Insomnia: Therapeutic Approach

, MD, , MD, , Department of Psychiatry and Behavioral Medicine, University of Louisville School of Medicine, Louisville, Ky

South Med J. 2001;94(9) 

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The most common therapy for insomnias has been the benzodiazepines, especially those of short to intermediate half-life. Binding of these drugs to -aminobutyric acid (GABA) receptors in the brain results in stimulatory effects on GABAergic transmission and hyperpolarization of neuronal membranes.[14,33] Benzodiazepines have sedative, anxiolytic, myorelaxant, and anticonvulsant properties.[33] Extensively prescribed since their introduction in the 1960s, they have a good efficacy record, have few side effects, and are safe even upon overdose.[34] There is risk for habituation, tolerance, addiction, and withdrawal.[17,33] Benzodiazepines enhance sleep duration and reduce arousals.[35] Exposure increases stage 2 sleep while decreasing REM and stages 3 and 4 sleep.[33,35,36]

Side effects are dose-dependent and vary according to the pharmacokinetics of each benzodiazepine.[5] They are usually recommended for short-term use only; this standard of care minimizes dependency. Many clinicians, however, have vast experience with reliable patients who responsibly use these drugs for years without abuses, while maintaining efficacy. Clinical discretion is required; monitoring should continue during all prescribing. The various benzodiazepines are similar in action but differ according to onset and duration. Table 4 outlines these parameters. The following are examples of commonly used compounds from each class.

Short Half-Life. Triazolam is the most rapidly acting and cleared of the oral benzodiazepines.[37] It is best indicated for sleep onset problems, common during high anxiety states, and for insomnias in younger individuals.[38] Shorter-acting benzodiazepines are well suited to active persons and the elderly, since they are readily eliminated and have minimal next-day sedation.[9,23,24] Major side effects of short-acting benzodiazepines include rebound insomnia, amnesia, and intoxication, which can occur even after brief exposure.[5] Triazolam is best used only for short durations because tolerance and addiction can easily develop with prolonged use.[5,35]

Intermediate Half-Life. Temazepam is a frequently prescribed benzodiazepine with a duration of action in the intermediate range and a slower rate of absorption than triazolam. Temazepam is less effective for inducing sleep and more indicated for sleep maintenance and decreasing nocturnal awakenings.[22] It is well tolerated by most geriatric patients,[20,22] but rebound insomnia and significant next-day sedation may follow temazepam administration.[39] With appropriate dosing and when taken only at 24-hour intervals, these effects and the risk of addiction can be minimized.[40]

Long Half-Life. Flurazepam exemplifies long-acting benzodiazepines and has a duration of several days. It is best indicated for people with insomnia plus concomitant daytime anxiety.[25,41] Flurazepam and its metabolites require days for elimination. Accumulation of active metabolites is most problematic in elderly patients or in those with impaired liver function.[15] Next-day sedative effects is a major concern, especially in older people and anyone who needs full daytime alertness.[7,34,41] Rebound insomnia is minimal, but it can occur after prolonged periods at high doses.[35] It is less highly associated with risk for addiction.


Zolpidem is a safe new drug with a short half-life ( Table 5 ).[37] It exhibits hypnotic effects with less significant myorelaxant, anticonvulsant, and anxiolytic properties than benzodiazepines.[25,30,42] This selective sedative action is thought to be mediated by its affinity for the GABA benzodiazepine-1 receptor.[25,33,43] Abuse remains, nevertheless, a theoretical concern.

The safety and efficacy of zolpidem for insomnia have been proven similar to those of short-acting benzodiazepines,[44,45,46,47,48] with less daytime sedation.[36] It is effective for reducing sleep latency and nocturnal awakenings and increasing total sleep time.[44,47,49] Rebound effects upon withdrawal and tolerance, even with prolonged use, are minimal.[36,45,49,50] As with other sedative medications, treatment optimally should not exceed 4 weeks, to minimize the risk of habituation.[34] Patient selection and monitoring by the physician are important safety factors, but again some physician experiences indicate longer usages without problems. Zolpidem is less disruptive of sleep stages than benzodiazepines.[14,49,51] The incidence of adverse events is low when adhering to recommended dosing.[50] The most commonly encountered side effects include drowsiness, dizziness, and headache.


Zaleplon recently was approved for the treatment of short-term insomnia. It also interacts with the GABA-receptor complex, with selective binding.[52] Zaleplon has a rapid onset of action and ultra brief duration, with a short elimination half-life.[52,53] It is effective for decreasing time to sleep onset but not for reducing nighttime awakenings or increasing total sleep time.[52,53,54,55,56] With this profile, zaleplon may be used as a sleep aid for middle-of-the night awakenings, if there still are a few hours of bedtime remaining.

No next-day sedation or rebound insomnia is documented with zaleplon at recommended doses.[52,54,55] There is concern about dependence, but insufficient data; however, development of tolerance does not appear to be significant.[55,57] Use over a few weeks at a time is discouraged; drug dependency risk is a theoretical possibility. This medication is well tolerated, but adverse effects include headache, dizziness, somnolence, and nausea.[55] There are two drug interactions of note: zaleplon plasma levels are increased when combined with cimetidine and are decreased with rifampin.[57] With limited time since its introduction, the true safety and benefits of zaleplon are yet to be determined.

Gabapentin is a relatively new anticonvulsant and mood stabilizer drug that can be safely and successfully used in pain management and to treat insomnia. Although structurally related to the neurotransmitter GABA, this pharmaceutical does not interact with GABA receptors. The mechanism of its action is unknown.

Gabapentin is eliminated unchanged from systemic circulation by renal excretion. The half-life at 5 to 7 hours is almost unaltered by dose or multiple administrations. Because gabapentin is not metabolized in the liver, it is safe even in patients with hepatic impairment. There is little indication for drug-to-drug interactions. This medicine is well tolerated and has few side effects. The most commonly observed adversities include mild degrees of somnolence, dizziness, ataxia, fatigue, and nystagmus. Abuse or dependence on gabapentin has not been reported; this factor is an important advantage, especially when treating insomnia in people with substance misuse histories.

Antidepressant agents are the primary pharmacotherapy for depression; they also are prescribed for pain, and sedating versions are advised for treating insomnia in patients with substance abuse risk factors. Using these drugs for sleeplessness without depression is common but not well studied.[7,34] Sedating antidepressants are not habituating and thus may be especially advantageous for extended treatment durations or for use in former alcoholics and other substance abusers.[7,35]

Tricyclic Antidepressants (TCAs). Sedating tricyclics such as amitriptyline, doxepin, and nortriptyline are effective for inducing sleep and improving sleep continuity.[58,59] Daytime sedation can be significant.[7] Side effects include anticholinergic activity, adrenergic blockade, and cardiac conduction prolongations -- all potentially problematic in geriatric patients and in overdose toxicities.[15,60] The TCAs can alter sleep architecture by reducing REM sleep.[59] Not all TCAs offer prominent sedation; desipramine causes little somnolence.

Trazodone. This drug is strongly sedating and improves sleep continuity.[58,59] Addiction or tolerance is not a problem.[20] Trazodone is popular for insomnia management, especially in persons prone to substance abuse. Side effects of trazodone include oversedation and a-adrenergic blockade. Anti-adrenergic effects with orthostatic hypotension can occur in young people but are more dangerous in elderly patients who are susceptible to injury from falling.[20,60] Postural blood pressure drop is the main risk of this pharmaceutical; priapism is an unlikely possibility.

New Generation Antidepressants. Some selective serotonin reuptake inhibitors (especially paroxetine) are prominently soporific, while others are not and may even cause insomnia (eg, fluoxetine, sertraline, etc). The same applies to other new generation antidepressants; certain ones are sedating (eg, mirtazapine) while others are alerting (eg, bupropion). Sedating versions may be effective even in nondepressed patients, and they are recommended for depression with sleep problems. The presence or degree of sedating or alerting effects from antidepressant drugs varies widely in individual expression. Without dependency problems, these drugs are useful in substance abuse cases. They are safe medications, even in overdoses, and are among the most frequently prescribed pharmaceuticals.

Antihistamines are included in many over-the-counter sleep products. They exhibit sedating properties and are effective for mild insomnia.[5,7,14] They are generally safe and popular, especially in lay usage. Psychomotor impairment with sedation and anticholinergic manifestations are common adverse effects.[7,15,61] Next-day sedation may be a problem, especially in older people. Tolerance may develop with repeated diphenhydramine use.[61,62] Physician prescribing of antihistamines is becoming less frequent with the entry of new, shorter action drugs.

Melatonin is not well studied, yet it may have utility in circadian rhythm-based sleep disorders. Barbiturates are not recommended because of their low therapeutic index, enzyme-induction, and addiction risks.


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