Benzodiazepines in anxiety disorders

Shader Ri, Greenblatt D). Use of benzodiazepines in anxiety disorders. N Engl) Med... 

The use of benzodiazepines in anxiety disorders represents a difficult issue because of the well-known addictive properties of this substance class furthermore, the depressogenic lability of benzodiazepines represents a major problem in the treatment of generalized anxiety disorders, in which concomitant depressive symptoms occur in up to 50% of patients [Gulley and Nemeroff 1993 Rickels and Schweizer 1993]. Therefore, a compound mimicking endogenous anxiolytic effects, and that might further possess potential antidepressive properties, is warranted. Neuroactive steroids could represent such a substance class. However, the following issues need to be addressed in this respect ... 

Benzodiazepines have a low risk for abuse in anxiety disorder patients without a history of alcohol or other substance abuse. Among the benzodiazepines there may be a spectrum of abuse liability, with drugs that serve as prodrugs for desmethyldiazepam (e.g., clorazepate), slow-onset agents (e.g., oxazepam), and partial agonists (e.g., abecarnil) having the least potential for abuse. However, there is no currently marketed benzodiazepine or related drug that is free of potential for abuse. 

Mueller TI, Goldenberg IM, Gordon AL, et al Benzodiazepine use in anxiety disordered patients with and without a history of alcoholism. J Clin Psychiatry 57 83-89, 1996... 

Posternak MA, Mueller TI Assessing the risks and benefits of benzodiazepines for anxiety disorders in patients with a history of substance abuse or dependence. Am J Addict 10 48-68, 2001... 

In this chapter, we discuss the pharmacology of medications that are classified as anxiolytic, sedative, or hypnotic—primarily the benzodiazepines, buspirone, zolpidem, eszopiclone, and zale-plon. Subsequently, we present diagnosis-specific treatment guidelines (outlined in Table 3-1). The commonly used anxiolytics and hypnotics, together with their usual doses, are shown in Table 3-2. Many antidepressant medications are also effective in the treatment of anxiety disorders. The pharmacology of antidepressants is discussed in Chapter 2 their clinical use in anxiety disorders is addressed in the diagnosis-specific sections later in this chapter. 

The detailed pharmacology of all the benzodiazepines used in anxiety disorders... 

Noyes, R. (1992, February). Discontinuing benzodiazepine use in anxiety disorder patients. Psychiatric Times, p. 39. 

GABAergic system in anxiety disorders has been firmly established by the proven efficacy of benzodiazepines in the treatment of anxiety disorders, and their therapeutic effects are related mainly to their capacity to target the tt2 and as subunits with consequent enhancement of the GABA-mediated inhibition of neuronal overexcitability that is thought to be present in many of the anxiety disorders. 

Benzodiazepines are amongst the most frequently prescribed drugs they have well-established uses in the treatment of anxiety disorders (anxiolytics) and insomnia, preanaesthetic sedation, suppression of seizures, and muscle relaxation. 

The definition of desired therapeutic and side effects in the case of the benzodiazepines very much depends on the clinical problem in question. The sedative and hypnotic actions are desired effects in the treatment of insomnia, but undesired effects in the treatment of anxiety disorders. Effects that are usually undesired include daytime drowsiness, potentiation of the sedative effects of ethanol, and anterograde amnesia. They are mediated via the benzodiazepine site of GABAa receptors, since they can be antagonized with flumazenil. 

Iwata N, Cowley DS, Radel M, et al Relationship between a GABA alpha g Pro385Ser substitution and benzodiazepine sensitivity. Am] Psychiatry 156 1447—1449,1999 Jacobson AF, Dominguez RA, Goldstein B, et al Comparison of buspirone and diazepam in generalized anxiety disorder. Pharmacotherapy 5 290—296, 1985 Jaffe JH, Ciraulo DA, Nies A, et al Abuse potential of halazepam and diazepam in patients recently treated for acute alcohol withdrawal. Clin Pharmacol Ther 34 623-630, 1983... 

Anxiety disorders are common in the population of opioid-addicted individuals however, treatment studies are lacking. It is uncertain whether the frequency of anxiety disorders contributes to high rates of illicit use of benzodiazepines, which is common in methadone maintenance programs (Ross and Darke 2000). Increased toxicity has been observed when benzodiazepines are co-administered with some opioids (Borron et al. 2002 Caplehorn and Drummer 2002). Although there is an interesting report of clonazepam maintenance treatment for methadone maintenance patients who abuse benzodiazepines, further studies are needed (Bleich et al. 2002). Unfortunately, buspirone, which has low abuse liability, was not effective in an anxiety treatment study in opioid-dependent subjects (McRae et al. 2004). Current clinical practice is to prescribe SSRIs or other antidepressants that have antianxiety actions for these patients. Carefully controlled benzodiazepine prescribing is advocated by some practitioners. 

Medical use of benzodiazepines has been declining. Prescribing trends show an overall decline in the number of all benzodiazepine prescriptions written, with a market shift to increased prescribing of short elimination half-life agents (lorazepam, alprazolam), compared with long-elimination half-life agents (diazepam, chlordiazepoxide) (Ciraulo et al. 2004). In 2001, alprazolam was the most widely prescribed benzodiazepine (Ciraulo et al. 2004), and it also was the most widely prescribed psychiatric medication in that year for mood and anxiety disorders (Stahl 2002). 

Lejoyeux et al. 1998). Similar to opioid-dependent persons, these patients reported that they use benzodiazepines to self-medicate anxiety, insomnia, and alcohol withdrawal and, less commonly, to enhance the effects of ethanol. Approximately l6%-25% of patients presenting for treatment of anxiety disorders abuse alcohol (Kushner et al. 1990 Otto et al. 1992). Controversy exists concerning appropriate benzodiazepine prescribing in this population (Cir-aulo and Nace 2000 Posternak and Mueller 2001). 

Pharmacodynamic tolerance to the psychomotor effects of benzodiazepines has been demonstrated after single or multiple doses (File 1985 Greenblatt and Shader 1978 Rosenberg and Chiu 1985). Pharmacodynamic tolerance to the anxiolytic effect (over a 6-month period) has not been demonstrated (Rickels et al. 1983), and clinical experience supports the view that many patients with anxiety disorders require long-term therapy with benzodiazepines or alternative antianxiety agents. An important clinical consequence of tolerance to sedative effects is observed in benzodiazepine overdoses, when patients may initially be... 

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