Benzodiazepines in anxiety

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 ... 

Lader MH. Limitations on the use of benzodiazepines in anxiety and insomnia are they justified Eur Neuropsychopharmacoi 1999 9(suppl 6) S399-S405. 

The benzodiazepine, lorazepam, acts allosterically on GABAa receptors to facilitate the actions of GABA. Lorazepam has some antiemetic activity in cancer chemotherapy. When used in combination therapy, it does not appear to add to antiemetic control but may contribute to a reduction in anxiety. 

Despite the risks of benzodiazepine dependence and overdose among alcoholic patients beyond the period of acute withdrawal, there may be a role for the judicious use of benzodiazepines in treating these patients. To the degree that early relapse, which commonly disrupts alcoholism treatment, is a result of continued withdrawal-related symptoms (e.g., anxiety, depression, insomnia) that can be suppressed by low doses of benzodiazepines, retention in treatment could be enhanced by the use of benzodiazepines (Kissin 1977). Moreover, for some patients, benzodiazepine dependence, if it does occur, may be more benign than alcoholism. 

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. 

Fyer AJ, Liebowitz MR, Gorman JM, et al Effects of clonidine on alprazolam discontinuation in panic patients a pilot study. J Clin Psychopharmacol 8 270—274,1988 Garvey MJ, Tollefson GD Prevalence of misuse of prescribed benzodiazepines in patients with primary anxiety disorder or major depression. Am J Psychiatry 143 1601-1603, 1986... 

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... 

Finally, the peptide can induce anxiety and panic in normal and anxious volunteers. Some synthetic CCK-B receptor antagonists are chemically similar to the benzodiazepine anxiolytics. Again, the clinical role of CCK manipulation in anxiety remains to be resolved. 

The undisputed efficacy of benzodiazepines in relief of anxiety led to the question of whether this disorder could arise from abnormal concentrations in the brain of an endogenous ligand or a malfunction of the benzodiazepine/GABA receptor system. An important study, aimed at distinguishing between these possibilities, has been carried out in humans (Nutt et al. 1990) and was based on the premise that anxiety could be caused by either ... 

If excessive noradrenergic transmission is a causal factor in anxiety, then it would be predicted that a lesion of central noradrenergic neurons would have an anti-anxiety effect in behavioural models of this condition. Unfortunately, the behavioural effects of such lesions are notoriously inconsistent and there are many reports of negative findings (e.g. Salmon, Tsaltas and Gray 1989). One study has even shown that a lesion of central noradrenergic neurons, induced by the selective neurotoxin, DSP-4, abolishes the anti-anxiety effects of tricyclic antidepressants and MAO inhibitors, but not those of the benzodiazepine, alprazolam, or the barbiturate, phenobarbitone (Fontana,... 

Antihistamines. Some clinicians have prescribed the antihistamine, hydroxyzine (Vistaril, Atarax) to treat anxiety. A typical regimen is 25 mg administered one to three times per day as needed for anxiety. The use of hydroxyzine to treat anxiety is largely driven by concern regarding the addictive potential of benzodiazepines. In reality, hydroxyzine does little to relieve anxiety other than produce drowsiness. Because other nonaddictive anxiolytics are available, we do not recommend routine use of this largely ineffective treatment. 

Benzodiazepines. These agents, particularly alprazolam and clonazepam, have been widely used in the treatment of PTSD, despite little evidence to demonstrate their effectiveness. The few studies exploring the effectiveness of benzodiazepines for PTSD suggest that they provide modest relief for anxiety in general but offer no benefit for the core symptoms of PTSD, namely, intrusive recollections and emotional numbing. Furthermore, a small controlled study investigating prophylactic treatment with a benzodiazepine in the immediate aftermath of trauma exposure failed to protect patients from the subsequent development of PTSD symptoms. Consequently, we do not recommend benzodiazepines for the routine management of PTSD. 

The development of tolerance is a major drawback to the use of benzodiazepines in the long-term treatment of insomnia. Whereas tolerance to the hypnotic effects of benzodiazepines permits them to be used without excessive sedation when treating anxiety disorders, this is counterproductive when attempting to treat insomnia. Patients often find themselves requiring higher doses to obtain the same sedative-hypnotic effect initially accomplished by lower doses. For this reason, careful consideration must be given before benzodiazepines are used to treat chronic insomnia. 

Benzodiazepines have similar pharmacological properties and are used in anxiety and insomnia. The choice of which benzodiazepine to use usually lies with the pharmacodynamic and pharmacokinetic properties, which vary across the class. For example, diazepam, flurazepam and nitrazepam have a prolonged duration of action whereas lorazepam and temazepam have a shorter duration of action. 

---