Risk Versus Benefit of Benzodiazepines

Perhaps the most vexing questions about benzodiazepines arise around the issues of safety and efficacy in long-term use. Many authorities have suggested that SSRIs and related medications be substituted for benzodiazepines in the long-term treatment of anxiety disorders.^18,19 However, treatment guidelines, promulgated in 1998 and after, favoring SSRIs over benzodiazepines for the treatment of generalized anxiety disorder and social phobia had only a modest impact when measured in clinical practice 4 to 5 years later.²⁰

Many practitioners draw on their own clinical experience to conclude that long-term therapy with benzodiazepines is relatively safe, even when compared with SSRIs.²¹

Long-term use must be understood in the context that, increasingly, many mental conditions are seen as recurrent or chronic disorders. Anxiety spectrum disorders certainly fit that model. In 1999, an international group of experts addressed this issue and recommended even the long-term use of benzodiazepines for anxiety disorders.²² A study of persistent users of alprazolam(Drug information on alprazolam) or lorazepam(Drug information on lorazepam) (Ativan, Lorazepam Intensol), who consulted the Addiction Research Foundation in Toronto, showed that most were not "abusing" the drugs nor were they "addicted" to them, as the terms are usually understood. A substantial proportion of patients were receiving appropriate maintenance therapy for a chronic psychiatric condition such as generalized anxiety or obsessive-compulsive personality disorder. Most patients used a constant or decreasing dosage of medication.²³

The same conclusion came from a recent analysis of longitudinal data in 2440 long-term (at least 2 years) users of benzodiazepines.²⁴ Most of these patients had serious physical and mental illnesses and long-term therapeutic use rarely resulted in escalation to a high dosage. "Pharmacy hopping" may identify the small number of patients who escalate to a high dosage.

As Shader and Greenblatt²⁵ pointed out, intermediate-term (2 to 6 months) efficacy for benzodiazepines has been shown repeatedly, and additional evidence of longer, continuing efficacy comes from controlled trials of drug discontinuation. In these studies, placebo was substituted in a double-blind fashion for a benzodiazepine in patients who received long-term treatment, frequently resulting in the return of symptoms. Follow-up studies of patients who discontinued benzodiazepine therapy again showed symptom return in a high proportion (but not all), even with gradual discontinuation. They concluded that periodic, careful discontinuation of benzodiazepines should identify the subgroup of patients who truly need ongoing long-term therapy and may be a reasonable compromise. However, there are continuing worries about long-term adverse effects of benzodiazepines that must be considered.

Cognitive impairment from long-term use of benzodiazepines is an issue that is drawing increasing attention. Memory (especially anterograde amnesia), visuospatial ability, speed of processing, and verbal learning could all be adversely affected by long-term benzodiazepine use. However, patients are usually unaware of or underestimate these difficulties. One complication is that anxiety disorders themselves are associated with cognitive deficits, particularly with regard to attention and concentration.

CT scans show no difference in the brains of patients taking benzodiazepines for the long term compared with controls.²⁶ Studies of long-term benzodiazepine effects using functional brain scans (positron emission tomography and functional MRI) would be more interesting, but are not yet available. In fact, only recently have these newer techniques been applied to the more basic question of where in the brain (amygdala, insula, fusiform gyrus) benzodiazepines are working to acutely lower anxiety.²⁷

A recent review of the literature concluded that after withdrawal from long-term benzodiazepine treatment, patients recovered in many cognitive domains but were still impaired when compared with controls. The clinical impact of these cognitive changes, however, may be insignificant in most patients in terms of daily functioning.²⁸

Benzodiazepines are likely to be prescribed for some subgroups, particularly patients with depressive disorders. In a study of patients with depression who were treated between October 1 and December 31, 2000, in 127 Veterans Affairs outpatient mental health settings, 36% filled a benzodiazepine prescription (89% also filled an antidepressant prescription). In the same study, patients older than 65 years with depression showed even higher use, with 41% filling a benzodiazepine prescription, most often for a 90-day supply (or more).

It must be remembered, however, that benzodiazepines are not effective alone in the treatment of depression and may be associated with the induction of dysphoria in vulnerable patients. That said, it is also true that some patients with depression benefit from benzodiazepines—particularly when the depression is accompanied by anxiety or insomnia.