Risk Versus Benefit of Benzodiazepines

Risk Versus Benefit of Benzodiazepines

Before benzodiazepines, alcohol and opiates were used for centuries to numb anxiety. Early in the 20th century, barbiturates promised relief for the anxious but had the risk of addiction and death from overdose. Meprobamate (Miltown, MB-Tab) was introduced in 1955 and became an overnight sensation—the first psychotropic "wonder drug" in medical history.2 However, that success was nothing compared with the debut of benzodiazepines, beginning with chlordiazepoxide (Librium, Limbitrol) in 1960, diazepam (Valium, Diazepam Intensol) in 1963, and eventually more than 10 other variations available by prescription. These drugs are more potent but less sedating than meprobamate and are vastly safer in overdose.

For many years, benzodiazepines were among the most frequently prescribed medications in the United States. However, prescribing trends changed when after more than 20 years of use the medical community focused on the possibility of dependency and addiction. In 1989, New York State ruled that benzodiazepines should be dispensed as controlled substances, with regulations requiring triplicate prescription forms.

That view was not shared by the American Psychiatric Association (APA) Task Force on Benzodiazepines, which reported the next year that these drugs were effective medications with mild adverse effects and low potential for abuse when prescribed properly.3,4 Much of the research on benzodiazepines in the 1990s was aimed at defining the specific effects of long-term use and examining the g-aminobutyric acid (GABA)-benzodiazepine receptor complex for ways to isolate anxiolytic effects. Recent research has examined alternatives to benzodiazepines and is addressing the issue of possible cognitive impairment in patients who use the drugs for long periods.

Mechanism of action

Benzodiazepines bind stereospecifically to unique portions of GABA receptors that are large protein complexes located on certain neurons in the CNS. This is important because GABA is the main inhibitory neurotransmitter in the brain. Benzodiazepines potentiate GABA-mediated transmission and are indirect GABA agonists.5 There are 3 types of GABA receptors: GABA-A, GABA-B, and GABA-C. Only GABA-A seems to be modulated by benzodiazepines (as well as barbiturates and steroids).5 Furthermore, a particular subunit, a2 GABA-A, seems to be responsible for the anxiolytic effects of benzodiazepines. Because the sedative and amnesic properties of benzodiazepines are mediated by other receptor subunits, it is theoretically possible to find a molecule that will more specifically target anxiety.6


Benzodiazepines are prescribed for severe muscle spasms, tremors, acute seizures, insomnia, and alcohol and drug withdrawal symptoms, but their main use is still for the treatment of anxiety disorders.7 The APA guideline for the treatment of panic disorder advocates the use of SSRIs, reserving benzodiazepines for the management of acute anxiety rather than for long-term treatment.8

While a moderate increase in SSRI use for panic disorder took place during the 1990s, more than two thirds of this increase occurred as part of concomitant treatment with a benzodiazepine.9 This may be because other medications—even SSRIs—are difficult to tolerate and do not work as quickly as benzodiazepines, and patients may discontinue the other medications unless benzodiazepines are being administered as well.10 Overall, benzodiazepines are still more widely prescribed than antidepressants for the treatment of anxiety disorders; alprazolam (Alprazolam Intensol, Xanax) is the single most prescribed agent for mood and anxiety disorders.11

Adverse effects

Benzodiazepines are associated with adverse effects such as daytime sedation, attention problems, ataxia, memory impairment, and slowed psychomotor performance.12 Some of the benzodiazepines with longer half-lives (eg, diazepam, flurazepam [Damane]) are on the Beers list of medications that are characterized as inappropriate for use in elderly persons.13 In particular, those benzodiazepines are associated with a somewhat increased risk of motor vehicle crash in elderly drivers.14 Another known problem is increased risk of hip fracture15 (although a recent study16 did not show any change in age-adjusted risk for hip fracture after New York State drastically reduced its use of benzodiazepines in 1989). Concomitant use of benzodiazepines and alcohol greatly increases the risk of adverse events and is a well-known cause of death, either by accident or intention.

However, adverse effects such as sedation and impaired attention are likely to develop over time, while the anxiolytic properties persist with long-term use.17


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