B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 6 ) , 1 8 8 , 1 8 8 ^ 1 8 9
Long-term outcome of two forms of randomised
benzodiazepine discontinuation
R. C. OUDE VOSHA
VOSHAAR,
AR, W. J. M. J. GORGELS, A. J. J. MOL,
A. J. L. M. VAN BALKOM, J. MULDER, E. H. VAN DE LISDONK,
M. H. M. BRETELER and F. G. ZITMAN
Summary Abouttwo-thirds of longterm users of benzodiazepines in the
population are able to discontinue this
drug with the aid of supervised
programmes for tapering off.Little is
known aboutthe long-term outcome of
such programmes, and they have never
been compared with usual care. After a
15-month follow-up of a randomised
controlled trial comparing such a programme with and without psychotherapy
with usual care, we found significantly
higher longitudinal abstinence rates in
long-term benzodiazepine users who
received a benzodiazepine tapering-off
programme without psychotherapy (25
out of 69, 36%) compared with those who
received usual care (5 out of 33,15%;
P¼0.03).
0.03).
Declaration of interest
None.
Almost two-thirds of long-term benzodiazepine users who take part in benzodiazepine discontinuation programmes are able
to achieve complete abstinence in the short
term (Oude Voshaar et al,
al, 2006). The longterm outcome studies that have been published are uncontrolled for the natural
course of benzodiazepine usage, and report
abstinence rates ranging from 16 to 82%
(Ashton, 1987; Golombok et al,
al, 1987;
Rickels et al,
al, 1991; Holton et al,
al, 1992;
Couvée
Couvee et al,
al, 2002). This paper presents
the results of a 15-month follow-up of
a previously published randomised controlled trial (RCT) comparing two benzodiazepine tapering-off conditions with a
control condition consisting of usual care
(Oude Voshaar et al,
al, 2003).
METHOD
A total of 180 individuals who had been
using benzodiazepine for over 3 months
18 8
and were unable to quit their usage of the
drug by themselves after receiving a discontinuation letter from their general
practitioner were randomly allocated to
tapering off with cognitive–behavioural
group therapy (CBT; n¼73),
73), tapering off
alone (n
(n¼73)
73) or usual care (n
(n¼34)
34) in
general practice. A detailed description of
the interventions and interview assessments
at baseline and end of treatment is given
elsewhere (Oude Voshaar et al,
al, 2003).
The present paper describes: a 15month follow-up; the use of prescription
data instead of self-reported benzodiazepine usage, with a significantly lower dropout rate as a consequence; and data on the
prescribing of other drugs during followup. All patients gave their informed consent
to participate in the follow-up study. Drug
prescription data were prospectively obtained from the computerised medical
records, and included date of issue, Anatomical Therapeutic Chemical classification
code (ATC code; World Health Organization Collaborating Centre for Drugs Statistics Methodology, 1996) and name of the
drug, number of tablets and dose. Gender,
date of birth and the administration number of individual participants were extracted to link the prescription data with
the results of the RCT. The primary outcome measure, benzodiazepine abstinence,
was based on the computerised prescription
data. We analysed the prevalence
prevalence rates of
benzodiazepine abstinence and the mean daily dosages in diazepam equivalents of all issued benzodiazepine prescriptions over
predefined 3-month periods using w2-tests,
Cox regression analysis and repeated-measures analysis of variance (ANOVA). The
secondary outcome measure was the prescription of psychotropic drugs other than
benzodiazepines.
In addition to the prescription data, we
also performed a follow-up assessment at
15 months (n
(n¼143)
143) which was identical
to the baseline (n
(n¼180)
180) and outcome
(n¼141)
141) assessments of the RCT. In this
S HOR T R E P OR T
report, we present the outcome and follow-up assessment data for self-reported
benzodiazepine usage.
RESULTS
Computerised drug prescription data were
available for 170 of the 180 participants
for the whole study period. However,
owing to patient withdrawal from the interview assessments, data on self-reported
benzodiazepine usage were available for
only 143 participants at the 15-month
follow-up. Baseline characteristics did not
differ across the three conditions. Patients
used benzodiazepines on average for 13.5
years (s.d.¼9.6)
(s.d. 9.6) at a mean dosage of
8.4 mg (s.d.¼8.3)
(s.d. 8.3) diazepam equivalents
before receiving the discontinuation letter
from their general practitioner, and at a
mean dosage of 5.9 mg (s.d.¼8.3)
(s.d. 8.3) thereafter. The mean age was 63 years
(s.d.¼12),
(s.d. 12), and 119 of the participants
(70%) were female.
The longitudinal abstinence rate based
on prescription data for participants who
received tapering off plus CBT (20 out of
68, 29%) was not significantly superior to
that for those who received usual care
(5 out of 33, 15%; w2¼2.4,
2.4, d.f.¼1,
d.f. 1,
P¼0.12),
0.12), whereas the opposite was the case
for participants who received tapering off
alone (25 out of 69, 36%, w2¼4.8,
4.8, d.f.¼1,
d.f. 1,
P¼0.03
0.03 in favour of tapering off alone;
see data supplement to the online version
of this paper). The two active treatment
groups only differed significantly at 1–3
months of follow-up (w
(w2¼4.6,
4.6, d.f.¼1,
d.f. 1,
P¼0.03),
0.03), in favour of tapering off alone.
The ‘survival curve’ to the first benzodiazepine prescription after the intervention
period confirmed these findings (Gehan–
Breslow test: 9.31; d.f.¼2,
d.f. 2, P¼0.02).
0.02). Of the
participants who restarted benzodiazepine
treatment during follow-up, 90% (113 out
of 126) restarted within the first 9 months.
Self-reported abstinence in the month
before the 15-month follow-up assessment
was not significantly different between the
three groups (tapering off plus CBT, 30
out of 58, 52%; tapering off alone, 37 out
of 59, 63%; usual care, 11 out of 26,
42%; w2¼3.3,
3.3, d.f.¼2,
d.f. 2, P¼0.19).
0.19). Kappa for
the agreement of computerised benzodiazepine prescription outcome at 13–15 months
and self-reported outcome at 15 months
was 0.73 (P
(P50.001). Most discrepancies
were found in participants who used benzodiazepines intermittently during follow-up.
LON G -T E R M OU T
TC
C O M E OF B E NZO D I A Z E P IN E D I S C ON T INUAT
I NUAT I ON
A repeated-measures ANOVA showed
that among participants who did not achieve
continued abstinence, those who received
active treatment used significantly lower
dosages at follow-up compared with those
who were assigned usual care (F
(F¼6.5,
6.5,
d.f.¼1,
d.f. 1, P¼0.01).
0.01). A significant time6
time6group
interaction (active treatment v. usual care)
indicated that this difference decreased
during follow-up (F
(F¼5.3,
5.3, d.f.¼1,
d.f. 1, P¼0.02).
0.02).
The prescription of antidepressants,
analgesics, antipsychotics and anti-epileptic
drugs remained stable, and patients were not
prescribed hypnotic or anxiolytic drugs other
than benzodiazepines during follow-up.
DISCUSSION
Although relatively low 15-month longitudinal rates for abstinence from benzodiazepines were found (29% for tapering off plus
CBT and 36% for tapering off alone), comparison with the control group confirmed
the long-term efficacy of tapering off alone.
The high point prevalence of benzodiazepine
abstinence in the 3-month follow-up periods
(see data supplement to the online version of
this paper) suggests that a number of
participants used the drug intermittently.
Our longitudinal abstinence rates are
relatively high compared with the values of
16% and 18% found by Couvée
Couvee et al
(2002) and Holton et al (1992) respectively.
It is unlikely that this is due to a shorter
follow-up period, because most relapses
(490%) occur within the first 9 months.
Two feasible explanations can be suggested.
First, there were differences in the
populations studied, as Holton et al (1992)
included referred participants in a psychiatric
setting, and Couvée
Couvee et al (2002) included a
subgroup of long-term benzodiazepine users
with depression. The results of several studies
suggest that people with depression experience greater difficulty in stopping benzodiazepine use (Lader, 1994). Second,
because of the prospective nature of our
study, both general practitioners and participants were aware that they would be
followed-up, whereas the follow-up in the
other studies was retrospective.
The self-reported abstinence rates during the last month of follow-up (52% for
tapering off plus CBT v. 63% for tapering
off alone) replicate the findings of Rickels
et al (1991) and Golombok et al (1987),
who found self-reported cross-sectional
success rates at follow-up of 58% and
54% respectively. Owing to the intermittent usage of benzodiazepines during
follow-up, cross-sectional success rates
R. C. OUDE VOSHAAR, MD, PhD, Department of Psychiatry, Radboud University Medical Centre Nijmegen;
W. J. M. J.GORGELS, MD, Department of General Practice and Family Medicine, Radboud University Medical
Centre Nijmegen; A. J. J. MOL, MSc, Department of Psychiatry, Radboud University Medical Centre Nijmegen;
A. J. L. M.VAN BALKOM, MD, PhD, Department of Psychiatry and Institute for Research in Extramural
Medicine,VU University Medical Centre, Amsterdam; J. MULDER, Ing, E. H.VAN DE LISDONK, MD, PhD,
Department of General Practice and Family Medicine, Radboud University Medical Centre Nijmegen; M. H. M.
BRETELER, PhD, Department of Clinical Psychology and Personality, Radboud University, Nijmegen; F.G.
ZITMAN, MD, PhD, Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands
Correspondence: Dr R.C.Oude Voshaar,
Voshaar,Department
Department of Psychiatry,Radboud University Medical Centre
Nijmegen, PO Box 9101, 650
6500
0 HB Nijmegen,The Netherlands. E-mail: r.oudevoshaar@
r.oudevoshaar @psy.umcn.nl
(First received 7 April 2005, accepted 5 May 2005)
overestimate the longitudinal effects. The
significance of self-reported cross-sectional
success rates is questionable, since we
included a control, in contrast to Rickels et
al (1991) and Golombok et al (1987), but
found no significant differences in the
self-reported success rate between active
treatment and the control group.
One study showed a longitudinal abstinence rate of 82% (Ashton, 1987). This
study differed from the others in that it
was an evaluation of a patient-tailored
withdrawal programme with tapering off
periods of up to 15 months at a tertiary
clinical pharmacology unit that offered
pharmacological as well as psychological
support during tapering off. It is impossible
to provide such highly specialised care in a
primary care setting.
In line with the findings of the primary
care study by Couvée
Couvee et al (2002), the participants in our study were not prescribed
more antidepressants or other psychotropic
drugs. This is in contrast to the results of
Rickels et al (1991), who found an increase
in the use of antidepressants by individuals
in psychiatric care who were taking part in
their tapering-off programme.
We did not find that the addition of
psychotherapy to a tapering-off programme
was efficacious among benzodiazepine
users in the general population. Most
previously published benzodiazepine discontinuation studies that have assessed the
efficacy of additional psychotherapy were
uncontrolled and evaluated a maximum of
21 patients per treatment arm (Oude
Voshaar et al,
al, 2006). However, welldesigned RCTs on the efficacy of additional
psychotherapy showed significantly superior short-term effects in some specific
patient groups, namely those with panic
disorder (Otto et al,
al, 1993) and insomnia
(Baillargeon et al,
al, 2003; Morin et al,
al,
2004), but not in others, such as multidrug
users (Vorma et al,
al, 2002).
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18 9
Data supplement
Benzodiazepine abstinence rates based on prescription record data and assessment of self-reported benzodiazepine usage at the baseline, end of
treatment and 15-month follow-up
Condition
Abstinence according to benzodiazepine prescription data
Months 1^3 Months 4^6 Months 7^9
(n¼170)
170)
(n¼170)
170)
(n¼170)
170)
Self-reported benzodiazepine usage
Months
Months
Baseline
End of
Follow-up
10^12
13^15
(n¼180)
180)
treatment
(n¼143)
143)
(n¼170)
170)
(n¼170)
170)
(n¼141)
141)
Tapering off+CBT
Point prevalence (%)
30/68 (44%)*{ 27/68 (40%) 26/68 (38%){ 31/68 (46%)* 29/68 (43%)
Longitudinal abstinence rate (%)
30/68 (44%)*{ 25/68 (37%) 22/68 (32%)
21/68 (31%)
0/73 (0%)
33/57 (58%)* 30/58 (52%)
0/73 (0%)
37/60 (62%)* 37/59 (63%)
20/68 (29%)
Tapering off alone
Point prevalence (%)
43/69 (63%)* 38/69 (55%)* 38/69 (55%)* 33/69 (48%)* 34/69 (49%)
Longitudinal abstinence rate (%)
43/69 (61%)* 35/69 (51%)* 29/69 (42%)* 25/69 (36%)* 25/69 (36%)*
Usual care
Point prevalence (%)
7/33 (21%)
7/33 (21%)
7/33 (21%)
8/33 (24%)
10/33 (30%)
Longitudinal abstinence rate (%)
7/33 (21%)
6/33 (18%)
5/33 (15%)
5/33 (15%)
5/33 (15%)
CBT, cognitive ^behavioural therapy.
*P50.05 v. usual care; {P50.05 v. tapering off alone.
DATA SUP P LE MENT TO B R IT I S H J O U R NA L O F P SYC H IAT RY ( 2 0 0 6 ) , 1 8 8 , 1 8 8 ^ 1 8 9
0/34 (0%)
5/24 (21%)
11/26 (42%)
Long-term outcome of two forms of randomised benzodiazepine
discontinuation
R. C. OUDE VOSHAAR, W. J. M. J. GORGELS, A. J. J. MOL, A. J. L. M. VAN BALKOM, J. MULDER, E.
H. VAN DE LISDONK, M. H. M. BRETELER and F.G. ZITMAN
BJP 2006, 188:188-189.
Access the most recent version at DOI: 10.1192/bjp.bp.105.012039
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