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1 Reviews
1.1 Expert Opinion
Gorgels WJ, Oude Voshaar RC, Mol AJ, et al. Long-term use of benzodiazepines. Ned Tijdschr Geneeskd. 2001;145(28):1342-6. Abstract
BZs are most Rxd drugs in Netherlands. There is scarcely indication for LT BZ use. LT use may lead to dependency, associated with an increased risk of accidents / falls and cognitive function impairment. National, international guidelines advocate conservative Rx policy, especially with respect to LT Rx. It appears these guidelines are not followed in practice. Standard sized general practice in Netherlands contains, on average, 75 LT BZ users. Both patient and GP related factors influence maintenance of LT BZ use.
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Salzman, c. Should benzodiazepines in an 87-year-old woman be tapered and discontinued? Reply. JAMA. 1999;282(12):1128. Article
In Reply: My comments should not be taken as support for inappropriate use of BZs in elderly. I agree cognition-impairing meds should not be given to elderly if effective alternatives available. Rational use of BZs in elderly requires appreciation of pharmacology of these compounds as well as appraisal of risk v benefit. There is no evidence LT use produces tolerance to anxiolytic effects or leads to escalation in dose. Cognitive impairment produced by BZs, although measurable in lab tests, is often clinically insignificant when low therapeutic doses used. Many elderly who take BZs regularly find meds useful, not troubled enough by cognitive impairment to wish to DC the drugs. There is little doubt that untreated chronic anxiety and sleep disturbance in elderly may contribute to cognitive impairment, social dysfunction. Decision to Rx BZs to elderly, continue their ongoing use, requires evaluation of risks (eg falls, sedation, cognitive impairment) v benefits (eg anxiety reduction, improved sleep, improved social function). Appraisal must be ongoing, flexible. Dr Portnoi correctly points out hazards of oversedation in elderly. For this reason, low doses of short half-life BZs only recommended. Whenever possible, ST use preferred. My comments in no way were meant to ignore other Rx of anxiety in elderly. However, withholding these effective meds because of generalizations about potential hazards may deprive elderly of rapid and safe Sx relief. Undertreatment may be as harmful as over-Rx.
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1.1.1 Guidelines
1.1.2 Meta – Analyses
1.1.3 Reviews
1.2 Definition of Long-Term Use
1.3 Epidemiology of Long-Term Use
Benítez CI, Smith K, Vasile RG, et al. Use of benzodiazepines and selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: a longitudinal and prospective study. Am J Geriatr Psychiatry. 2008;16(1):5-13. Abstract
Aim Examine use of BZs, SSRIs/SNRIs over 9y of follow-up in middle-aged and older adults with Dx with or without agoraphobia, social phobia, GAD.
Design Participants enrolled in Harvard/Brown Anxiety Research Project (HARP). HARP is naturalistic, longitudinal, multisite study of adults with anxiety disorders recruited from psych settings. Analytic sample consisted of 51 participants with anxiety disorders 55-70yo at baseline and younger cohort of 211 participants added for comparative analysis. Authors examined patterns of med use (BZs and SSRIs/SNRIs) in participants with anxiety disorders as they aged, by assessing the proportion of participants taking these meds using generalized estimating equation modeling. The present data derived from structured Dx interview administered at enrollment using combination of Structured Clinical Interview for DSM3-R Non-Affective Disorder, Patient Version, Research Diagnostic Criteria Schedule for Affective Disorders-Lifetime, and subsequent follow-up interviews over a 9y period using Longitudinal Interval Follow-up Evaluation-Pharmacia & Upjohn to assess the weekly course of disorders to indicate syndrome severity and document medication use by specific type and dose on a weekly basis.
Results Rates of BZ use high among both the older (53% at baseline) and younger (57%) age groups and did not significantly decrease over time, after controlling for time in episode of their anxiety disorders. There was statistically significant increase in SSRI/SNRI use over time in both groups. At beginning of study, 18% of older group and 21% of younger group were using SSRIs/SNRIs. At end of study, rates increased to 35% and 43%, respectively.
Conclusions Although there was increase in SSRI/SNRI use in older participants with anxiety disorders over course of study, at 9y follow-up, only 35% of participants were utilizing SSRI/SNRI med, while >1/2 of same participants continuing to use BZs. To the authors’ knowledge, there are no RCTs that have addressed comparative efficacy and safety of BZs and SSRIs/SNRIs in this population. There is documented evidence of AEs of chronic BZ use and the risk of developing dependency in older populations.
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Geiselmann B, Linden M. Prescription and intake patterns in long-term and ultra-long-term benzodiazepine treatment in primary care practice. Pharmacopsychiatry. 1991;24(2):55-61. Abstract
Background Pharmacoepidemiological data show LT Rx accounts for considerable part of BZ Rxs in 1º care.
Aim Prescription, intake patterns investigated in study of 196 patients who had been Rxd with BZs for >6m by internists / GPs in private practice.
Results Patients 64yo on average, 1/2 >65yo. Females 74%. Average duration of tranquilizer or hypnotic intake 11.0y, or 5.3y for the current BZ med. Mean qd dose 9 mg diazepam equivalent. All BZ hypnotics and 61% of BZ tranquilizers had been Rxd solely for night-time use. Only 6% patients were taking BZs as single med: on average they were taking 3.1 additional types of meds for other conditions, predominantly cardiac, anti-rheumatic / analgesic. 1 in 5 patients was taking additional psychotropic med. Compliance coefficient on average 0.8, showing patients did not tend to abuse BZs, with noncompliance generally being similar to noncompliance with other forms of meds.
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van Hulten R, Isacson D, Bakker A, Leufkens HG. Comparing patterns of long-term benzodiazepine use between a Dutch and a Swedish community. Pharmacoepidemiol Drug Saf. 2003;12(1):49-53. Abstract
Background There is much concern about the widespread LT use of BZs. Utilisation data can give a foundation for interventions for appropriate use.
Aim Compare LT usage patterns of BZs in a Dutch and a Swedish community in different periods.
Design 8y follow-up patterns of use investigated with respect to characteristics of those who continued use over whole follow-up period. In Dutch community of 13,500, data of a cohort of 1,358 BZ users analyzed 1984-1991; in Swedish community of 20,000 people, cohort of 2,038 BZ users followed from 1976.
Results At end of follow-up period, 33% of Dutch cohort and 33% of Swedish cohort had continued use of BZs. The 2 overall survival curves showed similar patterns. Stratification for age, gender, previous v initial use, heavy v non-heavy use showed comparable proportions of patients continuing BZ use over time.
Conclusions Parallels in results of 2 cohorts in different countries and different periods striking and give support to idea to stimulate interventions to reduce LT BZ use.
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Neutel CI. The epidemiology of long-term benzodiazepine use. Int Rev Psychiatry. 2005;17(3):189-97. Abstract
Background Recommendations for BZ use suggest durations of no more than a few weeks, but studies report use for months, years, decades.
Aim Examine the who (who are LT users), why (why do they use BZ), what (what are patterns of LT use) and how (how do they compare to all BZ users).
Design Study population from National Population Health Survey in Canada which interviewed respondents 4x at 2y intervals, asking about specific drugs used as well as demographic, lifestyle / health-related questions. LT BZ use defined as BZ use for 2 successive cycles.
Results 4% Canadians used BZ at any 1 time, 1/2 of whom reported use in previous cycle. BZ users more likely female, elderly, smokers, prefer speaking language other than English, have insurance coverage for med, completed HS education. Almost none of these determinants predicted LT use. Persons reporting BZ use in 2000 had OR of 39 for also using BZ in 1998, more likely to use antidepressants (OR=8.5), suffer from conditions eg poor health, stress, pain. Most determinants had no association with LT use or if they did at a considerably lower OR. Of 395 BZ users in 2000, 48% also used BZ in previous cycle, 17% in all 3 previous cycles. BZ use in any previous cycle made BZ use in 2000 more likely, with use determined by how recent and frequency of reported use, culminating in very high OR of 83 for use in all 3 previous cycles. Continued use for any of the individual BZ tended to be largely for the same BZ.
Conclusions 1) overriding determinant for BZ use was previous use; 2) LT use not determined by same factors as overall use, which is significant in developing approaches to dealing with LT BZ use.
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Zandstra SM, Furer JW, van de Lisdonk EH, et al. Different study criteria affect the prevalence of benzodiazepine use. Soc Psychiatry Psychiatr Epidemiol. 2002;37(3):139-44. Abstract
Background Different prevalences of BZ use are described in literature.
Aim Assess effects of employing various definitions of BZ use and various observation periods on prevalence rate of BZ use in an open population 18-74yo.
Design In a literature review, prevalence studies systematically compared. In a 2nd stage, a descriptive cross-sectional multi-practice study was analyzed using 48,046 prescriptions of BZ in past year given to a population of 80,315 patients at 31 general practices in the Nijmegen Health Area. From this database, prevalence rates calculated applying different definitions of BZ use and different observation periods.
Results 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 Rx database, depending on definitions of BZ use and observation period, prevalence rates ranged 0.2% to 8.9%. Ratio of female:male (2:1) remained constant irrespective of prevalence rate. Age distribution varied according to duration of use: among LT BZ users, approximately 80% >45yo; among ST BZ users, approximately 55% >45yo.
Conclusions Wide variation in prevalence rates of BZ use reported in literature can largely be explained by differences in definitions of BZ use and observation period. This affected distribution of some BZ-use-related variables eg age. For reliable comparisons of BZ use, standardization of definition of BZ use is required. A proposal for standardizing methodology is presented.
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1.4 Characteristics: Short-Term v Long-Term Users
Hawley C, Tattersall M, Dellaportas C, Hallstrom C. Comparison of long-term benzodiazepine users in three settings. Br J Psychiatry, 1994;165(6):792-6. Abstract
Background Most studies of chronic benzodiazepine users consider selected populations which may be unrepresentative. This study was undertaken to examine possible differences between groups.
Design Subjects chosen were benzodiazepine users in general practice, a hospital clinic, and attending TRANX trials. Descriptive data were collected on characteristics and outcome.
Results TRANX trial patients had best outcome (P=0.027). Hospital cases used high doses of anxiolytic BZs; concomitant mental disorder including schizophrenia common. General practice cases older, mainly used hypnotics (P < 0.05).
Conclusions Because groups of BZ users different, there cannot be 1 single management approach. Cases require individual med assessment.
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Isacson D. Long-term benzodiazepine use: factors of importance and the development of individual use patterns over time – a 13-year follow-up in a Swedish community. Soc Sci Med. 1997;44(12):1871-80. Abstract
Design Using data from research registry of Rxs, we studied BZ use in a Swedish community with general population of 20,000. Sample of BZ users in 1976 (n=561) >15yo identified, followed 13y with respect to continued BZ use.
Results Strong tendency towards continued use observed. 65%,continued BZ use during 1st follow-up year, 55% used BZs during 2nd. 1/4 sample continued using BZs during all years of 13y follow-up. Multivariate Cox regression analysis, showed frequent / qd use and age important factors. Gender and type of generic BZ of little importance. Patients Rxd BZs by doctors working at hospitals and those who obtained Rxs from both 1º and hospital care physicians continued to use BZs to greater extent v those who obtained Rxs only from private practitioners / health center doctors. Of those with BZ use persisting for >8y (n=119), between 1/2 and 2/3 frequent or qd users in each of those years. Because repeated measurements for same individuals analyzed, generalized estimating equations (GEE) method chosen for multivariate analyses. Among LT users, age, combined use of tranquilizers and hypnotics, Rxs from >1 of prescriber categories studied (ie doctors working at health centers, hospital doctors, private doctors) significant factors in frequent or qd use. Frequent / qd use increased among the identified LT users during time period analyzed.
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Kurko TA, Saastamoinen LK, Tähkäpää S, et al. Long-term use of benzodiazepines: definitions, prevalence and usage patterns – a systematic review of register-based studies. Eur Psychiatry. 2015;30(8):1037-47. Abstract
Background Numerous Rx guidelines recommend LT BZ be avoided due to tolerance, risk dependence. LT BZ use remains controversial. There is no explicit understanding of what is meant by LT BZ use.
Aim Assess different definitions, usage patterns, prevalence, other characteristics of LT BZ use based on published register-based studies. Synthesis of these characteristics is essential to derive meaningful definition of LT BZ.
Design Systematic review of register-based studies on LT BZ use published 1994-2014.
Results 41 studies met predetermined inclusion criteria. Length of BZ use defined as LT varied in studies ranging from 1m to several years – most common definition was >6m during a year. Prevalence of LT BZ use in general population estimated 3%. Relative proportion of LT BZ users (all definitions) in adult BZ users ranged 6-76% (mean 24%; 95%CI 13-36%). Estimates higher in studies only on elderly (47%; 95%CI 31-64%). LT use involved typically steady Rx with low BZ doses. In elderly, LT BZ use and exceeding recommended doses common. Several characteristics associated with LT found.
Conclusions LT BZ use common. Uniform definitions for LT in line with population-based evidence needed to have more comparable results between studies. Duration of BZ Rx over 6m most common definition for LT BZ use. It is useful starting point for further analyses on disadvantages but also potential advantages associated with LT BZ use.
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Neutel CI. The epidemiology of long-term benzodiazepine use. Int Rev Psychiatry. 2005;17(3):189-97. Abstract
Background Recommendations for BZ use suggest durations of no more than a few weeks, but studies report use for months, years, decades.
Aim Examine the who (who are LT users), why (why do they use BZ), what (what are patterns of LT use) and how (how do they compare to all BZ users).
Design Study population from National Population Health Survey in Canada which interviewed respondents 4x at 2y intervals, asking about specific drugs used as well as demographic, lifestyle / health-related questions. LT BZ use defined as BZ use for 2 successive cycles.
Results 4% Canadians used BZ at any 1 time, 1/2 of whom reported use in previous cycle. BZ users more likely female, elderly, smokers, prefer speaking language other than English, have insurance coverage for med, completed HS education. Almost none of these determinants predicted LT use. Persons reporting BZ use in 2000 had OR of 39 for also using BZ in 1998, more likely to use antidepressants (OR=8.5), suffer from conditions eg poor health, stress, pain. Most determinants had no association with LT use or if they did at a considerably lower OR. Of 395 BZ users in 2000, 48% also used BZ in previous cycle, 17% in all 3 previous cycles. BZ use in any previous cycle made BZ use in 2000 more likely, with use determined by how recent and frequency of reported use, culminating in very high OR of 83 for use in all 3 previous cycles. Continued use for any of the individual BZ tended to be largely for the same BZ.
Conclusions 1) overriding determinant for BZ use was previous use; 2) LT use not determined by same factors as overall use, which is significant in developing approaches to dealing with LT BZ use.
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Neutel CI, Walop W, Patten SB. Can continuing benzodiazepine use be predicted? Can J Clin Pharmacol. 2003;10(4):202-6. Abstract
Aim Examine characteristics of BZ users, identify predictors of continuing BZ use.
Design Health-related data collected x2 on same sample of Canadians 2y apart. Drug use based on question: What meds did you take over last 2d? while other variables used were age, sex, education, marital status, chronic conditions, non-BZ drug use, health status, pain level.
Results Of 11,624 respondents, 3.2% reported taking BZs in 1994. Logistic regression results showed highest odds of BZ use were for antidepressant users (OR=10.7, P<0.05), followed by poor health (OR=5.0, P<0.05), pain (OR=3.9, P<0.05), chronic conditions (OR=3.2, P<0.05). Of 371 individuals who reported BZ use in 1994, 53% reported BZ use in 1996. Logistic regression showed no variables mentioned above showed significant association with continuing (including gaps in use) BZ use in 1996. Regarding individual BZs, it could not be concluded definitively any BZ more likely to show continued use v any other, but possibility of linear relationship between proportion of continued use and half-life of BZ should be investigated. Main predictive factor for continuing BZ use is that of previous use.
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Simpson RJ, Power KG, Wallace LA, et al. Controlled comparison of the characteristics of long-term benzodiazepine users in general practice. Br J Gen Pract. 1990;40(330):22-6. Article
Design From 3 general practices, served by 11 principals, 205 LT BZ users identified, matched for age and sex with controls.
Results BZ users had significantly higher rates of previous physical illness, consultation, non-psych drug consumption v controls. Characteristics of those receiving Rxs for BZ hypnotics alone, anxiolytics alone and anxiolytics + hypnotics investigated. Significant differences emerged between these 3 groups. Patients receiving hypnotics only were older, had Hx of more physical illness, had received more non-psych med v patients receiving anxiolytics only. Anxiolytic + hypnotic group had previously received more hypnotics and currently receiving more med than group receiving anxiolytics alone.
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Zandstra SM, Van Rijswijk E, Rijnders CA, et al. Long-term benzodiazepine users in family practice: differences from short-term users in mental health, coping behaviour and psychological characteristics. Fam Pract. 2004;21(3):266-9. Abstract
Background Contrary to ST use, LT BZ use is undesirable. Nevertheless, prevalence high. To prevent LT use, it is important to know which ST users are at risk of becoming LT users.
Aim Identify patient-related factors of LT v ST use of BZs.
Design Cross-sectional study carried out in family practices among users of BZs with regard to DSM-IV Dx, coping, psychosocial characteristics. In multivariate logistic regression analysis, LT BZ was dependent variable.
Results 164 ST, 158 LT BZ users participated. Having DSM-IV disorder and psych co-morbidity, being older, less educated, lonely, using more avoidance coping behavior associated with BZ LT use v ST use.
Conclusions The associations found point to possibilities to reduce LT BZ use, for example if patients with these characteristics Rxd with alternatives or monitored closely for a short period after Rxd BZs.
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Zandstra SM, Furer JW, van de Lisdonk EH, et al. Differences in health status between long-term and short-term benzodiazepine users. Br J Gen Pract. 2002;52(483):805-8. Article
Background Despite generally accepted advice to keep Rx short, BZs often Rxd >6m. Prevention of LT BZ use could be facilitated by utilization of risk indicators for LT use. Characteristics of LT BZ users described in literature are based on studies in which LT users compared with non-users, which may be imprecise.
Aim Study characteristics of LT BZ users by comparing their demographic data, health status (mental, physical) with those of ST users.
Design Cross-sectional comparison of ST and LT BZ users. Patients from 32 GP practices of Nijmegen Health Area, Netherlands. Characteristics of 164 ST and 158 LT BZ users in general practice compared, using interview data, morbidity referral, Rx data from GP records.
Results LT BZ users a) older, b) had more severe Hx MH problems for which they had received more serious Rx, c) used more psych drugs, d) had higher hospital specialist consultation frequency, e) had more Dxs of DM, asthma, COPD, HTN, serious skin disorder, f) reported lower perceived general health status. No sex differences.
Conclusions Specific risk characteristics of LT BZ users can be used to develop risk profile for management of BZs in general practice. We believe (somatic) 2º care contributes to BZ use. It may be worthwhile to coordinate care for BZ users between GPs and hospital specialists.
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1.5 Long-Term Use Outcomes: Efficacy
Fava GA. Fading of therapeutic effects of alprazolam in agoraphobia. Case reports. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12(1):109-12. Abstract
Decrease in therapeutic effects of alprazolam after initial good response is described in 3 patients suffering from PD with agoraphobia. Possibility of fading of therapeutic effects of alprazolam (defined as progressive decrease of therapeutic effects refractory to dosage increase, after non-immediate Sx improvement) in such cases discussed. Fading may not be apparent from large scale controlled studies with alprazolam, since its detection requires a prolonged time of observation and a specific design.
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Hollister LE, Conley FK, Britt RH, Shuer L. Long-term use of diazepam. JAMA. 1981;246(14):1568-70. Abstract
Design Plasma concentrations of diazepam and its major active metabolite nordiazepam measured in 108 neurosurgical patients taking diazepam 5-40 mg/d for 1m to 16y.
Results Diazepam was used for relief of pain or muscle spasm, or anxiety and sleeplessness associated with these 2 Sxs, and was considered beneficial by 83%, although use of other drugs confounded this evaluation. Concentrations of total diazepam-nordiazepam ranged from 0 to 2,584 ng/mL, with nordiazepam being the predominant metabolite. Low concentrations (<250 ng/mL) found in 35 of the 108 patients, with 19 having concentrations <100 ng/mL. High concentrations (>900 ng/mL) found in 20 patients and did not occur more frequently than in other studies of LT diazepam ingestion.
Conclusions Even with LT use, diazepam seemed to retain its efficacy, did not lead to any clear-cut abuse.
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Nyström C. Effects of long-term benzodiazepine medication. A prospective cohort study: methodological and clinical aspects. Nord J Psychiatry. 2005;59(6):492-7. Abstract
Aim BZ impact on mental functions explored in a cohort study of 30 psych outpatients on LT BZ.
Design New questionnaire, Drug Impact on Mental Processes (DIMP) used, evaluated. Patients rated 3 times: on inclusion in study, after about 18m and only a few days later. Test-retest reliability evaluated for the 2 last ratings and was found acceptable for 19/23 items.
Results DIMP scores indicated negative effects on crisis reaction, intensified defense mechanisms and reduced cognitive, emotional, cognitive functions. LT BZ Rx intensified passive coping. Drug impact on mental functions ranged between mild and moderate degree. Clinical outcomes of psych disorders evaluated at 1y follow-up after continued / DCd BZ Rx. In subgroup that had DCd BZ Rx at follow-up, significantly more patients reported reduced severity of psych disorders and significantly more patients had paid jobs. Overall clinical improvement after DCd BZ Rx may be explained by recovery from addiction syndrome. It may also be related to a shift from passive to active coping.
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Oulis P, Konstantakopoulos G, Kouzoupis AV, et al. Pregabalin in the discontinuation of long-term benzodiazepines’ use. Hum Psychopharmacol. 2008;23(4):337-40. Abstract
Design 15 patients with LT, mostly high-dose dependence from BZ, Rxd with pregabalin in open-label study at doses 225-900 mg.
Results All patients DCd successfully BZ in 3-14w with significant reduction of their previous anxiety levels under BZ & showed significant amelioration in cognitive functioning. Pregabalin’s AEs mild and transient, lasting only during 1st 2w Rx.
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Pélissolo A, Maniere F, Boutges B, et al. Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice. Encephale. 2007;33(1):32-8. Abstract
Background Consumption rates of anxiolytic drugs, especially BZs, remain very high in France v other Western countries, whereas clinical guidelines limit indications to ST Rx and only for some precise anxiety disorders. Recent epidemiologic surveys in community indicated >15% of people used once or more anxiolytic in past year. Chronic Rx crucial because of poor benefit/risk ratio in most anxiety disorders (limited efficacy, cognitive AEs, WD / dependence problems).
Aim Explore psych Dxs in GP’s patients with chronic use of anxiolytic BZs.
Design We included 4,425 patients consuming BZs regularly for >6m, and assessed anxiety, depression Sxs through various clinical scales (Hospital Anxiety and Depressive scale – HAD, CGI, Sheehan Disability Scale – SDS, Cognitive Dependence to Benzodiazepines scale – CDB) and with Mini International Neuropsychiatric Interview for DSM IV criteria.
Results Only 2.2% of subjects had neither anxious nor depressive Sxs as indicated by low scores on both subscores (<8) of HAD scale, used as a screener. 73% had CGI scores of >5 (markedly ill to extremely ill). Social and familial disability high in >40% (marked to extreme disruption according to SDS scores). About 1/2 of sample had CDB scores suggesting BZ dependence. According to MINI, 85% had at least 1 current DSM IV Dx of affective disorder. Most frequent Dxs: major depressive episode 60%, GAD 61%, PD 23%. Anxiety and depressive comorbidity found in 43%. Methodological limitations: included patients were not supposed to be totally representative of all patients consuming anxiolytic BZs in general practice. However, size of our sample is sufficiently large to limit possible biases in patient selection.
Conclusions Great majority of patients had significant symptomatology, in particular major depressive episodes and GAD, often with marked severity, disability. These data are in line with knowledge of lack of efficacy of BZs in depressive, most anxiety disorders, despite LT Rx. They confirm current guidelines which recommend Rx serotoninergic antidepressants, and not BZs, when LT Rx needed for severe and chronic affective disorders. Specific and attentive Dx assessment should be done in all patients receiving BZs >3m, in order to purpose in many cases other LT therapeutic strategies.
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Romach MK, Busto UE, Sobell LC, et al. Long-term alprazolam use: abuse, dependence or treatment? Psychopharmacol Bull. 1991;27(3):391-5. Abstract
Background Concern about persistent BZ use should be informed by data about reasons for such use.
Design Consecutive LT alprazolam users (n=25) admitted to advertised outpatient program for DC were characterized with respect to alprazolam use patterns and lifetime and current Axis I and II disorders. Patient characteristics: females 50%; mean 46+12yo; prior med use – BZs 47%, antidepressants 23%; median duration of use 104+96w; median daily dose 0.5 mg; continued effectiveness of alprazolam 50%. Over duration of use patients shifted their initial pattern of use from as Rxd to self-controlled “as required” basis (p<0.05). Interviews using Structured Clinical Interview for DSM-III-R (SCID) yielded Dxs of DSM-III-R alprazolam dependence in all patients + at least 1 additional psych Dx in 65% (Axis I 65%; Axis II 39%).
Conclusions Most persistent alprazolam use does not represent abuse or addiction as usually understood. These data are most consistent with interpretation alprazolam is most recent BZ used by patients to help control clinically important psychopathology and that most users make efforts to control or stop use.
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van Balkom AJ, de Beurs E, Koele P, et al. Long-term benzodiazepine use is associated with smaller treatment gain in panic disorder with agoraphobia. J Nerv Ment Dis. 1996;184(2):133-5. Link
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1.6 Long-Term Use Outcomes: Physiologic Dependence
1.7 Long-Term Use Outcomes: Adverse Effects
1.8 Long-Term Use Outcomes: As Reflected Retrospectively by Discontinuation
Fava GA, Grandi S, Belluardo P, et al. Benzodiazepines and anxiety sensitivity in panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(7):1163-8. Abstract
BZs DCd in 16 patients who had recovered from PD with agoraphobia after exposure Rx. Drug DC yielded a significant decrease in anxiety sensitivity, state anxiety in these LT users. Several likely explanations for findings discussed. In ST, Rx PD with BZs may lower anxiety Sxs. However, in long run, it may decrease individual tolerance to anxiety, discomfort.
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Oulis P, Masdrakis VG, Karakatsanis NA, et al. Pregabalin in the discontinuation of long-term benzodiazepine use: a case-series. Int Clin Psychopharmacol. 2008;23(2):110-2. Abstract
Background Pregabalin (PGB), has successfully been tested in Rx anxiety disorders.
Design We report on 4 women with LT, high-dose dependence on BZ, who Rxd PGB 225-600 mg.
Results All 4 patients DCd BZ successfully in 3-7w, impressive reduction of their previous anxiety levels under BZ, significant amelioration in cognitive function. PGB AEs mild and transient, persisting only during 1st 2w Rx.
Conclusions Although preliminary, PGB might be promising in Rx BZ dependence.
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Specht U, Boenigk HE, Wolf P. Discontinuation of clonazepam after long-term treatment. Epilepsia. 1989;30(4):458-63. Abstract
Background Frequent unwanted AEs and development of tolerance are main disadvantages of clonazepam (CZP) in LT Rx epileptic patients. Review of literature shows CZP tolerance more often appears in severe forms of childhood epilepsy (West and Lennox-Gastaut syndromes) v other epileptic syndromes.
Design Prospectively studied consequences of CZP DC in 40 consecutive children with difficult-to-Rx epilepsies and multiple-drug therapy. CZP was reduced stepwise in a variable qd reduction rate (0.003-0.16 mg/kg), while serum levels of the co-med kept unchanged.
Results In only 3 children (7.5%), CZP was believed to have had some antiepileptic effect; in 30 (75%) it had been ineffective, whereas in 6 (15%), a decrease in seizure frequency after CZP DC suggested a negative therapeutic effect. DC Sxs, mostly in form of transitory exacerbation of seizure frequency, occurred in 19 children (47.5%). These children had a significantly higher CZP dose and longer duration of Rx v children without DC Sxs, but there was no difference between the 2 groups related to rate of CZP discontinuance.
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