University Medical Centre, Nijmegen, The Netherlands
Amsterdam Free University, The Netherlands
University of Nijmegen, The Netherlands
Leiden University, The Netherlands
Correspondence: R.C. Oude Voshaar,University Medical Centre St Radboud, Department of Psychiatry (hp 333), PO Box 9101, 6500 HB Nijmegen,The Netherlands. Tel: 24 3613489; fax: 24 3540561; e-mail: r.oudevoshaar{at}psy.umcn.nl
Declaration of interest None.The study was funded by the Dutch Health Care Insurance Council.
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ABSTRACT |
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Aims To evaluate the efficacy and feasibility of tapering off long-term benzodiazepine use in general practice, and to evaluate the value of additional group cognitivebehavioural therapy (CBT).
Method A 3-month randomised, 3-month controlled trial was conducted in which 180 people attempting to discontinue long-term benzodiazepine use were assigned to tapering off plus group CBT, tapering off alone or usual care.
Results Tapering off led to a significantly higher proportion of
successful discontinuations than usual care (62% . 21%). Adding group CBT
did not increase the success rate (58% v. 62%).Neither successful
discontinuation nor intervention type affected psychological functioning. Both
tapering strategies showed good feasibilityin general practice.
Conclusions Tapering off is a feasible and effective way of discontinuing long-term benzodiazepine use in general practice.The addition of group CBT is of limited value.
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INTRODUCTION |
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METHOD |
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Retirement
Long-term benzodiazepine use was identified by means of a computerised
search for benzodiazepine prescriptions at 30 general practices (58 doctors;
118 082 patients). The practices were chosen to maximise the variety of
locations throughout the Netherlands 12 were urban (Amsterdam,
Nijmegen and Almere) and 18 rural (villages near Nijmegen) and of
organisation type (4 health centres, 11 group practices and 15 solo
practices). Long-term use was defined as benzodiazepine use for
at least 3 months with a prescribed amount sufficient for at least 60 days of
consumption in accordance with the recommended dosage. Exclusion criteria were
current psychiatric treatment; current treatment for drug or alcohol
dependence; medical history of psychosis; epilepsy; insufficient mastery of
the Dutch language; or terminal illness. Furthermore, some people were
excluded specifically at general practitioner's request because of severe
comorbidity or for psychosocial reasons. People who met this definition of
long-term benzodiazepine use were sent a letter by their general practitioner
advising them to quit gradually and inviting them to the surgery 3 months
later to evaluate the effect of the letter. At this consultation the doctor
enquired whether the patient had been able to achieve complete abstinence and
if not, whether the patient would participate in this study. All participants
provided written informed consent.
Sample size and randomisation
The aim was to increase the success rate after the pre-selection procedure
(i.e. the letter from the general practitioner) from an expected 55% through
tapering off alone, to 80% by combining tapering off with group CBT
(Otto et al, 1993).
Based on a chi-squared test, this effect size required a sample size
(two-sided =0.05, ß=0.20) of 52 participants in each experimental
group, or 62 participants based on a corrected chi-squared or Fisher's exact
test (Dupont & Plummer,
1990). Participants were randomised in a ratio of 2:2:1 to achieve
maximum discriminative power between the two experimental groups. Computerised
randomisation took place after at least ten participants within a geographic
cluster had given informed consent, in order to form CBT groups with a minimum
of four participants at a location near to the participants' homes.
Intervention
Tapering off
Participants who were not using diazepam were transferred to an equivalent
dose of diazepam for 2 weeks by their own doctor, using the conversion table
of Zitman & Couvée
(2001). For participants
taking more than one benzodiazepine, the dosages were added together. The
daily dose of diazepam was reduced by 25% a week during four weekly visits. In
accordance with Schweizer et al
(1990) participants had the
opportunity to divide the last step into two steps of 12.5% for 4 days. The
last visit took place 2 weeks after the last reduction step. The general
practitioner filled in a case record form to monitor progress and any adverse
events during the intervention period. Two months later, we evaluated
participant and doctor satisfaction and the feasibility of the withdrawal
programme by means of a postal questionnaire.
Group cognitivebehavioural therapy
The participants who were randomised to tapering off combined with group
CBT attended five weekly 2-h sessions of group CBT in addition to the dose
reduction visits to their general practitioner. The sessions started halfway
through the tapering-off period and finished 2 weeks after the conclusion of
the withdrawal programme. The aim of the group therapy was to support the
participants during the tapering-off process and to prevent relapse
thereafter. The therapy programme included:
The sessions were led by registered psychologists, experienced in CBT, who received training and a detailed manual of the therapy. The therapists documented participation and reasons for non-participation at each session. Tape-recordings of a random sample of sessions 3 and 5 were judged by an independent assessor using previously defined criteria, and did not show any protocol violations. Two months later, we evaluated patient satisfaction with the group therapy by means of a postal questionnaire.
Usual care
Participants in the usual care control group were informed about the
randomisation by letter. They did not receive any help with benzodiazepine
reduction.
Measurements
Participants received a baseline assessment after giving informed consent,
and they received an outcome assessment 3 months after the start of the
intervention. Structured interview assessments were carried out at the
participants' homes by a trained research assistant, who explored the
self-reported use of benzodiazepines, administered the 15-words test, and
assessed the circumstances of filling in the self-report questionnaires.
Primary outcome measure
The primary outcome measure was the proportion of participants who
successfully discontinued long-term benzodiazepine use, defined as no
benzodiazepine use at the outcome self-report assessment. We checked
self-reported discontinuation of benzodiazepine use in the general
practitioners' prescription databases, which showed that less than 5% of the
participants who reported successful discontuation had received a
benzodiazepine prescription in the month before the outcome assessment.
Secondary outcome measures
Secondary outcome measures were the reduction in daily benzodiazepine
dosage by participants who did not successfully discontinue drug use; the use
of alcohol (including the number of problem drinkers, based on the 18-item
list of Cornel et al,
1994); psychological well-being assessed by the General Health
Questionnaire 12-item version (GHQ12;
Goldberg & Blackwell,
1970); memory (delayed recall of the 15-words test;
Saan & Deelman, 1986); mood (the scales of depression, anger, fatigue, vigour and tension of the
32-item shortened Profile of Mood States;
Wald & Mellenbergh, 1990);
and the number and severity of benzodiazepine withdrawal symptoms
(Benzodiazepine Withdrawal Symptom Questionnaire;
Tyrer et al,
1990).
Statistical analysis
To check for baseline differences between the three groups, a series of
univariate analyses of variance (ANOVAs) or nonparametric equivalents were
performed on psychiatric status and demographic variables. The primary outcome
measurements were analysed with a chi-squared test (number of participants who
discontinued successfully). A forward logistic regression analysis with
correction for treatment group was performed to identify independent
predictors (all baseline characteristics) of discontinuation success.
The dosage reduction in participants who failed to discontinue diazapam was analysed with one-way ANOVA (dosage quotient at outcome and baseline after natural log-transformation). Repeated-measures ANOVAs were performed on the other secondary outcome variables for continuous variables and chi-squared tests for dichotomous variables. Significant main effects were further analysed with pairwise comparisons.
Analyses were performed on an intent-to-treat basis. In the case of a missing outcome value, the last observation was carried forward to serve as the outcome measurement (whole sample, n=180). The analyses were repeated after excluding all those who had left the study at the outcome assessment (completers sample, n=141). A substantial number of participants had discontinued their use of benzodiazepines before the intervention started. For this reason, we also carried out a per protocol analysis on the participants who had been fully compliant with both the treatment programme and the outcome measurement (per protocol sample, n=78). We excluded the control group from this analysis, because only data on the experimental groups were available at the start of the intervention.
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RESULTS |
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Characteristics of the study participants
Comparisons of the three groups did not reveal any significant differences
in baseline characteristics (Table
1). In addition, no significant difference in baseline
characteristics was observed between those leaving and those completing the
study. In the sample as a whole, the decile scores on the 15-words test did
not differ from the norm. Sub-analyses revealed that participants who were
using 10 mg diazepam equivalents or more per day (n=35) had
significantly worse scores than the participants who were using less than 10
mg per day (t=2.25, d.f.=178, P=0.03) and the norm
population (t=5.93, d.f.=34, P<0.001).
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Benzodiazepine usage
The proportions of participants who successfully discontinued
benzodiazepine use differed significantly between the three groups in the
intent-to-treat analysis (Table
2). Subsequent pairwise comparisons revealed that the two
experimental groups did not differ significantly from each other in the
intent-to-treat analysis (whole sample P=0.51, completers sample
P=0.68). However, the two experimental groups were significantly more
successful than the control group: tapering off alone (whole sample
P<0.001; completers sample P=0.001) and tapering off
combined with group CBT (whole sample P=0.002; completers sample
P=0.002). Corroborating these findings, the per protocol analysis did
not show any significant difference between the two experimental conditions
(P=0.53). Logistic regression analysis yielded benzodiazepine dosage
as the only independent predictor of successful discontinuation (OR=4.5, 95%
CI 2.010.2). Patients who used 10 mg diazepam equivalents or more had a
significantly lower chance of successful discontinuation than patients using
less than 10 mg (35% v. 64%, P=0.009).
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Among those failing to quit, dose reduction differed significantly across the three groups (whole sample F2,102=3.33, P=0.04; completers sample F2,62=3.98, P=0.02). Tukey HSD post hoc tests showed a significant difference in dosage reduction between tapering off combined with group CBT and usual care (whole sample P=0.03; completers sample P=0.02).
Secondary outcome measures
We used repeated-measure ANOVAs across the three groups to evaluate the
effects of the severity of withdrawal symptoms, psychological distress, mood,
memory and problem alcohol use. There was a significant time effect only for
the delayed recall of the 15-words test, which indicated an improvement.
However, no significant interaction effect emerged for any of the secondary
outcome measures, thus these measures were fairly comparable in the three
groups (Table 3). Moreover,
comparing participants who successfully discontinued benzodiazepine use with
those who failed to do so did not result in significant timexoutcome
interaction effects for any of the secondary outcome measures. Neither the
prevalence of alcohol use, nor the amount consumed by alcohol users,
changed.
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Doctor and patient views of the tapering-off strategy
Participants (n=103) who entered the withdrawal programme visited
their general practitioner an average of 5.6 times (s.d.=1.4, range
19). The average number of visits did not differ between the
participants assigned to tapering off alone and those assigned to tapering off
combined with group CBT, and there was no difference between the participants
who successfully discontinued benzodiazepine fully use and those who did not.
A total of 43 out of the 58 participating doctors actually supervised the
patients during the tapering-off process; 42 of them returned the postal
evaluation questionnaire. Analysis of these questionnaires showed that 37
doctors (88%) had found the protocol feasible at their own practice, 35 (83%)
would encourage other general practitioners to taper off long-term
benzodiazepine use with the aid of the withdrawal protocol, and 22 (52%) had
already started using this protocol for patients not included in the trial. No
major adverse event during the reduction period (such as epileptic seizure or
psychotic episode) was reported in the case record forms.
A total of 91 (88%) of the 103 participants who entered the withdrawal programme returned the postal evaluation questionnaire. The results showed that 78 (86%) of those who responded were satisfied with the treatment received; 66 (73%) would be willing to follow the same treatment again if necessary. With respect to their supervision, 65 (76%) preferred treatment by their own general practitioner, 6 (7%) preferred referral to a specialised treatment setting, 12 (14%) preferred no support with tapering off and 3 (3%) had no preference.
Attrition rates and participants' views on group CBT
Seven (10%) of the 73 participants assigned to CBT discontinued their
benzodiazepine use before the start of the intervention. In order to prevent
relapse, we invited these participants to the therapy sessions; however, only
two actually participated. Of the participants who began the tapering-off
process combined with group CBT, only 34 (65%) attended three or more sessions
(Fig. 1). The discontinuation
success rates did not differ significantly between the patients who were
compliant with CBT and those who were not: 20/31 (65%) 6/15 (40%),
P=0.12. The postal evaluation questionnaire was returned by 30 (88%)
of the 34 compliant participants: 14 (47%) of them would have preferred more
sessions; 28 (93%) were satisfied with the group therapy in general. The
degree of satisfaction with group CBT was not related to taper success.
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DISCUSSION |
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Efficacy of tapering off
This was the first study to show the efficacy of tapering off long-term
benzodiazepine use by including a usual care control condition.
Although we pre-selected patients by sending a letter advising them to stop
their use, our success rates were comparable with those of other
benzodiazepine withdrawal studies
(Schweizer et al,
1990; Zitman &
Couvée, 2001). In the control group, 21% of the
participants stopped their benzodiazepine use spontaneously. In addition, 23
(16%) of the 146 participants assigned to the experimental groups discontinued
benzodiazepine use without any professional help while waiting for the
interventions to start. At first we considered this to be a methodological
(but inevitable) problem of our study, because it took some time to fill the
therapy groups. However, it appeared to be a cost-effective strategy in view
of the 60% success rate among those still using benzodiazepines, as was shown
by the per protocol analysis. The proportions of participants who stopped
spontaneously were much higher than the estimated 6%. Several explanations can
be put forward. First, actually taking part in a discontinuation trial could
provide an extra incentive to discontinue benzodiazepine use independently,
even if a previous attempt was not successful. Second, owing to the selection
process, the proportion of participants in discontinuation trials who are able
to stop their use without any professional help might be higher than in
long-term users in general.
Generalisability
A participation rate of 17.4% presumes significant selection processes.
Although patients gave a variety of reasons for non-participation, dependence
on benzodiazepines might have played an important part. Kan et al
(1997) found that 40% of all
those prescribed benzodiazepines in general practice were dependent on
benzodiazepines according to DSMIIIR criteria
(American Psychiatric Association,
1987), and Linden et al
(1998) found that two-thirds
of those who were long-term benzodiazepine users rejected a drug
holiday. Reluctance to enter group therapy as well as reluctance
to hold interview sessions at home might have also contributed to the small
number of participants. In clinical practice a higher recruitment rate might
be achieved if the patients are not asked to participate in a randomised
trial. As participants were representative with respect to not only age and
gender, but also to the (only) independent predictor of success,
benzodiazepine dosage, it is unlikely that we excluded treatment-resistant
patients. As we identified all patients who were long-term users before we
recruited participants, it is not possible to compare our attrition rate with
that of other studies that recruited referred participants from specialised
settings or by advertisement.
Efficacy of group CBT
In our study, adjunctive group CBT focused on the management of withdrawal
symptoms did not have any additional value. Previous studies evaluating
simultaneous psychological treatment to improve these success rates have
considerable methodological problems. Two studies did not compare the efficacy
of additional CBT tapering off alone
(Sanchez-Craig et al,
1987; Elsesser et al,
1996); the other studies did not use a controlled design
(Cormack & Sinnott, 1983;
Schmauss et al, 1987;
Crouch et al, 1988; Joughin et al, 1991),
did not randomise participants over the conditions
(Higgitt et al, 1987)
or studied a sample of fewer than 10 participants
(Tyrer et al, 1985;
Nathan et al, 1986).
The two studies without these methodological problems were restricted to
participants who met the criteria for panic disorder; here the addition of CBT
to tapering off significantly increased the proportion who successfully
discontinued benzodiazepine use (Otto
et al, 1993; Spiegel
et al, 1994). These results are difficult to generalise,
as the prevalence of panic disorder among those who are long-term
benzodiazepine users has been estimated to be at most 27%
(Rickels et al,
1986). Our success rate for CBT might have been increased by a
priori selection on psychiatric morbidity and by introducing
disorder-specific elements. A disadvantage of this strategy is that the
programme cannot then be used easily in general practice.
The lack of additional value might also be due to the limited number of sessions provided. However, the efficacy of brief psychotherapy in alcohol dependence and somatisation disorder in general practice has been supported by the results of randomised, controlled trials (Sandahl & Ronnberg, 1990; Lidbeck, 1997). In view of the relapse rate in the benzodiazepine withdrawal study by Zitman & Couvée (2001), and the delayed effects of psychotherapy in the treatment of cocaine dependence (Carroll et al, 1994) and in the tapering off of alprazolam in panic disorder (Otto et al, 1993), a long-term follow-up study is planned. Another possibility is to give CBT after instead of during tapering off. In our opinion, however, this strategy is of limited value in clinical practice: only two of the seven participants who stopped their use before the intervention could be motivated to attend the therapy sessions to help them remain benzodiazepine-free in the future.
Adherence to group CBT
Adherence to group therapy was poor, which may reflect an overall
resistance to group therapy among people who are long-term benzodiazepine
users. This is in line with findings in other studies
(Cormack & Sinnott, 1983; Nathan et al, 1986)
and with our interpretation of the personal reasons why patients refused to
attend group therapy sessions. Moreover, individual CBT sessions to
restructure dysfunctional cognition might be more successful. However, the
poor adherence cannot explain the lack of success, as the success rate of
patients who were compliant with CBT (n=34) was 65%. Although
sub-analyses lack statistical power, it is unlikely this would be superior to
the 57% success rate of tapering off alone.
Feasibility in general practice
Tapering off was tolerated well in general practice: the general
practitioners did not report any major adverse event during or after the
tapering-off process. The good compliance and high level of satisfaction with
the programme among both doctors and participants further strengthen the
feasibility of tapering off as a strategy to discontinue long-term
benzodiazepine use in general practice.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication May 7, 2002. Revision received January 13, 2003. Accepted for publication January 13, 2003.
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