Current Pharmaceutical Design - Volume 8, Issue 1, 2002

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.

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.

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.

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.

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.

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.