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

Use

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

Long-term use

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 or 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

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

Use in depression

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.

Dependence and abuse

Benzodiazepines taken regularly at therapeutic levels can produce physical dependence and withdrawal symptoms when abruptly discontinued. Symptoms such as rebound anxiety, agitation, insomnia, sensory disturbances, and even seizures may result if the medication is not gradually tapered.

In 1990, the APA Task Force on Benzodiazepines concluded that benzodiazepines are not drugs of abuse, although benzodiazepine abuse is common among people who are actively abusing alcohol, opiates, cocaine, or sedative hypnotics.²⁹ Particularly, there is little empirical evidence to guide the rational use of benzodiazepines in the common clinical situation of comorbid anxiety and alcohol use disorders.³⁰ There are advocates on both sides of this issue; extremely careful monitoring is a possible compromise in patients who are abstinent from alcohol.

As Salzman³¹ pointed out, "dependence" is not necessarily "addiction." Developing dependence is a predictable phenomenon, influenced by dosage, duration of treatment, and other patient factors. Most often, dependence is a normal consequence of long-term pharmacological receptor-site activity. Addiction implies not only dependence, but also nonmedical use, pleasure-seeking use, and often polysubstance abuse. Most benzodiazepine use is not addictive, but appropriate use can sometimes result in dependence.

Withdrawal

Whatever the reason for starting benzodiazepines, long-term use takes over many of the functions of the body's GABA neurotransmitter system, leaving a state of GABA underactivity when benzodiazepines are stopped, resulting in hyperexcitability of the nervous system.³² The key point is that it takes time to establish dependency. For example, in a 1983 study of 180 chronically anxious patients taking 15 to 40 mg/d of diazepam, only 3% experienced any symptoms of withdrawal when abruptly switched to placebo after 6 weeks of treatment. Even patients taking diazepam for 14 to 22 weeks had withdrawal symptoms at a rate of only 18%. However, 43% of patients taking diazepam for 8 months or more experienced withdrawal.³³ Clearly, patients who have taken a benzodiazepine regularly for many months or years will need very gradual tapering of the drug.

The dosage of a medication also affects withdrawal, but it does so in combination with the duration of treatment and half-life of the benzodiazepine involved. Withdrawal symptoms tend to be more severe and have a quicker onset in patients taking higher doses of benzodiazepines with shorter half-lives. For example, 2 to 10 mg/d of alprazolam for 8 weeks produced withdrawal symptoms in 35% of patients.³⁴ Shorter-acting drugs produce a briefer and more intense reaction that begins within 24 hours of discontinuation. Longer-acting benzodiazepines, in contrast, show a slower development of withdrawal symptoms, beginning several days after discontinuation, with peak effects in about 7 days.

The most common withdrawal symptoms are restlessness, irritability, insomnia, muscle tension, weakness, aches and pains, blurred vision, and a racing heart (in that order). Rarely, after long-term use of high doses or abrupt withdrawal of a short-acting benzodiazepine, a patient may have seizures or experience hallucinations.

Traditional advice for discontinuing benzodiazepines is to reduce the dosage by no more than a quarter of the usual daily dose per week, resulting in a minimum taper time from full dosage to discontinuation of 4 weeks.³⁵ Others recommend even slower tapers, with progressive withdrawal over 10 weeks.³⁶

Conclusion

Benzodiazepines still have a major role in the treatment of acute anxiety symptoms and other psychiatric and medical conditions that are accompanied by anxiety. Benzodiazepines continue to be widely used because, despite their risks and adverse effects, they work quickly, are quite safe when used properly, and have good patient tolerance. Clearly, benzodiazepine abusability and negative effects on wakefulness, attention, memory, and cognition are problems. The possibility of mild cognitive decline with long-term exposure needs further investigation.

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