Annales Pharmaceutiques Françaises (2009) 67, 408—413

UPDATE

Benzodiazepine dependence: Focus on

withdrawal syndrome
Dépendance aux benzodiazépines : 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, faculté de pharmacie, , 63000 Clermont-Ferrand,
France b Inserm 766, faculté de médecine, 63000 Clermont-Ferrand, France
c Pôle 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 galénique, faculté de pharmacie, 63000 Clermont-Ferrand, France

Received 21 April 2009; accepted 22 July 2009

Available online 18 September 2009

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

MOTS CLÉS Résumé Les benzodiazépines anxiolytiques et hypnotiques sont des médicaments dont le potentiel
Addiction ; addictif est maintenant bien connu. L’utilisation de ces molécules sur de longues péri-odes allant
Benzodiazépine ; de plusieurs semaines à plusieurs années provoque des manifestations psychiques et physiques de
Dépendance ; dépendance dont le coût socioéconomique, bien que difficile à estimer, semble être très 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 409

pour leur prescription, la sensibilisation des médecins et pharmaciens à cette dépendance

Sujet âgé ; trop souvent sous-estimée et la multiplication des actions d’information envers les patients
Grossesse ; devraient participer à minimiser le mésusage des benzodiazépines. Certaines populations de
Toxicomanie patients telles que les sujets âgés, les femmes enceintes, les enfants, les patients présentant
une autre addiction ou une pathologie psychiatrique doivent faire l’objet d’une attention
par-ticulière vis-à-vis de ce risque de dépendance aux benzodiazépines. Cet article met à
jour notamment les connaissances concernant la physiopathologie et la prise en charge de ce
syn-drome de sevrage.
© 2009 Elsevier Masson SAS. Tous droits réservés.

Introduction azepine use, were considerably less important for long-

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 identified in a study of 15 general
practices were still using them 8 months later [1,2]. According
to different National and European epidemiologi-cal surveys,
France had the highest annual rate of anxiolytic use, within a
range of 12% to 19%. Duration of benzodi-azepine 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 benefits 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 depen-dence (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 informa-tion is
deficient, 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 benzodi-
Table 1 Benzodiazepine main adverse effects and con-
sequences.
Principaux effets secondaires des benzodiazépines et leurs
conséquences.
Adverse effect Life consequences
Oversedation Increased risk of accident
Memory impairment Increased risk of
attempted suicide
Paradoxical stimulant Increased risk of antisocial
effects acts
Overdose (respiratory Increased risk of
failure) unemployment/job loss
Tolerance and Increased risk of marital
dependence breakdown
term users. It may be concluded that once benzodiazepine
use has started, specific 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 treat-ment.
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 prob-lems
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 benzodi-
azepines 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 peo-ple
should withdraw from benzodiazepines since, as age
advances, they become more proned to falls and frac-tures,
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. Pro-longed 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 symp-
toms) and psychological factors (anticipatory anxiety, fear of
rebound insomnia) can perpetuate the vicious cycle and lead
to hypnotic-dependent insomnia in this vulnerable popula-tion
[5,7]. Discontinuation is usually beneficial, 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 ‘‘floppy infant syndrome’’ of lax muscles, overse-
dation and failure to suckle. Withdrawal symptoms may
develop after about 2 weeks with hyperexcitability, high-
pitched crying and feeding difficulties. Benzodiazepines in
therapeutic doses doest not appear to have a strong terato-
genic potential. However, chronic maternal use may induce
preterm birth and impair foetal intrauterine growth, low birth
weight. There is increasing concern that such chil-dren in
later life may be prone to attention deficit disorder,
hyperactivity, learning difficulties and a spectrum of autistic
disorders [8,9].
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
symp-toms include tremors, agitation, inconsolable crying
and sleeplessness [10]. However, recognition of
withdrawal in pediatric intensive care unit may be
difficult 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, ces-
sation of use can be even more difficult 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 alco-
hol 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 benzodi-azepine abusers in
whom benzodiazepine use often forms a part of polydrug
abuse pattern, they need in- or outpatient detoxification for
the primary drug [5,12].
Psychiatric disorders
Other long-term prescribed users who are likely to be depen-
dent are patient with psychiatric problems and for whom we
can avoid prescribing anxiolytics. Indeed, considering the
license extension of antidepressants and some anticonvul-sant
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
prescriber’s therapeutic choices [13]. An italian epidemio-
logical 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
N. Authier et al.
Table 2 Benzodiazepine main withdrawal symptoms.
Principaux symptômes de sevrage des benzodiazépines.
Psychological symptoms Physical symptoms
Sleep disturbance Muscles symptoms
Memory impairment Pain
Sensor hypersensitivity Bodily sensations
Anxiety, panics and phobias Weakness and fatigue
Mood distortions Seizure
Psychotic symptoms
evidence to recommend benzodiazepines neither as a sole
nor as an adjunctive agent in schizophrenia or
schizophrenia-like psychoses. The only significant effects
were seen in terms of short-term sedation [15].
Clinical aspects
The development of tolerance is one of the reasons peo-ple
become dependent on benzodiazepines and also sets the
scene for the withdrawal syndrome. This syndrome is a key
sign of benzodiazepine dependence. Withdrawal symp-toms
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 individ-ual
person. Withdrawal symptoms are usually relieved by
administration of the substance from which the patient is
withdrawing. Three factors seem to influence the intensity
and/or the duration of the withdrawal:
• the amount of time spent in treatment (the most
signifi-cant);
• 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, psycholog-ical 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 well-known
that poor memory and concentration, but also impairment of
intellectual abilities and intrusive memo-ries 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, influenza-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,
difficulty 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 con-
tinue to improve until they eventually disappear.
Secondly, there is a difference between relapse and
withdrawal in the symptoms themselves. Certain symptom
clusters are par-ticularly 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 (pro-tracted
symptoms) that just don’t 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 benzo-
diazepines 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 benzodi-azepine
withdrawal are complex and still not clear. The result of a
rapid or abrupt withdrawal of the benzodiazepine is
underactivity of inhibitory GABA (g-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 expo-
sure 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 accum-bens,
Papez circuit and basolateral amygdala were observed on
withdrawal, implicating a common circuitry in the withdrawal
process. In addition, increases in AMPA (a-amino-3-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 hip-pocampus.
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, confirming that this neu-ronal
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 incor-
poration of GluR1-containing AMPA receptors. According to
Xiang et al. [21], withdrawal enhances high voltage-activated
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 suprahy-
pothalamic level by modulating neurotransmitters like
neuropeptide Y and cholecystokinin (CCK). During benzo-
diazepine withdrawal an increase in HPA axis activity was
reported, with significant 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 benzodi-azepine 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 blunt-ing,
depression, increasing anxiety, physical symptoms and
dependence, with important social and economic conse-
quences. All benzodiazepines can produce these effects
whether taken as anti-anxiety drugs or sleeping pills. Sev-
eral clinical options exist for discontinuing benzodiazepine
treatment, including gradual tapering of the current
benzo-diazepine, substitution with a long-acting
benzodiazepine, treating the symptoms of withdrawal and
psychological interventions.
First, we have to define 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 exis-tence
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, monitor-ing
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 patient’s need, taking into account factors such as
dosage, type of benzodiazepine, reason for prescription,
lifestyle, personality and environmental stresses. A person-
alised 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 proce-dure
judged more favourable by the patients. Switching from short
half-life benzodiazepine to long half-life benzo-diazepine
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, finally, 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 dis-
continuation of benzodiazepines, but the available data are
insufficient for recommendations to be made regarding its
use. When managing the withdrawal period, the treat-ment 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 grad-ual dose
reduction. A recent clinical trial studied, with positive
preliminary results, a new way in benzodiazepine
discontinuation using low-dose flumazenil continuous infu-
sions, a medication commonly used in the treatment of
benzodiazepine overdose. However, further developments are
needed, particularly about refinement of novel delivery
systems [29]. At present, the most conservative conclusion for
practitioners is that current evidence is not sufficient 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 significant additional
benefit over gradual dose reduction alone at postcessa-tion
and at follow-up. Psychological interventions range from
simple support through counselling to expert cognitive-
behavioural therapy (CBT). However, further studies are
needed to determine which kind of psychological interven-
tion is more effective and whether the intervention has to be
delivered face-to-face in order to make a signifi-cant 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 mini-
mized 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.
difficult to quantify. These consequences could be min-
imised if prescriptions for long-term benzodiazepines were
decreased. Yet, many doctors continue to prescribe
benzo-diazepines 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 clin-ical trials are
needed to confirm first 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 confirm 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 benefits
of several drugs such as carbamazepine, pregabaline,
flumazenil or antidepressants. Finally, differ-ent taper
schedules have never been directly compared in a randomised
controlled study.
Conflicts of interest
None.
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