Annales Pharmaceutiques Franaises (2009) 67, 408413

UPDATE

Benzodiazepine dependence: Focus on withdrawal

syndrome
Dpendance aux benzodiazpines : le syndrome de sevrage
N. Authier a,b,d,, D. Balayssac a,b, M. Sautereau c,
A. Zangarelli a, P. Courty c, A.A. Somogyi d, B. Vennat e,
P.-M. Llorca c, A. Eschalier b
a

Laboratoire de toxicologie, facult de pharmacie, , 63000 Clermont-Ferrand, France

Inserm 766, facult de mdecine, 63000 Clermont-Ferrand, France
c
Ple de psychiatrie, CHU de Clermont-Ferrand, 63000 Clermont-Ferrand, France
d
Discipline of Pharmacology, Medical School, University of Adelaide, North Wind, Frome
Road, Adelaide, SA 5005, Australia
e
Laboratoire de pharmacie galnique, facult de pharmacie, 63000 Clermont-Ferrand, France
b

Received 21 April 2009; accepted 22 July 2009

Available online 18 September 2009

KEYWORDS
Addiction;
Benzodiazepine;
Dependence;
Elderly;
Pregnancy;
Drug abuse

MOTS CLS
Addiction ;
Benzodiazpine ;
Dpendance ;

Summary Benzodiazepines are potentially addictive drugs: psychological and physical dependence can develop within a few weeks or years of regular or repeated use. The socioeconomic
costs of the present high level of long-term benzodiazepine use are considerable. These consequences could be minimised if prescriptions for long-term benzodiazepines were decreased.
However, many physicians continue to prescribe benzodiazepines and patients wishing to
withdraw receive little advice or support. Particular care should be taken in prescribing benzodiazepines for vulnerable patients such as elderly persons, pregnant women, children, alcoholor drug-dependent patients and patients with comorbid psychiatric disorders. The following
update gives recent research results on the withdrawal pathophysiology and practical information in order to treat or prevent benzodiazepine withdrawal syndrome.
2009 Elsevier Masson SAS. All rights reserved.

Rsum Les benzodiazpines anxiolytiques et hypnotiques sont des mdicaments dont le

potentiel addictif est maintenant bien connu. Lutilisation de ces molcules sur de longues priodes allant de plusieurs semaines plusieurs annes provoque des manifestations psychiques
et physiques de dpendance dont le cot socioconomique, bien que difcile estimer, semble
tre trs important compte tenu de leur large prescription. Le respect des recommandations

Corresponding author.
E-mail address: authier@hotmail.com (N. Authier).

0003-4509/$ see front matter 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.pharma.2009.07.001

The benzodiazepine withdrawal syndrome

Sujet g ;
Grossesse ;
Toxicomanie

pour leur prescription, la sensibilisation des mdecins et pharmaciens cette dpendance

trop souvent sous-estime et la multiplication des actions dinformation envers les patients
devraient participer minimiser le msusage des benzodiazpines. Certaines populations de
patients telles que les sujets gs, les femmes enceintes, les enfants, les patients prsentant
une autre addiction ou une pathologie psychiatrique doivent faire lobjet dune attention particulire vis--vis de ce risque de dpendance aux benzodiazpines. Cet article met jour
notamment les connaissances concernant la physiopathologie et la prise en charge de ce syndrome de sevrage.
2009 Elsevier Masson SAS. Tous droits rservs.

Introduction
Although recommendations for benzodiazepine use with
prescription suggest that duration be limited to a few weeks,
patients are known to take these drugs for months, years, or
even decades. In the 1996 Australian National Health Survey,
58% of the 359,300 benzodiazepine users had been taking
this medication for at least 6 months and in another study,
84% of 3234 benzodiazepine users identied in a study of 15
general practices were still using them 8 months later [1,2].
According to different National and European epidemiological surveys, France had the highest annual rate of anxiolytic
use, within a range of 12% to 19%. Duration of benzodiazepine use was more than 6 months in 70 to 75% of users
and increased with age [3,4]. Such long-term use occurs in
spite of evidence that the benets of benzodiazepine may
decrease with time, while the potential for adverse effects
remains. Potential adverse effects include cognitive decline,
unwanted sedation, reduced coordination, increases in risk
of accidents, as well as psychological and physical dependence (Table 1). Benzodiazepines have long been known to
cause amnesia, an effect that is utilised when the drugs are
used as premedication before major surgery or for minor
surgical procedures. Oral doses of benzodiazepines in the
dosage range used for insomnia or anxiety can also cause
episodic memory impairment. Acquisition of new information is decient, partly because of lack of concentration and
attention [5]. According to Neutel [6], the overriding factor
associated with likelihood of benzodiazepine use was that of
previous use. Other factors associated with benzodiazepine
use, whether related to the person or the reason for benzodiTable 1 Benzodiazepine main adverse effects and consequences.
Principaux effets secondaires des benzodiazpines et leurs
consquences.

Adverse effect

Life consequences

Oversedation
Memory impairment

Increased risk of accident

Increased risk of
attempted suicide
Increased risk of antisocial
acts
Increased risk of
unemployment/job loss
Increased risk of marital
breakdown

Paradoxical stimulant
effects
Overdose (respiratory
failure)
Tolerance and
dependence

409

azepine use, were considerably less important for long-term

users. It may be concluded that once benzodiazepine use
has started, specic reasons such as poor health pain or
chronic diseases become much less important in long-term
use than they are in the earlier phases of benzodiazepine
use.
In clinical practice, benzodiazepines should be used for
acute anxiety management rather than long-term treatment. However, benzodiazepines continue to be frequently
prescribed for the initial treatment of panic disorders, as
well as other anxiety disorders and chronic insomnia. These
medications are undoubtedly drugs associated with problems on attempted reduction in dosage or withdrawal. The
discontinuation syndrome can be severe and can prevent
the long-term user from ever stopping the medication. In
this update on benzodiazepine withdrawal syndrome, we
attempted to explain who is vulnerable, why this syndrome
exists and how to withdraw from these drugs.

Vulnerable patients to withdrawal

symptoms
Particular care should be taken in prescribing benzodiazepines for vulnerable patients such as elderly, pregnant
women and the foetus, children, alcohol and drug abuse
dependent patients and patients with comorbid psychiatric
disorders.

Older people
There are particularly compelling reasons why older people should withdraw from benzodiazepines since, as age
advances, they become more proned to falls and fractures, confusion, memory loss and psychiatric problems. The
high incidence of insomnia with aging is paralleled by an
increased use of hypnotic drugs among older adults. Prolonged users are mostly older adults who report greater
sleep dissatisfaction, higher psychological distress and more
chronic medical illnesses. Elderly residents of care homes
are particularly concerned by these chronic prescriptions of
benzodiazepines. Several physiological (withdrawal symptoms) and psychological factors (anticipatory anxiety, fear of
rebound insomnia) can perpetuate the vicious cycle and lead
to hypnotic-dependent insomnia in this vulnerable population [5,7]. Discontinuation is usually benecial, particularly
in the elderly as it is followed by improved psychomotor and
cognitive functioning.

410

Pregnant women and the foetus

About pregnant women, the foetus and neonate metabolise
benzodiazepines very slowly and appreciable concentrations
may persist in the infant up to 2 weeks after birth, resulting
in the oppy infant syndrome of lax muscles, oversedation and failure to suckle. Withdrawal symptoms may
develop after about 2 weeks with hyperexcitability, highpitched crying and feeding difculties. Benzodiazepines in
therapeutic doses doest not appear to have a strong teratogenic potential. However, chronic maternal use may induce
preterm birth and impair foetal intrauterine growth, low
birth weight. There is increasing concern that such children in later life may be prone to attention decit disorder,
hyperactivity, learning difculties and a spectrum of autistic
disorders [8,9].

N. Authier et al.
Table 2

Benzodiazepine main withdrawal symptoms.

Principaux symptmes de sevrage des benzodiazpines.

Psychological symptoms

Physical symptoms

Sleep disturbance
Memory impairment
Sensor hypersensitivity
Anxiety, panics and phobias
Mood distortions
Psychotic symptoms

Muscles symptoms
Pain
Bodily sensations
Weakness and fatigue
Seizure

evidence to recommend benzodiazepines neither as a sole

nor as an adjunctive agent in schizophrenia or schizophrenialike psychoses. The only signicant effects were seen in
terms of short-term sedation [15].

Children
Concerning children, withdrawal syndromes related to
benzodiazepine (midazolam) administration in pediatric
intensive care may affect 20% of exposed children and are
related to infusion duration and total dose. Common symptoms include tremors, agitation, inconsolable crying and
sleeplessness [10]. However, recognition of withdrawal in
pediatric intensive care unit may be difcult because the
symptoms may strongly overlap clinical signs of inadequate
sedation, such as agitation, anxiety and movement disorders
[11].

Alcohol, drugs, drugs abuse

While benzodiazepine withdrawal can be challenging, cessation of use can be even more difcult if there are other
co-addiction such as alcohol/drugs use disorders. Comorbid
alcohol use disorder patients are vulnerable to long-term
benzodiazepine prescriptions, managing themselves their
short-time withdrawal period but also in order to improve
chronic mood and anxiety disorders induced by chronic alcohol consumption. The use of benzodiazepine as recreational
drugs concern at least half of opiates, amphetamines,
cocaine and alcohol abusers. Many illicit benzodiazepine
users become dependent and present typical withdrawal
symptoms which can be severe. For high-dose benzodiazepine abusers in whom benzodiazepine use often forms a
part of polydrug abuse pattern, they need in- or outpatient
detoxication for the primary drug [5,12].

Psychiatric disorders
Other long-term prescribed users who are likely to be dependent are patient with psychiatric problems and for whom we
can avoid prescribing anxiolytics. Indeed, considering the
license extension of antidepressants and some anticonvulsant drugs, but also the development of agonist melatonin
for insomnia, newer drugs being generally better tolerated
without risk of dependence or abuse, this has open-up the
prescribers therapeutic choices [13]. An italian epidemiological study on benzodiazepine use in psychiatric practice
revealed that use was particularly frequent in individuals
with affective illness and in those with a long psychiatric
history [14]. According to a recent meta-analysis, there is no

Clinical aspects
The development of tolerance is one of the reasons people become dependent on benzodiazepines and also sets
the scene for the withdrawal syndrome. This syndrome is a
key sign of benzodiazepine dependence. Withdrawal symptoms occur when there is a decline in the blood or tissue
concentration of any dependence-forming substance that
an individual has been continuously taking. These symptoms
are generally the opposite of the acute effects of the drug,
or they may mimic the symptoms for which the drug was
originally taken. They are time-limited, usually occuring for
only 1 or 2 weeks after the discontinuation of the drug, but
the duration varies according to the drug and the individual person. Withdrawal symptoms are usually relieved by
administration of the substance from which the patient is
withdrawing. Three factors seem to inuence the intensity
and/or the duration of the withdrawal:
the amount of time spent in treatment (the most signicant);
the dose of medication (in combination with duration)
and;
the half-life of the benzodiazepine (short half-life) [16].
Benzodiazepine withdrawal symptoms can be divided
into two categories (Table 2). First of all, psychological symptoms such as increased anxiety, excitability,
insomnia and nightmares, panic attacks and agoraphobia,
social phobia, perceptual distortions, depersonalisation,
derealisation, hallucinations, misperceptions, depression,
obsessions, paranoid thoughts, irritability, poor memory
and concentration. About these last symptoms, it is wellknown that poor memory and concentration, but also
impairment of intellectual abilities and intrusive memories are also features of benzodiazepine withdrawal and
are probably due to continued effects of the drug. Most
studies on this question indicate that improvement may
be very slow. Secondly, physical symptoms are observed
like headache and pain/stiffness (limbs, back, neck, teeth,
jaw), seizure, tingling, numbness, altered sensation (limbs,
face, trunk), weakness, fatigue, inuenza-like symptoms,
muscle twitches, jerks, tics, electric shocks, tremor,
dizziness, light-headedness, tinnitus, hypersensitivity (light,
sound, touch, taste, smell), gastrointestinal symptoms (nau-

The benzodiazepine withdrawal syndrome

sea, vomiting, diarrhoea, constipation, pain, distension,
difculty swallowing), appetite/weight change, dry mouth,
metallic taste, unusual smell [5].
It is important to differentiate between benzodiazepine
withdrawal and relapse of anxiety. First, they differ by
the length of time between discontinuation of drug and
appearance of symptoms and tendency of the symptoms to
improve or worsen. Indeed, withdrawal symptoms usually
start within few days of stopping benzodiazepine and continue to improve until they eventually disappear. Secondly,
there is a difference between relapse and withdrawal in the
symptoms themselves. Certain symptom clusters are particularly characteristic of benzodiazepine withdrawal such
as hypersensitivity to light and sound, tinnitus, feelings of
electric shocks, tremors, myoclonic jerks, perceptual
changes.
Finally, a minority of people who have withdrawn from
benzodiazepines seem to suffer long-term effects (protracted symptoms) that just dont go away after months or
even years. It has been estimated that perhaps 10% to 15% of
long-term benzodiazepine users develop a postwithdrawal
syndrome. Many of these people have taken benzodiazepines for 20 years or more and/or have had bad
experiences in withdrawal. The symptoms most likely to be
long-lasting include anxiety, insomnia, depression, various
sensory and motor symptoms, gastrointestinal disturbances
and poor memory and cognition. The reasons why these
symptoms persist in some people are not clear [17].

Biological aspects
The pharmacological mechanisms underlying benzodiazepine withdrawal are complex and still not clear. The
result of a rapid or abrupt withdrawal of the benzodiazepine
is underactivity of inhibitory GABA (-aminobutyric acid)
functions and a surge in excitatory nervous activity, giving
rise to many of the benzodiazepine symptoms.
First, it is well-established that following chronic exposure to benzodiazepines, there are alterations in GABAergic
neurotransmission (up/down regulation GABA-a receptor
subunits), contributing to the symptoms of tolerance,
dependence and withdrawal. Changes in nucleus accumbens, Papez circuit and basolateral amygdala were observed
on withdrawal, implicating a common circuitry in the
withdrawal process. In addition, increases in AMPA (-amino3-hydroxyl-5-methyl-4-isoxazole-propionate) and N-Methyl
D-Aspartic acid (NMDA) receptor expression also occur upon
diazepam withdrawal, resulting in an increased expression
of the NR1 and NR2B NMDA receptors subunits in the hippocampus. These are downstream adaptations in response to
overstimulation of GABA-a receptors [18]. Recent preclinical
results in rats displayed that a blockade of AMPA-kainate and
NMDA receptors in the dorsal periaqueductal gray reduces
the effect of diazepam withdrawal, conrming that this neuronal hyperexcitability is mediated by glutamate [19]. Das
et al. [20] suggest that the enhanced glutamatergic strength
at hippocampal CA1 pyramidal neurons synapses during
benzodiazepine withdrawal is mediated by increased incorporation of GluR1-containing AMPA receptors. According
to Xiang et al. [21], withdrawal enhances high voltageactivated calcium channel function in transitory manner

411
preceding the potentiation of AMPA function and may be
central to CA1 neuron AMPA receptor synaptic plasticity and
benzodiazepine physical dependence.
Besides, clear evidence exists that benzodiazepines
interfere with the activity of the hypothalamic-pituitary
adrenocortical (HAP) axis, also acting on a suprahypothalamic level by modulating neurotransmitters like
neuropeptide Y and cholecystokinin (CCK). During benzodiazepine withdrawal an increase in HPA axis activity was
reported, with signicant increased adreno cortico trophin
hormone (ACTH) and corticosterone plasma levels [22]. A
preexisting dysregulation of the HPA axis could be correlated
to the severity of withdrawal symptoms [23]. Therefore,
CCK levels seem to be up-regulated, associated to an
increase in the number of CCK-8 receptors in the frontal
cortex and the hippocampus. Accordingly, CCK antagonists
have been reported to attenuate withdrawal reactions [24].
Finally, a recent preclinical study in rats showed that
the corticotropin-releasing factor (CRF) 1 receptor subtype
plays a major role in mediating the effect of CRF 1 on
neuroendocrine and behavioural responses during benzodiazepine withdrawal [25].

Clinical management
Why stopping benzodiazepine? Because long-term use of
benzodiazepines can give rise to many unwanted effects,
including poor memory and cognition, emotional blunting, depression, increasing anxiety, physical symptoms and
dependence, with important social and economic consequences. All benzodiazepines can produce these effects
whether taken as anti-anxiety drugs or sleeping pills. Several clinical options exist for discontinuing benzodiazepine
treatment, including gradual tapering of the current benzodiazepine, substitution with a long-acting benzodiazepine,
treating the symptoms of withdrawal and psychological
interventions.
First, we have to dene a realistic goal regarding the
expectations of both patient and doctor and to explain the
likely course of withdrawal (length, intensity, symptoms,
without forgetting the potential relapse) which may reduce
patient experiencing withdrawal severity [26]. The physician
also has to look into the history of the patient, the existence of a psychiatric disorder (anxiety or mood disorders)
whose symptoms could be mistaken for benzodiazepine
withdrawal symptoms. Secondly, the rate of reduction will
be scheduled with the patient (benzodiazepine withdrawal
is never an emergency). During the withdrawal phase,
doctor must maintain close contact with patient, monitoring anxiety/mood level but also being aware of potential
increased alcohol, nicotine or illicit drugs consumption. In
fact, the rate of withdrawal should be individually adjusted
to the patients need, taking into account factors such as
dosage, type of benzodiazepine, reason for prescription,
lifestyle, personality and environmental stresses. A personalised approach, with a patient in control of his own personal
reduction rate and proceed, is likely to result in fewer
patients dropping out [5].
Denis et al. [27], in a Cochrane review meta-analysis,
concluded that progressive withdrawal (over 10 weeks)
appeared preferable if compared to abrupt withdrawal,

412
since the number of dropouts was lower and the procedure judged more favourable by the patients. Switching
from short half-life benzodiazepine to long half-life benzodiazepine before gradual taper withdrawal did not receive
much support from this meta-analysis. In the literature,
the taper schedules vary from abrupt discontinuation to
25% weekly reduction of dosage, discontinuation in steps
of about one-eight to one-tenth of the daily dose every
fortnight to, nally, symptom-guided withdrawal with the
time needed for withdrawal varying from about 4 weeks to a
year or more. Another meta-analysis by Oude Voshaar et al.
[28] reported that providing a brief targeted intervention
was more effective than routine care, that psychological
intervention provided an additive effect to gradual dose
reduction alone and that substitutive pharmacotherapy was
also slightly more effective than the gradual reduction dose.
Carbamazepine was the only drug that appeared to have
any useful adjunctive properties for assisting in the discontinuation of benzodiazepines, but the available data
are insufcient for recommendations to be made regarding
its use. When managing the withdrawal period, the treatment of a preexisting anxiety or mood disorder is of major
importance and antidepressant agents or mood stabilizers
should be used and associated with the benzodiazepine gradual dose reduction. A recent clinical trial studied, with
positive preliminary results, a new way in benzodiazepine
discontinuation using low-dose umazenil continuous infusions, a medication commonly used in the treatment of
benzodiazepine overdose. However, further developments
are needed, particularly about renement of novel delivery
systems [29]. At present, the most conservative conclusion
for practitioners is that current evidence is not sufcient
to support the prescription of adjunctive pharmacotherapy
[30].
Otherwise, according to the most recent meta-analysis
on data available from the literature search, psychological
interventions may provide a small but signicant additional
benet over gradual dose reduction alone at postcessation and at follow-up. Psychological interventions range
from simple support through counselling to expert cognitivebehavioural therapy (CBT). However, further studies are
needed to determine which kind of psychological intervention is more effective and whether the intervention has
to be delivered face-to-face in order to make a signicant added contribution to cessation [30]. Group therapy
may be helpful as it, at least, provides support from other
patients. CBT needs to be administered by fully trained
and experienced personnel but seems effective, particularly
in obviating relapse [13]. Psychological support should be
available both during and after withdrawal since patients
may remain vulnerable to stress for a few months, from a
single brief consultation to a more formal therapy such as
CBT, relaxation techniques and stress-coping strategies.
Relapses rates, 1 to 5 years after withdrawal vary
between to 57% in different studies but are probably minimized by using individualized withdrawal programmes [5].

Conclusions
The socioeconomic costs of the present high level of
long-term benzodiazepine use are considerable, although

N. Authier et al.
difcult to quantify. These consequences could be minimised if prescriptions for long-term benzodiazepines were
decreased. Yet, many doctors continue to prescribe benzodiazepines and patients wishing to withdraw receive little
advice or support on how to go about it.
Due to the variability in medications and research
designs, it is not possible to assess conditions under which
substitutive pharmacotherapy provided a better outcome
than gradual dose reduction alone. So larger controlled clinical trials are needed to conrm rst that switching short
half-life benzodiazepine to long half-life benzodiazepine
before gradual taper withdrawal did not have any impact
regarding intensity of withdrawal symptoms, secondly to
conrm that failure rate was higher for short half-life than
long half-life benzodiazepine gradual taper. Thirdly, more
controlled clinical studies will be carried out to assess
potential benets of several drugs such as carbamazepine,
pregabaline, umazenil or antidepressants. Finally, different taper schedules have never been directly compared in a
randomised controlled study.

Conicts of interest
None.

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