Benzodiazepines (and the alternatives)

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Benzodiazepines (and the alternatives)

With the introduction of chlordiazepoxide (Librium) and diazepam (Valium) in the early 1960s, a new era in the treatment of insomnia and anxiety began. The benzodiazepines were more effective and far safer than the older drugs — barbiturates, meprobamate, and glutethimide — that had been prescribed for these purposes. For many years, they were the most popular prescription tranquilizers and sedatives. Since the mid-1980s, new alternatives have been assuming some of these roles, but benzodiazepines are not about to leave the stage.

As of late 2005, more than a dozen benzodiazepines are available by prescription. (See the table below for some of those most widely used). They have a common basic chemical structure, and they all increase activity at receptors for the neurotransmitter gamma-aminobutyric acid (GABA). This transmitter inhibits the activity of neurons, slowing down the brain and nervous system, so benzodiazepines are relaxing and calming and promote sleep when taken at bedtime. They differ mainly in how quickly they are absorbed, how long their effects last, and how long they take to leave the body.

Benzodiazepines are prescribed for severe muscle spasms, tremors, acute seizures, and alcohol and drug withdrawal symptoms. But their main uses are still in the treatment of anxiety and insomnia.

They are uniquely effective when taken by mouth or intravenously for the rapid relief of acute anxiety and agitation arising from any cause, including panic attacks, psychotic disorders, mania, and dementia. They can also be used to calm a person facing surgery or terrified by the prospect of an airplane ride. In patients with panic disorder, they reduce anticipatory anxiety and the resulting tendency to avoid places and situations that might provoke a panic attack. Benzodiazepines are also — perhaps most important — prescribed for generalized anxiety, the excessive and unrealistic worry that often accompanies other anxiety disorders as well as depression and other conditions.

Fast-onset, short-acting benzodiazepines are used for the treatment of insomnia with any cause, including depression. Because of tolerance and physical dependence, this use is FDA-approved for five weeks at most (although in practice, they are often used for much longer).

Several benzodiazepines are now available in extended-release form — a coated pill from which some of the drug is released immediately and the rest gradually. This smoothes out the drug’s action and helps to maintain sleep or the control of anxiety.

Side effects

Benzodiazepines are remarkably safe, especially compared to most other sedatives and tranquilizers. They can be used by people with most medical illnesses and in combination with most other medications. An overdose of benzodiazepines is almost never lethal. They depress breathing very little, creating a problem only for some patients with pulmonary disease. They have little effect on normal sleep patterns, although they may reduce deep sleep a little. Because they may carry some risk of birth defects, physicians are cautious about prescribing them for pregnant women.

The most common side effect is daytime grogginess or drowsiness, mainly with longer-acting drugs. Short-acting drugs may cause rebound insomnia the night after they are used. At higher doses, benzodiazepines may affect physical coordination and balance, raising the risk of falls and other accidents. Some benzodiazepines can impair memory or the ability to learn and retain new information. Older people are more sensitive to all these side effects.

The danger of accidents and falls may have been exaggerated. In a recent study, nursing home residents who took benzodiazepines for insomnia had a greater risk of falling than those without insomnia — but were less likely to fall than insomniac patients taking no drugs, who may have been waking up in the night and walking around in the dark.

Alcohol intensifies almost all benzodiazepine side effects, so physi­cians usually recommend that patients taking benzodiazepines avoid drinking or at least minimize their alcohol consumption.

Some benzodiazepines are metabolized by the same liver enzyme systems that break down the antibiotic erythromycin, protease inhibitors used to treat HIV infection, and calcium-channel blockers used to treat high blood pressure. When the benzodiazepine is used along with one of these drugs, its effect may last longer than usual.

Dependence and addiction

In part because GABA neurons adapt to the presence of the drug and are underactive when it is withdrawn, benzodiazepines can cause physical dependence and a withdrawal reaction. With longer-acting drugs, the withdrawal reaction usually develops after a month or two; with shorter-acting drugs, it may take as little as a week of daily use. Shorter-acting drugs produce a briefer and more intense reaction that begins within 24 hours after withdrawal. With benzodiazepines that leave the body more slowly, the symptoms begin several days after withdrawal and peak in about a week.

The most common withdrawal symptoms are restlessness, irritability, insomnia, muscle tension, weakness, aches and pains, blurred vision, and a racing heart, in that order. Sometimes these symptoms are difficult to distinguish from returning insomnia or anxiety. Rarely, after use of high doses for a long time or abrupt withdrawal of a short-acting benzodiazepine, a patient may suffer seizures or hallucinations.

To ease withdrawal, the dose is reduced gradually. If the patient has been using benzodiazepines for a long time, the process may take months. Sometimes a longer-acting drug is substituted for a shorter-acting one before withdrawal. Anti­convul­sants or beta blockers (which reduce physical symptoms of anxiety) may also be helpful.

Physical dependence on benzodiazepines is almost universal after a couple of months of daily use, but true addiction is rare. Users rarely develop a lingering craving that leads to misuse and abuse. Some take a benzodiazepine without medical supervision, but few lose control or use the drugs for pleasure, and those who do usually have other drug problems. Most addicts take benzodiazepines only to counteract the undesirable or intensify the desirable effects of their favorite drug. In the treatment of alcohol, cocaine, and heroin addiction, supervised withdrawal (detoxification) is only a beginning. In the treatment of benzodiazepine dependence, it is usually the end.

Alternatives: Benzodiazepine receptor agonists (BRAs)

Benzodiazepines are no longer the favored drug treatment for insomnia, either short term or long term. In the mid-1990s, triazolam (Halcion) was the most commonly prescribed sleeping pill, but today it is used less and less. It and other benzodiazepines are giving way to a new class of drugs, called non-benzodiazepine hypnotics or benzodiazepine receptor agonists (BRAs). These drugs act at only one of several benzodiazepine-GABA receptors. Because they are more selective, they are thought to have little effect on anxiety and fewer side effects — less risk of daytime drowsiness, rebound insomnia, loss of coordination, tolerance, dependence, and abuse.

Zolpidem (Ambien) is the first or second most widely prescribed sleeping pill as of 2005 and has become available in extended-release form.

Zaleplon (Sonata) is less popular, mainly because its effect lasts for only an hour or two, and users may wake up at 3 a.m. It can be helpful for people who have difficulty falling asleep but no trouble staying asleep.

Eszopiclone (Lunesta) became available only in 2004. It is the first prescription sleeping pill approved for long-term use; in controlled studies, it has been found effective for up to six months. Still, some experts doubt whether it differs greatly from other BRAs — or from the standard benzodiazepines.

Indiplon is a new drug, awaiting FDA approval in late 2005, that is said to have less daytime carryover effect than other sleeping pills. It is also being developed in an extended-release form.

Whether the enthusiastically marketed new benzodiazepine receptor agonists will justify the claims made for them is still uncertain. They have rarely been compared directly with benzodiazepines in controlled studies. Disappointment often follows when large numbers of patients use drugs that have been declared particularly safe and effective on the basis of clinical trials.

Alternatives: Antidepressants

While the new BRAs begin to replace benzodiazepines in the treatment of acute insomnia, antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft), have been replacing them in the long-term treatment of panic disorder and generalized anxiety. Antidepressants have the advantage of relieving depression as well as anxiety, and they are believed to create less risk of dependence and abuse (although they can cause symptoms when they are discontinued). Unlike benzodiazepines, they are not controlled substances, restricted by federal law. But because antidepressants take weeks to work, benzodiazepines are often prescribed to tide patients over. The dose of the benzodiazepine is gradually reduced as the antidepressant takes effect.

At least that is the theory. But surveys show that benzodiazepines are still being used widely to treat chronic anxiety. Patients often prefer them to antidepressants because they act immediately and do not cause weight gain or sexual problems. Physicians may go along partly to ensure that the patient remains in treatment.

The patients may be right, especially if they are suffering from both anxiety and depression. A pooled analysis of nine studies found that patients taking both a benzodiazepine and an antidepressant for anxiety were more likely to recover and less likely to drop out of treatment than those taking an antidepressant alone.

In treating anxiety disorders, physicians prescribe benzodiazepines more often and antidepressants less often than experts recommend. In treating insomnia, it is the other way around. Benzodiazepines and the new BRAs (with the exception of eszopiclone) have not been approved for chronic insomnia, so physicians have turned to antidepressants. Trazodone (Desyrel), an antidepressant with some sedative effects, is (or was until recently) the first choice of most psychiatrists for long-term treatment of insomnia, although experts point out that there is little evidence for its effectiveness, or for the effectiveness of other antidepressants widely used as sedatives, amitriptyline (Elavil) and mirtazapine (Remeron). Use of these drugs may decline now that eszopiclone is available.

Alternatives: Other drugs

Buspirone (BuSpar), used in the treatment of chronic anxiety, enhances the effect of the neurotransmitter serotonin. It is less effective than benzodiazepines and takes longer to work (several weeks), but it is less likely to cause physical dependence. Some believe it may be more effective at doses higher than those usually prescribed.

Ramelteon, a recently introduced treatment for insomnia, acts at receptors for melatonin, a hormone that helps to regulate the body’s circadian (24-hour) cycles. It is approved for long-term use.

Antihistamines are over-the-counter drugs sometimes used as sedatives. Diphenhydramine (Benadryl) is the most widely available. They are safe but not highly effective, and tolerance develops quickly. Side effects include daytime drowsiness and blurred vision.

Kava is an extract of a pepper plant marketed for insomnia as a dietary supplement. Recent controlled studies have found it to be no more effective than a placebo. It can cause liver failure and has been banned in several European countries.

Valerian is another plant extract marketed for insomnia. This drug has also been found no more effective than a placebo in recent studies.

Alternatives: Treatment without drugs

Exercise, muscle relaxation training, yoga, breath training, and hypnosis can be used to relieve both insomnia and anxiety. Psychotherapy of various kinds is helpful for the long-term treatment of both. The most carefully studied and often best alternative to benzodiazepines and related drugs is cognitive behavioral therapy.

For insomnia, the cognitive behavioral approach involves recording and changing both sleep habits and ways of thinking about sleep. Patients learn to go to bed only when sleepy, to exercise regularly but not near bedtime, to avoid eating, reading, or watching television in bed, and to rise at the same time no matter how little they have slept. They learn how to use relaxation techniques and breathing exercises, visualize soothing scenes, or repeat neutral sounds to fall asleep. They also learn to recognize and change unrealistic ideas, such as the belief that they will never be able to sleep well without drugs.

In cognitive behavioral treatment of anxiety, patients record, examine, and analyze their thoughts and feelings, with special attention to those that provoke or relieve anxiety. While the therapist helps them to become aware of unrealistic thinking, they also learn new ways to respond to anxiety-provoking situations, and practice the techniques of exposure and systematic desensitization.

In most studies, cognitive behavioral therapy is found to be as effective as benzodiazepines and other medications, and its impact often lasts longer. A combination of drugs and cognitive behavioral therapy may be more effective than either alone. But in some studies of insomnia, cognitive behavioral therapy alone has been found superior to the combination, possibly because patients are less committed to the behavioral and cognitive techniques if they know they can fall back on a drug.

Cognitive behavioral therapy has few risks. Its main disadvantage is that it requires training and experience that many clinicians lack.

The future

Despite the many ostensibly preferred alternatives, benzodiazepines almost certainly do have a future. Time will tell whether antidepressants replace them in the treatment of chronic anxiety and non-benzodiazepine hypnotics in the treatment of insomnia. They are still the most effective treatment for acute anxiety and one of the best ways to treat muscle spasms or interrupt a seizure. In 2004, they accounted for 75 million prescriptions in the United States. Nearly 50 years after their introduction, the benzodiazepine era has not ended.

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Last updated:	August 21, 2006