Sedatives: Adverse Consequences of Chronic Use

SEDATIVES: ADVERSE CONSEQUENCES OF CHRONIC USE

Sedative drugs are also called hypnotics or Sedative-Hypnotics. They are sometimes referred to as "minor tranquilizers" or "anxiolytics" (antianxiety medications). Technically, a sedative decreases activity and calms, while a hypnotic produces drowsiness, allowing for the onset and maintenance of a state of Sleep similar to natural sleep and from which the sleeper may be easily awakened. The same drug used for sedation, pharmacologically induced sleep, and general systemic anesthesia may be seen to induce a continuum of central nervous system (CNS) depression. Such drugs are usually referred to, therefore, as sedative-hypnotics, and they are widely prescribed in the treatment of insomnia (sleep problems). Although some people take these drugs only occasionally and for specific sleep problems (grief, time-limited stress, long-distance flights), many more take them over prolonged periods (months and even years) as a presumed aid to nightly sleep. They do this despite medical advice to restrict such drugs to about two weeks of use.

All the sedatives are available in tablets or capsules for oral dosage, and some are also available for intravenous or intramuscular administration. Almost all sedatives have the same behavioral effects as alcohol (ethanol). Many persons who abuse sedatives, are, or have been problem drinkers. According to guidelines published by the American Psychiatric Association (1990), patients with a history of alcoholism or other drug abuse problems should not be treated with benzodiazepine sedatives on a chronic basis because they are at high risk of developing benzodiazepine abuse.

USE OF HYPNOTICS

Sleep problems in adults are of three main types (1) problems of falling asleep (sleep initiation), (2) problems staying asleep (sleep maintenance), and (3) early-morning wakening. Sleep-onset problems vary little with age; early-morning wakening is often secondary to depression; and sleep-maintenance problems show a clear and marked increase with aging. Whereas approximately 10 percent of young adults complain of serious sleep problems, this increases to 30 to 50 percent of those aged seventy or older (Morgan, 1990).

This age-related pattern for complaints of insomnia is reflected in the pattern of use of sedative-hypnotic drugs. For example, in the United States 2.6 percent and in Britain 4 percent of adults take a benzodiazepine as a sleep inducer during any given year (Mellinger, Balter, & Uhlenhuth, 1985; Dunbar et al., 1989). In the elderly, this increases to 16 percent use in a year, with 73 percent of those taking the drug regularly for a year or more. Indeed, 4 percent of people older than 65 had used the drug continuously for more than a decade (Morgan et al., 1988). Across all age groups, roughly twice as many women as men take sedative-hypnotic drugs.

The most commonly prescribed hypnotics include several benzodiazepines: flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion). Other hypnotics not related to the benzodiazepines are chloral hydrate (Noctec), a chloral derivative, and hydroxyzine (Vistaril), an antihistamine.

BENZODIAZEPINES

Benzodiazepines remain by far the most frequently used sedative-hypnotic drugs (although there are some new compounds with differing modes of action). The key concerns in the hypnotic use of the benzodiazepines are (1) adverse effects experienced while the patient is taking the drug; (2) possible physical and psychological dependence; and (3) rebound insomnia and Withdrawal symptoms when the patient stops taking the drug.

Classification.

Benzodiazepines can be classified on pharmacokinetic grounds into long-acting (e.g., flurazepam, diazepam [Valium], chlordiazepoxide [Librium]); medium-acting (temazepam) and short-acting (triazolam, oxazepam [Serax], lorazepam [Ativan]) sedative-hypnotics. Their efficacy, at least in short-term use, has been well documented. The pattern of improvement in sleep corresponds fairly closely with the pharmacokinetic properties of each drug, providing that factors of absorption and elimination are taken into account. For example, temazepam is absorbed relatively slowly and has little effect on sleep-initiation time, whereas triazolam is absorbed relatively rapidly, which brings sleep on more quickly.

Each sedative-hypnotic has a minimally effective dose, but the dose that is usually effective may be twice as high as the minimum. Further increases may, however, cause side effects and rebound insomnia without substantially improving sleep. In sleep-laboratory studies, many benzodiazepines are found to lose their efficacy after about two weeks of nightly use. Subjectively, however, patients often feel that their sleep is improved for longer periods than this.

Adverse effects.

Benzodiazepine sedatives have three major adverse effects: cumulative effects with repeated dosage, particularly if the patient has not yet metabolized the previous dose; additive effects when given with other classes of sedatives or with alcohol; and residual effects after the medication is discontinued. Patients taking benzodiazepines may feel drowsy, have reduced psychomotor speed, and impaired concentration. These in turn can adversely affect their ability to function; patients should be cautioned about driving and operating machinery while taking these drugs. The longer-acting the drug, the more pronounced are these effects. Tolerance to these sedative effects builds up to some extent over repeated use of the drug. Age-related changes in the way that drugs are metabolized and excreted mean that benzodiazepines accumulate more in older patients and, therefore, adverse effects are more pronounced in the elderly.

All benzodiazepines can impair the users ability to learn and remember new information. This memory impairment is most pronounced a few hours after taking the drug, so when taken as a sleep aid, such effects may be much reduced by the time the person wakes the next morning. Again, the elderly are particularly prone to such effects. As with other adverse effects, higher doses cause greater problems. Rarer adverse effects include disinhibition and aggressive behavior. These effects have been reported for some benzodiazepines (e.g., triazolam, flunitrazepam) more than others.

Rebound insomnia refers to the heightened insomnia that may occur when the patient stops taking the drug, such that the sleep pattern is actually worse than it was before the medication. Studies have established that rebound insomnia is generally at its worst following the shorter-acting benzodiazepines and its least following the longer-acting benzodiazepines (Roehrs et al., 1986). Rebound is clearly dose-related, so the lowest effective dose should be prescribed, with rebound effects described to warn the patient about overdosing for "faster" or "better" drug-induced sleep.

Abuse, dependence and withdrawal.

Some argue that rebound insomnia is itself a sign of physiological dependence on benzodiazepine hypnotics (e.g., Morgan, 1990). Others insist that dependence is shown only when withdrawal from a drug leads to symptoms other than a rebound of the original problems. In general, psychological dependence on benzodiazepines can develop rather rapidly. After only a few weeks, patients who attempt to discontinue the medication may experience restlessness, disturbing dreams, paranoid ideas and delusions, and feelings of tension or anxiety in the early morning. Withdrawal following moderate-dose usage may include dizziness, increased sensitivity to light and sound, and muscle cramps. Withdrawal following high-dose usage may result in seizures and delirium.

The syndrome of withdrawal from benzodiazepines may be slow in onset because these drugs remain in the body for relatively long periods. Withdrawal appears to be most severe in patients who used benzodiazepines that are absorbed rapidly and have a rapid decline in blood serum levels (alprazolam, lorazepam, and triazolam). In patients who abused both benzodiazepines and alcohol, a delayed benzodiazepine withdrawal syndrome may complicate withdrawal from alcohol. Patients who are high-dose abusers of benzodiazepines usually require inpatient detoxification.

Abuse.

Animal studies indicate that benzodiazepines, like cocaine and opioids, activate a brain reward pathway in the brains of most mammals. In humans, the benzodiazepines have reinforcing effects that appear to be more pronounced in frequent users of other recreational drugs. For example, alcoholics and Heroin addicts will at times use benzodiazepines to eke out their supply of first-preference drug, since Alcohol and heroin are also depressants.

Abuse of benzodiazepines by themselves is relatively unusual, but sometimes occurs among users who seek a "high" from massive amounts of these drugs. Street drug dealers sell benzodiazepines at a relatively low cost in most major cities. Some abusers combine benzodiazepines with other drugs to enhance the effects; for example, some believe that taking diazepam half an hour after an oral dose of methadone will produce a "high" that is more intense than can be obtained from taking either drug by itself.

Overdose.

Overdosing on benzodiazepines is a medical emergency. It is marked by respiratory depression, low blood pressure, shock, coma, and eventual death. Flumanezil (Romazicon) is a benzodiazepine antagonist that can be given intravenously to reverse the sedative effects of an overdose.

OTHER SEDATIVE/HYPNOTIC DRUGS

Barbiturates.

Barbiturates were used until the 1950s as sleeping pills but were superseded by the benzodiazepines. With the exception of phenobarbital (Luminal), which is still used as a sedative and as an anticonvulsant, the barbiturates are rarely prescribed.

Chloral Derivatives.

These compounds, which include chloral hydrate, are sometimes used with elderly patients since they are less likely to cause restlessness in confused or demented patients. They are also relatively safe to give to children for sedation before or after surgery. Chloral derivatives can, however, cause gastric irritation and rashes.

Antihistamines.

Diphenhydramine (Benadryl, Nytol, Sominex) and hydroxyzine (Atarax, Vistaril) are often prescribed for patients who need only a mild sedative. They are safe and do not produce dependency. They should not, however, be used together with alcohol. The most common side effect of these medications is dry mouth.

Newer Medications.

Newer compounds include such nonbenzodiazepine hypnotics as zopiclone and zolpidem (Ambien), which act either atypically or selectively on benzodiazepine receptors. They are chemically distinct from benzodiazepines and from each other. Both are short-acting drugs and at normal clinical doses cause little residual (hangover) sedation. The risk of rebound insomnia or dependence with these compounds is thought to be low but not absent (Lader, 1992).

Buspirone (BuSpar) is the only antianxiety medication that is not a sedative. Because it does not produce depressant effects or dependence, it is being used increasingly in the treatment of depression as well as anxiety. Unlike the sedatives, buspirone does not affect the patient's alertness or motor skills, it does not intensify the effects of alcohol, and it does not produce a withdrawal syndrome.

(See also: Accidents and Injuries from Drugs ; Addiction: Concepts and Definitions ; Aging, Drugs, and Alcohol ; Barbiturates: Complications ; Benzodiazepines: Complications ; Drug Interaction and the Brain ; Drug Interactions and Alcohol ; Memory, Effects of Drugs on ; Prescription Drug Abuse )

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Valerie Curran

Revised by Rebecca J. Frey