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Current Pharmaceutical Design, 2002, 8, 23-43
23
The Experimental Pharmacotherapy of Benzodiazepine Withdrawal

J. Podhorna*
Dalhousie University, Department of Psychology, Halifax, Nova Scotia, B3H 4J1 Canada
Abstract: In many people, long-term benzodiazepine (BZ) use produces dependence with manifestation of
withdrawal symptoms after abrupt cessation of BZ treatment. The current therapy of BZ dependence in humans
utilizes gradual dose-taper to avoid withdrawal symptoms and supportive psychotherapy to help patients
cope with withdrawal reactions. The failure of dose-taper in many patients has triggered intensive animal
research to find additional pharmacological treatments. The present article reviews evidence from animal
studies on effectiveness of pharmacological treatment for BZ dependence and withdrawal. It explores the riskbenefit profiles of putative therapies for BZ withdrawal, including drugs acting via benzodiazepine receptors,
serotonergic and noradrenergic agents, cholecystokinin-B receptor antagonists, calcium channel blockers, Nmethyl-D-aspartate (NMDA) antagonists, and other miscellaneous agents.
INTRODUCTION
Benzodiazepines (BZs) are one of the most frequently
used drugs in the treatment of insomnia and generalized
anxiety disorder [1]. They were introduced on the market in
1960 [2] and rapidly replaced older sedative-hypnotics, such
as barbiturates and meprobamate, mainly because of their
high therapeutic index and low organ toxicity.
The disadvantages of long-term BZ use lie in the
rebound of anxiety and insomnia, and in the possible
development of signs of physical dependence, upon BZ
discontinuation [3,4]. A significant number of patients
experience withdrawal following abrupt termination of longterm BZ treatment (for reviews see [4-6]). BZ withdrawal
symptoms
include
increased
anxiety,
perceptual
disturbances, insomnia, depression, weight loss, and
autonomic symptoms [5,7-9]. Severe withdrawal symptoms
such as seizures can also occur, usually after high dosage
therapy [8,10]. Clearly, developing new anxiolytics with the
efficacy of BZs but lower dependence liability would be a
significant therapeutic advance. However, BZ tranquilizers
still remain one of the most frequently used drugs for the
treatment of generalized anxiety and sleep disorders.
The most common management of BZ dependence and
withdrawal utilizes a gradual dose-taper to avoid withdrawal
reactions [11-14]. Unfortunately, withdrawal symptoms have
been shown to occur even with slow dose-taper from
relatively low doses of BZs [4,11,14]. The failure of dosetaper in some patients has initiated the search for additional
treatment strategies. Two general approaches have been
made: the search for effective psychotherapy that would help
the patients cope with BZ withdrawal reactions (reviewed
[15]) and the search for effective pharmacotherapy to treat or
*Address for correspondence to that author at the Psychopharmacological

Research, H. Lundbeck A/S, Otiiliavej 9, DK-2500 Copenhagen-Valby,
Denmark
1381-6128/02 $35.00+.00
prevent the development of BZ withdrawal reactions. The

current review article provides a critical overview of the
experimental evidence on the risk-benefit ratio of various
drugs that have been tested in terms of their ability to
prevent or alleviate BZ withdrawal signs in animals.
MECHANISM OF ACTION OF BZ TRANQUILIZERS
The mechanism of action of the BZs has been thoroughly
explained in several excellent reviews [16-20]. Briefly, BZs
act via central benzodizepine receptors (BZRs) located at the
gamma-aminobutyric acid-A (GABAA) receptor complex.
The GABA A receptor is a pentameric complex that is formed
from at least five subunits (1-6, 1-4, 1-2, , 1-2) and
gates a chloride channel. The main function of the GABAA
receptor complex is to mediate changes in the chloride
conductance of the neuronal membrane. In the presence of
gamma-aminobutyric acid (GABA), the channel opens,
resulting in chloride influx and inhibition [21]. In addition
to the GABA receptor itself, other modulatory binding sites
are located at the GABA A receptor complex [18]. The BZR
has been studied extensively (for a review see [17]) but other
binding sites, such as sites for barbiturates, neurosteroids,
alcohol and some bivalent ions, have been identified [18,20].
The unique property of the central BZR is that it
mediates two opposite effects on the function of the GABAA
receptor. Drugs binding to the BZR can either facilitate
(agonists) or inhibit (inverse agonists) GABAA receptor
function [16,17]. Both the facilitation and inhibition of
GABAA receptor function can be blocked with BZR
antagonists such as flumazenil [17]. However, a large
number of drugs have been synthesized that bind to the
central BZRs but produce only partial facilitation (partial
agonists) or partial inhibition (partial inverse agonists) of
GABAA receptor function [17,21]. In vivo, BZR agonists (or
full agonists) such as BZ tranquilizers display anxiolytic and
anticonvulsant therapeutic effects accompanied with side
effects, such as sedation, muscle relaxation, as well as the
2002 Bentham Science Publishers Ltd.
24
Current Pharmaceutical Design, 2002, Vol. 8, No. 1
development of tolerance and dependence [21,22]. Partial

agonists, on the other hand, have a lower incidence of
unwanted side effects (e.g., sedation) and lower dependence
liability, with maintained therapeutic anxiolytic and
anticonvulsant properties [23,24].
Further studies on the pharmacology and distribution of
central BZRs have discovered different subtypes of these
receptors [16]. Two subtypes, BZ1 and BZ2 receptors, were
originally proposed based on differences in the expression of
the subunit. Specifically, BZ1 receptors contain the 1
subunit while receptors containing the 2 or 3 subunit are
classified as BZ2 receptors [16]. Compounds with selective
preference for either subtype of BZRs have been developed.
For example, imidazopyridines such as zolpidem and
alpidem selectively bind to BZ1 receptors [23]. The
importance of receptor selectivity has not yet been clarified as
selective BZ1 receptor agonists can act as nonsedative
anxiolytics (abecarnil) or sedative hypnotics (zolpidem) [16].
MECHANISMS UNDERLYING BZ DEPENDENCE

AND WITHDRAWAL
The development of tolerance, dependence, and
withdrawal reactions upon cessation of BZ treatment implies
that adaptive cellular, molecular or biochemical changes have
occurred. Although it has been suggested that shared
mechanisms are involved in the development of BZ
tolerance, dependence, and the manifestation of withdrawal
upon BZ discontinuation [25], animal research in this area
suggests that the situation is far more complex. Changes in
BZR and GABAA receptor function, changes in the
serotonin, noradrenaline, cholecystokinin (CCK), glutamate,
and acetylcholine neurotransmitter systems, altered brain
metabolism, as well as altered function of calcium channels
have all been suggested as mechanisms which may underlie
BZ tolerance, dependence, and/or the manifestation of
withdrawal.
Changes in GABAA/BZ Receptor Function
Although changes in GABAA/BZ receptor function
during chronic benzodiazepine treatment and following
withdrawal have received much research interest, results from
various laboratories are conflicting. Chronic treatment with
BZs has been found to reduce BZR binding in several
studies [26-30], but no changes in BZR binding have also
been reported [31,32]. Following withdrawal from BZs,
BZR binding has been found to be either increased [33-37]
or unchanged [38,31,39] with no changes in the number of
BZRs [38]. Down-regulation of the GABAA receptor has
also been reported [40,41] but K+ -evoked [3H]-GABA
release has been found to remain unchanged in the cortex and
hippocampus 24 h after withdrawal from 21-day diazepam
treatment in rats [42]. Several investigators found increased
GABA-stimulated or muscimol-stimulated Cl - influx into
cerebral cortical membrane vesicles [37,41,43]. Detailed
coverage of GABAA receptor/BZR changes occurring during
chronic exposure to BZs are reviewed by Bateson [44].
J. Podhorna
Changes in the Central Neurotransmission

The serotonergic system is believed to play a role in BZ
action [45,46]. Both acute [46-48] and chronic [42,49-52]
BZ treatments modulate the release and turnover of serotonin
(5-HT). Chronic diazepam treatment for 21 days has been
shown to lead to an increase in K + -evoked [3H]-5-HT release
in the hippocampus, assessed 24 h following withdrawal
[42,49,50]. Serotonin concentrations were decreased in the
hypothalamus 24 hours after 40-day diazepam treatment [53].
These findings suggest increased 5-HT turnover and are in
agreement with early findings of Rastogi, Lapierre, and
Singhal [54] who reported lower concentrations of serotonin
and increased concentrations of the 5-HT metabolite, 5hydroxyindoleacetic acid, in rats withdrawn for 48 h from 22
days of diazepam treatment. Hitchcott et al. [51] found
reduced K+ -evoked [3H]-5-HT release in the frontal cortex,
but not in the hippocampus, during withdrawal from 21-day
diazepam treatment in rats. Hypersensitivity of 5-HT1A
autoreceptors in the dorsal raphe nucleus 5 days after
cessation of 2-week diazepam treatment has also been
reported [55].
Increased activity of noradrenergic neurotransmission is
believed to underlie withdrawal from CNS depressant drugs,
such as opiates [56], alcohol [57], and BZs [52,58]. Rastogi
et al. found decreased noradrenaline levels in several brain
areas during spontaneous withdrawal from diazepam in rats
[52]. Grant et al. [58] detected an elevated concentration of
the major noradrenaline metabolite
3-methoxy-4hydroxyphenylglycol
(MHPG)
during
precipitated
withdrawal from diazepam in the vervet monkey. Both
decreased levels of noradrenaline and increased MHPG
concentration suggest increased noradrenaline turnover. In
line with this hypothesis, the spontaneous firing rate of
Purkinje cerebellar cells, which are under inhibitory
noradrenaline control from the pontine locus coeruleus, was
decreased in rats withdrawn from 12-day treatment with
alprazolam, diazepam, or lorazepam. Destruction of
catecholamine neurons with the neurotoxin, 6hydroxydopamine, reduced this effect [59], providing
evidence for increased central noradrenaline activity during
BZ withdrawal.
With regards to other neurotransmitters and
neuromodulators, Harro et al. [31] found increased density of
CCK-8 receptors in the frontal cortex and hippocampus 24
hours following withdrawal from 2-week diazepam treatment.
Several studies showed increased [3H]dizocilpine (MK-801)
binding in the cerebral cortex following withdrawal from
diazepam [60-62] suggesting upregulation of NMDA
receptors. Increased acetycholine release in the hippocampus
during flumazenil-precipitated withdrawal from 3-week
diazepam treatment has also been reported [63].
Brain Metabolism During BZ Withdrawal
Autoradiographic [14C]2-deoxyglucose (2-DG) uptake is
a quantitative procedure that measures and visualizes glucose
metabolism in the brain following experimental
manipulations. It is based on the assumption that there is a
Pharmacotherapy of Benzodiazepine Withdrawal
direct relationship between nerve function and glucose

utilization. Acute BZ administration reduces 2-DG uptake in
many brain regions [39,64,65] while chronic BZ treatment
leads to the development of tolerance to this reduction
[39,64,65].
In contrast to the acute effect of BZs on brain
metabolism, withdrawal from prolonged BZ treatment has
been found to increase glucose utilization in several brain
areas. Spontaneous withdrawal from 21-day chlordiazepoxide
treatment increased 2-DG uptake in the cingulate and frontal
cortex, globus pallidus, hypothalamus, dorsal geniculate
body, raphe nuclei, dorsal tegmental nucleus, ventral
tegmental area, olfactory tubercle, and superior colliculus
[65]. Spontaneous withdrawal from high doses of diazepam
(100 mg/kg/day) administered for 5 weeks increased 2-DG
uptake in the frontal cortex, dorsal portion of the lateral
geniculate body, and the thalamic nuclei [66,67].
Withdrawal, precipitated with the BZR antagonist
flumazenil, from 2-week diazepam treatment (20 mg/kg/day)
led to increased 2-DG uptake in the thalamic nuclei, medial
geniculate body, and the mamillary body [64]. Flumazenilprecipitated withdrawal from 4-week treatment with
diazepam (5 mg/kg/day) increased 2-DG utilization in the
mamillary body, anterior thalamic nuclei, cingulate cortex,
nucleus accumbens, and basolateral amygdala [39]. Thus,
increased 2-DG utilization in the frontal cortex, geniculate
body, mamillary body, and thalamic nuclei during BZ
withdrawal is consistent over studies, regardless of drug,
dose, duration of treatment, or withdrawal procedure used.
Other Biochemical Changes
Voltage-sensitive calcium channels in the CNS play a
role in a wide range of physiological and behavioral
functions and have also been implicated in a number of
pathological neural conditions (for a review see [68]). There
is growing evidence that calcium channels are inolved in the
mechanism of drug dependence and withdrawal. Altered
function of calcium channels has been reported during
withdrawal from barbiturates and ethanol [69,70] and has
also been assumed to occur during withdrawal from BZs
[71]. Increased 45Ca2+ uptake into hippocampal
synaptosomes 24 hours following withdrawal from 21-day
diazepam treatment (2 mg/kg/day) [42] but not into cortical
synaptosomes 42 h after withdrawal from 28-day diazepam
treatment (4mg/kg/day) was found in rats, although animals
showed withdrawal-induced anxiogenic response in both
experiments [72]. The number of dihydropyridine binding
sites, i.e., for calcium channel blockers, was found to be
unchanged in mouse whole brain 24 hours after cessation of
7-day flurazepam treatment (40 mg/kg/day) [73]. It remains
unclear whether these conflicting results are due todifferences
in doses, duration of treatment, and/or withdrawal procedure
used, or whether changes in calcium channel function during
withdrawal occur only in certain brain areas.
ANIMAL STUDIES ON BZ DEPENDENCE AND
WITHDRAWAL
An abstinence syndrome following withdrawal from high
doses of chlordiazepoxide in humans was reported soon after
25
the introduction of BZs into clinical practice [10]. Animal

research on BZ dependence and withdrawal was rare in the
early period of BZ use, presumably due to the lack of
suitable animal models. An historical overview of animal
studies on BZ tolerance, dependence, and withdrawal can be
found in an excellent review by File [74] and, therefore, will
not be discussed here in detail.
Convulsions after withdrawal from BZs were first
reported in the early 1970s [75]. In the late 1970s, the first
reports of locomotor hyperactivity during BZ withdrawal
were published [52,76]. Biochemical changes during
withdrawal, such as reduced monoamine levels in various
areas of the brain, were described at that time [52]. Intensive
animal research into BZ dependence and withdrawal
responses started in the 1980s. It was found that the most
frequently observed BZ withdrawal signs in animals include
increased anxiety-like behavior [49,77-80], seizure
threshold reduction [81-83] and spontaneous convulsions
[79,84-86], locomotor hyperactivity [34,37,87-89], tremor
[85,90], and decreased food intake and weight loss [91-93].
Other behavioral withdrawal signs such as an increase in
aggressive behavior were reported in some [58,94-97], but
not all [98], animal studies.
ANIMAL MODELS TO STUDY BZ DEPENDENCE

AND WITHDRAWAL
Drug self-administration (SA) and conditioned place
preference (CPP) paradigms are used to study the reinforcing
and rewarding properties of drugs [99]. Self-administration is
a very accurate indicator of a drugs abuse potential in
humans. When this paradigm is used with animals, subjects
are trained to perform a task, such as lever pressing, in order
to receive reinforcement, i.e., injection of a drug. High rates
of responding by the animal correlates with a high abuse
liability of the drug. Research using the SA paradigm with
animals suggests that BZs can serve as reinforcers, although
their reinforcing efficacy is intermediate in comparison with
classic sedative and CNS stimulant drugs (for a review see
[100]). The conditioned place preference (CPP) paradigm is
based on the classical conditioning of drug effects to
environmental stimuli. The apparatus is a shuttle box with
two compartments. Animals are conditioned to associate one
compartment with the drug and the other one with vehicle.
On the testing day, time spent in each compartment by the
drug-free animal is measured to determine its preference for
either side [101]. Animals treated with classic drugs of
abuse such as morphine or amphetamine show preference for
the side associated with the drug [102]. However, this
paradigm is probably less sensitive for assessing reinforcing
properties of BZs as diazepam has produced a place
preference in some [101,103,104], but not all [105], studies.
As mentioned above, the most common withdrawal
reactions from BZs in animals include increased anxiety-like
behavior, seizure threshold reduction and spontaneous
convulsions, locomotor hyperactivity, autonomic changes
and tremor, and decreased food intake and body weight.
Although some withdrawal signs can be measured directly
(changes in body weight), empirical behavioral models have
to be used to assess signs such as changes in anxiety-like
26
behavior. It should be mentioned here that the availability of

a competitive BZR antagonist, flumazenil (Ro 15-1788),
enables us to study not only spontaneous but also
precipitated withdrawal [90,106]. The use of flumazenil to
precipitate withdrawal is particularly desirable if BZs with a
long half-life are used to produce dependence. Slow clearance
of long-acting BZs resembles dose-taper and spontaneous
withdrawal reactions from long-acting BZs are, therefore, of
smaller magnitude.
Simple screening tests can measure food intake,
changes in body weight, as well as can assess some
autonomic symptoms such as diarrhea, piloerection, and
tremor. Changes in spontaneous locomotor activity are
measured in an open field arena that often automatically
records horizontal (walking) and vertical (rearing)
locomotion. Brain EEG activity during withdrawal is
measured using electrophysiological devices, often with
implanted electrodes for long-term EEG monitoring
[79,106]. EEG activity is monitored to assess withdrawalinduced changes in sleep pattern [107] and seizures [79] as
well as to determine reduction in the seizure threshold
following seizure-inducing stimuli such as electrical current
[108] or an injection of a convulsant drug, such as
pentylenetetrazol [109]. A scale for scoring convulsions has
been developed [110] but recording EMG activity during
convulsions is more common [79].
Increased anxiety (the anxiogenic response) represents the
predominant symptom of BZ withdrawal. However, anxiety
is a subjective human experience and there is not a single
physiological measure that reliably reflects changes in
anxiety levels [111]. It is, therefore, impossible to measure
anxiety in animals directly. At best, human anxiety can be
modeled [112] and several animal models have been
developed and validated using BZR compounds. Models
based on exploration are the most frequently used animal
models of anxiety. They utilize the natural tendency of
rodents to explore new environments and to fear (i.e., avoid)
open, elevated, or brightly-lit spaces. The elevated plusmaze test [113], the light/dark transition test [114], and the
open field test [115] are used extensively, mainly for their
simplicity. Description, validity, and sensitivity to both
anxiolytic (anxiety-reducing) and anxiogenic (anxietyenhancing) effects of experimental manipulations can be
found in previous reviews [114,116]. Briefly, BZ anxiolytics
increase behaviors indicative of confidence, i.e., animals
show increased open-arm activity in the elevated plus maze
[117,118], increased transitions between compartments,
and/or increased time in the light compartment in the
light/dark transition test [119], and increased exploration of
the central sector of the open field [120]. The main
disadvantages of these models are the variability in results
between laboratories and the low sensitivity for drugs with a
different mechanism of action than that of BZs (e.g., 5-HT
agents or CCK-B antagonists) [121].
Animal models of anxiety that record changes in social
behavior include the social interaction test in rats [111] and
the social conflict test in mice [122]. In the social interaction
test, the time spent by a pair of male rats in active social
interaction is measured. High levels of illumination and
unfamiliarity of the test arena suppress the time spent in
J. Podhorna
social interaction an anxiogenic response [111]. BZ

tranquilizers increase time spent in the social interaction
under these conditions an anxiolytic response [111]. In the
social conflict test in mice, drug-free subjects that have been
previously housed individually for 3-4 weeks react in either a
timid (anxious) or aggressive way when encountering nonaggressive group-housed partners [122]. A broad spectrum of
behaviors can be recorded following a given experimental
manipulation. These include measures of timidity
(anxiety), aggression, and locomotion. BZ tranquilizers
decrease timidity and aggression in this model [122,123].
The main advantage of these social behavior models is
that they measure a wide range of behavioral activities and,
thus, detect a broad profile of drug action [124].
Technical devices have been developed that allow
researchers to record ultrasonic vocalizations emitted by
animals during various situations. A paradigm involving
isolation-induced ultrasonic vocalizations in infant rodents
[125] measures distress ultrasonic vocalizations that are
emitted by rodent pups following separation from their
mother and littermates. This paradigm has been validated as
a model of anxiety. BZ tranquilizers reduce emission of
ultrasonic calls by pups while anxiogenic drugs increase
ultrasonic vocalizations [126]. As emission of ultrasonic
vocalizations caused by social separation decreases abruptly
around the age of 14-16 days [127], ultrasonic vocalizations
in adult rodents must by evoked by fearful stimuli such as
auditory startle [128], air-puffs [129], or electric foot-shock
[130]. Again, a decrease in stimuli-induced ultrasonic
vocalizations is indicative of anxiolytic drug activity while
increased ultrasonic vocalizations indicate an anxiogenic
response (for a review see [131]).
The Geller-Seifter test [132,133] represents a conflict
model of anxiety and measures changes in punished
responding. Food-deprived rats are trained to press a lever to
obtain food. Once the rat learns the task, a conflict period
is introduced. This period is signaled with a light or a
sound and each response, i.e., lever pressing, is punished
with a foot-shock. This leads to a suppression of responding
during the punished period. BZ tranquilizers attenuate this
response inhibition [132]. The Geller-Seifter test requires
time-consuming training of animals and is, therefore, used
less frequently to study BZ withdrawal reactions. The Vogel
punished drinking test [134] is a modification of the GellerSeifter procedure in which water-deprived rats are shocked
when trying to drink water during the conflict period.
Again, BZ anxiolytics attenuate the response suppression
during the punished period [134]. The main advantage of
both these paradigms is that baseline measures assessed in
these models are consistent and reproducible [135]. In the
shock probe conflict test [136], rats are placed in a novel
environment that contains a probe. Rats show less time
exploring the probe when it is electrified. BZ tranquilizers
attenuate this response, i.e., they increase the time spent
exploring the electrified probe [137]. The main advantage of
the Vogel punished drinking test and the shock probe
conflict test, in comparison to the Geller-Seifter test, is that
they do not require time-consuming training of animals.
The drug-discrimination paradigm [112,138,139]
provides a measure of the subjective awareness by an animal
of interoceptive cues caused by the drugs presence in the

body. Food-deprived animals are trained to make a response
for food rewards by pressing one of a pair of levers when a
drug has been administered (drug lever) and the other lever
when given saline. When animals respond on a drug lever
following injection of a novel compound, it is inferred that
the novel drug produces effects that mimic those of the
training drug. Although this technique is used rarely to
study BZ withdrawal, it provides a reliable measure of
subjective feelings caused by drug withdrawal. For example,
it can be concluded that withdrawal from BZs produced
internal feelings of fear or anxiety when the animal makes the
same response during withdrawal as it would for an
anxiogenic drug.
ANIMAL STUDIES ON THE TREATMENT OF BZ

DEPENDENCE AND WITHDRAWAL
Treatment of BZ withdrawal would be best accomplished
using pharmacological agents that have minimal interactions
with clinically used BZs, have minimal side effectprofiles,
and are without (or have minimal) dependence potential. The
problem of dependence liability particularly arises with drugs
that have mechanisms of action similar to those of BZ
tranquilizers (e.g., partial BZR agonists and neurosteroids).
However, another issue requires critical attention. BZ
withdrawal reactions include a variety of symptoms ranging
from autonomic hyperactivity to severe anxiety, depression,
and convulsions. Although the exact mechanism underlying
each withdrawal reaction remains unclear, it might be that
some withdrawal symptoms (weight loss, autonomic
symptoms) are secondary to primary withdrawal symptoms
such as anxiety. Thus, drugs that do not alleviate primary
BZ withdrawal symptoms may have limited clinical benefit.
A large number of compounds have been used to
alleviate, reverse, or prevent BZ withdrawal reactions in
animals. Three main approaches have been taken in the
selection of the therapy drug. In one approach, interest has
focused on the suppression of withdrawal symptoms, i.e., on
functional antagonism. For example, reversal of anxiety and
seizures has been accomplished with drugs that possess
anxiolytic and anticonvulsant effects but are believed to
produce minimal dependence liability on their own (e.g.,
partial BZR agonists). The second approach has focused on
antagonism of neurochemical changes that are believed to
underlie BZ dependence and withdrawal. For example, if
increased noradrenergic activity following BZs cessation is
the
main
mechanism
involved
in
BZ
dependence/withdrawal,
then
drugs
that
decrease
noradrenergic activity should suppress BZ withdrawal signs.
Finally, the success of some drugs in the management of
withdrawal from other addictive drugs has led some
researchers to test their efficacy in treating BZ withdrawal.
For example, calcium channel blockers have been shown to
be helpful in ethanol and barbiturate withdrawal
[69,140,141], and the alpha-2 agonist clonidine has been
shown to be useful in treating ethanol [142] and opiate
withdrawal [143]. Additionally the 5-HT3 antagonist
ondansetron has been shown to inhibit behavioral
consequences of withdrawal from ethanol, nicotine, or
27
cocaine [144], and carbamazepine has been demonstrated to

be helpful in treating ethanol withdrawal [145]. These results
have led some investigators to speculate that such drugs
might also be beneficial in treating BZ withdrawal.
Drugs Acting at the GABAA/BZ Receptor Complex
As mentioned in section 2, clinically used BZs are
classified as full BZR agonists [17]. It is well known that an
acute administration of traditional BZs such as diazepam
during withdrawal can reverse withdrawal signs [91,146] but
of course, such drugs fail to treat dependence. On the other
hand, some of the drugs with lower intrinsic activity (partial
agonists) or with receptor subtype selectivity (selective BZ1
or BZ2 agonists) are believed to have a lower dependence
liability, while retaining therapeutic anxiolytic and
anticonvulsant actions [16,17,80,147-151]. Thus, acute
administration of partial or selective agonists should reverse
withdrawal signs, and substitution of traditional BZs with
these drugs could serve as a pharmacological dose-taper.
Such substitution should prevent the development of BZ
withdrawal without the risk that withdrawal reactions occur
following cessation of the therapy drug.
Partial and Selective BZ1 Receptor Agonists
Partial BZR agonists are drugs that bind to central BZRs
with no selectivity for either BZ receptor subtype, while
selective BZ 1 agonists selectively bind to the BZ1 subtype
of the central BZR [152]. However, classification of new
compounds as partial agonists or selective BZ1 agonists is
not always clearly distinguished. For example, abecarnil is
referred to as a partial BZR agonist in some studies [153155] but as a selective BZ1 receptor agonist in other studies
[156,157]. Therefore, effects of both partial BZR agonists
and selective BZ1 agonists on BZ withdrawal will be
discussed collectively in the following section.
The beta-carboline, abecarnil, possesses anxiolytic
properties in various animal models of anxiety
[23,152,158,159] but has reduced dependence liability in
both animals [80,149,151,158,160] and humans [161,162].
Moreover, abecarnil has been shown to successfully reduce
alcohol withdrawal signs in both animals [163] and humans
[164]. The effect of abecarnil substitution for chronic
alprazolam was examined in mice in a study by Pinna et al.
[79]. Mice withdrawn from 12-day daily alprazolam
treatment showed increased anxiety-like behavior, increased
muscle tone, and seizures between day 1 and day 28 after
discontinuation. The development of these withdrawal
symptoms was prevented if alprazolam treatment was
followed by 1-week treatment with the beta-carboline
abecarnil [79]. Emmett-Oglesby et al. [158] used the drugdiscrimination paradigm to study the effect of abecarnil on
spontaneous chlordiazepoxide withdrawal. Rats were treated
with chlordiazepoxide for 2 weeks (100 mg/kg/day) and then
were trained to discriminate flumazenil from saline. Since
flumazenil precipitated withdrawal in these animals, it served
as the control anxiogenic stimulus. During spontaneous
withdrawal from chlordiazepoxide, rats showed preference for
the flumazenil lever as spontaneous withdrawal resembled
the effect of flumazenil, i.e., produced an increase in anxiety.
28
This effect was reversed by a single administration of

abecarnil or chlordiazepoxide in a dose-dependent manner
[158] suggesting that both abecarnil and chlordiazepoxide
had similar efficacy in reversing the withdrawal-induced
anxiogenesis. Moreover, rats treated with abecarnil for 3 days
following withdrawal from chlordiazepoxide selected the
saline lever [158] suggesting that abecarnil prevented the
development of a withdrawal reaction.
The partial BZR agonist, Ro 19-8022, has anxiolytic
effects comparable to those of clinically available BZs in
various animal models of anxiety [147,152,165-167]. Its
dependence liability is minimal and withdrawal reactions are
weaker than those of traditional BZs [165,168]. The effect of
a single administration of Ro 19-8022 on withdrawal from
alprazolam was investigated in the social conflict test in
mice [95]. Mice withdrawn for 72 hours from 8-day
alprazolam treatment (1 mg/kg b.i.d.) showed less social
behavior and were more aggressive toward their nonaggressive partners. An acute administration of Ro 19-8022
reversed these behavioral withdrawal signs, without causing
side effects such as sedation or ataxia [95].
In the same model, decreased social and increased
anxiety-like behaviors were found 72 hours after withdrawal
from 8-day diazepam treatment [169]. A non-sedative dose of
the selective BZ1 receptor agonist, zolpidem (1 mg/kg
b.i.d.), given for 3 days following cessation of diazepam
treatment reduced the severity of withdrawal signs, but only
to some extent [169]. A complete reduction of withdrawal
signs in this model may require a high dose of zolpidem that
would produce the side effect of significant sedation. The
sedative properties of zolpidem, however, are not the only
factor that limits its use for therapy of BZ withdrawal.
Although zolpidem has been shown to have minimal
dependence liability in some studies [168,170,171], studies
using self-administration techniques in baboons have found
that zolpidem has a higher dependence liability than
clinically used BZs, as indicated by a higher rate of selfadministration [172,173]. Moreover, withdrawal from
zolpidem has been shown to cause seizures in humans [174]
suggesting that the use of zolpidem for therapy of BZ
withdrawal could be dangerous.
Alpidem is another member of the selective BZ1 receptor
agonist family [175]. Although alpidem has been shown to
reduce anxiety in patients with generalized anxiety disorder
[176-178], its effects in animal models of anxiety are
generally less clear [159,167]. There have been no studies on
the effects of alpidem on BZ withdrawal in animals, but in
humans, alpidem, given during the BZ dose-taper, worsened
the anxiety in BZ users [179].
Animal studies have shown that good anxiolytic and
anticonvulsant effects of partial and/or selective BZ receptor
agonists could be a reliable predictor of their success in
preventing or reversing BZ withdrawal symptoms.
Specifically, drugs with good anxiolytic and anticonvulsant
effects in animals, such as abecarnil and Ro 19-8022, are also
effective in reducing withdrawal reactions from traditional
BZs. In contrast, drugs with weak anxiolytic-like effects,
such as zolpidem or alpidem, are not useful for the therapy of
BZ withdrawal. Other BZR compounds possess good anti-
J. Podhorna
anxiety effects and lower dependence liability in animals, for

example
imidazenil
[147,152,180],
bretazenil
[23,152,159,181,182], and Y-23684 [183]. However, no
attempt has yet been made to assess their usefulness for
treatment of BZ withdrawal. It should be highlighted again
that drugs acting via BZRs might have addictive potential
themselves that should be examined carefully before any of
these drugs is recommended for therapy of BZ dependence
and withdrawal in humans.
Competitive BZ Receptor AntagonistFlumazenil
The use of flumazenil (Ro 15-1788) for preventing and
treating BZ withdrawal was originally based on the
presumption that the predominant symptom of BZ
withdrawal, increased anxiety, was caused by an elevated
level of anxiogenic endogenous ligands (for a review see
[40]). Thus, flumazenil could antagonize the anxiogenic
effects of these endogenous ligands by blocking their binding
site. Indeed, a peptide with anxiogenic properties, which
could be a candidate for an inverse agonist-like
endogenous ligand, has been found in rat and human brains
[184-186]. A second hypothesis proposed that flumazenil
might act by restoring the altered BZR function (for reviews
see [187,188]) that is seen following chronic treatment with
BZs [26-30].
Acute administration of flumazenil has been shown to
reverse withdrawal-induced anxiogenic responses in rats in
the elevated plus maze 24 hours after withdrawal from 21-day
chlordiazepoxide treatment [189] and 7-day diazepam
treatment [187]. Acute administration of flumazenil has also
been shown to reverse withdrawal-induced anxiogenic
responses in the social interaction test after 27 days of
chlordiazepoxide treatment [190]. Similarly, cessation of
chronic alprazolam treatment (14-21 days) and chronic
chlordiazepoxide treatment (35 days) produced withdrawal
signs of increased anxiety and locomotion in rats, that were
reversed with an acute injection of flumazenil [191]. In
contrast, co-administration of flumazenil with flurazepam for
7-days had little effect on the incidence of seizures
precipitated with the partial BZR inverse agonist (FG7142)
twenty-four hours after cessation of flurazepam treatment
[192].
These data suggest that changes in anxiety, but not other
withdrawal signs such as decreased seizure threshold, may be
caused by elevated levels of endogenous anxiogenic
ligands and/or by altered BZR function. However, it is also
possible that endogenous ligands with BZ-like properties
might exist, and that suppression of their synthesis during
chronic BZ treatment might lead to the manifestation of
withdrawal after abrupt treatment discontinuation. Of course,
in such a case, flumazenil would be ineffective as a treatment
for BZ withdrawal.
There is only one clinical study that has reported
flumazenil to be useful in BZ-dependent patients [193].
Unfortunately, the situation with flumazenil in the
management of BZ dependence is further complicated by the
fact that flumazenil is generally used to precipitate
withdrawal in both BZ-treated rodents [194-197] and
primates [85,90,198,199]. Thus, in spite of some positive
results in animal studies [50,187,189,200], and in one study

with humans [193], clinical application of flumazenil for BZ
withdrawal therapy appears problematic because of the
possible risk of precipitating withdrawal reactions in BZ
users.
Neurosteroids
Neuroactive steroids are synthesized within the central
nervous system and act as endogenous modulators at the
GABAA receptor complex [201-203]. Some neurosteroids,
such
as
allopregnanolone,
dehydroepiandrosterone,
pregnenolone, and progesterone, enhance GABA-induced
inhibition and, therefore, represent a class of putative
anxiolytic and anticonvulsant drugs [202]. As some
neurosteroids have been found to protect against bicucullineinduced seizures during ethanol withdrawal in rats [204],
Pesce et al. [195] investigated the effect of progesterone on
precipitated withdrawal from chronic diazepam treatment. An
acute administration of progesterone during precipitated
withdrawal significantly reduced the incidence of jerks and
seizures that were present in withdrawn mice [195]. Reddy
and Kulkarni [205] studied the protective effect of various
neurosteroids on BZ withdrawal in mice. A concomitant
treatment of allopregnanolone and pregnenolone sulfate with
triazolam for 8 days, as well as co-administration of
progesterone with diazepam for 21 days, attenuated
withdrawal-induced hyperlocomotion and anxiety. No
withdrawal response was observed after withdrawal from
chronic treatment with these neurosteroids, when
administered alone.
This latter finding from the [205] study is rather
surprising as neurosteroids have been repeatedly shown to
induce dependence with increased anxiety as a characteristic
withdrawal reaction following their discontinuation [206209]. Moreover, another study showed that rats undergoing
withdrawal from progesterone had an increased incidence of
seizures precipitated with the GABAA antagonist picrotoxin
when compared to controls, and that a combined
administration of progesterone with diazepam produced a
synergistic effect upon the severity of withdrawal signs [210].
In addition, clinical data have showed no benefit of
neurosteroids for the therapy of BZ withdrawal as
administration of progesterone during dose-taper from
diazepam failed to reduce the severity of withdrawal reactions
[211].
Serotonergic Drugs
The serotonergic neurotransmitter system is involved in
certain aspects of BZ action [45,46]. In various parts of the
brain, the release and turnover of serotonin (5-HT) is
modulated by acute [46,47] and chronic [42,49,58] BZ
treatment. It is almost certain that changes in serotonergic
neurotransmission play a role in the development of BZ
dependence and withdrawal, as BZ withdrawal increases 5HT release (for review: [50]), decreases 5-HT concentration
in the brain [53,54], and leads to hypersensitivity of 5-HT 1A
autoreceptors in the dorsal raphe nucleus in rats [55].
However, the exact mechanism of how the 5-HT system is
involved in the processes of BZ dependence and withdrawal
remains unclear.
29
Partial Agonists at the 5-HT1A Receptor Subtype

Although serotonergic drugs have been among the most
extensively investigated for their anxiolytic action, as well as
for the therapy of BZ withdrawal, results from both animal
and human studies are conflicting. The only serotonergic
agent available for clinical practice, the 5-HT1A partial
agonist buspirone, has anxiolytic properties in man [212215]. Chronic treatment with buspirone and other 5-HT1A
partial agonists does not lead to rebound anxiety or
withdrawal reactions upon cessation [216-219]. However,
compared to BZs, buspirone has a delayed onset of action
[212,220] and a lower rate of response in patients with
anxiety disorders, particularly those previously treated with
BZs [221,222].
Effects of buspirone and other 5-HT1A partial agonists on
BZ withdrawal have been examined in several animal
studies. Co-administration of buspirone with diazepam for 7
days increased the incidence of withdrawal-induced
convulsions precipitated by a partial BZR agonist, FG 7142
[223]. After withdrawal from 7-day diazepam treatment,
buspirone failed to reverse anxiety-like behavior in the social
interaction test in rats, or the light/dark transition test in
mice, nor did it antagonize withdrawal-induced weight loss
[91]. Likewise, ipsapirone [93] and gepirone [224] given
during the withdrawal phase had no effect on
chlordiazepoxide withdrawal-induced anorexia and weight
loss, and even worsened these withdrawal signs at higher
doses. Findings with 5-HT1A agonists in clinical studies are
in agreement with animal studies as buspirone failed to
reverse or prevent BZ withdrawal symptoms in humans
[225,226].
However, positive results have been obtained with low
doses of 5-HT1A partial agonists in animal studies. Low
doses of buspirone reversed anxiogenic responses in the
elevated plus-maze and in the social interaction test in rats
withdrawn for 24 h from 21-day diazepam treatment.
However, higher doses were anxiogenic in both withdrawn
and control rats [49,227]. The authors suggested that low
doses of buspirone act at 5-HT1A autoreceptors and, thus,
decrease 5-HT release while high doses act at postsynaptic
receptors to facilitate 5-HT transmission [49]. Similarly, low
doses of gepirone antagonized the increased ultrasonic
vocalizations in response to acoustic startle in adult rats
withdrawn for 24 h from 5-day diazepam treatment [128].
Surprisingly, acute administration of diazepam during
withdrawal (3 to 20 mg/kg) did not reverse withdrawalinduced increase of ultrasonic vocalizations in this study
[128]. This is contrary to the generally accepted fact that BZ
withdrawal symptoms can be easily antagonized with an
acute administration of BZ tranquilizers [91,146] and raises
the question as to whether the increase of acoustic startleinduced ultrasonic vocalizations in the [128] study was
actually a result of BZ withdrawal.
Although no withdrawal signs after long-term use of 5HT 1A
partial
agonists
have
been
reported
[93,216,220,228,229], this class of drugs has generally failed
to prevent or alleviate BZ withdrawal in the majority of
animal studies. Some effects have been found with low doses
of 5-HT1A agonists but the clinical significance of this
30
finding is questionable. Clinicians would be unlikely to

prescribe a drug to outpatients if there is a risk of aggravation
of withdrawal symptoms at higher doses. Moreover,
buspirone has been shown to have no benefit [225,226], and
sometimes to aggravate BZ withdrawal symptoms, in
humans [225]. In addition, clinical practice has shown that
prior BZ experience may attenuate the anxiolytic actions of
buspirone and other 5-HT1A agents [221,222]. These
considerations suggest that 5-HT 1A agonists are probably of
limited value in the treatment of BZ dependence and
withdrawal.
5-HT3 Antagonists
In line with research on the therapy of BZ withdrawal
using drugs acting via 5-HT1A receptors, there has also been
interest in 5-HT3 antagonists. The 5-HT3 antagonists have
been reported to have anxiolytic effects in some [230-232],
but not all [232-235], animal studies.
Similar
inconsistencies can be found in the animal literature dealing
with effects of 5-HT3 antagonists on BZ withdrawal. Costall
et al. [91] studied the effects of the 5-HT3 antagonist
ondansetron on diazepam withdrawal reactions (20 mg/kg/d),
using the social interaction test in rats and the light/dark
transition test in mice. Both mice and rats showed an
anxiogenic response that was accompanied by weight loss 8
- 96 hours following diazepam withdrawal. Ondansetron,
given either daily during the withdrawal phase or once before
behavioral testing, reversed both the withdrawal-induced
anxiogenic response and weight loss [91]. Similarly,
ondansetron attenuated the anxiogenic response observed in
rats during flumazenil-precipitated withdrawal from 7-day
chlordiazepoxide treatment [236]. Ondansetron also
antagonized withdrawal-induced weight loss in a study by
Goudie and Leathly [92], but only at an intermediate dose
(0.1 mg/kg) and only to some extent. Similarly, low doses
of the 5-HT3 antagonist, zacopride, reversed increased
anxiety-like behavior in the elevated plus-maze in rats
withdrawn for 24 h from 21-day diazepam treatment.
However, higher doses of zacopride were found to be
anxiogenic in control rats [49,237].
Prather et al. [238] conducted three experiments to assess
the efficacy of ondansetron on withdrawal from 7-day
chlordiazepoxide treatment (100 mg/kg/d). In the first
experiment, ondansetron antagonized the withdrawal-induced
anxiogenic effect (decreased open arm activity) in the elevated
plus maze. However, the highest dose (0.16 mg/kg) also
decreased total arm entries, indicating that high dose
ondansetron produced sedative side effects. In the second
experiment, ondansetron failed to reverse the withdrawalinduced suppression of responding in the conflict paradigm
[238]. In the third experiment, chlordiazepoxide-dependent
rats were trained to discriminate flumazenil (that precipitated
withdrawal in these animals) from saline in a drugdiscrimination paradigm. Ondansetron, given prior to the
withdrawal-inducing flumazenil injection, had no effect on
the animals subjective experience of chlordiazepoxide
withdrawal. Rats continued to press the flumazenil lever
suggesting that ondansetron did not prevent the development
of chlordiazepoxide withdrawal [238].
Likewise, 5-HT 3 antagonists, ondansetron, ICS 205-930,
MDL 72222, metoclopramide, and zacopride, had no effect
J. Podhorna
on BZ and alcohol withdrawal in a study by Mehta and

Ticku [239]. In this study, rats withdrawn from 3-week
diazepam or 6-day alcohol treatment showed locomotor
hyperactivity and increased sensitivity to pentylenetetrazolinduced convulsions. 5-HT3 antagonists, given during the
withdrawal phase, failed to attenuate the locomotor
hyperactivity, and even increased the sensitivity to
pentylenetetrazol [239]. The 5-HT3 antagonist ICS 205-930,
administered
during
withdrawal
from
21-day
chlordiazepoxide treatment, also failed to reduce withdrawalinduced anorexia and loss of body weight [240]. Similarly,
co-administration of the 5-HT3 antagonist ondansetron with
diazepam for 7 days failed to protect against convulsions
precipitated with the partial BZR agonist FG 7142 twentyfour hours after the last diazepam treatment [223].
Ondansetron also failed to modify suppression of responding
in the operant paradigm that was observed in female rats
withdrawn from 42-day chlordiazepoxide treatment [241].
Results from animal studies with 5-HT3 antagonists are
rather discouraging. Although 5-HT3 antagonists do not
produce dependence liability [91,230], they seem to be
ineffective either as anxiolytics [232,233,235] or for the
treatment of BZ withdrawal [92,223,238,239]. Clinical
findings are in agreement with animal studies as the 5-HT3
antagonist, ondansetron, had no significant effects on severity
of withdrawal symptoms and levels of anxiety in patients
undergoing dose-taper from alprazolam or lorazepam [242].
Other Serotonergic Agents
The 5-HT1C antagonist, mianserin, and the 5-HT2
antagonist, ketanserin, showed no protective effect on FG
7142 (a partial BZR agonist) precipitated seizures following
withdrawal from 7-day diazepam treatment in mice [223].
The 5-HT2 antagonist ketanserin, administered for 6 days
following cessation of 26-day chlordiazepoxide treatment,
exacerbated withdrawal-induced anorexia and weight loss in
rats [243]. These data are discouraging and suggest that
these alternative serotonergic agents have minimal value as
therapies for the management of BZ withdrawal.
There are three major classes of drugs used to treat
human depression, monoamine oxidase inhibitors (MAOIs),
tricyclic antidepressants (TCAs), and the second generation
antidepressants including selective serotonin reuptake
inhibitors (SSRIs). While MAOIs and TCAs increase
synaptic concentrations of serotonin and noradrenaline,
SSRIs, such as fluoxetine (Prozac), increase only serotonin
synaptic concentrations [244]. Although the main therapeutic
use of SSRIs is for the treatment of depression, they also
have well-documented efficacy in treating panic disorder
[245] and obsessive-compulsive disorder [246], and are
currently being studied for the therapy of social phobia, posttraumatic stress disorder, and generalized anxiety disorder
(for a review see [247]).
It has been proposed that antidepressants could be useful
in the treatment of patients undergoing BZ withdrawal,
particularly in patients with depression as a prominent
symptom of withdrawal [11]. However, both animal and
clinical studies using antidepressants for the management of
BZ withdrawal are scanty. The antidepressant tianeptine has
the unique property of enhancing (rather than inhibiting)

serotonin reuptake [248]. It has been shown to reverse the
anxiogenic effect of diazepam withdrawal in rats studied in
the social interaction test [49]. No research has yet examined
the effects of tianeptine in BZ dependent patients. Dothiepin,
a TCA with both antidepressant and anxiolytic properties in
animals [249], failed to attenuate BZ withdrawal reactions in
a clinical study by Tyrer et al. [250]. Nonetheless, the
interpretation of the results of the study by Tyrer et al. [250]
is problematic because of a high patient dropout rate.
A study by Lacerra, Martijena, Bustos, and Molina [251]
examined the effects of various antidepressant drugs, such as
desipramine (a TCA), fluoxetine (an SSRI), and phenelzine
(an MAOI), on withdrawal from 21-day diazepam treatment
in rats. The model used in this study was the learned
helplessness paradigm, a classical animal model of
depression [252,253]. Rats treated daily with diazepam were
subsequently exposed to inescapable shock. Forty-eight
hours following cessation of diazepam, rats were tested in an
active avoidance paradigm. Withdrawn rats showed increased
escape failure, a sign that parallels human depression.
Desipramine and phenelzine, but not fluoxetine, given
during the withdrawal period, reversed the increased escape
failure observed in withdrawn rats [251].
Novakova et al. [96] investigated the effect of fluoxetine
on diazepam withdrawal in the social conflict model in mice
[122]. Two-week treatment with diazepam increased anxietylike behavior in timid (anxious) mice and increased
aggression in aggressive mice. A single administration of
fluoxetine 48 hours after the withdrawal suppressed
aggression in aggressive mice without producing motor
impairment, but had no effect on anxiety-like behavior in
timid mice. When fluoxetine was co-administered with
diazepam during the last three days of chronic treatment,
neither withdrawal-induced anxiety nor aggression was
observed [96]. This is not surprising, as repeated
administration of SSRIs is required to achieve therapeutic
effect. The most interesting finding of this study was the
suppressant effect of fluoxetine on withdrawal-induced
aggression, as this is in agreement with clinical data. The
SSRIs are effective in the treatment of aggressive and violent
behaviors in human addicts [254], although both animal
[255,256] and clinical [257] data suggest that SSRIs have
minimal effect on aggression per se.
The SSRIs have been previously found to be useful in
the management of ethanol [258] and cocaine withdrawal in
humans [259]. However there is no clinical data yet available
on the efficacy of the SSRIs for the treatment of BZ
withdrawal. Unfortunately, there is little animal data with
fluoxetine and other antidepressants available to draw any
firm conclusions as to the potential usefulness of SSRIs in
the treatment of BZ withdrawal.
Noradrenergic Drugs
Two major adrenoreceptor families, alpha () and beta
(), mediate the effects of noradrenaline and adrenaline in the
CNS and periphery [260]. Receptor subtypes for both and
adrenoreceptors have been identified [261]: the 1
31
postsynaptic receptors, the 2 presynaptic autoreceptors, and

the 1, 2, and 3 receptors. Hyperactivity of the
noradrenergic system is believed to underlie withdrawal
reactions from CNS depressant drugs such as morphine
[143], alcohol [57], and BZs [52,58]. Moreover, drugs that
suppress noradrenergic hyperactivity are useful in the
management of morphine withdrawal in rats [262,263] and
in man [143], as well as in the management of alcohol
withdrawal in alcoholic patients [142,264]. Such findings
have led some investigators to study the effects of drugs that
decrease noradrenergic activity, such as 2 adrenoreceptor
agonists and antagonists, on BZ withdrawal.
Kunchandy and Kulkarni [89] investigated the effects of
2 adrenoreceptor agonists, drugs that decrease noradrenaline
release due to activation of presynaptic 2 autoreceptors
[261], on withdrawal from 3-week diazepam treatment in
rats. The 2 adrenoreceptor agonist clonidine given twice a
day during the withdrawal period prevented the development
of withdrawal reactions such as locomotor hyperactivity and
diarrhea. However, other 2 adrenoreceptor agonists,
guanfacine and B-HT 920, at doses equivalent to that of
clonidine, prevented only diarrhea; higher doses were
required to reverse hyperactivity. In contrast to the results of
the Kunchandy and Kulkarni study [89] both the 2
adrenoreceptor agonist, clonidine, and the antagonist,
propranolol, failed to suppress the anxiogenic withdrawal
reaction detected 24 h after cessation of 4-week
chlordiazepoxide treatment in rats [77].
These data suggest that autonomic symptoms and
hyperactivity, but not anxiogenic withdrawal responses, may
be mediated by increased noradrenergic activity. Clinical
results are in agreement with these animal findings. In
humans, the antagonist propranolol has been shown to
relieve autonomic withdrawal symptoms such as palpitations
and tremor, but to have little effect on subjective withdrawal
symptoms such as anxiety [265,266]. The 2 adrenoreceptor
agonist clonidine has been shown to decrease withdrawal
severity in some [267,268], but not all [269], clinical
studies. Thus, blockade of noradrenergic neurotransmission
with 2 agonists and antagonists (-blockers) appears to
have little effect on anxiety as the predominant symptom of
BZ withdrawal, and limits the use of these drugs to serving
as supplements to other therapies for BZ withdrawal.
Cholecystokinin-B (CCK-B) Receptor Antagonists
Cholecystokinin (CCK) is a gut-brain peptide widely
distributed throughout the mammalian brain where it acts as
a neurotransmitter and neuromodulator [270]. CCK has been
implicated in the neurobiology of anxiety, particularly of
panic attacks [271-273]. CCK is co-localized with other
neurotransmitters, including GABA [274], and can modulate
their action [270,271]. Chronic BZ treatment has been
proposed to
induce
changes
in
brain
CCK
neurotransmission. For example, an increased number of
CCK receptors was found in the frontal cortex and
hippocampus 24 hours after cessation of 2-week diazepam
treatment [31].
CCK-B receptor antagonists have been reported to have
an anxiolytic effect over a wide dose range in many
32
[272,275-281], but not all [113,282-284], animal studies.

Side effects typical for BZ tranquilizers, such as sedation,
muscle relaxation, or ataxia, have not been observed with
CCK-B antagonists [276,277,281]. In addition, neither
development of tolerance to anxiolytic effects nor signs of
withdrawal were found after 7-day treatment with CCK-B
antagonists [277]. In a study by Hughes et al. [277], the
CCK-B antagonists, PD 134308 and PD 135158, were used
to suppress the increased anxiety found during withdrawal
from 7-day diazepam treatment. Both drugs, given either
once 24 hours after the last dose of diazepam, or coadministered with diazepam for 7 days, attenuated the
withdrawal-induced anxiogenic effect in the mouse light/dark
transition test of anxiety [277]. Likewise, acute
administration of CI-988 dose-dependently reversed the
increased anxiety in the mouse light/dark transition test
following withdrawal from 7-day diazepam treatment [285].
Moreover, CI-988 also antagonized the proconvulsant effect
of withdrawal, assessed in the pentylenetetrazol (PTZ) model
[285], even though CCK-B antagonists do not possess
anticonvulsant properties when given to non-addicted
animals [281]. Rasmussen, Helton, Berger, and Scearce
[286] studied the effect of the CCK-B antagonist, LY288513,
on the enhanced auditory startle reflex following withdrawal
from 12-day diazepam treatment. An acute administration of
LY288513 on the fourth day of withdrawal dose-dependently
blocked the withdrawal-induced increase in the auditory
startle reflex [286].
In contrast, Goudie and Leathley [287] found no
protective effect of the CCK-B antagonist, L-365, 260, on
the withdrawal-induced decrease in food intake (hypophagia).
Rats withdrawn from 21-day chlordiazepoxide treatment had
hypophagia, with maximum intensity 2-3 days after
withdrawal. L-365, 260 given at a wide range of doses for 5
days following chlordiazepoxide withdrawal had no effect
either in withdrawn or control groups [287]. The authors
concluded that anxiogenesis is sensitive to the effects of
CCK-B antagonists while other BZ withdrawal signs (i.e.,
hypophagia and weight loss) remain resistant because of
different underlying mechanisms. This speculation is
plausible, as CCK-A rather than CCK-B receptors play a
role in food intake [288-290]. However, the results of the
Goudie and Leathley [287] study are rather confusing as a
significant decrease in food intake was found in the
withdrawn group (i.e. chlordiazepoxide-vehicle) as compared
to the chlordiazepoxide-chlordiazepoxide group. In contrast,
there was no significant food-intake decrease between the
withdrawn and control (i.e., saline-vehicle) groups, making
interpretation of the results difficult.
Although some CCK-B antagonists have failed as
anxiolytics and anti-panic agents in some animal
[113,282,283] and clinical studies [291,292], they appear to
alleviate both the anxiogenic and proconvulsant effects of BZ
withdrawal. The failure of CCK-B antagonists in the therapy
of anxiety disorders might suggest different mechanisms
underlying anxiety per se versus anxiety following
withdrawal from BZs. Since subchronic treatment with
CCK-B antagonists does not produce withdrawal responses
[277,285], CCK-B antagonists appear to be promising
candidates for the therapy of BZ withdrawal. Clinical studies
J. Podhorna
are needed to confirm the positive results of animal studies,

however.
Antagonists of Excitatory Amino Acids
The excitatory amino acid neurotransmitter system,
particularly the N-methyl-D-aspartate (NMDA) subtype of
glutamate receptors, is believed to contribute to the
neurobiology of anxiety disorders [150,293,294]. NMDA
receptor antagonists possess anticonvulsant, muscle relaxant,
and anxiolytic properties in animal models of anxiety
[150,295-299]. Moreover, chronic treatment with diazepam
has been reported to cause upregulation of NMDA receptors
[60-62]. The involvement of glutamate in withdrawal from
CNS depressant drugs such as morphine has also been
reported [300,301]. Both competitive and non-competitive
NMDA antagonists as well as metabotropic glutamate
antagonists have been shown to attenuate naloxoneprecipitated withdrawal signs in morphine-dependent
animals [300,301].
Steppuhn and Turski [86] examined effects of the
competitive NMDA receptor antagonist, 3-[()-2carboxypiperazin-4-yl]-propyl-1-phospho-nate (CPP), on
withdrawal-induced changes in EEG activity, muscle tone,
and anxiety-like behavior in mice. Withdrawal from 12-day
diazepam treatment led to seizures, muscle rigidity, and
increased anxiety-like behavior, with maximum withdrawal
reactions observed between days 4 -10 after discontinuation.
The competitive NMDA antagonist, CPP, given from the
third to 14th day of withdrawal prevented the manifestation of
these withdrawal signs [86]. In a study by Koff et al. [35],
withdrawal from 2-week lorazepam led to decreased seizure
threshold and increased BZR binding, assessed on the fourth
day of withdrawal. The competitive NMDA antagonist CPP,
given concomitantly with lorazepam as well as during the
withdrawal period, abolished these withdrawal signs [35].
Tsuda, Suzuki, and Misawa [61,302,303] conducted
several studies to investigate the effects of the noncompetitive NMDA antagonists, MK-801 (dizocilpine) and
ifenprodil, on withdrawal from 30-day diazepam treatment in
rats. Rats withdrawn from diazepam for 72 h showed tremor,
muscle rigidity, reduced body weight, and emotional
responses such as vocalization and aggression. Withdrawn
rats also had reduced seizure threshold that was induced
either by pentylenetetrazol or the BZR inverse agonist
DMCM
(methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3carboxylate). Administration of non-competitive NMDA
antagonists during the withdrawal period had a protective
effect on the development of withdrawal signs [61,302,303].
Although NMDA antagonists show some promise in the
treatment of BZ withdrawal in animals, two additional
points have to be considered. First, both competitive and
non-competitive NMDA antagonist produce vast muscle
relaxation and ataxia [295,304,305] that might limit their
use for treatment of any condition where motor impairment
is undesirable. It is also difficult to conclude whether the
decrease in withdrawal-induced anxiety following treatment
with NMDA antagonists [86,303] actually reflects a
therapeutic success (i.e., anxiolysis), or whether these effects
are merely secondary to the vast muscle relaxation and ataxia

caused by these drugs. Secondly, non-competitive NMDA
antagonists such as MK-801 have been shown to produce
phencyclidine (PCP)-like behavior and PCP-like catalepsy
[306-308]. Such serious side effects place in doubt the
usefulness of NMDA antagonists as anxiolytics or as drugs
for the therapy of BZ withdrawal.
Calcium Channel Blockers
There are at least three types of calcium channels (T-, L-,
N-types) but only the L-type is sensitive to clinically
available calcium channel blockers, such as verapamil,
nifedipine, or diltiazem [309]. Although calcium channel
blockers are an important group of drugs for the treatment of
cardiovascular diseases, they penetrate the CNS in sufficient
quantities to produce central effects [310]. The CNS effectsof
calcium channel blockers are broad (for a review see [68]).
With respect to the focus of the current review, it is
interesting to note that calcium channel blockers have not
only putative anxiolytic [311] and anticonvulsant [312,313]
effects, but also attenuate withdrawal symptoms from CNS
depressant drugs such as alcohol [70,140], barbiturates
[69,141], and morphine [314,315].
Since changes in calcium channel function have been also
found in the brain during withdrawal from BZs [42,72,73],
the effects of calcium channel blockers on BZ withdrawal
have been investigated in several animal studies. Dolin et al.
[73] found that nitrendipine (an L-type calcium channel
blocker) dose-dependently decreased the incidence of seizures
that were precipitated by the partial BZR agonist, FG 7142.
This protective effect was achieved when nitrendipine was
given 24 h after withdrawal from 7-day flunitrazepam
treatment but not when nitrendipine was given concurrently
with flunitrazepam throughout the 7-day dependenceinducing period. In the same study [73], nitrendipine failed
to reduce withdrawal-induced seizures that were precipitated
with more potent convulsant drugs (i.e., the GABAA
antagonist bicuculline and the full inverse agonist methyl6,7-dimethoxy-4-ethyl-B-carboline-3-carboxylate (DMCM)),
suggesting only partial efficacy of nitrendipine in reversing
withdrawal-induced seizures. Similar results were obtained
with nitrendipine during barbiturate withdrawal, using the
same animal model [141]. Mizoguchi et al. [71] studied
effects of flunarizine (a T-type calcium channel blocker),
nifedipine, and diltiazem (L-type calcium channel blockers)
on the incidence of FG 7142 precipitated seizures 24 h after
diazepam withdrawal. When co-administered with diazepam
for 7 days, flunarizine significantly, and nifedipine
nonsignificantly, suppressed the occurrence of FG 7142
precipitated seizures, while diltiazem failed to produce any
protective effect [71]. Since nitrendipine, nifedipine and
diltiazem block the same type of calcium channels [309],
these data suggest that T-type, rather than L-type, calcium
channel blockers are beneficial in protecting against
withdrawal-induced seizures.
In a study by Chugh et al. [87], 3-week diazepam
administration followed by 4-day treatment with verapamil
(an L-type calcium channel blocker) or cinnarizine (a T-type
calcium channel blocker) prevented the development of
33
withdrawal-induced locomotor and autonomic hyperactivity.

Behavioral withdrawal signs indicative of fear (i.e.,
irritability and increased startle response) were antagonized
by high doses of cinnarizine but not of verapamil. Similarly,
isradipine (an L-type calcium channel blocker) and
flunarizine (a T-type calcium channel blocker), but not
diltiazem (an L-type calcium channel blocker), attenuated
withdrawal-induced hypermotility, rigidity, and convulsions
that were observed 24 h after cessation of 20-day lorazepam
treatment [196]. These results further confirm that T-type,
rather than L-type, calcium channel blockers can alleviate
major symptoms of BZ withdrawal such as increased anxiety
or seizures.
However, more promising results with L-type calcium
channel blockers have been obtained when a different seizure
model was used. Gupta, Nath, Patnaik, and Saxena [316]
studied the effects of the L-type calcium channel blockers,
verapamil, nifedipine, and nimodipine, on a variety of
lorazepam withdrawal signs (i.e., body weight, food intake,
spontaneous locomotor activity, foot shock-aggression,
reaction to pain, body temperature, audiogenic seizures).
Rats treated with these three L-type calcium channel blockers
following withdrawal from lorazepam did not develop
withdrawal signs including audiogenic seizures, although
nifedipine was only partially effective against audiogenic
seizures [316].
Hitchcott et al. [72] found verapamil (an L-type calcium
channel blocker) to be effective in preventing the
development of diazepam withdrawal. Rats withdrawn for 42
h from 4-week diazepam treatment showed increased anxietylike behavior in the elevated plus maze. Co-administration of
verapamil with diazepam for 4 weeks abolished the
anxiogenic withdrawal response and actually produced an
anxiolytic-like effect. This is not surprising as calcium
channel blockers have been previously found to possess
anxiolytic properties in animals and humans (for a review see
[68]).
In conclusion, complete protective effects of L-type
calcium channel blockers against withdrawal-induced
anxiogenesis are questionable. Certainly, calcium channel
blockers have some protective effect against seizures
occurring during withdrawal from CNS depressant drugs,
particularly those calcium channel blockers that block T-type
calcium channels. Calcium channel blockers have also been
shown to antagonize withdrawal-induced seizures after
chronic ethanol [140] and barbiturate [69] administration, as
well as seizures of other origins [317,318]. Such findings
confirm that calcium channel blockers have putative
anticonvulsant effects [312,313] and may be useful in the
management of seizures that can occur during withdrawal
from some psychoactive drugs, including BZs.
Miscellaneous Agents
Baclofen
Baclofen is a GABA B receptor agonist which, due to its
action at presynaptic GABAB receptors, inhibits
neurotransmitter release, particularly that of GABA,
34
glutamate, 5-HT, and noradrenaline [319]. Since increased

turnover of these neurotransmitters is believed to underlie the
manifestation of BZ withdrawal (for a review see [74]), the
effects of baclofen on BZ withdrawal was investigated by File
et al. [146]. Acute administration of baclofen reversed
increased anxiety-like behavior in the social interaction test
in rats withdrawn for 24 h from 21-days of diazepam
treatment [146]. However, the withdrawal-induced
anxiogenic response was antagonized only at low doses of
baclofen (0.5 and 1 mg/kg). The high dose of baclofen (2
mg/kg) was ineffective in reversing the withdrawal-induced
anxiogenic response, and produced sedation in both controls
and withdrawn rats [146]. Since low doses of baclofen also
antagonized increased [3H]-5-HT release from the
hippocampus under the same experimental conditions [42],
it was suggested that the efficacy of low doses of baclofen are
attributable to presynaptic inhibition of 5-HT release
[49,51].
Based on this limited evidence, it is difficult to evaluate
the risk-benefit profile of baclofen for the therapy of BZ
withdrawal. However, like 5-HT1A agonists, the efficacy of
baclofen only in low doses raises doubts as to the clinical
usefulness of this agent. Moreover, baclofen has been shown
to worsen signs of alcohol withdrawal in mice, as it induced
convulsions [320]. Since the neurochemical mechanisms
underlying withdrawal from various CNS depressant drugs
(e.g., alcohol, BZs) appear to overlap [1,321], it is possible
that baclofen might also trigger seizures in BZ withdrawn
subjects.
Carbamazepine
The anticonvulsant carbamazepine has been shown to
have benefit in reducing the symptoms of alcohol [145,322]
and BZ (for review: [323]) withdrawal in humans. Galpern et
al. [34] studied the effects of carbamazepine on withdrawal
from 7-day alprazolam (2 mg/kg/day) treatment in mice.
Mice withdrawn from alprazolam showed increased open
field locomotor activity and increased BZR binding in the
cortex and hypothalamus, with maximum intensity of signs
between days 2-4 after cessation of alprazolam.
Carbamazepine given for 7 days following withdrawal from
alprazolam attenuated manifestation of withdrawal-induced
hyperactivity and receptor upregulation. Carbamazepine
given to controls (i.e., animals treated with vehicle during
the first week), had no effects on locomotor activity or
receptor binding [34]. Interestingly, large variability in the
response between animals was found in this study [34],
similar to that found in humans [324]. In a study by
Martijena, Lacerra, and Molina [325], rats withdrawn for 96
h from 21-day diazepam treatment (2 mg/kg/day) showed
impairment in the forced swim test and in the active
avoidance paradigm. Behavioral changes following cessation
of diazepam were reversed by a single injection of
carbamazepine given before behavioral testing [325].
The mechanism of action of carbamazepine on BZ
withdrawal symptoms remains unknown. The ability of
carbamazepine to inhibit electrical excitation in the limbic
system may play an important role [326]. Another possible
mechanism that has been proposed pertains to inhibition of
J. Podhorna
sodium channel-mediated
carbamazepine [327].
neurotransmitter
release
by
Carbamazepine is an anticonvulsant, and thus can protect

against withdrawal-induced seizures. It has also been found
to increase open-arm activity in the elevated plus maze in
rats [328] suggesting that carbamazepine may also possess
anxiolytic properties. Carbamazepine appears to be effective
in treating BZ withdrawal in studies with rodents [34,325]
as well as in several clinical studies [324,329-334]. Patients
receiving carbamazepine prior to or during withdrawal from
BZs had more rapid and better-tolerated discontinuation with
less intense withdrawal symptoms than if gradual taper was
used alone [324,332,333,335]. These results are encouraging
and support carbamazepine as a possible pharmacological
tool in the therapy of BZ withdrawal. On the other hand, the
variability in responses to carbamazepine in mice [34] and in
man [324] might indicate that carbamazepine can be useful
only in some individuals. Unfortunately, the characteristics
of patients most likely to respond to carbamazepine in the
treatment of BZ withdrawal remain unknown.
Other Drugs
The putative anxiolytic, umespirone, has affinity for the
dopamine D2, serotonergic 5-HT1A receptors and 1adrenoreceptors. The pharmacological profile of umespirone
and its effects on BZ withdrawal signs were investigated by
Barnes et al. [336]. Acute administration of umespirone
produced anxiolytic-like effects in the mouse light/dark
transition and in the rat social interaction tests but no
withdrawal signs were observed if umespirone was
administered for 2 weeks [336]. Moreover, 7-day diazepam
treatment followed by a daily administration of umespirone
during the withdrawal phase prevented the development of
diazepam withdrawal-induced anxiogenesis, measured in the
mouse light/dark transition test [336].
F 2692 is a new putative anxiolytic drug with antianxiety action similar to that of BZs and minimal
dependence liability, although its mechanism of action
remains unknown [337,338]. Chopin, Assie, and Briley
[339] found that F 2692, given either acutely 24 h after
diazepam cessation or for one week following withdrawal
from diazepam, completely reversed the anxiogenic response
of withdrawal from 21-day diazepam treatment in rats
measured in the elevated plus maze.
Tiapride, a selective dopamine D2 receptor antagonist, is
an atypical antipsychotic drug that has been recommended
for the management of alcohol withdrawal (for a review see
[340]). Vinklerova et al. [97] investigated the effect of
tiapride on aggressive and anxiety-like behavior produced by
withdrawal from 2-week diazepam treatment in the social
conflict test in mice. Increased aggressive behavior in
withdrawn mice was abolished with a single injection of
tiapride (25 mg/kg) while a high dose of tiapride (100
mg/kg) was necessary to suppress withdrawal-induced
anxiogenic responses [97].
Although these pilot results are encouraging, additional
research is necessary to confirm the efficacy of the above
mentioned agents for the management of BZ withdrawal.
SUMMARY AND CONCLUSIONS

It is now well established that rebound anxiety and
insomnia are not the only problem associated with the
abrupt cessation of long-term BZ therapy (for a review see
[25]) as withdrawal reactions are relatively frequent (for a
review see [341]). Clinicians commonly deal with the
problem of BZ dependence and withdrawal using a gradual
dose-taper to avoid withdrawal reactions (for reviews see
[11,12]) but this is often ineffective [4,11,14]. These
problems have generated an intensive search to find effective
psychotherapy (reviewed by Otto et al., [15], this issue)
and/or effective pharmacotherapy to aid or replace the current
treatment strategy. Although there is not a single drug that
could be claimed as generally effective, animal research has
yielded some promising drugs that attenuate predominant
withdrawal reactions such as anxiety and convulsions, have
minimal side effect profiles, and have no or minimal
dependence potential.
Some partial and/or selective BZR agonists appear to be
promising drugs as they have minimal dependence liability,
low incidence of side effects, and good efficacy in suppressing
BZ withdrawal reactions, presumably due to functional
antagonism. Moreover, treatment with partial BZR agonists
following withdrawal from BZ tranquilizers resembles dosetaper with a low risk that withdrawal reactions would occur
after their own cessation. Animal research suggests that
CCK-B antagonists could be beneficial for the therapy of BZ
withdrawal as they appear to treat both predominant
symptoms of BZ withdrawal, i.e., withdrawal-induced
anxiety and seizures. Carbamazepine has already
demonstrated benefit in reducing severity of BZ withdrawal
symptoms in several clinical studies. However, the large
variability in response across individuals and some
undesirable side effects [342] limit carbamazepines general
usefulness. Still, in those patients who respond well and
who tolerate its side effects, carbamazepine may provide a
useful tool for BZ discontinuation.
Drugs that alleviate some, but not all, withdrawal
symptoms, could be used as supplements to other therapies
for BZ withdrawal. Calcium channel blockers might be
beneficial for preventing seizures that are particularly likely
to occur following withdrawal from high dose BZ treatment.
Drugs that decrease noradrenergic activity, such as clonidine
or propranolol, can help to manage symptoms of autonomic
hyperactivity such as palpitations and tremor.
NMDA antagonists produce severe side effects that
restrict their utility in clinical practice. Nevertheless, it is
possible that other NMDA antagonists lacking those side
effects, maybe with a different site of action, will be
discovered in the future. Serotonergic drugs, with the
exceptions of some antidepressants, appear to be ineffective
even though attenuated serotonergic system function is
thought to underlie the neurobiology of BZ withdrawal
[42,49,54]. It is difficult to explain the general failure of
serotonergic agents in the treatment of anxiety and/or BZ
withdrawal. One possibility is that there are many receptor
subtypes for serotonin [214,121,343] and each subtype can
control different functions, depending on the region of action
in the mammalian brain. This makes it difficult to find a
35
compound that would be able to affect one specific function

by acting at one particular receptor subtype in the right
brain region. This difficulty is further attested to by the fact
that 30 years of research on the efficacy of serotonergic drugs
in the treatment of anxiety has yielded many new findings
but, except for buspirone, no clinically useable drug.
As a result of animal research on BZ dependence and
withdrawal, we understand a great deal more about this
important clinical phenomenon. This knowledge has been
used to investigate possible pharmacological treatments for
BZ withdrawal. Although there is not a single agent that
could be claimed as generally effective, several
pharmacological drug classes seem to be promising in
animal studies. However, whether these drugs finally make it
into general practice must be confirmed in controlled clinical
trials.
ABBREVIATIONS
BZ
Benzodiazepine
BZR
Benzodiazepine receptor
CCK
Cholecystokinin
EEG
Electroencephalogram
GABA
Gamma-aminobutyric acid
NMDA
N-methyl-D-aspartate
5-HT
5-hydroxytryptamine (serotonin)
ACKNOWLEDGEMENT
I am grateful to Dr. Keith J. B. Franklin from the
Department of Psychology, McGill University, Montreal,
Canada, for his kind review of earlier versions of this article.
I would also like to thank Dr. Radan Capek from the
Department of Pharmacology and Therapeutics, McGill
University for his helpful comments in the preparation of this
review.
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Current Pharmaceutical Design, 2002, 8, 23-43

The Experimental Pharmacotherapy of Benzodiazepine Withdrawal

*Address for correspondence to that author at the Psychopharmacological

prevent the development of BZ withdrawal reactions. The

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

development of tolerance and dependence [21,22]. Partial

MECHANISMS UNDERLYING BZ DEPENDENCE

Changes in the Central Neurotransmission

Pharmacotherapy of Benzodiazepine Withdrawal

direct relationship between nerve function and glucose

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

the introduction of BZs into clinical practice [10]. Animal

ANIMAL MODELS TO STUDY BZ DEPENDENCE

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

behavior. It should be mentioned here that the availability of

social interaction an anxiogenic response [111]. BZ

Pharmacotherapy of Benzodiazepine Withdrawal

of interoceptive cues caused by the drugs presence in the

ANIMAL STUDIES ON THE TREATMENT OF BZ

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

cocaine [144], and carbamazepine has been demonstrated to

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

This effect was reversed by a single administration of

anxiety effects and lower dependence liability in animals, for

Pharmacotherapy of Benzodiazepine Withdrawal

results in animal studies [50,187,189,200], and in one study

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

Partial Agonists at the 5-HT1A Receptor Subtype

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

finding is questionable. Clinicians would be unlikely to

on BZ and alcohol withdrawal in a study by Mehta and

Pharmacotherapy of Benzodiazepine Withdrawal

the unique property of enhancing (rather than inhibiting)

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

postsynaptic receptors, the 2 presynaptic autoreceptors, and

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

[272,275-281], but not all [113,282-284], animal studies.

are needed to confirm the positive results of animal studies,

Pharmacotherapy of Benzodiazepine Withdrawal

are merely secondary to the vast muscle relaxation and ataxia

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

withdrawal-induced locomotor and autonomic hyperactivity.

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

glutamate, 5-HT, and noradrenaline [319]. Since increased

Carbamazepine is an anticonvulsant, and thus can protect

Pharmacotherapy of Benzodiazepine Withdrawal

SUMMARY AND CONCLUSIONS

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

compound that would be able to affect one specific function

Nutt, D. J. Pharmacology and Therapeutics, 1990a, 47 ,

Sternbach, L. H. In E. Costa (Ed.), The Benzodiazepines:

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Lader, M. European Neuropsychopharmacology, 1994,

Owen, R., Tyrer, P. Drugs, 1983, 25 , 385-398.

Current Pharmaceutical Design, 2002, Vol. 8, No. 1

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