Article

Long-term therapeutic use of benzodiazepines: I. Effects of abrupt discontinuation

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  • Paladin Labs
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Abstract

We compared the effect of abrupt discontinuation of therapeutic doses of short half-life and long half-life benzodiazepines in 57 benzodiazepine-dependent patients (daily use, greater than 1 year). Despite the use of a mean daily dose of 14.1 mg of diazepam equivalents, there were notable residual symptoms of anxiety and depression present at intake (Hamilton Rating Scale for Anxiety score, 17.0; Hamilton Rating Scale for Depression score, 14.0). Benzodiazepine intake was stabilized for 3 weeks before double-blind assignment to placebo (n = 47), or continued benzodiazepine use (n = 10). Clinical assessments were performed daily, including benzodiazepine plasma levels. Depending on the outcome criteria used, anywhere from 58% to 100% of patients were judged to have experienced a withdrawal reaction, with a peak severity at 2 days for short half-life and 4 to 7 days for long half-life benzodiazepines. Relapse onto benzodiazepines occurred in 27% of patients who were receiving long half-life benzodiazepines and in 57% of patients who were receiving short half-life benzodiazepines. Baseline predictors of relapse were nonpanic diagnoses, a higher benzodiazepine dose, and a higher Eysenck neuroticism score. A short half-life and higher daily doses were associated with greater withdrawal severity, as were personality traits, such as dependency and neuroticism, less education and higher baseline levels of anxious and depressive symptoms. Patients who were able to remain free of benzodiazepines for at least 5 weeks obtained lower levels of anxiety than before benzodiazepine discontinuation. These results provide a detailed picture of the symptoms, time course, and multidimensional determinants of the benzodiazepine withdrawal syndrome.

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... One RCT found that patients who were successful in cessation and able to remain BZRA free for at least 5 weeks had modestly lower levels of anxiety than before benzodiazepine discontinuation. 49 Although the prevention of future falls and fractures has not been confirmed in RCT meta-analyses and requires further study, a recent systematic review found that deprescribing BZRAs improves cognitive function across multiple domains (mean weighted effect size 0.41, standard deviation 0.22). 50-52 ...
... 58 Limited observational evidence in blinded BZRA deprescribing trials suggests that gradual dose reduction offers the advantage of decreased incidence and severity of withdrawal symptoms for long-term benzodiazepine users when compared to abrupt discontinuation. 49,54 However, very slow tapering does not appear to be superior to faster tapering regimens in terms of successful cessation. 54,59 Expert opinion and clinical experience also suggest that BZRAs can be abruptly discontinued safely in select situations where patients are closely monitored (e.g. ...
... With BZRA discontinuation, rebound insomnia occurs in about half of patients where sleep latency is increased, sleep is more disturbed and overall sleep is shorter in duration. 49,54,66 This unfortunately often leads to the erroneous conclusion that the BZRA had a beneficial pharmacological effect and premature drug resumption is a common response. Clinicians and patients should be aware that these symptoms will improve over time if one persists with the deprescribing plan as these changes are transient and typically short in duration (< 1 week). ...
Article
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Long-term benzodiazepine receptor agonist (BZRA) use for insomnia is common and highly prevalent in adults in all care settings. Evidence syntheses suggest that the therapeutic benefits of benzodiazepines for insomnia are marginal and very short term. On the harm side, BZRAs are associated with daytime sedation and confusion. Long-term use increases the risk of falls, fractures, cognitive impairment, and motor vehicle accidents. An evidence-based clinical practice guideline has been developed to assist with deprescribing BZRAs. This review highlights the rationale for deprescribing BZRAs used for insomnia and summarizes key messages for clinicians from the new BZRA deprescribing guideline and their supporting evidence.
... Benzodiazepines are often recommended in the patients who are conceded in emergency clinic without adequate archived record. Nervous system science (35.6%) and orthopedic (26%) are the two significant strengths answerable for the recommending of benzodiazepines in subsequent to checking the pace of benzodiazepines remedy into various claims to fame [11]. One examination from Pakistan detailed that the benzodiazepines were utilized in 21% of all out conceded patients [12.13]. ...
... The present investigation shows the pervasiveness and use of the benzodiazepines in the patients other than the psychiatry and nervous system science claims to fame [7]. As it was accounted for one examination that the psychiatrics are for the most part answerable for the administration of the sleep deprivation and liable for the benzodiazepine endorsing and nervous system science is likewise liable for high level of benzodiazepine recommending while this investigation indicated the use of the benzodiazepine other than psychiatry what's more nervous system science claim to fame [11,12]. Pervasiveness of the benzodiazepine use is practically comparative in both male and female in this examination as contrast with different investigations [18,19] which demonstrated huge distinction of benzodiazepine use between the two sexual orientations. ...
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The main objective of this research was to evaluate the prescribing ratio of benzodiazepines in the patients suffering from a disease other than a mental disorder. A prospective cross-sectional study was conducted at 24 different community pharmacies and medical stores of District Sukkur. Participants with age more than 18 years and using Benzodiazepines were included in this study. Average age of the Participants, who were participated, was 38 ± 20 years. From the 177 study subjects who visited the community pharmacies or medical stores for the purchase of benzodiazepines 104 were male and remaining 73 were female. From 177 patients 132 were married and remaining 45 were unmarried or widow. It was concluded that the consumption of benzodiazepine drugs is terrifyingly very high, especially as a self-medication without any prescription.
... Sin embargo, son el grupo farmacológico que engloba el 80% de la farmacodependencia (Rickels, 1990), debido a que generan tolerancia (cada vez se requieren dosis mayores para alcanzar el efecto deseado), abstinencia (cambios cognoscitivos, comportamentales y fisiológicos cuando se suspende o disminuye la ingesta) y consumo compulsivo, que en su conjunto constituyen un cuadro de dependencia (APA, 2013). ...
... La interrupción brusca del consumo de benzodiacepinas a dosis terapéuticas posteriores a un año de tratamiento, ocasiona un pico de abstinencia de benzodiacepinas de acción corta a los 2 días y de acción prolongada entre 4 a 7 días (Rickels, 1990). Estudios más recientes corroboran estos datos (Authier, 2009). ...
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A clinical guidance instrument was designed to allow the first contact physician to identify patients with customary consumption of a drug, such as benzodiazepines, to offer a therapeutic scheme to patients of their competence and refer complex cases to the specialty service. Reducing with this the health risks of benzodiazepines such as tolerance, withdrawal, dependence, cognitive deficits, traffic accidents, falls and fractures, sleep disturbances, changes in cerebral perfusion and increased risk of mortality compared to the general population, also associated with overdose and suicidal behaviors. It will also allow compliance with international, national and state legal regulations for the benefit of the population in the face of a public health problem.
... Thus the exclusion of benzodiazepines may affect the physical and mental health of economically disadvantaged elderly persons and beneficiaries with disabilities-those most requiring these medications. Without drug coverage, those who are currently clinically stabilized on benzodiazepines may face life-threatening abrupt discontinuation (18) or be switched to a less desirable alternative (15,17). ...
... Benzodiazepines are recommended for short-term treatment of anxiety disorders (12,26). Although gradually switching from benzodiazepines to selective serotonin-reuptake inhibitors (SSRIs) or nonbenzodiazepine anxiolytics is recommended for long-term management of anxiety (18), the initial and immediate relief of benzodiazepine therapy is still valuable. Furthermore, although restricting access to benzodiazepines is generally perceived to reduce related risks (27), a recent study suggests that policies resulting in significant reductions in benzodiazepine use in the elderly population failed to decrease the incidence of hip fracture (28). ...
Article
Objectives: Benzodiazepines are excluded from prescription drug coverage under Medicare Part D. The objectives of this study were twofold: to provide national estimates of benzodiazepine utilization and expenditure patterns and to examine the impact of drug coverage and other factors associated with utilization of benzodiazepines and potential benzodiazepine substitute classes. Methods: The 2002 Medicare Current Beneficiary Survey provided national estimates of benzodiazepine use and expenditures among Medicare beneficiaries. Multivariate logistic regression was conducted to assess the relationships between independent variables and use of benzodiazepines and potential substitute classes. The independent variable of interest was drug coverage, assessed by payer source. Other covariates included in the models were chronic conditions associated with benzodiazepine use, age, sex, race, and income. Results: In 2002, 13.7% of Medicare beneficiaries received at least one benzodiazepine fill, with an average of 5.8 benzodiazepine prescriptions filled at an annual cost of 190 dollars. Specific sources of prescription drug coverage were not significantly associated with benzodiazepine use. Female gender, chronic mental illness, age under 65, and lower income were significantly positively associated with benzodiazepine use in the Medicare population, whereas black and other races were significantly negatively associated with benzodiazepine use in this population. Compared with Medicare beneficiaries without supplemental drug coverage, beneficiaries with supplemental drug coverage were more likely to use potential benzodiazepine substitute classes than benzodiazepines. Conclusions: Benzodiazepines were widely used by Medicare beneficiaries. Drug coverage influences access to benzodiazepines and potential substitute classes. These findings have important implications for identifying beneficiaries potentially affected by the exclusion of benzodiazepine coverage under Medicare Part D.
... Nach langfristiger Behandlung mit Benzodiazepinen kann sich eine Abhängigkeit entwickeln (Bradwejn, 1993;Livingston, 1994;Nelson u. Chouinard, 1999;Rickels et al., 1990;Schweizer et al., 1990b;Shader u. Greenblatt, 1993;Smith u. ...
... AOK-Versicherten aufgrund der ICD-Diagnose F13 in stationären Einrichtungen behandelt (Soyka et al., 2005). Absetzphänomene haben ihr Maximum nach 2 Tagen bei Benzodiazepinen mit kurzer Halbwertzeit und bei 4-7 Tagen bei Benzodiazepinen mit langer Halbwertzeit (Rickels et al., 1990). ...
Article
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Die deutsche S3-Leitline zur Behandlung von Angststörungen (Panikstörung/Agoraphobie, generalisier- te Angststörung, soziale Phobie, spezifische Phobie) bei Erwachsenen wurde unter Beratung und Mode- ration durch die Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) von einem Gremium erstellt, das 20 Fachverbände und andere Organisationen aus den Bereichen Psy- chotherapie, Psychologie, psychosomatische Medizin, Psychiatrie und Allgemeinmedizin sowie Patien- tenvertreter und Selbsthilfeorganisationen umfasst. Die Empfehlungen dieser Leitlinie basieren auf ei- ner Sichtung der Evidenz der verfügbaren randomisierten klinischen Studien zu Angststörungen nach ICD/DSM und einer Synthese der Empfehlungen anderer Leitlinien.
... A study of 57 benzodiazepine patients who were abruptly discontinued from benzodiazepines after > 1 year of treatment and a mean daily dose of 14.1 mg diazepam equivalents reported that peak severity of withdrawal effects occurred in the first 2 days for short-acting and in the fourth to seventh days for long-acting agents. 13 This study followed patients for 5 weeks after their last dose of benzodiazepines and thus could not report on long-term symptoms. The perspective of physicians has been that short-term detoxification or tapering is equally effective, but our survey results suggest that only 22.8% of respondents could abruptly discontinue benzodiazepines. ...
... Rickels et al. found that 58-100% (criteria dependent) of benzodiazepine users experience some type of withdrawal reactions upon discontinuation. 13 Up to 44% of long-term benzodiazepine users have persistent moderate to severe withdrawal symptoms when they attempt to discontinue the drug. 3,19 This survey and other reports suggest that benzodiazepine withdrawal symptoms show considerable interindividual variability and do not follow a predictable trajectory. ...
Article
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Background Over 92 million prescriptions for benzodiazepines are dispensed in the United States annually, yet little is known about the experiences of those taking and discontinuing them. Objective The aim of this study is to assess the experiences of those taking, tapering, or having discontinued benzodiazepines. Methods An online survey ( n = 1207) elicited information about benzodiazepine use, including long-term use, tapering, discontinuation, and withdrawal symptoms. Results Symptoms associated with benzodiazepine use, tapering, and discontinuation were numerous and ranged from symptoms such as anxiety, insomnia, and nervousness to digestive problems, irregular heart rhythms, uncontrollable anger, photosensitivity, balance problems, and others. When asked how benzodiazepine symptoms affected their lives, 82.9% reported work problems, 86.3% had problems with social interactions and friendships, and 88.8% had problems with fun, recreation, and hobbies. Suicidal thoughts or attempted suicide was reported by 54.4%, and 46.8% said benzodiazepines caused lost employment. Most of the respondents for whom benzodiazepines were prescribed (76.2%) stated they had not been informed that benzodiazepines were indicated for short-term use only and that discontinuation might be difficult. About a third (31.5%) reported food allergies and/or seasonal allergies that occurred only after benzodiazepine use. Conclusion The trajectory of those who taper or discontinue benzodiazepines is unpredictable, and many patients experience a range of protracted and severe symptoms, even years after benzodiazepines were completely discontinued. Greater awareness is needed for both prescribers and patients about the potential for a difficult withdrawal from benzodiazepines.
... Decades later, 13 other BZDs have been approved by the US Food and Drug Administration (FDA); unfortunately, there is still much that is not understood. Prevalence of discontinuation symptoms in research ranges from 20 to 100%, dependent on a number of measurement variables [2][3][4][5]. Ashton estimated 10-15% of long-term users develop a ''post-withdrawal syndrome'' [6], and other literature suggests 15-44% have protracted symptoms of at least moderate severity [7]. Although investigations have significant methodologic limitations and are uncertain, the FDA has recently required a class-wide boxed warning for BZDs emphasizing the risk of physiologic dependence. ...
... BZD physiologic dependence may be evident as tolerance or the loss of effect with repeated exposure [8,27]. Principally, though, it is distinguished by symptoms that emerge with discontinuation or dosage reduction [2][3][4][5][6][7][8]. A withdrawal picture may also be present in the absence of dose decrements due to developing tolerance in the context of waning BZD blood (brain) levels prior to the next scheduled dose: interdose withdrawal [8,28]. ...
Article
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Although benzodiazepines have been used for 6 decades, many questions remain unanswered by research. The lived experiences of those adversely affected long term can provide insights into how these agents might be more thoughtfully prescribed. Here, perspectives of one such experience encompassing benzodiazepine initiation, ongoing use with adverse consequences and difficult discontinuation are presented through the eyes of an affected individual and a clinician. This experience highlights the importance of limited initiation and duration of use (2-4 weeks) as well as a supported, slow tapering process led by patients. Because researched evidence about deprescribing benzodiazepines is insufficient and because individual experiences vary so widely, it is the patient's expertise-that of her or his lived experience-that should assume a primary role in determining the course and pace of discontinuing these medications.
... All the included subjects will be advised to taper their benzodiazepines over 4 weeks according to a protocol as suggested by Rickels et al. [30]. The baseline benzodiazepine dosage in diazepam equivalent will be calculated based on the average daily consumption in the 2 weeks prior to baseline [31]. ...
Article
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Background Conventional approaches for benzodiazepine tapering have their limitations. Anecdotal studies have shown that acupuncture is a potential treatment for facilitating successful benzodiazepine tapering. As of today, there was no randomized controlled trial examining its efficacy and safety. The purpose of the study is to evaluate the efficacy of using electroacupuncture as an adjunct treatment to gradual tapering of benzodiazepine doses in complete benzodiazepine cessation in long-term benzodiazepine users. Methods/DesignThe study protocol of a randomized, assessor- and subject-blinded, controlled trial is presented. One hundred and forty-four patients with histories of using benzodiazepines in ?50% of days for more than 3 months will be randomly assigned in a 1:1 ratio to receive either electroacupuncture or placebo electroacupuncture combined with gradual benzodiazepine tapering schedule. Both experimental and placebo treatments will be delivered twice per week for 4 weeks. Major assessments will be conducted at baseline, week 6 and week 16 post-randomization. Primary outcome is the cessation rate of benzodiazepine use. Secondary outcomes include the percentage change in the doses of benzodiazepine usage and the severity of withdrawal symptoms experienced based on the Benzodiazepine Withdrawal Symptom Questionnaire, insomnia as measured by the Insomnia Severity Index, and anxiety and depressive symptoms as evaluated by the Hospital Anxiety and Depression Scale. Adverse events will also be measured at each study visit. DiscussionResults of this study will provide high quality evidence of the efficacy and safety of electroacupuncture as an adjunct treatment for benzodiazepine tapering in long-term users. Trial registrationClinicalTrials.govNCT02475538.
... To identify the effects of ASP3652 on mood and drug withdrawal, specific questionnaires were incorporated, that is, the Profile of Mood States questionnaire 12 and Physician Withdrawal Checklist. 13 ...
Article
Objectives: To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH-) inhibitor ASP3652 on safety and efficacy outcomes in Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). Inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors. Methods: In this adaptive, randomized, double-blind, placebo-controlled study adult male patients with moderate to severe CP/CPPS were treated for 12 weeks with an oral dose of ASP3652 (25, 75, 150 or 300mg twice daily [BID], or 300mg once daily) or placebo. A Bayesian model was used for adaptive prospective modeling of randomization, study continuation decisions and analysis of the efficacy variables. Results: The study was stopped for futility at pre-planned interim analysis when 239 patients were randomized (226 were included in the intention-to-treat set): the 25mg group showed the largest reduction of the primary endpoint NIH-CPSI total score (7.0 points), but the placebo group showed a mean reduction of 7.3 points (difference: 0.3 [95% confidence interval: -1.9 to 2.6]). Micturition outcomes improved compared to placebo in all ASP3652 groups, e.g., in the 300mg bis in die (BID, twice daily) group voiding frequency decreased by -1.10 (95% CI -2.0 to -0.2) voids/24hr vs. placebo. Safety outcomes were comparable across the treatment groups. Conclusions: ASP3652 was generally safe and well-tolerated. It did not show efficacy on pain symptoms in patients with CP/CPPS. However, results indicate that FAAH-inhibition may attenuate lower urinary tract symptoms. Dedicated studies in patients with lower urinary tract dysfunction are needed to confirm this.
... These symptoms can last up to four weeks and more serious, although rare, reactions can include seizures and psychosis (Lader, 2014;Dell'Osso et al., 2015). In addition, the risk of the patient developing such withdrawal symptoms also increases with the length of use and dose of the drug (Rickels, et al.,1990). ...
... 23 Benzodiazepines are prescribed for anxiety, 24 insomnia, 25 and agitation. They can cause withdrawal 26 and have potential for abuse. 27 Benzodiazepines are associated with cognitive decline, 28 impaired driving, 29 falls, 30 and hip fractures 31 in older adults. ...
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Managing medications is a major part of providing care to older adults. Polypharmacy is common in the elderly and is fraught with risks. A careful and systematic approach is needed for managing drug therapy in these patients, recognizing the patient's specific goals.
... There are no methodologically sound studies, but clinical probing of families and professionals regarding their experiences with the cooccurrence of SUD and ASD showed substance-related problems to be common among both adolescents and adults with ASD [17]. About treatment choices, we have combined a standard treatment for BD, based on valproic acid and lithium carbonate [32,36,37], with an integrated treatment for alcohol and BDZ abuse, including disulfiram, nalmefene, and clonazepam; this latter was chosen as agonist substitution treatment for BDZ dependence, in virtue of his high potency and slow-onset, long lasting action [38][39][40][41]. We debate whether this patient belongs to a subgroup of well-adapted, double-diagnosis patients, where autism spectrum symptomatology, together with mood instability and reward sensitivity features, influences addictive manifestations. ...
Article
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This case report draws attention to the potential relevance of undetected autism spectrum symptoms in a bipolar patient with high work functioning showing a peculiar addictive profile with impulsive and antisocial behaviors. A 23-year-old man with a diagnosis of Bipolar Disorder (BD) and Substance Use Disorder (SUD) was hospitalized at the Psychiatric Clinic of the University of Pisa for diuretics and β -2 adrenergic agonist abuse in a remission phase of benzodiazepines and substance abuse. He reported a history of behavioral addictions in the framework of a global high work functioning with particular skills in computer science. When assessed for adult autism spectrum symptoms, despite not fulfilling a DSM-5 diagnosis of Autism Spectrum Disorder (ASD), he reported a score of 93/240 at the Ritvo Autism and Asperger Diagnostic Scale (RAADS-r) and of 88/160 at the Adult Autism Subthreshold Spectrum (AdAS Spectrum), both indicative of ASD. We argue the possible role of adult subthreshold autism spectrum features, generally disregarded in adult psychiatry, in the peculiar addictive profile developed by this patient with BD that may deserve appropriate treatment.
... Методика очень плавного снижения (на 25% каждые 2 нед, далее на 12,5% каждые 2 нед до полной отмены). Переход на пролонгированные бензодиазепины перед депрескрайбингом не выявил значимого улучшения синдрома отмены [7,8]. Меньший срок приема бензодиазепинов и меньшая суточная доза -прогностически благоприятные факторы успешной отмены. ...
Article
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Deprescribing is the opposite of prescribing drugs, the purpose of which is to improve quality of life and reduce the risk of adverse drug reactions. The paper considers the process of deprescribing benzodiazepines. It analyzes relevant studies on this problem, as well as recommendations to help decide whether it is a need for deprescribing and how to accurately do this. There are also the results of original investigations demonstrating the tapering of benzodiazepine tranquilizers: comparison of simple tampering, use of psychotherapy, or replacement pharmacotherapy. The use of a deprescribing algorithm is the safest way to discontinue benzodiazepines in patients who do not have serious indications for their long-term use.
... 39 In studies detailing benzodiazepine withdrawal symptoms, such symptoms tend to appear and peak more quickly (1 to 2 days) and be more severe with abruptly stopping short-acting benzodiazepines compared with after tapering long-acting benzodiazepines (4 to 10 days). 64,65 Gradual taper of short-acting agents does not eliminate withdrawal symptoms but ameliorates their severity, with symptoms beginning to appear once doses are reduced to about 25% of baseline. 55 While common, resulting insomnia is typically mild, and patients should be assured that there is no difference in insomnia compared with usual care or continuation of BZRAs at 12 months. ...
Article
Objective: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper and stop benzodiazepine receptor agonists (BZRAs); to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes. Methods: The overall team comprised 8 clinicians (1 family physician, 2 psychiatrists, 1 clinical psychologist, 1 clinical pharmacologist, 2 clinical pharmacists, and 1 geriatrician) and a methodologist; members disclosed conflicts of interest. For guideline development, a systematic process was used, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence was generated by conducting a systematic review of BZRA deprescribing trials for insomnia, as well as performing a review of reviews of the harms of continued BZRA use and narrative syntheses of patient preferences and resource implications. This evidence and GRADE quality of evidence ratings were used to generate recommendations. The team refined guideline content and recommendations through consensus and synthesized clinical considerations to address front-line clinician questions. The draft guideline was reviewed by clinicians and stakeholders. Recommendations: We recommend that deprescribing (tapering slowly) of BZRAs be offered to elderly adults (≥ 65 years) who take BZRAs, regardless of duration of use, and suggest that deprescribing (tapering slowly) be offered to adults aged 18 to 64 who have used BZRAs for more than 4 weeks. These recommendations apply to patients who use BZRAs to treat insomnia on its own (primary insomnia) or comorbid insomnia where potential underlying comorbidities are effectively managed. This guideline does not apply to those with other sleep disorders or untreated anxiety, depression, or other physical or mental health conditions that might be causing or aggravating insomnia. Conclusion: Benzodiazepine receptor agonists are associated with harms, and therapeutic effects might be short term. Tapering BZRAs improves cessation rates compared with usual care without serious harms. Patients might be more amenable to deprescribing conversations if they understand the rationale (potential for harm), are involved in developing the tapering plan, and are offered behavioural advice. This guideline provides recommendations for making decisions about when and how to reduce and stop BZRAs. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients.
... 30 Gradual taper of long-half life benzodiazepines appear to increase the rate of successful discontinuation. 31 Difficulty in tapering, with more pronounced withdrawal symptoms, does not seem to predict inability to successfully complete the taper. Psychological support, appears to be a critical factor in this process. ...
Article
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Background: Selective serotonin reuptake inhibitors ameliorate depression and anxiety slowly and in fact increase anxiety or insomnia initially. Addition of clonazepam to escitalopram improves response: thereby improving symptoms associated with depression, reducing side-effects and alleviating core depressive symptoms. The aim of study was to assess the benefits of adding benzodiazepines in management of depression.Methods: It was an open label prospective study of 8 weeks of escitalopram group versus escitalopram with benzodiazepine group in moderate to severe depression. 51 subjects who gave written informed consent and were fulfilling the inclusion and exclusion criteria were included in the study and grouped into escitalopram alone or escitalopram with benzodiazepines.Results: In the present study nearly 60% of the patients were prescribed clonazepam. Though combined group with benzodiazepines had faster onset of action in controlling depressive symptoms than escitalopram group alone at 4 weeks of treatment, there was no significant difference in the pattern of reduction of MADRS score in both the groups at 8 weeks of follow up.Conclusions: Augmenting benzodiazepines to antidepressants are more effective in management of depression associated anxiety and sleep disturbances initially till SSRIs start action.
... Over the past decades, several pharmacological anxiety treatments have been developed, including barbiturates, benzodiazepines (BZD) [3], and antidepressants (tricyclics, monoamine oxidase inhibitors--MAOI, selective serotonin reuptake inhibitors --SSRIs, selective serotonin and norepinephrine reuptake inhibitors --SNRIs). However, none of them is optimal from a therapeutic point of view: apart from the life-threatening CNS depression and abuse potential of barbiturates, BZDs are associated with cognitive and motor impairment and pose a significant risk for dependence [4,5]; SSRIs and SNRIs have a delayed onset of effect and are associated with sexual side effects [6], serotonin syndrome and potentially increased risk of suicidal ideation or behavior in some sub-populations [7,8]. ...
... [42,43] Abrupt discontinuation of chronic treatment with BDZ drugs can cause withdrawal symptoms, especially increased anxiety. [44,45] Anxiety-like behaviour after BDZ withdrawal in rats is commonly seen in the EPM 12-96 h after abrupt drug discontinuation. [46][47][48] Moreover, an increased susceptibility to seizures, loss of body weight and decrease in food consumption has also been observed in mice and rats after abrupt discontinuation of repeated treatment with DZP. ...
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Objectives To investigate whether mice develop tolerance to the anxiolytic‐like and anticonvulsant effects of subchronic treatment with EA (the styryl‐2‐pyrones and dihydrostyryl‐2‐pyrones‐rich fraction of Polygala sabulosa), as well as any withdrawal symptoms after abrupt discontinuation; to compare the effects of EA with those of diazepam (DZP) on withdrawal‐induced anxiety; and to evaluate the toxicity of EA according to OECD guidelines. Methods Male or female mice were acutely or subchronically treated with EA or DZP, and their tolerance to anxiolytic (evaluated in the elevated plus maze, EPM) and anticonvulsant effects (measured against pentylenetetrazole (PTZ)‐induced convulsions) were investigated. Other groups received EA or DZP for 28 days followed by withdrawal, being the anxiety‐like behaviour evaluated in the EPM. Key findings Both acute and subchronic treatments with EA induced an anxiolytic effect in the EPM. The anticonvulsant activity of DZP, but not EA, was reduced by protracted treatment. EA withdrawal retained the anxiolytic profile, while DZP withdrawal induced anxiogenesis. EA counteracted the anxiogenic‐like actions of DZP withdrawal. EA has low toxicity as it did not cause any changes in the biochemical, haematological and histopathological markers. Conclusions EA avoids the development of tolerance to its anxiolytic‐like and anticonvulsant actions, and does not promote withdrawal syndrome. EA does not cause relevant toxic effects in rodents.
... The effectiveness of the benzodiazepines exceeds the placebo in controlling a wide range of anxiety related symptoms [2,3] and reducing the onset of insomnia [4]. The use of benzodiazepines for long periods can induce dependence, abuse and symptoms of withdrawal [5,6]. Based on these risks, several guidelines have warned against the use of benzodiazepines for long periods, especially in older population [7]. ...
Article
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OBJECTIVE: This study analyzed the appropriateness of drug therapies prescribed for a particular category of patients: the seafarers. We investigated an important problem of this area: the off-label use of drugs, which resulted to be a consequence of major shortcomings in the on-board pharmacies of ships. The off-label use of drugs is allowed, but can lead to some not negligible ethical and health problems, compromising the quality of provided healthcare. MATERIALS AND METHODS: The analysis was performed on electronic health records of patients onboard ships without physicians, and assisted by the CIRM from 2011 to 2015. This work is divided into two phases: in the first one, we classified the diagnoses registered on-board on the basis of the ICD-10 classification proposed by the WHO. In the second phase, we evaluated the congruence of the pharmacological therapies prescribed by CIRM physicians, according to the MICROMEDEX Database, which provides comprehensive information about drugs and their use. RESULTS: From the analysis emerged that prescribed drugs were not always corresponded to their primary indication of use. In particular, in 2011 off-label drug use was widely spread (more than 30%) in some ICD-10 classes. In the following years (2012-2015) a decrease of off-label use of drugs was noticed. CONCLUSIONS: The results suggest that a standardization of onboard pharmacies is crucial , in order to have a complete on-board pharmacy that will allow preventing and counteracting any situation of health danger, which may occur onboard, ensuring high quality healthcare to seafarers all over the world.
... They were all treated with clonazepam: in 1 case the response was good; in another it was very limited, and symptoms subsided when paroxetine was administered again; in the third, clonazepam yielded no improvement, and the symptoms went on for 3 years before fading (he refused taking paroxetine again). Nothing like this had happened with BZD; indeed, anxiety improved upon discontinuation [6], in line with the published literature [10]. ...
... Benzodiazepines (BZDs) and z-drugs (BZD derivatives, e.g., zolpidem and zopiclone) are among the most commonly used anxiolytics and hypnotics worldwide (Fassaert et al., 2007;Rogers et al., 2007). While BZD and z-drugs have been demonstrated to be effective in short-term use (Canadian Agency for Drugs and Technologies in Health, 2014), their intake is associated with serious adverse effects, including increased risk of cognitive impairments (Barker et al., 2004;McAndrews et al., 2003;Paterniti, Dufouil & Alperovitch, 2002) as well as stumbling and falling, which may result in hip fractures (Takkouche et al., 2007;Zint et al., 2010) as withdrawal symptoms (Rickels et al., 1990). The main serious problem associated with long-term use is the development of tolerance and dependence (Ashton, 2005;Voyer et al., 2009;Zint et al., 2010). ...
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Background Benzodiazepines (BZDs) and z-drugs are effective drugs, but they are prescribed excessively worldwide. International guidelines recommend a maximum treatment duration of 4 weeks. Although these drugs are effective in the short-term, long-term BZD therapy is associated with considerable adverse effects, the development of tolerance and, finally, addiction. However, there are different interventions in terms of patient-centered care that aim to reduce the use of BZDs and z-drugs as well as assist health care professionals (HCPs) in preventing the inappropriate prescription of BZDs. Aim The aim of this systematic review was to identify interventions that promote patient-centered treatments for inappropriate BZD and z-drug use and to analyze their effectiveness in reducing the inappropriate use of these drugs. Methods To identify relevant studies, the PubMed, EMBASE, PsycINFO, Psyndex, and Cochrane Library databases were searched. Studies with controlled designs focusing on adult patients were included. Trials with chronically or mentally ill patients were excluded if long-term BZD and z-drug use was indicated. Study extraction was performed based on the Cochrane Form for study extraction. To assess the quality of the studies, we used a tool based on the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials. Results We identified 7,068 studies and selected 20 for systematic review. Nine interventions focused on patients, nine on HCPs, and two on both patients and HCPs. Intervention types ranged from simple to multifaceted. Patient-centered interventions that provided patient information effectively increased the appropriate use of BZDs. The educational approaches for HCPs that aimed to achieve appropriate prescription reported inconsistent results. The methods that combined informing patients and HCPs led to a significant reduction in BZD use. Conclusions This is the first review of studies focused on patient-centered approaches to reducing the inappropriate prescription and use of BZDs and z-drugs. The patient-centered dimension of patient information was responsible for a decrease in BZD and z-drug consumption. Further, in some studies, the patient-centered dimensions responsible for reducing the prescription and use of BZDs and z-drugs were the clinician’s essential characteristics and clinician-patient communication.
... There are no standard ta- pering regimens and the rate of tapering (Brett and Murnion, 2015) and the tapering schedule can range from a month to year ( Dou et al., 2018). The 4-week benzodiazepine tapering schedule, based on the protocol used in previous studies ( Rickels et al., 1990;Schweizer et al., 1990;Voshaar et al., 2003), advised a 25% reduction of daily benzo- diazepine consumption in the first and second weeks and following with 25% reduction for the remaining 50% of benzodiazepine every 3-4 days. Subjects' withdrawal symptoms were evaluated by a research assistant every week during the treatment period. ...
Article
Objective: To evaluate the efficacy of using electroacupuncture as an adjunct treatment in enhancing the benzodiazepine cessation rate in long-term benzodiazepine users. Methods: This was a randomized, assessor- and subject-blinded, controlled trial. One hundred and forty-four long-term benzodiazepine users were randomly assigned to receive either electroacupuncture or placebo acupuncture (a sham itervention using non-invasive placebo needles) combined with a gradual benzodiazepine tapering schedule for 4 weeks. The primary outcome was the cessation rate of benzodiazepine use. Subjects were assessed on their benzodiazepine usage, benzodiazepine withdrawal symptoms, insomnia severity, and anxiety and depressive symptoms at baseline, week 6 and week 16. Results: The cessation rates of the electroacupuncture and placebo acupuncture groups at 12 weeks post-treatment were 9.17% and 10.83%, respectively. Both groups showed a reduction in benzodiazepine usage by a self-completed drug record at week 16 (compared to baseline: electroacupuncture group -40.23% versus placebo acupuncture group -48.76%). However, no significant between-group differences were found in the benzodiazepine cessation rate, reduction in benzodiazepine usage, and other secondary measures across all the study time points. Conclusions: Electroacupuncture showed a similar cessation rate in benzodiazepine use to that of non-invasive placebo acupuncture in long-term users during a 4-week gradual tapering schedule. The evidence did not support advantages of electroacupuncture over non-invasive placebo acupuncture on reducing insomnia, anxiety, depression, or other withdrawal symptoms during the gradual tapering schedule. Despite a 40% decrease in the benzodiazepine usage in both groups, the effects may be attributed to the non-specific effects of acupuncture. Trial registration: ClinicalTrials.gov # NCT02475538.
... The effectiveness of the benzodiazepines exceeds the placebo in controlling a wide range of anxiety related symptoms [2,3] and reducing the onset of insomnia [4]. The use of benzodiazepines for long periods can induce dependence, abuse and symptoms of withdrawal [5,6]. Based on these risks, several guidelines have warned against the use of benzodiazepines for long periods, especially in older population [7]. ...
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Background: Benzodiazepines are drugs widely used for the treatment of anxiety and insomnia. The present study has analysed the prescriptions of this class of drugs among sailing seafarers, to evaluate the appropriateness of prescribed therapies. Materials and methods: This study assessed the benzodiazepine prescriptions made by Centro Internazionale Radio Medico (CIRM) doctors from 2011 to 2015. A total of 17,844 medical records were examined. Analysis considered the prescriptions of benzodiazepines in monotherapy, or in association with other drugs. Diagnoses of pathologies for which benzodiazepines were prescribed were made according to the ICD-10 classification system proposed by the World Health Organisation. Results: Among medical records analysed, benzodiazepines were prescribed in 765 cases (3.29% of total cases assisted by CIRM). Benzodiazepines were prescribed as a single-drug treatment in 626 (81.83%) cases, whereas in 139 cases they were associated with other classes of drugs. In case of opioids prescribed in association with benzodiazepines, the drug used was codeine. This therapeutic association was prescribed in cases of severe pain. Conclusions: Although the "off label" use of benzodiazepines is not uncommon in medical practice, clear evidence indicates their potential side effects for human health. In this respect, medical professionals should comply with international guidelines on the use of benzodiazepines, both when prescribed as a single drug or in combination with other classes of drugs. These recommendations should be considered seriously in case of limited medical facilities such as on board of sailing ships.
... The progressive rise in concurrent use of non-selective and selective benzodiazepine receptor modulators is also concerning, given the many serious potential adverse effects of these drugs. Adverse events associated with benzodiazepine receptor modulators include abuse, 14,46 withdrawal symptoms, 47 impaired cognitive function, 48 dementia, [49][50] ...
Article
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.
... The relatively higher prevalence of hypnotic use in this study might be explained by the fact that most psychiatric outpatients had psychiatric disorders, including neurotic disorders and affective disorders. Previous studies have shown that long-term use of benzodiazepines is associated with increased risk of adverse effects [26], increased risk of accidents such as falling [27,28], and increased cognitive decline in the elderly [29]. Zolpidem has been considered safer than benzodiazepines, and it is associated with a lower probability of abuse and dependence [30]. ...
Article
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(1) Background: Limited studies have utilized nationwide data to assess the patterns of psychiatric practice in other countries. In this study, data from the National Health Insurance Research Database in Taiwan (NHIRD-TW) for 2012 was analyzed to determine the patterns of psychiatric outpatient practice in Taiwan; (2) Methods: To determine the patterns of psychiatric outpatient practice in Taiwan, the data were drawn from the datasets of Taiwan's National Health Insurance Research Database for 2012, with 619,760 records of outpatient visits representing 1/500 of all the claims in Taiwan for that year. The analysis of psychiatric outpatient visits included patient demographics, diagnoses, and prescribed medications; (3) Results: Neurotic disorders were the most prevalent diagnoses (43.1%, n = 5714). Hypnotics-sedatives and anxiolytics were prescribed in 51.7% (n = 6850) and 39.1% (n = 5181) of psychiatric visits, respectively, with zolpidem being the most commonly prescribed drug (22.6%, n = 2998); and (4) Conclusion: Hypnotics and sedatives were widely prescribed for the outpatient population, and zolpidem had the highest annual prevalence of use. These findings deserve the attention of clinicians and policy makers for monitoring the abuse and dependence of these agents and subsequent adverse events.
... Several studies were performed to evaluate the influence of various factors on the development of dependence. A general consensus is that: 1) timing and rate of exposure(s); 2) dose; and 3) drug potency, critically impact the formation of dependence, where with a longer timeframe of use, higher dose, and higher drug potency, the likelihood of dependence formation increases (MacKinnon and Parker, 1982;Owen and Tyrer, 1983;Roy-Byrne et al., 1989;Rickels et al., 1990;Busto and Sellers, 1991;Noyes et al., 1991;Chouinard, 2004;Kan et al., 2004). ...
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The purpose of this article is to describe dependence and withdrawal phenomena related to CNS drugs discontinuation and to clarify issues related to the evaluation of clinical drug withdrawal and rebound as they relate to safety in new drug development. The article presents current understanding and definitions of drug dependence and withdrawal which are also relevant and important features of addiction, though not the same. Addiction, called substance use disorder in DSM-5, affects an individual's brain and behaviour, represents uncontrollable drug abuse and inability to stop taking a drug regardless of the harm it causes. Characteristic withdrawal syndromes following abrupt discontinuation of CNS-active drugs from numerous drug classes are described. These include drugs both scheduled and non-scheduled in the Controlled Substances Act, which categorizes drugs in five schedules based on their relative abuse potentials and dependence liabilities and for regulatory purposes. Schedules 1 and 2 contain drugs identified as those with the highest abuse potential and strictest regulations. Less recognized aspects of drug withdrawal, such as rebound and protracted withdrawal syndromes for several drug classes are also addressed. Part I presents relevant definitions and describes clinical withdrawal and dependence phenomena. Part II reviews known withdrawal syndromes for the different drug classes, Part III describes rebound and Part IV describes protracted withdrawal syndromes. To our knowledge, this is the first compilation of withdrawal syndromes for CNS drugs. Part V provides details of evaluation of dependence and withdrawal in the clinical trials for CNS drugs, which includes general design recommendations, and several tools, such as withdrawal questionnaires and multiple scales that are helpful in the systematic evaluation of withdrawal. The limitations of different aspects of this method of dependence and withdrawal evaluation are also discussed.
... The scheduled GDR steps may be fixed throughout the process [29, 33, 34, 62, 73, 88-90, 93, 95, 96] or be made smaller and/or slower as the GDR progresses [16,47,75,97]. The schedules do not differentiate between slow and fast metabolizers, which sometimes results in complicated detox courses [62]. ...
Article
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Purpose Many harms secondary to benzodiazepine (BZD) dependence force users towards detoxification treatment. However, even strongly motivated patients tolerate the process badly or experience early relapse. The detoxification procedure has not yet been standardized. The objective of this paper is to examine the hypothesis that faulty detoxification routines may have caused some failures. Methods The detoxification approaches found in the literature were compared stage by stage. The review was used to identify possible common, across-the-board systematic errors. Results The presented literature review confirms that the widespread divergence in the BZD metabolism rate is effectively neglected during detoxification routines. Without laboratory measurements, these differences, additionally interfered with by auxiliary drugs, undermine not only the scheduled but even the symptom-driven procedures. An initial substitution with a long-acting BZD, although recommended, may lead to over-accumulation. This excess, varying between patients and incompatible with the current tapering stage, may lead to repeated overestimation of the patient’s adjustments to reduced doses. Consequently, the patient’s good clinical presentation at withdrawal, resulting in a conclusion of detoxification, may actually reflect a persistently high serum BZD concentration. The low-concentration stage, if shifted past the end of treatment, exposes patients to unexpected, unassisted withdrawal crises. With laboratory feedback, these crises, unlike the symptoms related to deficient re-adaptation mechanisms, could be prevented. Moreover, by minimizing the high-concentration phase, time can be saved for properly assisted low-concentration challenges. Conclusion A customized detoxification procedure driven not only by the intensity of withdrawal symptoms but also by serum BZD monitoring may prevent some failures. As the standard regimen, it would make detoxification from BZDs more reliable and effective.
... Withdrawal severity was measured using a 34-item physician withdrawal checklist. 15 Nine of the 63 patients reported tinnitus as a withdrawal symptom. Seven of 25 patients tapering off of long half-life agents (diazepam and clorazepate) experienced tinnitus compared to only 2 out of 38 patients tapering off of short half-life agents (lorazepam and alprazolam; P , .01). ...
Article
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In light of the ongoing opioid crisis, many have encouraged the medical community as well as local and national US government agencies to reconsider the prevalent use of benzodiazepines. As prescribers continue to weigh the risks and benefits of ongoing benzodiazepine use, care must be taken when the decision is made to taper and discontinue these medications in patients who have been maintained on them chronically. We present a case of an adult patient maintained on a benzodiazepine for several years who developed tinnitus during a gradual dose taper. This patient developed tinnitus within 7 weeks of gradual reduction of the patient's clonazepam dose to 50% of the original dose in an outpatient clinic. The persistence of these symptoms prevented further dose reductions. Upon review of the available literature, several other cases were identified describing development of tinnitus upon discontinuation or tapering of a benzodiazepine. In weighing the risks and benefits of chronic benzodiazepine therapy, tinnitus must be considered as a rare but debilitating and long-term risk of benzodiazepine withdrawal. Providers must be prepared to individualize benzodiazepine tapers and be vigilant about emergence of withdrawal symptoms to prevent undue stress in patients.
... Perhaps of greatest concern is the development of physiologic dependence which develops in 20-100% of those on BZs even at normal doses for more than a month [150][151][152][153][154]. Withdrawal symptoms may occur during medication [139], after as little as 2-6 weeks of exposure [155], and be quite severe [133][134][135]139]. ...
Article
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Introduction: Controversy and uncertainty exist about the use of benzodiazepine receptor agonists (BZRAs) in pain management. This article curates available research to determine the appropriate role of BZRAs in the course of pain management, and how prescribers might address these challenges. Methods: A narrative review was performed to determine the appropriate role of BZRAs in pain management and to develop practice recommendations. Publications were identified by a search of PubMed, references of retrieved reports, guidelines, and the author's personal files. Results: BZRAs were found to have analgesic benefit for two pain conditions: burning mouth syndrome and stiff person syndrome. Absence of research, heterogeneity of trials, and small sample sizes precluded drawing conclusions about efficacy of BZRAs for the other 109 pain conditions explored. Data supports the use of BZRAs to treat co-occurring insomnia and anxiety disorders but only when alternatives are inadequate and only for short periods of time (2-4 weeks). The utility of BZRAs is limited by loss of efficacy that may be seen with continued use and adverse reactions including physiologic dependence which develops in 20-100% of those who take these agents for more than a month. Conclusions: BZRAs are often used inappropriately in pain management. Their initiation and duration of use should be limited to a narrow range of conditions. When prescribed for 4 weeks or more, patients should be encouraged to discontinue them through a supported, slow tapering process that may take 12-18 months or longer.
... The Columbia-Suicide Severity Rating Scale (C-SSRS) is perhaps the most commonly used instrument, though several others exist (Posner et al. 2011;Erford et al. 2018). Side effects arising from discontinuation of antidepressants and benzodiazepines can be assessed with the Physician Withdrawal Checklist (Rickels et al. 1990(Rickels et al. , 2008 or the Discontinuation Emergent Signs and Symptoms assessment (Rosenbaum et al. 1998). ...
... In fact, some prescribers appear to use PMPs to detect patient "dishonesty", and with proof of multiple prescribers promptly "drop" their patients [73,74]. For patients prescribed BDZs, being abandoned by their prescriber puts them at risk of experiencing acute withdrawal, as coming off BDZs cold turkey can lead to severe withdrawal symptoms and increases the likelihood of protracted withdrawal [6,[75][76][77][78]. This may also account for the increase in BDZ-related hospital presentations in the wake of PMPs [79]. ...
Article
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: Internationally there is an escalation of prescription-related overdose deaths, particularly related to benzodiazepine use. As a result, many countries have implemented prescription monitoring programs (PMPs) to increase the regulation of benzodiazepine medications. PMPs centralize prescription data for prescribers and pharmacists and generate alerts to high-doses, risky combinations, or multiple prescribers with the aim to reduce inappropriate prescribing and subsequently the potential of patient harm. However, it has become clear that prescribers have been provided with minimal guidance and insufficient training to effectively integrate PMP information into their decision making around prescribing these medications. Accordingly, this paper discusses how PMPs have given rise to a range of unintended consequences in those who have been prescribed benzodiazepines (BDZs). Given that a gradual taper is generally required to mitigate withdrawal from BDZs, there are concerns that alerts from PMPs have resulted in BDZs being ceased abruptly, resulting in a range of unintended harms to patients. It is argued that best practice guidelines based upon a patient-centered framework of decision-making, need to be developed and implemented, in order to curtail the unintended consequences of PMPs. This paper outlines some key considerations when starting the conversation with patients about their BDZ use.
... Long-term use of benzodiazepines has been known to produce complications related to discontinuation, withdrawal symptoms, increased risk of accidental overdose when combined with other central nervous system depressants, persistence of benzodiazepine-related adverse effects, physical dependence, and benzodiazepine use disorders. [1][2][3] In 2008, approximately 272,000 emergency department visits in the United States involved nonmedical use of benzodiazepines. In many of these visits (40%), benzodiazepines were used in conjunction with alcohol. ...
... There is a subgroup of PD patients comorbid with substance use disorders more likely to present a dose escalation of BZs and to exhibit a dependency syndrome on dosage reduction or discontinuation of this class, with BZ withdrawal symptoms (Ait-Daoud et al., 2018). However, withdrawal reactions may ensue with either BZs or SSRIs (Belaise et al., 2012;Bhanji et al., 2006;Fava, 2006;Fava et al., 2015;Greenblatt et al., 1990;Nardi et al., 2010;Nielsen et al., 2012;Rickels et al., 1990;Schweizer et al., 1990). In both classes, this syndrome is characterized by symptoms such as anxiety, crying, dizziness, headache, increased dreaming, insomnia, irritability, myoclonus, nausea, paresthesia, and tremor (Nielsen et al., 2012;Starcevic, 2012b). ...
Article
Background: Benzodiazepines (BZs) and selective serotonin reuptake inhibitors (SSRIs) are effective in the pharmacologic treatment of panic disorder (PD). However, treatment guidelines favor SSRIs over BZs based on the belief that BZs are associated with more adverse effects than SSRIs. This belief, however, is currently supported only by opinion and anecdotes. Aim: The aim of this review and meta-analysis was to determine if there truly is evidence that BZs cause more adverse effects than SSRIs in acute PD treatment. Methods: We systematically searched Web of Science, PubMed, Cochrane Central Register of Controlled Trials, and clinical trials register databases. Short randomized clinical trials of a minimum of four weeks and a maximum of 12 weeks that studied SSRIs or BZs compared to placebo in acute PD treatment were included in a meta-analysis. The primary outcome was all-cause adverse event rate in participants who received SSRIs, BZs, or placebo. Results: Overall, the meta-analysis showed that SSRIs cause more adverse events than BZs in short-term PD treatment. Specifically, SSRI treatment was a risk factor for diaphoresis, fatigue, nausea, diarrhea, and insomnia, whereas BZ treatment was a risk factor for memory problems, constipation, and dry mouth. Both classes of drugs were associated with somnolence. SSRIs were associated with abnormal ejaculation, while BZs were associated with libido reduction. BZs were protective against tachycardia, diaphoresis, fatigue, and insomnia. Conclusion: Randomized, blinded studies comparing SSRIs and BZs for the short-term treatment of PD should be performed. Clinical guidelines based on incontrovertible evidence are needed.
... 11 Já outros estudos referenciam que os sintomas mais graves e as taxas de recaída são maiores em BZD de semivida curtas quando abruptamente retiradas, comparativamente às BZD de semivida longa. 12 ...
Article
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Introduction: The inaugural convulsive crisis is a frequent cause of recurrence to the emergency department. It is estimated that only 40 to 50% of these cases have recurrent episodes. Thus, in the face of an inaugural convulsive crisis, it is important to exclude some conditions that may mimic the onset of convulsions. Case description: Female, 45 years old, married, diagnosed with uterine myoma, fibrocystic breast disease, anxiety disorder and medication abuse (alprazolam). In September 2016, she went to the emergency department due to an inaugural tonic-clonic convulsive crisis, with no apparent triggering factors. After exclusion of infectious, vascular and space occupant lesions of the central nervous system, she was discharged with the diagnosis of an epileptic seizure with unknown etiology, medicated with levetiracetam. In January 2017, she applied to the family physician to show the discharge note when questioned she admitted the abrupt withdrawal of alprazolam a few days before the seizure, despite indications of gradual reduction of the drug. In March she was hospitalized for delirious ideas and incoherent speech after acute gastroenteritis. She was discharged with the diagnosis of an acute confusional episode of organic/iatrogenic etiology. After the discharge, she went to the family physician and admitted to continuing abusing alprazolam, which she suddenly stopped when she had the gastroenteritis. The patient did not recognize the abusive use of the drug. The family, although initially having difficulties in dealing with the situation, ended up being an important ally in the treatment of this patient. Comment: This clinical case illustrates several complex situations in clinical practice, namely the difficulty in understanding the patient as a whole in the context of urgency, the absence of an effective communication system between the different levels of care, the omission of information by patients and the abuse of certain drugs. It highlights the importance of the family involvement in the treatment and follow-up of different clinical situations, as well as the role of the family physician, who through the longitudinal follow-up of the patient and a better doctor-patient relationship better knows him.
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In der Planung einer individuell angepassten Therapie einer generalisierten Angststörung ist ein mehrdimensionales Vorgehen erforderlich, bei dem Primärsymptomatik, Komorbidität und die Verfügbarkeit therapeutischer Interventionen abgeklärt werden müssen. Eine vorwiegend psychopharmakologisch ausgerichtete Therapie kann im Einzelfall gerechtfertigt sein, wenn hierbei psychoedukative und verhaltenstherapeutische Aspekte nicht ausgeklammert werden.
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Benzodiazepines are a drug group widely prescribed in clinical practice. Its pharmacological effects are shared but their pharmacokinetic profile changes their usefulness in different clinical scenarios. Benzodiazepines irrational prescribing is a global public health concern, including chronic consumption and its associated risks. They are subject to frequent drug-drug interactions, and there are recognized risk populations, such as the elderly. Some of its most frequently adverse reactions include falls and the emergence of dependence and tolerance associated with chronic use. Rational use guidelines must be known in order to improve benzodiazepines prescription
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Benzodiazepines have proven to be highly effective for treating insomnia and anxiety. Although considered safe when taken for a short period of time, a major risk–benefit dilemma arises in the context of long-term use, relating to addiction, withdrawal symptoms, and potential side effects. For these reasons, benzodiazepines are not recommended for treating chronic sleep disorders, anxiety disorders, nor for people over the age of 65, and withdrawal among long-term users is a public health issue. Indeed, only 5% of patients manage to discontinue using these drugs on their own. Even with the help of a general practitioner, this rate does not exceed 25 to 30% of patients, of which approximately 7% manage to remain drug-free in the long term. Cognitive Behavioral Therapies (CBT) offer a crucial solution to this problem, having been shown to increase abstinence success to 70–80%. This article examines traditional and novel CBT techniques in this regard, such as Acceptance and Commitment Therapy, which address both the underlying condition (insomnia/anxiety) and the substance-related disorder. The theoretical framework and evidence supporting the use of these approaches are reviewed. Finally, current research gaps are discussed, and key research perspectives are proposed.
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Background: Inappropriate use of clonazepam by the elderly patients is associated with cognitive impairment, delirium and falls. Strategies to optimize its use are important to increase patient safety. Objective: To evaluate the feasibility of a clonazepam deprescription protocol in the elderly. Methods: This is a quasi-experimental study. Elderly people with chronic use of clonazepam and attended in primary care units in two Brazilian municipalities were selected. A deprescription protocol was used, which included five fortnightly meetings between the older adults and the research team, to reduce the dose by 25 %. Patients received instructions on sleep hygiene behaviors and the advantages of clonazepam deprescription; family physicians followed a flowchart for gradual dose reduction. In the 1st and 5th meetings, there were medical appointments for anamnesis and discharge. The monitoring of patients and the application of tests were carried out by the research team. Results: Of the 35 elderly people included in the study, 27 reached the end; 81.5 % achieved deprescription: 22.2 % stopped completely and 59.3 % decreased the dose. At the last meeting, 20 % of elderly patients reported an increase in blood pressure. Conclusions: The high rate of deprescription and the little relevance of clonazepam withdrawal reactions, showed that the use of the protocol was effective. However, the increase in blood pressure and the worsening of sleep quality in the last meeting show the need for adjustment in the last stage of the deprescription process. Trial Registration: The Brazilian Registry of Clinical Trials (ReBEC) RBR-524ys9; registered June 10, 2019.
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This study aimed to refine and validate the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS). The 12-item prototype version of the BHWSS was administered to a sample of 346 patients with chronic insomnia (161 males and 185 females, mean age: 52.8 ± 16.6 years) who had been taking hypnotics (benzodiazepines [BZDs] or BZD receptor agonists) for at least 3 months. The item information curve indicated that two of the 12 BHWSS items should be excluded. As a result of analyzing the 10-item version of the BHWSS (revised-BHWSS), the contribution rate in the case of the factor 1 was 0.49, Cronbach's α was 0.90, and the reliability coefficient ω was 0.91. An analysis of the item information curve for the revised-BHWSS indicated that the information amount per item increased from 3.90 for the original 12-item BHWSS to 4.37 for the 10-item revised-BHWSS. The receiver operating characteristic curve indicated that 6.5 points on the revised-BHWSS was the most appropriate cutoff for estimating moderate or severe withdrawal symptoms using the Benzodiazepine Dependence Self-Report Questionnaire as a reference. These results suggest that the 10-item revised-BHWSS has sufficient reliability and validity for evaluating the severity of withdrawal symptoms after discontinuing BZDs.
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Benzodiazepines are a drug group widely prescribed in clinical practice. Its pharmacological effects are shared but their pharmacokinetic profile changes their usefulness in different clinical scenarios. Benzodiazepines irrational prescribing is a global public health concern, including chronic consumption and its associated risks. They are subject to frequent drug-drug interactions, and there are recognized risk populations, such as the elderly. Some of its most frequently adverse reactions include falls and the emergence of dependence and tolerance associated with chronic use. Rational use guidelines must be known in order to improve benzodiazepines prescription
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Age‐related changes in disposition of diazepam and its principal active metabolite, desmethyldiazepam (DMDZ), during and after extended dosage with diazepam were studied in healthy volunteers. Eight elderly subjects (ages 61‐78 years) and 7 young subjects (21‐33 years) received 2.5 mg of diazepam twice daily for 15 days. Predose (trough) concentrations of diazepam and DMDZ were measured during the 15 days of dosing, and in the postdosage washout period. Kinetic properties were determined by nonlinear regression using a sequential drug‐to‐metabolite pharmacokinetic model. Steady‐state plasma concentrations of diazepam and DMDZ were 30% to 35% higher in elderly subjects compared to young volunteers, and steady‐state clearances correspondingly lower, though differences did not reach significance. Large and significant differences were found between young and elderly groups in mean half‐life of diazepam (31 vs 86 hours; P < .005) and DMDZ (40 vs 80 hours; P < .02). Half‐life values from the multiple‐dose study were closely correlated with values from previous single‐dose studies of diazepam (R2 = 0.85) and DMDZ (R2 = 0.94) in the same subjects. With extended dosing of diazepam in the elderly, slow accumulation and delayed washout of diazepam and DMDZ is probable. After discontinuation, withdrawal or rebound effects are reduced in likelihood, but delayed recovery from sedative effects is possible due to slow elimination of active compounds. Safe treatment of elderly patients with diazepam is supported by understanding of age‐related changes in pharmacologic and pharmacokinetic properties.
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According to rough estimates, at least one third of the population in developed countries suffers, to varying degrees, from certain forms of primary headache, the modern pharmacotherapy of which is not always effective and has a number of limitations. The non-pharmacological treatment of headache can be an alternative to the prescription of pharmacological agents and the only possible assistance option for patients developing drug-resistant cephalalgias. This review describes various methods of electrical neuromodulation that are used for the management of primary headaches. The authors provide information on current stages in implementation of implantable and non-invasive equipment into clinical practice, which makes possible electrical stimulations of peripheral nerves and of the sphenopalatine ganglion, as well as allows transcranial magnetic stimulation. Also the appearance and usage of portable electrical devices available on the world market are described, and mechanisms that can underlie anticephalgic action of neuromodulation therapy are discussed. Special attention is paid to the methods that are applied for electrostimulation of the vagus nerve and occipital nerves.
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Patients with chronic insomnia are commonly prescribed hypnotic medications. The long-term effects of chronic hypnotics are not known and discontinuation is encouraged but often difficult to achieve. A gradual taper is preferred to abrupt cessation to avoid rebound insomnia and withdrawal symptoms. Written information provided to the patient about medication discontinuation may be helpful. Cognitive behavioral therapy or behavioral therapies alone can improve hypnotic discontinuation outcomes. There is limited evidence for adjunct medications to assist in hypnotic cessation for insomnia.
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Benzodiazepines (BZDs; including the related Z-drugs) are frequently targets for deprescribing; long-term use in older people is harmful and often not beneficial. BZDs can result in significant harms, including falls, fractures, cognitive impairment, car crashes and a significant financial and legal burden to society. Deprescribing BZDs is problematic due to a complex interaction of drug, patient, physician and systematic barriers, including concern about a potentially distressing but rarely fatal withdrawal syndrome. Multiple studies have trialled interventions to deprescribe BZDs in older people and are discussed in this narrative review. Reported success rates of deprescribing BZD interventions range between 27 and 80%, and this variability can be attributed to heterogeneity of methodological approaches and limited generalisability to cognitively impaired patients. Interventions targeting the patient and/or carer include raising awareness (direct-to-consumer education, minimal interventions, and ‘one-off’ geriatrician counselling) and resourcing the patient (gradual dose reduction [GDR] with or without cognitive behavioural therapy, teaching relaxation techniques, and sleep hygiene). These are effective if the patient is motivated to cease and is not significantly cognitively impaired. Interventions targeted to physicians include prescribing interventions by audit, algorithm or medication review, and providing supervised GDR in combination with medication substitution. Pharmacists have less frequently been the targets for studies, but have key roles in several multifaceted interventions. Interventions are evaluated according to the Behaviour Change Wheel. Research supports trialling a stepwise approach in the cognitively intact older person, but having a low threshold to use less-consultative methods in patients with dementia. Several resources are available to support deprescribing of BZDs in clinical practice, including online protocols.
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(English version) Popularity of benzodiazepines with elderly patients is caused by a transient relief these drugs provide from a chronic stress associated with an advanced age. The standards limiting the indications for and the duration of benzodiazepine therapy are particularly seldom followed for the patients in this age group. Beliefs of practitioners contribute to this state of affairs: the belief about rarity of the emergence of the substance tolerance among the elderly, and reservations concerning safety and purpose of radical detoxification for the senior patients. The paper presents the collection of arguments supporting the detoxification recommendation and the results of actual execution of this procedure with 29 patients age 66-83. The presented results show that patients aged 65 and above tolerate detoxification not worse than the general population, what allows the practice of withdrawing of substitute benzodiazepine within a similar time frame. The total hospitalization period of the elderly was significantly increased as compared to general population, owning to the longer total elimination time of the substitute benzodiazepine and the resulting delay of the onset of withdrawal symptoms peaks, particularly the last one. Above fact (delayed peaks of withdrawal symptoms) promotes the risk of the tired patient prematurely leaving the hospital and consequential onset of withdrawal symptoms at home. To prevent that, an undue accumulation of the drug should be prevented through meticulous monitoring of the serum levels and the radical dose reduction in the first week after commencement of the benzodiazepine substitute therapy. (wersja (wersja polska) Popularność benzodiazepin wśród osób starszych wynika z przejściowej ulgi, jaką przynoszą w przewlekłych sytuacjach stresowych związanych z wiekiem podeszłym. W tej grupie wiekowej szczególnie rzadko przestrzegane są standardy ograniczające czas i wskazania do ich stosowania. Przyczyniają się ku temu opinie lekarzy: z jednej strony – przekonanie o rzadkim rozwijaniu się w tej grupie wiekowej tolerancji na benzodiazepiny, z drugiej – sceptycyzm dotyczący zarówno bezpieczeństwa, jak i celowości radykalnej detoksykacji starszych osób. Artykuł zawiera zestawienie argumentów przemawiających za decyzją o podejmowaniu detoksykacji a następnie – wynik praktycznych doświadczeń z jej przeprowadzenia u 29 osób w wieku 66-83 lat. Wykazują one, że pacjenci powyżej 65 roku życia znoszą detoksykację nie gorzej, niż pozostali, co umożliwia odstawienie benzodiazepiny substytucyjnej w podobnym czasie. Czas hospitalizacji starszych osób ulega jednak istotnemu wydłużeniu ze względu na wydłużenie czasu całkowitej eliminacji benzodiazepiny substytucyjnej, a w konsekwencji – opóźnienie kolejnych szczytów objawów odstawiennych, szczególnie – ostatniego. Fakt ten niesie ze sobą ryzyko przedwczesnego wypisania się pacjenta zmęczonego długą hospitalizacją oraz wystąpienia objawów odstawiennych w warunkach domowych. Aby temu zapobiec, należy przeciwdziałać zbędnej kumulacji leku, poprzez szczególnie dokładne monitorowanie poziomu w surowicy i zdecydowane redukowanie dawek w pierwszym tygodniu po wprowadzeniu benzodiazepiny substytucyjnej.
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For a number of antidepressants in current clinical use, concentrations in serum or plasma are a more reliable index of target drug concentrations than is dosage. For such drugs, therapeutic drug monitoring (TDM) may be a useful clinical guide for the purpose of maximizing the likelihood of favorable therapeutic outcome while minimizing the probability of clinical ineffectiveness or adverse side effects. TDM is of greatest benefit when a therapeutic range of serum concentrations has been well established. Even if such a range is not definitively determined, TDM can be of help in situations in which patients are refractory to therapy despite adequate or high dosages, when adverse events supervene even with low doses, or when noncompliance with the intended dosage plan is suspected. Serum antidepressant concentrations from TDM should be interpreted in the full context of the patient’s demographic characteristics and clinical status, along with an understanding of the pharmacokinetics of the medication being taken, the timing of the sample in relation to the dosage regimen, and the specific laboratory assay procedure. TDM measurements may be costly, and the potential benefits of the information need to be weighed against the cost to the patient or to the health care system.
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