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 Benzodiazepines are effective drugs for short-term treatment of insomnia and anxiety, although the clinical benefit of long-term use is uncertain (1,2) and has been associated with dependence (3), increased risk of falls (leading to injuries) and traffic accidents (4,5), and cognitive decline (6). Chronic benzodiazepine use can effectively be discontinued by tapering off in two-thirds of patients, with one-third remaining abstinent in the long term (7–14). Knowledge of factors predicting long-term abstinence in primary care may contribute to mechanisms of benzodiazepine continuation, enhance the efficiency with which chronic use is managed in primary care as well as the efficiency of referral to second-line care, and consequently, provide psychiatrists with clues for further treatment. Interpreting predictors for long-term benzodiazepine abstinence is limited by the scarcity of follow-up studies and also by differences in the selection of potential predictors and in the definition of abstinence (such as longitudinal abstinence compared with no use in the last month) (8–13,22). Only 2 studies performed a multivariate analysis, and both found successful short-term outcome to be the main predictor for long-term abstinence (10,22). A third study specifically examined relapse after short-term discontinuation in patients with insomnia; it found that adding cognitive-behavioural therapy to a tapering off condition, fewer sleep disturbances, and less psychological distress were preventive for relapse (23). Short-term outcome studies consistently identified a lower benzodiazepine dosage at the start of tapering off as the most important predictor (14–17). Further, a higher level of psychopathology, especially anxiety and depressive symptoms, resulted in lower abstinence rates, as did the personality traits of neuroticism, dependence, and vulnerability (10,11,15–18). The impact of benzodiazepine withdrawal symptoms varies, probably owing to mediation by personality traits (16–18,20). However, neither the severity of benzodiazepine dependence nor the diagnosis of benzodiazepine dependence have been examined in relation to taper outcome (21), despite its apparent importance in long-term use (3). ObjectivesOur first objective was to explore (independent) predictors of taper outcome and, if possible, to identify subgroups who do or do not benefit from tapering off with respect to benzodiazepine use during follow-up. We did this by performing a multivariate prediction analysis of long-term taper outcome in 180 patients included in a benzodiazepine discontinuation trial in general practice. Our second objective was to test our hypothesis that aspects of the severity of benzodiazepine dependence predict treatment outcome independent of benzodiazepine (use) characteristics, personality traits, and psychopathological symptoms. Materials and MethodsStudy Design The study is part of a 2-step treatment study aimed at the reduction of chronic benzodiazepine use (> 3 months) in 30 general practices in The Netherlands. The clinical outcome of both interventions has been described elsewhere (14,24). Of the 2004 individuals advised to stop their benzodiazepine use by a personal letter from their GP (the first and minimal intervention), 1321 visited their GP 3 months later; 285 had quit their use and 1036 were unable to do so. Of this latter group, 180 patients participated in the present study (the second intervention), which consisted of a randomized controlled trial on the differential efficacy of tapering off with brief psychotherapy (n = 73), tapering off alone (n = 73), and a nonintervention control condition (n = 34). Participants and nonparticipants in the second intervention were similar with respect to age, sex, and benzodiazepine dosage (see Oude Voshaar and others for full discussion of generalizability and representativeness; 14). Patients assigned to 1 of the 2 active treatment conditions in the second intervention visited their own GP 6 times to taper their benzodiazepine dosage in steps of 25% weekly after being transferred to an equivalent dosage of diazepam for 2 weeks. Patients assigned to the first condition additionally received 5 sessions of group therapy during tapering off. The therapy was based on cognitive-behavioural principles and consisted of psychoeducation, relaxation exercises, and restructuring of maladaptive cognitions related to withdrawal symptoms and relapse. Patients in the control condition were treated as usual and did not receive any attention regarding the reduction of benzodiazepine use. The mean age of the 180 patients was 63 years, SD 12 years, and 70% were women. Patients used benzodiazepines for a mean duration of 13.5 years, SD 9.6 years, in a mean daily dosage of 8.4 mg diazepam equivalent (percentile 25 = 4.1 mg, percentile 50 = 6.3 mg, percentile 75 = 9.9 mg). The continued abstinence rate for the tapering-off only condition was superior to the rate for the nonintervention control condition (36%and 15%, respectively; P = 0.03), but the tapering-off with brief psychotherapy condition did not reach statistical superiority, compared with the nonintervention control condition (29% and 15%, respectively; P = 0.12) (13). The study received ethical approval from the Radboud University Nijmegen Medical Centre. We obtained signed informed consent from all participants MeasurementsBenzodiazepine use was monitored prospectively in the GPs’ medical records. Success was defined as receiving no GP prescriptions for a benzodiazepine during the entire 15-month follow-up period. Drug prescription data were extracted at the patient level from the GP information system (that is, from computerized medical records). In The Netherlands, individuals are linked to only one GP, who collects all medical information, including the use of prescribed medication. Moreover, more than 90% of GPs use commercially available electronic medical dossiers, which enables reliable data collection. The following data were extracted: date prescription issued, ATC classification (25), drug name, number of tablets and dosage, and prescription rules. Patients’ sex, birth dates, and administration numbers were extracted to link prescription data with the baseline assessment (see below). For patients who left the practice before the end of the follow-up, the date and reason for leaving the practice were recorded. In addition to the computerized benzodiazepine prescription records, we administered self-report questionnaires at baseline to extract the following information: exclusively hypnotic use of the benzodiazepine (yes–no); use and amount of caffeine, nicotine, and alcohol (including the number of problem drinkers, assessed with Cornel 18-item list; 26), psychological well-being (assessed with the GHQ, 12-item version); mood (assessed with the 32-item shortened POMS dimensions of depression, anger, fatigue, vigour, and tension); the number and severity of benzodiazepine withdrawal symptoms (assessed with the BWSQ-v2); 4 dimensions of the severity of benzodiazepine dependence (assessed with the Bendep-SRQ subscales for Problematic Use, Preoccupation, Lack of Compliance, and Withdrawal); and the 5 personality traits of negativism, somatisation, shyness, psychopathology, and extraversion (assessed with the Dutch shortened MMPI). All questionnaires were tested previously in a Dutch population and have presented good psychometric properties (21, 26–30). Although the Dutch shortened MMPI does not separately assess dependent or neurotic personality traits that have been related to taper outcome, psychometric studies showed no decrease in its informational value, compared with the original MMPI (31). Statistical Analysis We analyzed potential predictors of continued abstinence by means of Cox regression analysis, using forward (Wald) procedures with time to the first prescription after the intervention period as the dependent variable. Patients lost to follow-up were analyzed until the moment of loss to follow-up as censored observations. We examined the following independent variables: more than 50% dosage reduction by the first, minimal intervention (yes–no), benzodiazepine dosage at the start of tapering off, half-life of benzodiazepine (dichotomized at 24 hours), use of a high-potency benzodiazepine (yes–no, according to the presence of a 4-aryl group), use of more than one benzodiazepine (yes–no), use of antidepressants (yes–no), use of pain medication (yes–no), and all clinical variables measured at the baseline assessment. Variables with HRs of P < 0.10 after correction for the intervention received (that is, the crude HRs) were entered into a multivariate Cox regression analysis to identify independent predictors of long-term successful taper outcome (that is, the adjusted HRs). To test our hypothesis, we performed multiple Cox regression analyses, adding age, sex, treatment group, benzodiazepine use, psychopathology, and personality characteristics in a first block, using a forward Wald procedure. Subsequently, benzodiazepine dependence severity variables (measured by the Bendep-SRQ and BWSQ-v2 subscales) were added separately into a second block. We used SPSS version 10.0 (SPSS Inc, Chicago, IL) to perform all analyses. ResultsFollow-up was completed for 170/180 patients (94%). We analyzed patients lost to follow-up (moved homes, n = 9; unknown, n = 1) until the moment of loss to follow-up (range 1 to 456 days) as censored observations .Table 1 presents all variables associated (P < 0.10) with outcome during follow-up after correction for the intervention received. We did not find significant differences in the success rate between individual benzodiazepines in patients who used exclusively one benzodiazepine (147/170, 86%). Success rates for the patients using only one benzodiazepine were as follows: oxazepam, 21/53; temazepam 9/34; diazepam, 6/18; nitrazepam, 2/9; lorazepam, 1/6; lormetazepam, 2/5; benzodiazepines used by fewer than 5 patients lumped together, 3/22. Although the use of high-potency benzodiazepines (n = 27) was associated with a less successful outcome, this association was not detected for individual high-potency benzodiazepines owing to low patient numbers within these subcategories.
Figure 1 shows the survival curves of the 3 intervention groups. Of the 12 variables, the multivariate Cox regression analysis identified 5 independent predictors of continued abstinence: a low benzodiazepine dosage before the start of tapering off, active treatment instead of no intervention, a dosage reduction of more than 50% after the minimal intervention, no use of alcohol, and finally, a low score on the Bendep-SRQ dimension Lack of Compliance with the Therapeutic Regime.
 Visual inspection of the independent predictors showed that only 2 of the 22 patients who used more than 10 mg diazepam equivalents daily (the recommended therapeutic dosage) were able to achieve continued abstinence (9%). Further, none of the 9 patients who scored 3 or more on the Lack of Compliance dimension, and also none of the 14 patients who consumed over 2 units of alcohol daily, achieved longitudinal abstinence. Thirty-eight patients fulfilled at least 1 of these 3 criteria. For the predictors intervention and dose reduction after the minimal intervention, we found no clear cut-off rates for achieving continued abstinence. Further, for none of the independent predictors could clear cut-off rates be identified that guaranteed successful long-term taper outcome. To test our hypothesis that benzodiazepine dependence characteristics influence long-term outcome, we performed multiple stepwise regression models in which all benzodiazepine dependence characteristics were added separately in a second block, after correction for age, sex, treatment condition, benzodiazepine use characteristics (that is, reduction after discontinuation letter, baseline dosage, duration of use, potency, and half-life), psyhopathology (according to GHQ-12 and POMS subscales), and personality (according to the Dutch shortened MMPI) in a first block using a forward Wald procedure. This yielded a significant independent effect for the Bendep-SRQ subscales Preoccupation (HR 1.47; 95%CI, 1.01 to 2.16; P = 0.047) and Lack of Compliance (HR 2.33; 95%CI, 1.07 to 5.10; P = 0.034) but not for the Bendep-SRQ subscale Problematic use (P = 0.74) or for withdrawal symptoms as measured with the BWSQ-v2 (P = 0.12). DiscussionIn this study, 5 variables were independently related to long-term taper outcome of benzodiazepine discontinuation in general practice. These variables accounted for 58% of variance in outcome, with 18.9% for active treatment (intervention type); 13.7% for dosage reduction after the minimal intervention; 12.5% for benzodiazepine dosage at the start of tapering-off; 8.2% for the use of alcohol, and finally, 4.8% for lack of compliance with the therapeutic regime. For interpretation, Cohen considers 1% variance as a small effect, 9% as a medium effect, and 25% as a large effect (32). Patients motivated to cut down their benzodiazepine use, but unable to do so by themselves with the aid of a minimal intervention, were more likely to achieve long-term taper success when offered a taper-off program, compared with treatment as usual as provided in the nonintervention control condition (HR 2.4 and HR 2.9, respectively). These results are in line with Rickels and others’ (10) and Couvée and others’ (22) finding that successful cessation directly after the taper-program is predictive for long-term taper success. However, their prediction models could not estimate the impact of offering a taper-off program to patients motivated for tapering off because neither study randomized patients over active treatment and a nonintervention control condition. In line with short-term outcome studies, we found a significant effect of benzodiazepine dosage at the start of tapering off (10,15 7). Interestingly, benzodiazepine dosage and a dosage reduction of more than 50% by a minimal intervention carried out prior to the tapering-off program independently contributed to a successful long-term outcome. This suggests that a dosage reduction by patients themselves before the start of tapering off is not just a matter of starting at a lower dosage and may be a proxy for their motivation for benzodiazepine discontinuation. The negative effect of alcohol consumption on taper outcome may be explained by addictive behaviour in chronic benzodiazepine users because, in social drinkers, the liability of benzodiazepines to abuse has been related to alcohol use (33,34). An effect of alcohol use on taper outcome has never been reported before (15–17), but Schweizer and others found that mild-to-moderate alcohol use predicted a more severe benzodiazepine withdrawal syndrome on discontinuation (19). Moreover high-dosage benzodiazepine users were more often alcohol-dependent, compared with control subjects (35). This association is in line with biological theories, since alcohol potentiates the effect of benzodiazepines on the GABA-A receptor in the central nervous system. Although benzodiazepine dependence is frequently mentioned as an adverse effect of chronic benzodiazepine use, it has never been diagnosed according to ICD or DSM criteria in chronic benzodiazepine users taking part in a discontinuation program. In this study, we administered the Bendep-SRQ, a multidimensional self-report questionnaire that establishes comprehensively the severity of benzodiazepine dependence (21). Low scores on the subscales Lack of Compliance With the Therapeutic Regime and Preoccupation predicted good taper outcome, even after correction for other predictors of successful taper outcome. These findings suggest that diagnosing benzodiazepine dependence might be relevant in patients discontinuing chronic benzodiazepine use. Previous benzodiazepine discontinuation trials only evaluated benzodiazepine withdrawal symptoms on discontinuation (15, 19,36) and reported mixed results (37). These mixed results can be partly explained by the relation between withdrawal symptoms and personality characteristics (16,18) since patients who dropped out early during the benzodiazepine discontinuation process had mild withdrawal symptoms but relatively more personality disturbances, whereas the opposite was found in patients who dropped out later on (16). Because we tried to identify predictors for taper success before the start of tapering off, we did not assess benzodiazepine withdrawal symptoms during the discontinuation phase. Although some personality traits, as well as the level of anxiety and depressive symptoms, have been reported to affect taper outcome (10,11,15–18), we only found significant univariate relations for negativism and tension. Moreover, both variables were correlated to benzodiazepine dependence severity (withdrawal symptoms, preoccupation, and lack of compliance; data not shown), supporting the claim that personality traits are important in influencing patients’ dependence potential (11,18). In addition, whether the benzodiazepine was used as a hypnotic or anxiolytic drug was irrelevant. Further, female sex and older age, which are associated with chronic benzodiazepine use in the population (38), did not influence benzodiazepine discontinuation outcome. Previous research yielded inconsistent results, since both female and male sex, as well as younger and older age, have been associated with successful taper outcome (8–10,16,39). In our study, shorter duration of benzodiazepine use was only univariately associated with better outcome. The follow-up studies of Rickels and others (10) and Couvée and others (22) found a relation between a shorter duration of benzodiazepine use and successful taper outcome, in contrast to Holton and others, who found the opposite (11). We did not observe significant differences among individual benzodiazepines, which for some benzodiazepines might be attributable to low patient numbers. In line with previous research, the elimination half-life of the drug did not influence taper outcome (18). However, in the case of abrupt cessation, use of benzodiazepines with a shorter elimination half-life results in lower abstinence rates (15,19). The use of high-potency benzodiazepines was univariately associated with a less successful outcome, although this finding did not reach statistical significance in the multivariate analyses. As only 27 patients in our population used a high-potency benzodiazepine, we suggest that this finding be further explored in future research. This study can be criticized for the lack of psychiatric diagnosing and for its use of prescribed, rather than actual, benzodiazepine use as the main outcome measure. Although benzodiazepine discontinuation might be more difficult for patients with certain psychiatric disorders, these findings would probably have been masked in our study by the low prevalence figures of the separate disorders. Therefore, we decided to measure psychopathological symptoms dimensionally. A second limitation concerns the main outcome measure. Although it remains uncertain whether a prescription was really filled and taken by the patient, we suspect noncompliance with the intake of benzodiazepines to be minimal because patients were aware that such noncompliance was considered the most favourable outcome. Further, the unique position of GPs in The Netherlands (see Methods) makes the prescribing of benzodiazepines by other physicians unlikely without the GP’s knowledge. In The Netherlands, 89% of all benzodiazepine prescriptions are issued by GPs, and only 9% by specialists, more than one-half of the latter being psychiatrists (40), whereas current psychiatric treatment was an exclusion criterion of our study to prevent such treatment being interrupted by a discontinuation letter. Further, benzodiazepine use by illicit sources is negligible in an elderly primary care population. Since most patients take benzodiazepine intermittently after a discontinuation program (12,13), biochemical corroboration of abstinence status would not have additive value. We can conclude that active treatment increases the likelihood of long-term abstinence in a general practice population of chronic benzodiazepine users motivated to reduce their benzodiazepine consumption. In addition, the outcome of tapering off depends on the dosage used by these patients and the ability of patients to lower their dosage first by themselves. Moreover, our data suggest that alcohol use and benzodiazepine dependence severity affect taper outcome, independent of the level of psychopathology, personality traits, or benzodiazepine type. Psychiatrists treating patients that failed to discontinue benzodiazepine use in primary care should pay attention to the dependence potential of these agents during treatment. We were able to identify a subgroup of patients who failed to achieve continued abstinence. These included patients using more than 2 units of alcohol daily, patients scoring 3 or more on the Bendep-SRQ subscale Lack of Compliance With the Therapeutic Regime, and patients using more than 10 mg diazepam at the start of tapering off after having received a minimal intervention. Because more intensive treatment is probably necessary for this subgroup, a priori referral to second-line treatment can be considered. Funding and SupportThe study was funded by the Dutch Health Care Insurance Council (grant number: OG 97 15), The Hague, The Netherlands. References1. Ashton H. Guidelines for the rational use of benzodiazepines. When and what to use. Drugs 1994;48:25–40. 2. Committee on the Review of Medicines. Systematic review of the benzodiazepines. BMJ 1980;1:910–2. 3. Kan CC, Breteler MH, Zitman FG. High prevalence of benzodiazepine dependence in out-patient users, based on the DSM-III-R and ICD-10 criteria. Acta Psychiatr Scand 1997;96:85–93. 4. Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and meta-analysis: I. Psychotropic drugs. J Am Geriatr Soc 1999;47:30–9 . 5. Hemmelgarn B, Suissa S, Huang A, Boivin JF. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 1997;278:27–31. 6. Paterniti S, Dufouil C, Alpérovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the epidemiology of vascular aging study. 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A comparison of alpidem and placebo in relieving benzodiazepine withdrawal symptoms. Int Clin Psychopharmacol 1993;8:31–6. 40. Piepenbrink JF. Geneesmiddelen Informatie Project (GIP-signaal). Gebruik van benzodiazepinen 1993 998. Amstelveen (NE): College voor Zorgverzekeringen; 2000. Author(s)Manuscript received July 2005, revised, and accepted March 2006. 1. Psychiatrist, Department of Psychiatry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 2. General Practitioner, Department of General Practice and Family Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 3. Psychologist, Department of Psychiatry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 4. Professor of Psychiatry, Department of Psychiatry and Institute for Research in Extramural Medicine, VU University Medical Centre Amsterdam, Amsterdam The Netherlands. 5. Statistician, Department of General Practice and Family Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 6. Associate Professor of General Practice, Department of General Practice and Family Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 7. Associate Professor in Psychiatry, Department of Clinical Psychology, Radboud University Nijmegen, Nijmegen, The Netherlands. 8. Professor of Psychiatry, Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. Address for correspondence: Dr RC Oude Voshaar, Radboud University Nijmegen Medical Centre, Department of Psychiatry (966), PO Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: r.oudevoshaar@psy.umcn.nl
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