Current Pharmaceutical Design, Volume 8, No. 1, 2002
Benzodiazepine Side Effects: From the Bench to the Clinic
Introduction to
the Special Issue on:Benzodiazepine Side-Effects: From the Bench to the Clinic Pp-1-3
S. H. Stewart and
H. A. Westra
Basic
Pharmacologic Mechanisms Involved in Benzodiazepine Tolerance and Withdrawal Pp-5-21
A.N. Bateson
The Experimental
Pharmacotherapy of Benzodiazepine Withdrawal Pp-23-43
J. Podhorna
Cognitive and
Sedative Effects of Benzodiazepine Use Pp-45-58
S. E. Buffett-Jerrott
and S. H. Stewart
As-needed Use of
Benzodiazepines in Managing Clinical Anxiety: Incidence and Implications Pp-59-74
H. A. Westra and
S. H. Stewart
Benzodiazepine
Discontinuation Difficulties in Panic Disorder: Conceptual Model and Outcome
for Cognitive- Behavior Therapy Pp-75-80
M. W. Otto, J. J.
Hong and S. A. Safren
[Back to
top] Introduction to
the Special Issue on:Benzodiazepine Side-Effects: From the Bench to the Clinic
S. H. Stewart and
H. A. Westra
This
article introduces a special isssue of Current Pharmaceutial Design focusing on
the various side effects of benzodiazepine medications. We argue that an
increased awareness of the risk of dependence, withdrawal symptoms upon
discontinuation, and cognitive side effects of the benzodiazepines has likely
contributed to the decline in their prescription rate over the last two
decades, as has increased availability of alternative pharmacologic and
non-pharmacologic treatments for anxiety and insomnia. The present special
issue consists of series of five papers covering current issues in the area of
benzodiazepine side effects. These reviews cover a wide range of topics
pertaining to adverse, unintended consequences of this class of pharmacologic
agents including their potential for tolerance and withdrawal, their profile of
associated cognitive impairments, as well as current understanding of means for
minimizing these unintended effects. The reviews also cover a variety of
methodologies and disciplines from laboratory-based research findings with
animals, to laboratory-based studies wth healthy human volunteers, to findings
obtained in the clinic with anxious patients. All reviews are timely
contributions, covering highly relevant topics for consideration of
benzodiazepine side effects at present. The papers presented herein should
serve to stimulate future research that may ultimately help improve the quality
of life of those patients living with debilitating anxiety-related conditions.
[Back to
top] Basic
Pharmacologic Mechanisms Involved in Benzodiazepine Tolerance and Withdrawal
A.N. Bateson
Benzodiazepines
are widely prescribed for the treatment of anxiety and sleep disorders.
Although safe, tolerance develops rapidly to their sedative activity and more
slowly to their anticonvulsant activity. In animals anxiolytic tolerance has also
been measured. Abrupt cessation of benzodiazepine treatment leads to symptoms
of withdrawal. The mechanisms responsible for these phenomena are not known.
Benzodiazepines act via GABAA
receptors, but do not appear to produce tolerance and dependence by simple
downregulation of receptor number. GABAA
receptors are hetero-oligomers comprised of multiple subunits encoded by a
multigene family. The molecular effects of long-term benzodiazepine exposure
are reviewed and a model is presented that draws on results from a number of
research groups working in this area.
[Back to
top] The Experimental
Pharmacotherapy of Benzodiazepine Withdrawal
J. Podhorna
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
risk-benefit profiles of putative therapies for BZ withdrawal, including drugs
acting via benzodiazepine receptors, serotonergic and noradrenergic agents,
cholecystokinin-B receptor antagonists, calcium channel blockers,
N-methyl-D-aspartate (NMDA) antagonists, and other miscellaneous agents.
[Back to top] Cognitive and
Sedative Effects of Benzodiazepine Use
S. E.
Buffett-Jerrott and S. H. Stewart
This paper reviews the effects of benzodiazepines (BZs) on the performance of tasks measuring human cognitive abilities. The paper reviews the most common cognitive side effects of BZs: increased sedation, decreased attention, and anterograde amnesia. In particular, this paper focuses on recent findings regarding time course-related effects on BZ-induced deficits in explicit and implicit human memory performance. Specifically, we reviewed recent research indicating that both explicit memory and “priming” are impaired by BZs if the encoding task takes place near the time of the theoretical peak plasma concentrations of the drug. Although BZs also appear to increase objective and subjective sedation, as well as to impair attentional processing, these other cognitive impairments do not appear to fully account for the widespread memory deficits caused by BZ administration. The theoretical and clinical implications of benzodiazepine-induced memory impairments are discussed.
p class=MsoBodyText>[Back
to top] As-needed Use of
Benzodiazepines in Managing Clinical Anxiety: Incidence and Implications
H. A. Westra and
S. H. Stewart
Benzodiazepines
(BZs) have been widely investigated in terms of clinical efficacy, factors
underlying dependence, associated cognitive impairments, and interactions with
psychotherapy for anxiety control. However, few studies have systema- tically
considered manner of BZ administration in relation to these variables. Studies
of chronic BZ users indicate that as-needed or p.r.n. use is a very common
practice, increases with chronicity of BZ use, and is preferred compared to
regularly scheduled BZ administration. Moreover, a recent study of physician
prescription practices indicated that p.r.n. BZ use is a commonly recommended
BZ use regimen for anxiety disorder management. Physician advocates of p.r.n.
BZ prescriptions for anxiety disorders cite enhanced patient control over
symptoms, facilitation of exposure to fear-provoking situations, and reduced
frequency of use as rationales supporting this practice. Available data
however, do not consistently support these hypothesized advantages of p.r.n. BZ
use. And in general, findings from different investigations relevant to this
question suggest that p.r.n. BZ administration may be associated with increased
patient preference for BZs over placebo, continued use, and greater impairment
on cognitive factors associated with positive long-term anxiety management.
Ironically, p.r.n. BZ administration may also be associated with reduced
anxiolytic efficacy over time. These suggestive findings argue for greater
systematic investigation of manner of BZ administration as an important medication
use parameter. Such investigations may also yield practical guidelines for
navigating BZ discontinuation and promoting more successful long-term
management of anxiety.
[Back
to top] Benzodiazepine Discontinuation Difficulties in Panic
Disorder: Conceptual Model and Outcome for Cognitive-Behavior Therapy
M. W. Otto, J. J.
Hong and S. A. Safren
There is consistent support for
the efficacy of cognitive-behavior therapy (CBT) to aid the successful
discontinuation of benzodiazepine (BZ) medication in patients with panic
disorder, and help these individuals maintain treatment gains while
off medication. In this article, we provide a conceptual model for BZ
discontinuation difficulties in patients with panic disorder. Outcome studies
are reviewed, and are placed in the context of other evidence for the efficacy
of CBT in patients with this disorder.