Benzodiazepines: Complications

BENZODIAZEPINES: COMPLICATIONS

As medicines, Benzodiazepines have been widely used—as tranquilizers, to allay anxiety. Until the 1990s, they were believed to be both effective and extremely safe; however, beginning in the early 1980s, problems with these drugs started to become evident. Currently, the medical profession in many countries is trying to inculcate a cautious attitude toward their prescription and use. Lay people and the media have also become increasingly critical of the widespread use of these medicines for apparently trivial indications. To understand these problems, some aspects of the different types and effects of these medicines will be outlined.

WHAT ARE BENZODIAZEPINES?

These medicines are used to lessen a patient's anxiety; they include such drugs as Chlordiazepoxide (Librium), diazepam (Valium), lorazepam (Ativan) and oxazepam (Serenid; Serox). The term benzodiazepine describes a basic chemical structure. Some, like diazepam, are long acting and can be taken once daily; others, like lorazepam and alprazolam (Xanax), need to be taken more often. Most sleeping tablets (hypnotics) are benzodiazepines, and these include short-acting drugs such as triazolam (Halcion), medium-acting drugs such as temazepam (Restoril), and long-acting drugs such as flurazepam (Dalmane) and nitrazepam (Mogadon).

Other medicines are used in psychiatry, such as Antidepressants, Antipsychotics, and lithium. These have effects that differ from the benzodiazepines, effects both therapeutic and unwanted.

WHAT DO BENZODIAZEPINES DO?

Tranquilizers promote calming, soothing, and pacifying—without sedating or depressant effects. They are effective in lessening Anxiety whatever its context. Thus, they are useful in treating generalized anxiety, which is often quite severe and comes on without apparent cause. Tranquilizers can also be used to deaden the upset of normal anxiety, the anxiety felt by people under stress, feeling threatened by life's problems. In these instances, the reasons for feeling anxious are clear, the degree of anxiety seems in line with the stress experienced—but despite this, help is sought for the symptoms. Unfortunately, the borderline between the medical disorder of clinical generalized anxiety and the normal response to stress is not always clear. The professional consulted will usually try to make the distinction and avoid using tranquilizers to treat people upset by adverse circumstances—thereby "medicalizing" everyday social and personal problems.

Similar considerations apply to the use of benzodiazepines as sleeping tablets. Short-term use of these drugs—for example, for disturbed sleep with jet travel across time zones, severe stress, or shift work—is generally accepted. Long-term use in the chronically poor sleeper is not usually encouraged, however.

Benzodiazepines can also be used as sedatives before surgical operations, as light anesthetics during operations, and to lessen muscle spasms, such as occur with sports injuries. Some benzodiazepines can be used to treat some forms of epilepsy. Benzodiazepines are prescribed mainly by general family practitioners, although they vary greatly in how often they use these medicines. Some still prescribe them widely, some hardly at all. Other doctors who use benzodiazepines include psychiatrists, orthopedic specialists, and gynecologists.

HOW MUCH ARE THEY USED?

An international survey at the beginning of the 1980s showed that tranquilizers and sedatives of any type had been used at some time during the previous year by 12.9 percent of U.S. adults, 11.2 percent in the United Kingdom (U.K.), 7.4 percent in the Netherlands, and 15.9 percent in France. Persistent long-term users comprised 1.8 percent of all U.S. adults, 3.1 percent in the U.K., 1.7 percent in the Netherlands and 5.0 percent in France. The proportion of repeat prescriptions for tranquilizers has increased steadily since about 1970 in many countries, the U.K. in particular. This suggests that fewer people are being newly started on tranquilizers but that a large group of long-term users is accumulating. People starting tranquilizers have at least a 10 percent chance of going on to long-term use, that is for more than 6 months. Some of these chronic users have chronic medical or social problems, and the tranquilizer blunts the unpleasant feelings of tension, anxiety, insomnia and, to a lesser extent, depression.

UNWANTED (SIDE) EFFECTS

Side effects are reactions to drugs that are not therapeutic or helpful, and they are therefore unwanted. The most common side effects from taking benzodiazepine are drowsiness and tiredness, and they are most marked within the first few hours after large doses. Other complaints of this type include dizziness, headache, blurred vision, and feelings of unsteadiness. The elderly are particularly sensitive to tranquilizers and may become unsteady on their feet or even mentally confused.

The feelings of drowsiness are, of course, what is wanted with a sleeping tablet. With the longer-acting benzodiazepines and with higher doses of medium-duration or with short-acting drugs, drowsiness can still be present the morning after taking a sleeping tablet; the drowsiness may even persist into the afternoon. The elderly are more likely to experience such residual, or "hang-over," effects.

As well as these feelings of sedation, special testing in a psychology laboratory indicates that alertness, coordination, performance at skilled work, mental activities, and memory can all be impaired. Patients should be warned about this, and advised not to drive or operate machinery, at least initially until the effects of the benzodiazepine can be assessed and the dosage adjusted if necessary. If driving is essential—that is, to the patient's livelihood—small doses of the benzodiazepines should be taken at first and the amount built up gradually under medical supervision. Judgment and memory are often impaired early in treatment, so important decisions should be deferred.

As with many drugs affecting the brain, benzodiazepines can interact with other drugs, especially Alcohol. People taking tranquilizers or hypnotics should not also drink alcoholic beverages. Other drugs whose effects may be enhanced include anti-histamines (such as for hay fever), painkillers, and antidepressants. Cigarette smoking may lessen the effect of some benzodiazepines.

Patients taking benzodiazepines may show so-called paradoxical responses—that is to say, the effects produced are the opposite of those intended. Feelings of anxiety may heighten rather than lessen, insomnia may intensify, or, more disturbing, patients may feel hostile and aggressive. They may engage in uncharacteristic criminal activities, sexual improprieties or offenses such as importuning or self-exposure, or show excessive emotional responses such as uncontrollable bouts of weeping or giggling. All these are signs of the release of inhibitions, and they are also characteristic of alcohol effects in some people. Although these paradoxical effects may not last long, it is better to stop the benzodiazepine.

Benzodiazepines can affect breathing in individuals who already have breathing problems, such as with bronchitis. Other side effects that may be occasionally encountered include excessive weight gain, rash, impairment of sexual functioning, and irregularities of menstruation. Benzodiazepines should be avoided during pregnancy whenever possible, as there may be a risk to the fetus. Given during childbirth, benzodiazepines pass into the unborn infant and may depress the baby's breathing after birth. They also pass into the mother's milk and may sedate the suckling baby too much. Many people have taken an overdose of a tranquilizer as a suicidal attempt or gesture. Fortunately, these drugs are usually quite safe and the person wakes up unharmed after a few hours' sleep.

SIDE EFFECTS VERSUS MAIN EFFECTS

There are more subtle side effects of benzodiazepines, effects that interfere in various ways with the treatment of the anxiety or sleep disorder. The benzodiazepine lessens the symptom but does not alter the underlying problem—say, an unhappy marriage or a precarious job. Indeed, by lessening the symptoms, the individual may lose his or her motivation to identify, confront, and tackle the basic problems. Giving benzodiazepine medicalizes the problem by making the nervous or sad person into a patient, implying that there is something physically wrong. Finally, some events like bereavement need "working through"—typically by grieving—but benzodiazepines can stop this normal process and actually prevent the bereaved individual from coming to terms with loss.

LONG-TERM EFFECTS OF BENZODIAZEPINES

It is not clear whether benzodiazepines and hypnotics continue to be effective after months or years of daily use. Undoubtedly, many patients believe that they continue to benefit in being less anxious, or in sleeping better. The effect of the drug may be more to stop the anxiety or insomnia that follows withdrawal, however, than to combat any continuing, original anxiety. Most of the side effects lessen over time, a process known as tolerance. Some impairments, however, such as memory disturbances, may persist indefinitely, but patients usually come to terms with this—for example, by resorting to written reminders.

REBOUND

Rebound occurs when stopping the drug makes the underlying condition worse. Most is known about rebound in insomnia. Sleeping tablets may improve sleep by inducing it more rapidly, making it sounder, and prolonging it. When the sleeping tablet is stopped, rebound may occur on the following night or two, with the insomnia being worse than ever. Eventually, the rebound insomnia subsides, but the patient may have been so distressed as to resume medication, thereby running the risk of indefinite use. The risk of rebound is greatest with short-acting benzodiazepines, especially in higher dose.

A similar problem follows stopping a daytime tranquilizer, particularly lorazepam. Anxiety and tension rebound to levels higher than those experienced on treatment and often higher than the initial complaints. Tapering off the tranquilizer over a week or two lessens or avoids this complication. Rebound may even be seen in the daytime between doses of tranquilizer. The patient, increasingly anxious as the effect of the earlier dose wears off, watches the clock until his or her next dose is due. Rebound may also occur later in the day after taking a short-acting sleeping tablet the night before.

WITHDRAWAL

In withdrawal, symptoms occur which the patient has not previously experienced. They come on a day or two after stopping alprazolam or lorazepam, after a week or so on stopping diazepam or chlordiazepoxide. The symptoms rise to a crescendo and then usually subside over two to four weeks. In an unfortunate few, the symptoms seem to persist for months on end—sometimes called the post-withdrawal syndrome. The existence of this condition is disputed by some doctors, who ascribe the symptoms to return of the original anxiety for which the drug was given.

Patients commonly experience bodily symptoms of anxiety such as tremor, palpitations, dry mouth, or hot and cold feelings. Insomnia is usually marked. Some complain of unpleasant feelings of being out of touch with reality or with their own bodies. Severe headaches and muscle aches and pains can occur, sleep is greatly disturbed, appetite is lost as is several pounds of weight. Disturbances of perception are characteristic of benzodiazepine withdrawal and include intolerance to loud noises or bright lights, numbness or pins and needles, unsteadiness, a feeling of being in motion (as on a ship at sea), and a sensing of strange smells and tastes. Some people become quite depressed; rarely, some experience epileptic fits or a paranoid psychosis (with feelings of persecution and loss of contact with reality).

HOW BIG IS THE PROBLEM?

The withdrawal symptoms are evidence of physical dependence—that is, the body has become so used to the effects of the benzodiazepine that it cannot manage without. About a third of long-term (over a year) steady users show withdrawal, even when the tranquilizer or hypnotic is tapered off. Some users have tried to stop and have encountered problems. Many others have never tried to stop and so are unaware whether they are dependent. Because these people continued to take the doses prescribed by their doctors, the medical profession was reluctant for a long time to admit the scale of the problem—perhaps 500,000 people dependent on tranquilizers in the U.K. alone. In addition, the similarity between some withdrawal symptoms and features of the original anxiety has led to confusion in the mind of both the patient and the doctor. True withdrawal symptoms, however, arise at a predictable time after stopping the benzodiazepine and are new experiences for the patient; the old anxiety and insomnia symptoms are familiar to the patient and may return at any time, depending on external stresses.

HOW TO WITHDRAW

Essentially, the patient must be prepared for withdrawal by being told what to expect; he or she should be taught other ways of combatting anxiety; and withdrawal should be by graded tapering off the dose over six to twelve weeks, occasionally longer. Many people experience little or no upset, a few undergo much distress. Sometimes substituting diazepam in the lorazepam or alprazolam user helps. Antidepressants may be needed if the patient becomes very depressed, but by and large, other drugs are unhelpful.

Family and social support is essential. Usually the family doctor can supervise the withdrawal quite safely, but occasionally specialist advice is sought. A self-help group may provide useful continued advice and support.

It is important that tranquilizers are never stopped abruptly. There is a greatly increased risk of severe complications such as seizures or convulsions.

ABUSE OF TRANQUILIZERS

Only a few patients prescribed benzodiazepines push the dose up above recommended levels. If this happens, the user may become intoxicated, with slurred speech and incoordination. Some people with alcohol problems also abuse benzodiazepines. Intravenous (IV) injection of benzodiazepines and hypnotics has become an increasing problem and has led to controls on these drugs concerning manufacture and prescription in various countries, including the United States and the U.K. Some addicts abuse benzodiazepines alone; others combine it with heroin-type drugs. Injection of benzodiazepines can result in clotting of the veins. It also carries the risk of getting infectious diseases from sharing dirty syringes, such as hepatitis and the human immunodeficiency virus (HIV or the AIDS virus).

ALTERNATIVES TO THE TRANQUILIZERS

Dissatisfaction with the benzodiazepine tranquilizers and hypnotics has led to numerous initiatives to find better alternatives. Some drugs have been developed that are better benzodiazepines, in that they are less sedative and perhaps less likely to induce dependence. Others are chemically not benzodiazepines but share many of their properties, both therapeutic and unwanted. Other compounds seem to act in a totally different way in the brain and are less sedative and probably much less likely to induce dependence. One such compound—buspirone (Buspar)—has been available for a few years, but many others are in the process of development. Finally, interest has been rekindled in the use of other types of older drugs to treat anxiety; examples include the antihistamines and the beta blockers.

Problems with the benzodiazepines has led to a reevaluation of the whole role of prescribed medicines in the management of anxiety, insomnia, and stress-related disorders. Numerous nondrug methods have been developed and improved, among them relaxation training; cognitive therapy, in which patients learn to think less anxious thoughts; behavior therapy, in which the patient learns to confront stressful situations; and sleep counseling. Alternative medicine, like Acupuncture, is enjoying a vogue and helps some anxious people.

CONCLUSIONS

Hailed as wonder drugs, prescribed widely and for long periods of time, the benzodiazepines have now been shown to be problematic medicines with undoubted benefits but definite risks. For short-term treatment in the severely anxious and sleepless, they are still useful—although other drugs are beginning to supplement and even supplant them. For the bulk of anxious people, though, nondrug treatments are increasingly popular.

(See also: Addiction: Concepts and Definitions ; Complications ; Iatrogenic Addiction ; Sleep, Dreaming, and Drugs ; Tolerance and Physical Dependence ; Withdrawal )

BIBLIOGRAPHY

American Psychiatric Association. (1900). Task force report: Benzodiazepine dependence, toxicity, and abuse. Washington, DC: Author.

Curran, H.V., & Golombok, S. G. (1985). Pill popping: How to get clear. Boston: Faber & Faber.

Woods, J. H., Katz, J. L., & Winger, G. (1987). Abuse liability of benzodiazepines. Pharmacological Reviews, 39 (4), 251-419.

Malcolm H. Lader