Current use of benzodiazepines in anxiety disorders

Jean-Marc Cloos and Valerie Ferreira

ZithaKlinik, rue Ste Zithe, Luxembourg, Luxembourg
Correspondence to Jean-Marc Cloos, ZithaKlinik, 36,
rue Sainte Zithe, 2763 Luxembourg, Luxembourg
E-mail: cloos.jm@internet.lu
Current Opinion in Psychiatry 2008, 22:9095

Purpose of review
The aim of this study is to provide a review of articles published between July 2007 and
August 2008 on the current use and rationale of benzodiazepines in anxiety disorders.
Recent findings
Recent review articles confirm selective serotonin reuptake inhibitors as first-choice
drugs for treating anxiety disorders, alongside newer agents such as pregabalin or
serotoninnorepinephrine reuptake inhibitors, and combined with cognitive
behavioural therapy. Benzodiazepines are still widely used by clinicians for these
disorders, as shown by recent surveys, even though their anxiolytic effectiveness is
questioned. Newer agents are in development and may in the future resolve the
therapeutic dilemma.
Summary
Despite current guidelines, benzodiazepines are still considered by many clinicians to
remain good treatment options, in both the acute and the chronic phase of the treatment
of anxiety disorders, partially because of their rapid onset of action and their efficacy with
a favourable side effect profile, and also because of the sometimes only incomplete
therapeutic response and the emergence of side effects of alternative medications.
Having experienced good initial symptom relief with benzodiazepine treatment, patients
may also be reluctant to taper it down. Clinicians should, however, bear in mind the
frequent physiological dependence associated with these substances, and suggest
both pharmacological and psychological treatment alternatives before opting for a longterm benzodiazepine treatment, which may remain necessary in certain clinical
conditions.
Keywords
antidepressant, anxiety disorders, anxiolytic, benzodiazepine, cognitivebehavioural
therapy
Curr Opin Psychiatry 22:9095
2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7367

Introduction
The American Psychiatric Association (APA, 1998)
guideline for the treatment of panic disorder [1] and
the National Institute for Health and Clinical Excellence
(NICE, 2004, amended 2007) guideline on the management of anxiety [panic disorder, and generalized anxiety
disorder (GAD)] [2] actually recommend selective
serotonin reuptake inhibitors (SSRIs), now all available
as generics, as the best choice for the treatment of
these anxiety disorders, alongside cognitivebehavioural
therapy (CBT) and self-help based on CBT principles.
The protocols of the Cochrane library on benzodiazepines (BZDs) for GAD and panic disorder have
unfortunately been withdrawn.
According to the NICE guidelines, BZDs are associated
with a less good outcome in the long term and should not
be prescribed for the treatment of individuals with panic
disorder and, for GAD, they should not usually be used
beyond 24 weeks. The APA guideline points out that,
0951-7367 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

with BZDs, consideration must be given to the fact that

all of them will produce physical dependency in most
patients and that this may make it difficult to discontinue
treatment. The administration of high-potency BZDs
may remain an option in situations in which patients
express an urgent need for a diminution of high levels of
anticipatory anxiety and a reduction in the severity of
their panic attacks, especially because non-BZD antianxiety medication and CBT often take weeks before
there is any beneficial effect.
The APA guideline also recommends that the potential
benefits of BZDs during the initial stages of treatment
with another modality should be balanced against the
potential risks, and summarizes several concerns associated with the prescription of BZDs. First, even though
BZDs mainly have a favourable side effect profile,
patients may experience sedation, fatigue, ataxia, slurred
speech, memory impairment and weakness. Second,
even when antianxiety medication or CBT has probably
started to work, the patient may still believe that the
DOI:10.1097/YCO.0b013e32831a473d

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Current use of benzodiazepines in anxiety disorders Cloos and Ferreira 91

BZD is the effective agent and then have difficulty

discontinuing it. Third, BZDs may relieve anxiety to
such an extent that the patient loses motivation to follow
all the steps of CBT. Finally, even after relatively brief
periods of BZD treatment often only a few weeks
some patients experience withdrawal reactions upon
discontinuation and may believe that they are experiencing an anxiety relapse; thus, they have great difficulty in
discontinuing the use of the BZD.
For all these reasons, BZDs are currently recommended
only in the initial stages of the treatment of anxiety
disorders, until more definitive treatment is likely to
work. In order to prevent addiction, the clinician should
avoid unnecessarily high doses of BZDs, ask the patient
to take these medications only when needed, and favour
psychotherapy or antidepressants or both. Clinicians
should not prescribe BZDs to patients with a history of
substance abuse, owing to a higher prevalence of BZD
abuse and a greater euphoric response to BZDs in these
patients, and be careful when prescribing them in the
elderly.
Despite these limitations, BZDs are still frequently used
along with SSRIs for the treatment of anxiety disorders.
The following review summarizes the literature on this
topic over the past year.

What are the current treatment choices in

anxiety disorders?

[5] showed that a longer DUI may be associated with a

worse clinical course for both the antidepressant and the
BZD group. Clinicians should, therefore, start antidepressant treatment early.
A literature review on the rationale of using a combination treatment with BZDs and SSRIs/SNRIs in the
case of comorbid anxiety and depression [6
] also considers the latter as a first-line therapy, but states that
many patients have only a partial response or have
difficulty tolerating efficacious doses of antidepressant
monotherapy. BZDs appear to improve treatment outcomes when an anxiety disorder co-occurs with depression or for depression characterized by anxious features.
Specifically, they may provide benefits in terms of both
speed of response and overall response. The authors,
therefore, conclude that long-term management plans
for anxiety disorders, with or without comorbid depression, should include strategies for acute or short-term
care, long-term maintenance, and episodic or breakthrough symptoms. Combination therapy with BZDs
and antidepressants in appropriate clinical settings may
improve outcomes over monotherapy in some patients.
Clinicians should, however, remain careful when prescribing BZDs to potentially suicidal patients. It has been
suggested that a BZD treatment of anxiety in depression
in the first several weeks may decrease suicides, but
BZDs have disinhibitory effects in approximately 5%
of the patients, even though there is no clear evidence
that their brief use in the early phase of the treatment
really increases the suicide risk [7].

A comprehensive review of the pharmacotherapy of

anxiety disorders [3

] summarizes the evidence from
randomized, placebo-controlled trials (RCTs) and metaanalyses and supports the use of SSRIs as a first-line
treatment in these disorders, alongside serotonin
norepinephrine reuptake inhibitors (SNRIs). The study
points out that BZDs are also effective treatments,
especially because of the advantage of a rapid onset of
action, but that their use is limited by their potential for
abuse and lack of antidepressant properties. The authors
finally review the evidence for novel uses of other agents,
including anticonvulsants and atypical antipsychotics in
anxiety disorders.

Are benzodiazepines really effective in

anxiety disorders?

An effect size analysis of the pharmacological treatments

for GAD [4] showed the highest effect size for pregabalin
(0.50), now being considered a valuable alternative to
antidepressants for this condition. The effect size was
0.45 for the antihistamine hydroxyzine, 0.45 for the SNRI
venlafaxine, 0.38 for the BZD and 0.36 for the SSRI
treatment. One might point out that a short duration of
untreated illness (DUI) may be important in the treatment response to antidepressants in GAD. A preliminary
study investigating the time elapsing between the onset
of GAD and the first adequate pharmacological treatment

This may be a provocative question, but it has been

recently rediscussed in two interesting papers a systematic review and meta-analysis of RCTs, as well as a
basic research report. The objective of the first paper [9
]
was to access the effectiveness and efficacy of BZDs in
the treatment of GAD on the basis of trial drop-out rates.
It did not find any convincing evidence of the short-term
effectiveness of BZDs in GAD. On the other hand, the
efficacy of BZDs was significantly higher than that of
placebo. The reasons for these results are discussed in the
paper: possible publication bias, the quality of the trial
literature and a nondifferential response to the placebo

Finally, concerning psychological treatments, a metaanalysis of RCTs of CBT versus placebo [8] showed that
CBT is efficacious as a monotherapy for adult anxiety
disorders, the weakest effect sizes being, however, found
in GAD and panic disorder, thus raising the question of
whether combination therapy for these conditions may
not be preferred.

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92 Personality disorders and neurosis

effect. A recent evaluation of this review paper [10]

summarizes and comments on it, and giving a 5-year
view predicts that, despite better knowledge, the
present BZD prescribing pattern will persist for some
years to come.
Equally interesting was a research report [11
] assessing
the effects of diazepam and chlordiazepoxide in mice
exposed to a three-dimensional maze, which showed that
administration of these BZDs did not reduce anxiety in
the animals, but produced sedation only when given in a
higher dosage; thus, demonstrating for the first time that
it is likely that the primary effect of BZDs is not anxiolytic. The authors, therefore, raise concerns about the
methodological foundations in the current assessment of
anxiety and anxiolytic compounds in both animal and
human studies. In animals, behavioural tests are mainly
developed to screen for anxiolytic drugs rather than
assessing anxiety; in humans, the assessment of anxiety
through interviews and questionnaires is prone to subjectivity. The study suggests a radically new approach for
the assessment of both human and animal anxiety, based
on improved behavioural tests with a proven construct
and predictive validity.

How often and when are benzodiazepines

prescribed?
Several recent studies examined the prevalence of BZD
prescriptions, the determinants of their coprescription
with antidepressants and the impact of comorbidity on
the treatment choice.
The European study of the epidemiology of mental
disorders (ESEMeD) looked at the factors associated
with the use of antidepressants and BZDs in six European countries [12]. Respondents (n 21 425) were asked
about their BZD and antidepressant use, and whether
they seeked specific help for emotional problems in the
previous year. In the nonhelp-seeking population, BZDs
were used more commonly than antidepressants, whereas
in help-seeking respondents, with a 12-month prevalence
of major depressive disorder (MDD) or of an anxiety
disorder, BZDs were used as commonly as antidepressants. Help seeking remained the most important predictor for the use of an antidepressant or BZD [odds ratio
(OR) 13.58 and 5.17, respectively], even without a
formal [Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV)] psychiatric diagnosis, suggesting
that the usage of these medications is not always according to the licensed DSM-IV indication. Individuals with
a diagnosis of an anxiety disorder in the preceding
12 months were approximately twice as likely to use
BZDs than those without such a history (OR 1.85),
and the use of BZDs was also significantly associated
with MDD (OR 2.82) and both painful physical symp-

toms (n 8780; OR 1.60) and chronic somatic disorder

(OR 1.50).
A study comparing general practitioners pharmacological
treatment patterns for anxiety in patients (n 4604), with
and without comorbidity [13], found that, compared with
patients with a single diagnosis of anxiety, anxious
patients who also had chronic somatic morbidity or social
problems were prescribed more BZDs (effect size 0.44
and 0.67, respectively), but no more antidepressants.
When simultaneously having other psychiatric conditions, they received twice as many antidepressants
(effect size 2.07) and BZDs (effect size 1.98) during
the year after diagnosing anxiety. For all subgroups, the
prescription rate of BZDs remained high throughout the
year after diagnosing anxiety and was inconsistent with
guideline recommendations.
A high BZD prescription rate was also seen in a smaller
French study [14] in which general practitioners completed consultation questionnaires for patients with an
MDD diagnosis and then returned them (n 258). Sixty
percent of the patients with MDD received BZDs with
antidepressants. BZDs were prescribed more frequently
by male general practitioners who reported feeling not at
ease in treating MDD, or detected suicidal ideation
or anxiety in their patients, and finally to patients with
stable jobs.

Do older patients have higher risks?

The first author of this article recently examined the
ambulatory BZD prescription patterns over a 12-year
period (19952006) in the general population of the
Grand-Duchy of Luxembourg (n 387 862 in 1995 versus
n 449 972 in 2006). The data still need to be looked at in
detail, but remain comparable with previous international
findings on some major points: around 17% of the general
population has at least one BZD prescription per year,
nearly two-thirds of the BZD consumers are women and
the same are aged 50 years or more. Even though a
quarter of the consumers have long-term prescriptions
(>3 months), high-dose usage remains relatively rare, but
seems to increase with age (around 1% of the general
population in 1995, but nearly 2% in 2006). As there is
evidence of higher risks of adverse effects and dependence in the elderly, the rationale of continuing or
initiating BZD prescriptions in this population needs
to be discussed and has been addressed by several articles
in the past year.
An Australian study [15] also found that 16% of the
adults aged 65 years or more (n 3970) had at least
one BZD prescription in the year 2002, the female/male
ratio was 2/1 and the prescription prevalence increased
with age.

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Current use of benzodiazepines in anxiety disorders Cloos and Ferreira 93

A longitudinal and prospective study examined the patterns of BZD and antidepressant use in elder patients
with anxiety disorders (n 55) over a 9-year period [16].
It found that, even though there was an increase of SSRI/
SNRI use in these patients, this treatment is still underutilized in older adults: only 35% of the participants were
taking such medication at the end of the study (despite its
relative safety in the geriatric population), whereas more
than one-half of them continued to use BZDs.
In conclusion, BZDs are still widely prescribed for the
elderly, most of them being women [17]. As pointed out
by a qualitative study in 50 users aged 6195 years
[18,19], many depend on BZDs for their unique soothing
effects, and denied and minimized side effects. They
showed reluctance to discontinue or taper the medication
down, fearing suffering without it, and perceived such a
measure an arduous, low priority and time-intensive task.
Both duration and cumulative exposure to BZDs in the
elderly may have negative effects on their cognitive
performance and functioning in the community [20],
and long-term prescription may have some important
secondary effects such as driving problems and falls,
although the risk of hip fractures may have been overestimated in the past [21]. There is a need to inform older
adults about the risks of BZDs, offering effective discontinuation programmes and managing their somatic, sleep
and anxiety problems by providing alternative psychopharmacological and psychological treatments, which
may help them to reduce these prescriptions.

Is the benzodiazepine prescription a

necessary evil?
Three recent studies address the current clinicians prescribing dilemma for BZDs.
A qualitative study [22] on general practitioners
perspectives (n 35) showed that clinicians feel overwhelmed by the psychosocial problems of their patients
and considered themselves to be empathic by giving
them BZDs as a relief. In the lack of adequate alternatives and due to limited time, it was felt that in certain
situations there are no other solutions and BZDs were
perceived as the lesser evil. The addictive nature of
BZDs was not considered to be a problem with first-time
users, and that under-usage of BZDs because of a fear of
addiction may leave patients suffering.
A UK survey [23] investigated BZD prescribing in a
specialist psychiatric hospital: of the 412 inpatients,
18.7% received 90 BZD prescriptions for psychiatric
disorders, half of the prescriptions being for anxiety
problems. The majority of the usage was chronic.
Although concerned about the addictive nature of BZDs
for these patients, consultants perceived the UK

prescription guidelines of BZDs as too narrow, given

the complex and extreme cases they encountered and
reported a favourable riskbenefit ratio for BZDs in the
treatment of certain patients.
These two examples show that BZD prescribing practices
do not always reflect guidelines, and these guidelines
sometimes lack provision of all the practical strategies
required to manage difficult clinical conditions, as pointed
out by a study [24
] proposing a model for rational
prescribing of BZDs.

What is the future of anxiolytic therapy?

The answer may be diversification and more specific
treatments. The fact that many patients are, for several
reasons, treatment refractory to the current first-line
recommendations of anxiety disorders partly explains
the ongoing widespread use of BZDs. A recent study
has discussed the understanding of mechanisms involved
in anxiety disorders and reviewed all emerging medications [25

]. Novel pharmacological agents that modulate particular receptors, ion channels, or transporters
relevant to glutamatergic neurotransmission are being
developed and may become potential new treatments
for anxiety disorders [26,27]. Some examples published
in the last year are listed in the references [2831]. New
methods identifying mechanisms based on biologically
relevant (endo)phenotypes may also be helpful in finding
better pharmacological targets [32]. Hopefully, the new
compounds will not cause discontinuation symptoms
after short-term or long-term treatment, and they need
to be assessed for that [33].

Conclusion
The BZDs, success story is not yet finished and they
remain a mainstay of anxiolytic pharmacotherapy. The
future will show whether newer BZDs, or other gammaaminobutyric acid-ergic (GABAergic) drugs, may replace
them by having a better efficacy and a more favourable
addiction profile. Until then, and despite current treatment guidelines, a diagnosis of an anxiety disorder
remains frequently associated with a BZD prescription,
even though the effectiveness of such a measure is
questionable. Choosing a pharmacotherapy for these
disorders is guided by considerations of adverse effects
and, often, by the physicians and the patients personal
preferences. Although SSRIs, now all available as generics, have a good balance of efficacy, cost and adverse
reactions in most cases, their side effects (especially on a
sexual level) may lead to other treatment choices, and
BZDs are still considered to be valuable alternatives by
many clinicians. They should, however, carefully balance
the risks and benefits associated with these molecules
and also consider other antidepressants such as SNRIs,

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94 Personality disorders and neurosis

tricyclics (TCAs) or monoamine oxidase inhibitors

(MAOIs), as well as pregabalin, anticonvulsants and
atypical antipsychotics, as possible treatment options.
CBT (and self-help based on CBT) does not have the
adverse side effects of pharmacotherapy and may be
proposed alone or in combination with a medication,
especially if the patient is motivated to undergo such a
psychological treatment and is reimbursed for it.
A concomitant BZD prescription may be helpful in the
early phase of the treatment when rapid control of symptoms is needed, for example in the case of severe panic
attacks or high levels of anticipatory anxiety, as a treatment with either SSRIs or CBT may take several weeks
before the onset of action. BZDs may also be helpful in
reducing phobic avoidance in CBT, but after experiencing the benefits of alternative treatments, BZDs should
be gradually tapered down, eventually with adjunctive
CBT. The dosage and duration of the BZD treatment
should always be minimized, considering the relatively
quick emergence of a physiologic dependence, even with
low dosages. The sole use of BZDs in anxiety disorders,
without having tried the alternatives, is to be avoided and
BZDs are contraindicated for patients with a history of
substance use disorder. Clinicians should generally use
half the dose in the elderly and be careful when prescribing them to patients with cognitive impairments.
In the past, major concerns about BZD tolerance, dependence and withdrawal have led to restrictive recommendations concerning the length of treatment of these drugs.
Currently, as the long-term therapeutic use of BZDs is
seldom associated with dose escalations or recreational
usages, many clinicians still consider that, if all alternative
treatment options have not shown sufficient efficacy, the
BZD (co)prescription remains a necessary evil and that
the optimum BZD treatment length in these patients may
be much longer than usually recommended. Dont ask,
dont tell, but BZDs are still the leading treatments for
anxiety disorders was the provocative title of an article
published 5 years ago [34] and these words still remain true
today. More specific treatments are, however, on their way
or already available, and clinicians should have the courage
to try every existing pharmacological and psychological
treatment alternative, inform about potential risks associated with BZDs and establish a therapy plan together with
the patient.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:


of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 124).
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