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Current use of benzodiazepines
in anxiety disordersJean-Marc Cloos and Valerie Ferreira
ZithaKlinik, rue Ste Zithe, Luxembourg, Luxembourg

Correspondence to Jean-Marc Cloos, ZithaKlinik, 36,rue Sainte Zithe, 2763 Luxembourg, LuxembourgE-mail: [email protected]

Current Opinion in Psychiatry 2008, 22:90–95

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

serotonin–norepinephrine 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 long-

term benzodiazepine treatment, which may remain necessary in certain clinical

conditions.

Keywords

antidepressant, anxiety disorders, anxiolytic, benzodiazepine, cognitive–behavioural

therapy

Curr Opin Psychiatry 22:90–95� 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins0951-7367

IntroductionThe 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 manage-

ment 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 cognitive–behavioural

therapy (CBT) and self-help based on CBT principles.

The protocols of the Cochrane library on benzo-

diazepines (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 2–4 weeks. The APA guideline points out that,

opyright © Lippincott Williams & Wilkins. Unautho

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 anti-

anxiety 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 associ-

ated 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

rized reproduction of this article is prohibited.

DOI:10.1097/YCO.0b013e32831a473d

mailto:[email protected]

http://dx.doi.org/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 experien-

cing 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 inanxiety disorders?A comprehensive review of the pharmacotherapy of

anxiety disorders [3��] summarizes the evidence from

randomized, placebo-controlled trials (RCTs) and meta-

analyses 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.

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 treat-

ment response to antidepressants in GAD. A preliminary

study investigating the time elapsing between the onset

of GAD and the first adequate pharmacological treatment

opyright © Lippincott Williams & Wilkins. Unauth

[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 anti-

depressant treatment early.

A literature review on the rationale of using a combi-

nation treatment with BZDs and SSRIs/SNRIs in the

case of comorbid anxiety and depression [6�] also con-

siders 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 out-

comes when an anxiety disorder co-occurs with depres-

sion 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 depres-

sion, should include strategies for acute or short-term

care, long-term maintenance, and episodic or break-

through 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 pre-

scribing 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].

Finally, concerning psychological treatments, a meta-

analysis 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.

Are benzodiazepines really effective inanxiety disorders?This may be a provocative question, but it has been

recently rediscussed in two interesting papers – a sys-

tematic 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

orized reproduction of this article is prohibited.

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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 anxio-

lytic. 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 sub-

jectivity. 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 benzodiazepinesprescribed?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 Euro-

pean countries [12]. Respondents (n¼ 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 antidepress-

ants. Help seeking remained the most important pre-

dictor for the use of an antidepressant or BZD [odds ratio

(OR)¼ 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 accord-

ing 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 (OR¼ 1.85),

and the use of BZDs was also significantly associated

with MDD (OR¼ 2.82) and both painful physical symp-


toms (n¼ 8780; OR¼ 1.60) and chronic somatic disorder

(OR¼ 1.50).

A study comparing general practitioners’ pharmacological

treatment patterns for anxiety in patients (n¼ 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 size¼ 0.44

and 0.67, respectively), but no more antidepressants.

When simultaneously having other psychiatric con-

ditions, they received twice as many antidepressants

(effect size¼ 2.07) and BZDs (effect size¼ 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 com-

pleted consultation questionnaires for patients with an

MDD diagnosis and then returned them (n¼ 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 (1995–2006) in the general population of the

Grand-Duchy of Luxembourg (n¼ 387 862 in 1995 versus

n¼ 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 depen-

dence 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 (n¼ 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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A longitudinal and prospective study examined the pat-

terns of BZD and antidepressant use in elder patients

with anxiety disorders (n¼ 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 under-

utilized 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 61–95 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 over-

estimated in the past [21]. There is a need to inform older

adults about the risks of BZDs, offering effective discon-

tinuation programmes and managing their somatic, sleep

and anxiety problems by providing alternative psycho-

pharmacological and psychological treatments, which

may help them to reduce these prescriptions.

Is the benzodiazepine prescription a‘necessary evil’?Three recent studies address the current clinician’s pre-

scribing dilemma for BZDs.

A qualitative study [22] on general practitioners’

perspectives (n¼ 35) showed that clinicians feel over-

whelmed 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 altern-

atives 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 risk–benefit 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 medi-

cations [25��]. Novel pharmacological agents that modu-

late 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 [28–31]. 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].

ConclusionThe BZDs, success story is not yet finished and they

remain a mainstay of anxiolytic pharmacotherapy. The

future will show whether newer BZDs, or other gamma-

aminobutyric acid-ergic (GABAergic) drugs, may replace

them by having a better efficacy and a more favourable

addiction profile. Until then, and despite current treat-

ment 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 physician’s and the patient’s personal

preferences. Although SSRIs, now all available as gen-

erics, 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 symp-

toms is needed, for example in the case of severe panic

attacks or high levels of anticipatory anxiety, as a treat-

ment 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 experien-

cing 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 pre-

scribing them to patients with cognitive impairments.

In the past, major concerns about BZD tolerance, depen-

dence and withdrawal have led to restrictive recommen-

dations 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. ‘Don’t ask,

don’t 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 associ-

ated with BZDs and establish a therapy plan together with

the patient.

References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:� of special interest�� of outstanding interest

Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (p. 124).

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