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23
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
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sodium channel-mediated
carbamazepine [327].
neurotransmitter
release
by
35
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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