Hypnotics

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

Pharmacokinetics
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.

Pharmacodynamics
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.

Zaleplon is also a selective compound with a very short half-life that averages only 1 hour. The drug shortens sleep onset without usually prolonging total sleep time. Residual effects are absent, and memory is minimally disturbed.

A meta-analysis of benzodiazepines and related drugs in the treatment of insomnia found definite efficacy with respect to prolonging total sleep duration by over an hour but only a nonsignificant reduction in sleep latency.¹⁰ Memory impairment was reported in several of the studies that were cited.

Another risk-to-benefit meta-analysis in the elderly concluded that the risks may outweigh the benefits.¹¹ The newer compounds, including eszopiclone and ramelteon, may be more effective in the elderly and better tolerated than standard hypnotic benzodiazepines.¹²

Adverse effects
The most common adverse effects of the hypnotic benzodiazepines are tiredness, drowsiness, and torpor-all features of oversedation. The effects are dose- and time-related and are maximal within the first 2 hours after large doses. This presents a danger if the person with insomnia takes a dose of medication and then wakes up.¹³ Next-day drowsiness is most noticeable during the first week of treatment, after which it largely disappears, probably because of a true tolerance effect. Patients should be warned of the potential adverse effects of any prescribed benzodiazepine and the initial dosage should be considered carefully. Most benzodiazepines can cause problems, especially when given at higher doses and in the elderly.

Residual effects can be a problem, especially when long-acting drugs are used repeatedly. Dosage is important because as the dosage is increased, residual effects increase in both magnitude and duration. Remember that hypnotics are the only class of drugs in which the main therapeutic effect (drowsiness) is the same as the main unwanted effect; the 2 are merely separated by 8 hours. Psychomotor performance may be affected the next day, with elderly drivers at particularly high risk. In addition, potentiating effects of alcohol can occur. Paradoxical behavioral responses (such as uncontrollable weeping; increased aggression and hostility; and acute rage reactions or uncharacteristic criminal behavior, such as shoplifting) can develop in patients taking a benzodiazepine.

Other unwanted effects include respiratory depression, excessive weight gain, rash, impaired sexual function, menstrual irregularities and, rarely, blood dyscrasias. The use of benzodiazepines in pregnancy is generally regarded as reasonably safe, but benzodiazepines pass into the fetus and can produce respiratory depression in the neonate. Benzodiazepines and related drugs cross over into the mother’s milk and can oversedate the baby. Breastfeeding should therefore be discouraged if benzodiazepines are prescribed, especially in high dosages.

Overdosing
Overdosing with benzodiazepines is common; death is not. By themselves, benzodiazepines are only hazardous to children and the physically frail, especially those with respiratory illness. Typically, the person falls into a deep sleep but can be roused with the benzodiazepine antagonist, flumazenil. However, the combination of a benzodiazepine and alcohol can be lethal.

Rebound
Discontinuation of many hypnotics is often followed by worsening of sleep disruptions relative to pretreatment levels. In practical terms, patients with insomnia find that their sleep is disturbed for a night or 2 after abrupt discontinuation of what appeared to be effective medication. The risk of rebound is greater with drugs that have a short half-life than with those that have a longer half-life. Tapering lessens the likelihood of rebound. However, there is little evidence that rebound insomnia leads to the resumption of medication.¹⁴

Dependence
Dependence may supervene on the longer-term use of hypnotics; giving a long-acting benzodiazepine drug only once in 24 hours does not protect against such an eventuality. Because of such concerns, hypnotics are usually prescribed for no more than 2 to 4 weeks. Tapering manages the withdrawal syndrome.

A growing problem with these drugs is abuse-nonmedical use, on a regular or sporadic basis, often in a polydrug context. The injected drug has a marked sedative and/or disinhibiting effect, and its use may result in chaotic behavior.

Clinical use
Insomnia is common, especially in the elderly.^15,16 In patients who complain of severe insomnia secondary to physical concerns-pain, breathlessness, or pruritus-the primary symptoms are treated first. In other cases, the insomnia may be either a symptom of psychiatric distress, anxiety, or depression, or it may be iatrogenic, caused by the very drugs prescribed to relieve it. In this instance, a careful regimen of drug withdrawal, or substitution and subsequent withdrawal, should be initiated.

Nonetheless, many complaints of insomnia are unfounded because the patient has unreal expectations concerning sleep. Elderly people fail to appreciate that it is normal to sleep less and less deeply as they age. Napping during the day also decreases the need for sleep at night. Some people can manage on 5 to 6 hours of sleep a night indefinitely, and yet worry that this is insufficient. Explanation and reassurance relieve their worries.

A substantial number of patients, in general, persistently complain of insomnia (primary insomnia). However, careful evaluation may reveal a link to stress, both transient and persistent. Giving drugs may initiate a long-term process that ends in drug-related insomnia without the basic problems being solved.

Short-term symptomatic relief is acceptable when the stress is undoubtedly severe but transient. Even so, the hypnotic agent must be chosen carefully. The elimination half-life is the most important consideration. Drugs with half-lives of more than 12 hours, such as flurazepam, are only appropriate when an anxiolytic effect is required during the day and sleep induction is needed at night. Drugs with shorter half-lives encourage sleep onset but do not cause too many residual sedative effects the next day.

The management of chronic insomnia is much more problematic, especially in the elderly.^17,18 Eszopic­lone and zolpidem are short-acting and can-at a modest dosage-help ensure a good night’s sleep without much risk of residual sedative effects.19 Eszopiclone is licensed in the United States for long-term use in chronic insomnia and is already used extensively, but further evaluation in real-life settings is necessary.

Zolpidem and zaleplon can be used in a way that is strategically different from the way other longer-acting drugs are used. Hypnotics are traditionally taken every night before bed to induce or maintain sleep. However, the severity of insomnia usually varies from night to night. Consequently, regular use may often be unnecessary, and it increases the risk of habituation and dependence. Very short-acting compounds are unlikely to leave residual effects, even if taken up to 5 hours or so before the expected time of wakening. Consequently, the patient with insomnia can refrain from regular use of a hypnotic for sleep and instead wait an hour or so after going to bed to see whether natural sleep supervenes before resorting to medication.

Other hypnotics
A series of compounds is being developed based on melatonin. This hormone is important in the regulation of sleep and is secreted at night. Some elderly persons with insomnia seem to be deficient in melatonin. Preparations include long-acting formulations of melatonin, such as Circadin.^20,21 Ramelteon is a melatonin (MT)1 and MT2 agonist. It is approved in the United States for insomnia and is effective in maintaining sleep. It has a favorable safety profile (dizziness and nausea are the most common adverse effects).²²

A long history exists of using histamine antagonists such as pro­methazine and diphenhydramine hydrochloride as hypnotics. These tend to be rather unselective and can produce excessive sedation and sometimes weight gain. They are not associated with dependence or abuse, however. Selective histamine H1 antagonists are under development.²³ Sedative antidepressants such as trazodone, low-dose doxepin, and mirtazapine are also widely used as hypnotics, particularly in patients with insomnia and comorbid depression.²⁴ This use is unsupported by convincing controlled data.²⁵ Any antiarousal sleep-promoting effects are largely mediated through antihistaminic effects.

Conclusions
In many countries, insomnia is still largely treated with benzodiazepines. Nevertheless, controversy and disagreement continue to rage about the risk-to-benefit ratio of these compounds.²⁶ Short-term use is well established, and a database showing favorable results serves as a rationale for this approach. However, studies on long-term use are still limited. While both the efficacy and safety of long-term use remain unclear, acceptance of current guidelines that limit the use of benzodiazepines seems wise. Of all the hypnotics, the z-drugs are still the drugs of choice and their use is supported by comprehensive databases. Many newer compounds with novel modes of action are in development.²⁷

The management of insomnia is complex and is hampered by a dearth of information concerning the relative merits of various treatment modalities. Educating the patient about sleep hygiene may be the simplest way to reduce insomnia (Table 2). Much research is also needed on the optimum strategies for combining both drug and nondrug therapies, and on identifying predictors of response

References:

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Evidence-Based References
Glass J, Lanctôt KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331:1169.
Holbrook AM, Crowther R, Lotter A, et al. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162:225-233.