Numerous prescription and nonprescription agents have been used to treat insomnia. Agents currently approved by the U.S. Food and Drug Administration (FDA) for treatment of insomnia include eight benzodiazepine receptor agonists (BzRAs) and one melatonin receptor agonist. Although several barbiturate and miscellaneous nonbarbiturate drugs (e.g., chloral hydrate, ethchlorvynol) are also approved as sedative-hypnotics, they are not recommended for clinical use given their low therapeutic index. Approved BzRAs include a set of drugs that are true benzodiazepines as defined by their chemical structure and a set of drugs that are not benzodiazepines but appear to share a common mechanism of action. BzRAs act at a specific recognition site on γ-aminobutyric acid type A (GABAA
) receptors in the CNS; this recognition site is distinct from the GABA recognition site itself (26
). Benzodiazepines have affinity for several subtypes of GABAA
receptors, which are defined by the specific composition of five protein subunits. Some nonbenzodiazepine BzRAs have greater selectivity for GABA receptors containing an alpha1
protein subunit. The sedating and amnestic effects of BzRAs both appear to be related to affinity for alpha1
receptors, but the clinical significance of drug specificity in vivo is uncertain.
BzRAs differ from each other mainly in terms of pharmacokinetic properties, and particularly in terminal elimination half-life (). Available agents have terminal elimination half-lives ranging from 1 to 120 hours. The duration of action of a drug is most strongly, although not exclusively, related to half-life. Therefore, selection of a particular drug often depends on the ideal duration of action for a particular patient, rather than on any specific distinctions between drugs.
Pharmacokinetic Properties of Hypnotic Drugs Approved by the U.S. Food and Drug Administrationa
BzRA drugs as a class reduce sleep onset latency and increase total sleep time; depending on the specific pharmacokinetics of the drug in question, decreased wakefulness after sleep onset may also result. Qualitative and quantitative analyses of clinical trials with BzRAs demonstrate their efficacy as judged by self-report and objective outcomes (29
). However, as is the case with psychological and behavioral treatments, few studies have paid attention to functional outcomes or to the broader insomnia syndrome.
BzRAs also share a similar set of adverse effects, which include anterograde amnesia, postural instability, and sleepiness (16
). The presence of such side effects may be related to the specific drug’s half-life; impaired memory and daytime sedation are more likely with agents having long half-lives. A range of more serious behavioral adverse consequences, including sleep-related eating, sexual behavior, and even driving, have been reported anecdotally and in the lay press. Although most of these reports have occurred in association with zolpidem, which is the most widely prescribed drug in this class, it seems likely that similar adverse effects are possible with any agent in this class.
BzRAs may also be associated with rebound insomnia, withdrawal, tolerance, and dependence (16
). Rebound insomnia has been demonstrated predominantly with short-acting drugs, and it can be minimized by gradual dose tapering and even by alternate-day dosing after the dose has been reduced. Withdrawal symptoms can also be minimized by dose and frequency tapering. Abuse of BzRA drugs as agents of first choice is not common. However, individuals who abuse these drugs commonly abuse other substances, and the use of higher-than-prescribed doses or requests for early prescription refills should raise concern. Hypnotic dependence has both physiological and psychological determinants. Physiological aspects of dependence are related to the discontinuation effects noted above. Psychological aspects of dependence are related to the fear or belief that good sleep will not be possible without medications. This may lead some individuals to continue taking medications for extended periods, even in the absence of clear therapeutic benefits.
BzRAs have also been shown to be useful for individuals with comorbid insomnia, including those with comorbid depression (32
). They also reduce insomnia in perimenopausal women with hot flashes (33
). Both nightly dosing and intermittent (e.g., three times per week) dosing have been shown to be efficacious (34
). Although most clinical trials have been conducted for 1 week or less, recent evidence from double-blind studies shows continued evidence for efficacy for up to 6 months of nightly use (35
One melatonin receptor agonist, ramelteon, has been shown to be efficacious for treatment of insomnia (36
). Its primary effect appears to be on sleep onset latency, with little effect on wakefulness during the middle of the night. Its side effect profile appears to be relatively benign, although increased blood levels have been observed in older adults, and some hormonal alterations (e.g., reduced testosterone) have been observed.
A wide variety of drugs that have not been approved by the FDA for the treatment of insomnia have been used in clinical practice. These include sedating antidepressant drugs, sedating antipsychotic drugs, and sedating anticonvulsant drugs, often used in low doses. Small clinical trials have supported the efficacy of low doses of trazodone and sedating tricyclic drugs for treatment of insomnia (16
). Their role in the routine treatment of chronic insomnia has not been defined, but they are likely to be most useful in patients who have a history of substance use and those who have a contraindication or poor response to BzRAs. Important side effects of these drugs include orthostatic hypotension and anticholinergic effects, which are of particular concern in the elderly. Even greater concerns are raised by the use of sedating antipsychotic drugs, which may have metabolic and neurologic side effects. Therefore, their use for treatment of sleep disturbance is recommended only in cases of insomnia that is comorbid with psychiatric disorders that independently warrant their use, such as severe bipolar disorder.
Alcohol and antihistamines are the most commonly used self-treatments for insomnia. Alcohol may help promote sleep initially, but it disrupts sleep for the remainder of the night and raises the additional issues associated with chronic alcohol use. Very little evidence is available supporting the efficacy or safety of diphenhydramine or other antihistamines for the treatment of insomnia. In addition, their anticholinergic properties raise safety questions, particularly in older people. Finally, naturopathic remedies such as valerian (37
) have been assessed in some clinical trials. However, substantial difficulties arise in the standardization of these products, and their overall efficacy is marginal at best.