In This Special Report:

The Art of Psychopharmacology, David S. Janowsky, MD

Hypnotics: How Effective Are They for Insomnia?, Malcolm H. Lader, MD, PhD, LLB

Antidepressants: Brand Name or Generic?, James W. Jefferson, MD

Antipsychotic Combination Strategies in Bipolar Disorder, David J. Muzina, MD and Martha Sajatovic, MD

Several classes of hypnotic medication are available: the older barbiturates and their derivatives; benzodiazepines; chemically distinct “z-compounds”; antihistamines and antihistaminic antidepressants; and melatoninergic compounds. The use of hypnotic medications continues at a high rate. However, some switching to the shorter-acting benzodiazepines has occurred. The z-compounds—eszopiclone, zolpidem, and zaleplon—have become popular; they seem to have fewer residual effects than the benzodiazepines. Even so, care is needed in prescribing such hypnotics for the elderly.

Newer nonsedative hypnotics are becoming available. The rational use of all hypnotics requires minimal dosage; short duration of administration; and simultaneous exploitation of nonpharmacological methods, such as sleep hygiene education.

The first barbiturate was introduced more than 100 years ago. Those used as hypnotics are short-acting or intermediate-acting. Disadvantages include drowsiness, tolerance, potential for overdose, and possible physical and psychological dependence with severe withdrawal syndromes.1

Many benzodiazepines have been synthesized and used as hypnotics. Their popularity reflects their perceived safety in overdose compared with the barbiturates. In turn, there has been mounting concern about the adverse effects of benzodiazepines and risk of dependence.2 The FDA has urged greater caution in

prescribing benzodiazepines and warns of the potential risk of anaphylactic shock and complex sleep-related behaviors (such as sleep-driving and preparing and eating food while asleep).3

Benzodiazepines are fully absorbed orally and exert a hypnotic effect. Although temazepam enters the brain quite rapidly, it still takes some time to induce sleep. The redistribution phase can be pronounced and largely determines the duration of effect of single doses of benzodiazepines such as flunitrazepam. The metabolic half-lives of the benzodiazepines also vary greatly (Table 1). Metabolism of most of these drugs is appreciably slower in the elderly and in patients with liver damage. Benzodiazepines with a 3-hydroxyl grouping, such as lorazepam, oxazepam, and temazepam, have half-lives averaging 12 hours or less. Liver damage has to be severe before the metabolism of these drugs is affected.

The benzodiazepines potentiate the widespread inhibitory neurotransmitter g-aminobutyric acid, but they have their own receptors. This inhibitory effect alters the turnover of neurotransmitters, such as norepinephrine and serotonin. The benzodiazepines act on the limbic and cortical areas involved in the organization of alertness and sleep.

The depressant effects of a single therapeutic dose of a benzodiazepine can usually be readily detected. Sustained impairment of functioning can be detected in patients who have insomnia who are given repeated doses. The benzodiazepines exert marked and selective effects on memory, independent of any sedation or attentional impairment.4 Alcohol adds to the cognitive impairment induced by the benzodiazepines.

The largest gap in our knowledge concerns the long-term use of these drugs, which has been evaluated in relatively few studies.5 It is unclear whether therapeutic effects are maintained in most patients for more than a few weeks and when dependence supervenes in patients who encounter problems with long-term use.

Treatment of insomnia
The main groups of drugs used to treat insomnia are the benzodiazepines and the newer compounds, zopiclone, eszopiclone, zolpidem, and zaleplon. Other benzodiazepines sometimes prescribed as hypnotics include diazepam, chlordiazepoxide, and clonazepam.

Flurazepam is long-acting and still widely used; it has a very long-acting metabolite that can produce psychological impairment at standard dos­age, especially in the elderly. Of the intermediate-acting compounds, temazepam has no active metabolites; at a modest dosage (10 to 15 mg daily), it results in few residual effects and is fairly well tolerated by the elderly. However, major problems with abuse have limited its popularity.2

Triazolam is the archetypal short-acting benzodiazepine. Daytime sedation is seen after high dosages (0.5 mg daily) but usually not with lower dosages. These higher dosages have also been associated with an increased incidence of adverse effects, such as anterograde amnesia and unusual behaviors, including depressive reactions and hostility.

Zopiclone is believed to bind close to, but not exactly at, the benzodiazepine receptor. It is a racemic mixture: eszopiclone is the S-enantiomer licensed for the long-term treatment of insomnia in the United States.6 Its approval is pending in Europe.7 Its sedative and hypnotic effects are similar to those of the benzodiazepines, but its adverse-effect profile is generally superior, with fewer CNS effects such as sedation, confusion, and memory impairment. Long-term efficacy of zopiclone at a dosage of 3 mg daily has been established, with improved daytime functioning and health-related quality of life.8 Residual effects can be detected, but rebound, withdrawal, and tolerance seem to be minimal or absent. Zolpidem is an imidazopyridine compound that binds selectively to one subtype of the benzodiazepine receptor. It is rapidly absorbed and has a short half-life of 0.7 to 3.5 hours (mean, 2.4 hours). It is effective in decreasing sleep-onset latency, but it has less consistent effects on total sleep time.9 Residual effects are minimal, as are memory disturbances. Rebound and withdrawal are uncommon but have been documented.


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