitations, and future directions for research.
Methods: PubMed and PsychINFO databases were searched through February 2019 for peer-reviewed publications on benzodiazepine misuse (e.g., use without a prescription; at a higher frequency or dose than prescribed). Eligibility criteria included human studies that focused on the prevalence, trends, correlates, motives, patterns, sources, and consequences of benzodiazepine misuse.
Results: The search identified 1,970 publications, and 351 articles were eligible for data extraction and inclusion. In 2017, benzodiazepines and other tranquilizers were the third most commonly used illicit or prescription drug in the U.S. (approximately 2.2% of the population). Worldwide rates of misuse appear to be similar to those reported in the U.S. Factors associated with misuse include other substance use, receipt of a benzodiazepine prescription, and psychiatric symptoms and disorders. Benzodiazepine misuse encompasses heterogeneous presentations of motives, patterns, and sources. Moreover, misuse is associated with myriad poor outcomes, including mortality, HIV/HCV risk behaviors, poor self-reported quality of life, criminality, and continued substance use during treatment.
Conclusions: Benzodiazepine misuse is a worldwide public health concern that is associated with a number of concerning consequences. Findings from the present review have implications for identifying subgroups who could benefit from prevention and treatment efforts, critical points for intervention, and treatment targets.
Background
The study objectives were to explore trends in prevalence of co-use of benzodiazepine receptor modulators and opioids, and non-selective and selective (i.e., Z-drugs) benzodiazepine receptor modulators, in the United States, as well as risk factors for these drug utilization patterns.
Methods
This was a multi-year, cross-sectional, population-level study, using United States health survey data. Data from eight National Health and Nutrition Examination Survey (NHANES) cycles were analyzed, from 1999–2000 until 2013–2014, with each survey cycle containing information on ~10,000 individuals. The main measure was prevalent prescription drug use within 30 days preceding survey administration. Drug usage was objectively confirmed for a large majority of participants though direct inspection of prescription bottles.
Results
The estimated prevalence of concurrent benzodiazepine receptor modulator and opioid use in the United States was 0.39% in 1999–2000 and 1.36% in 2013–2014, reflecting absolute and relative changes of +0.97% and +249%. The estimated prevalence of non-selective and selective benzodiazepine receptor modulator co-use steadily rose in the United States from 0.05% in 1999–2000 to 0.47% in 2013–2014, reflecting absolute and relative increases of +0.42% and +840%. Independent risk factors for these two forms of psychoactive medication polypharmacy were identified.
Conclusion
In this exploratory analysis, concurrent use of benzodiazepine receptor modulators and opioids, and non-selective and selective benzodiazepine receptor modulators, was found to have progressively risen in the United States. The progressive increases in these two forms of psychoactive medication polypharmacy is concerning, given that these drug use patterns are associated with increased risk for serious adverse outcomes.
Points essentiels
Toutes les benzodiazépines et les médicaments apparentés possèdent des effets pharmacodynamiques soumis à tolérance. Cette tolérance pharmacologique aux benzodiazépines peut se manifester rapidement, entre une semaine et un mois, et concerne en particulier les propriétés hypnotiques et anxiolytiques.
Des études anciennes ont montré une réelle mais faible efficacité à court terme des benzodiazépines sur l’anxiété et les troubles du sommeil.
L’efficacité à long terme des benzodiazépines peut se confondre avec la survenue d’effets rebond, de symptômes de sevrage ou d’une rechute à l’arrêt qui contribuent à une apparence d’efficacité, d’autant que la réintroduction du médicament va supprimer ces symptômes.
Il existe une tolérance pharmacologique à la fois pour l’efficacité et certains effets indésirables des benzodiazépines, qui diminuent de façon marquée dès les premières semaines de traitement. Le principal corollaire de cette tolérance est la survenue d’un syndrome d’interruption à l’arrêt du traitement, parfois sévère et douloureux.
Dans la lutte contre les traitements à long terme, il apparaît pertinent de cibler la primo-prescription de benzodiazépines : il est essentiel de limiter à la fois les indications et la durée des traitements dès leur initiation.
Les co-addictions aux benzodiazépines sont fréquentes chez les patients en soins pour une addiction à l’alcool ou aux drogues illicites, avec des complications plus fréquentes, notamment surdoses et tentatives de suicide.
La prescription des benzodiazépines reste essentielle dans la prévention des complications de sevrage de l’alcool et des benzodiazépines elles-même chez les patients traités pour un trouble lié à l'usage de substances, mais une durée de prescription limitée et des modalités de délivrance contrôlées sont utiles dans les soins de cette population spécifique.
Aims:
To examine prescribing trends for benzodiazepines and Z-drugs to General Medical Services (GMS) patients in Ireland.
Methods:
A repeated cross-sectional analysis of the national pharmacy claims database was conducted for GMS patients aged ≥16 years from 2005-2015. Prescribing rates per 1000 eligible GMS population were calculated with 95% confidence intervals (CIs). Negative binomial regression was used to determine longitudinal trends and compare prescribing rates across years, gender and age groups. Duration of supply and rates of concomitant benzodiazepine and Z-drug prescribing were determined. Age (16-44, 45-64, ≥65 years) and gender trends were investigated.
Results:
Benzodiazepine prescribing rates significantly decreased from 225.92/1000 population (95% CI 224.94-226.89) in 2005 to 166.07/1000 population (95% CI 165.38-166.75) in 2015 (p<0.0001). Z-drug prescribing rates significantly increased from 95.36/1000 population (95% CI 94.73-96.00) in 2005 to 109.11/1000 population (95% CI 108.56-109.67) in 2015 (p=0.048). Approximately one third of individuals were receiving long-term prescriptions (>90 days) for either benzodiazepines or Z-drugs. The proportion of those receiving >1 benzodiazepine and/or Z-drug concomitantly increased from 11.9% in 2005 to 15.3% in 2015. Benzodiazepine and Z-drug prescribing rates were highest for older women (≥65 years) throughout the study period.
Conclusions:
Benzodiazepine prescribing to the GMS population in Ireland significantly decreased from 2005 to 2015, and was coupled with significant increases in Z-drug prescribing. The study shows that benzodiazepine and Z-drug prescribing is common in this population, with a third receiving long-term prescriptions. Targeted interventions are needed to reduce potentially inappropriate long-term prescribing and use of these medications in Ireland.
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.
There are well-recognised harms from long-term use of benzodiazepines. These include dependency, cognitive decline and falls. It is important to prevent and recognise benzodiazepine dependence. A thorough risk assessment guides optimal management and the necessity for referral. The management of dependence involves either gradual benzodiazepine withdrawal or maintenance treatment. Prescribing interventions, substitution, psychotherapies and pharmacotherapies can all contribute. Unless the patient is elderly, it is helpful to switch to a long-acting benzodiazepine in both withdrawal and maintenance therapy. The dose should be gradually reduced over weeks to lower the risk of seizures. Harms from drugs such as zopiclone and zolpidem are less well characterised. Dependence is managed in the same manner as benzodiazepine dependence. © 2015, Australian Government Publishing Service. All rights reserved.
Although psychoactive substances vary in many ways, they have important commonalties, particularly in their ability to lead to an addiction syndrome. The field lacks an updated review of the commonalities and differences in the phenomenology of alcohol, cannabis, tobacco, stimulants, opioids, hallucinogens, sedatives/tranquilizers, and inhalants and their related substance use disorders (SUDs).
DSM-IV and DSM-5 SUD diagnostic criteria were reviewed, as was evidence from recent epidemiological and clinical research: psychometric studies (test-retest reliability, latent trait analysis); physiological indicators (tolerance, withdrawal); prevalence and age of onset. Information was incorporated from previous reviews, PubMed and Scopus literature searches, and data from large U.S. national surveys.
Empirical evidence in the form of test-retest reliability and unidimensionality supports use of the same DSM-IV dependence or DSM-5 SUD diagnostic criteria across substances. For most substances, the criteria sets were generally most informative in general population samples at moderate-to-severe levels of SUD. Across substances, 2 criteria (tolerance and use in hazardous situations) were identified as functioning differently in population subgroups. Since substances have different pharmacological effects, withdrawal is assessed using substance-specific symptoms, while tolerance is not; issues remain with the assessment of tolerance. Alcohol, tobacco, and cannabis were consistently identified as the substances with earliest onset of use, highest prevalence of lifetime use, and highest prevalence of lifetime disorder.
Despite differences between psychoactive substances, the generic DSM criteria set appears equally applicable across substances. Additional studies of tolerance and hazardous use will be useful for future nosologies. Alcohol, cannabis, and tobacco are the substances with the greatest public health impact due to the high prevalence and early onset of their use, and the potential all 3 substances have to lead to addiction.
Copyright © 2015 by the Research Society on Alcoholism.
sPsychotropic dose equivalence is an important concept when estimating the approximate psychotropic doses patients receive, and deciding the approximate titration dose when switching from one psychotropic agent to another. It is also useful from a research viewpoint when defining and extracting specific subgroups of subjects. Unification of various agents into a single standard agent facilitates easier analytical comparisons. On the basis of differences in psychopharmacological prescription features, those of available psychotropic agents and their approved doses, and racial differences between Japan and other countries, psychotropic dose equivalency tables designed specifically for Japanese patients have been widely used in Japan since 1998. Here we introduce dose equivalency tables for (1) antipsychotics, (2) antiparkinsonian agents, (3) antidepressants, and (4) anxiolytics, sedatives and hypnotics available in Japan. Equivalent doses for the therapeutic effects of individual psychotropic compounds were determined principally on the basis of randomized controlled trials conducted in Japan, and consensus among dose equivalency tables reported previously by psychopharmacological experts. Since these tables are intended to merely suggest approximate standard values, physicians should use them with discretion.
Psychiatric polypharmacy refers to the prescription of two or more psychiatric medications concurrently to a patient. It can be categorised as same-class, multi-class, adjunctive, augmentation and total polypharmacy. Despite advances in psychopharmacology and a better understanding of the principles of therapeutics, its practice is increasing rapidly. The prevalence of polypharmacy in psychiatry varies between 13%-90%. There are various clinical and pharmaco-economic factors associated with it. Dealing with polypharmacy requires an understanding of its associated factors. Education, guidelines and algorithms for the appropriate management of various conditions are effective ways to avoid irrational polypharmacy.
The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies.
Medline, Iowa Drug Information Service, International Pharmaceutical Abstracts, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4-methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drug-drug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate.
The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent's therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate.
Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies.
Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.
Lormetazepam, a new short-acting benzodiazepine, was tested multicentrally in 15 general practices. The subjects were 62 chronically sleep-disturbed patients. The first 7 days served as a placebo baseline week, the next 14 days were either lormetazepam or placebo in a randomized double-blind design, and during the last week placebo was given again to measure rebound effects. Lormetazepam was found to be an effective hypnotic that causes virtually no hangover the next morning. In this study no rebound effects could be measured. Visual analogue scales, among others, were used for the assessment of sleep characteristics.
A common approach to the management of hypertension suggests the use of an initial drug and the addition of a second agent if goal blood pressures (BPs) are not achieved. The Sixth Report of the Joint National Committee (JNC VI) suggests that the use of low dose combination therapy may be an appropriate alternative to initial treatment. In this prospective, randomized, open label, blinded end point (PROBE) study, following a 2 week single blind placebo washout period, qualified patients were started on a calcium channel blocker, felodipine 5 mg for 2 weeks. Patients who were nonresponders (DBP equals 90 mm Hg) were randomized to either felodipine 10 mg (n equals 17, mean age 52.4, 12 males), an ACE inhibitor, enalapril 5 mg/felodipine 5 mg (n equals 20 mean, mean age 52.1, 13 males), or another ACE inhibitor, benazepril 10 mg/amlodipine 5 mg (n equals 18, mean age 53.9, 15 males) for an additional 6 weeks. Ambulatory BP monitoring was performed at the end of the single blind placebo washout period and again at the end of the study. All three treatment groups had significant reductions in mean 24 hour systolic and diastolic BP compared to baseline. The reduction in mean 24 hour systolic and diastolic BPs in the benazepril/amlodipine treated patients (-17.2/-9.7 mm Hg) was significantly greater (p equals 0.05) than in the felodipine 10 mg treated patients (-11.9/-6.4 mm Hg) and was also numerically but not statistically significantly greater than in the enalapril/felodipine treated patients (-14.2/-8.2 mm Hg). Similar differences were seen when assessing daytime BP (06:00-21:59) and nighttime BP (10:00-05:59). The reductions in morning systolic and diastolic BP (6 am-noon) in the benazepril/amlodipine treated patients (-18.6/-10.7 mm Hg) were numerically but not statistically significantly greater than the enalapril/felodipine treated patients (-13.6/-7.5 mm Hg) and the felodipine 10 mg treated patients (-14.9/-8.3 mm Hg). The data from this study suggests that using low dose combination therapy in patients who are nonresponders to first line monotherapy with a calcium channel blocker provides greater blood pressure control than up titration to higher dose monotherapy. Low dose combination therapy may therefore be an important early alternative to up titration of monotherapy in patients who are nonresponders. These data confirm other observations with combination therapy with à -blockers/ diuretics, ACE inhibitors/diuretics, and angiotensin II (AII) receptor blockers/diuretics. (c)1999 by Le Jacq Communications, Inc.
Different prevalences of benzodiazepine (BZ) use are described in the literature. The present study assessed the effects of employing various definitions of BZ use and various observation periods on the prevalence rate of BZ use in an open population aged 18-74 years.
In a literature review, prevalence studies were systematically compared. In a second stage, a descriptive cross-sectional multipractice study was analysed using 48,046 prescriptions of BZ in the past year given to a population of 80,315 patients at 31 general practices in the Nijmegen Health Area. From this database, prevalence rates were calculated applying different definitions of BZ use and different observation periods.
In the literature, prevalence rates varied between 2.2 and 17.6%. There was wide variation in definitions of BZ use and observation period. In our prescription database, depending on the definitions of BZ use and observation period, prevalence rates ranged from 0.2% to 8.9%. The ratio of female:male (2:1) remained constant irrespective of the prevalence rate. Age distribution varied according to the duration of use: among long-term BZ users, approximately 80% were older than 45 years; among short-term BZ users, approximately 55% were older than 45 years.
The wide variation in prevalence rates of BZ use reported in the literature can largely be explained by differences in definitions of BZ use and observation period. This affected the distribution of some BZ-use-related variables such as age. For reliable comparisons of BZ use, standardisation of the definition of BZ use is required. A proposal for standardising methodology is presented.
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.