Medication Summary
Many agents are useful in treating insomnia. Short-term drug therapy is preferred to restore a normal sleep pattern. Generally, hypnotic drugs are approved for 2 weeks or less of continuous use. In chronic insomnia, longer courses may be indicated, which require long-term monitoring to ensure ongoing appropriate use of the medication.
Benzodiazepines
Class Summary
Benzodiazepine receptor agonists are the mainstay in treatment of insomnia. Flurazepam, temazepam, quazepam, estazolam, and triazolam are the benzodiazepines that are approved by the US Food and Drug Administration (FDA) as hypnotics. These drugs bind to a special benzodiazepine site on the gamma-aminobutyric acid (GABA) receptor complex, enhancing the activity of this neurotransmitter. All have variable half-lives and different metabolites that affect their onset and duration of action.
This class of drugs suppresses rapid eye movement (REM) sleep and reduces stages 3 and 4 sleep while increasing stage 2 sleep. The drug described here, temazepam, is only 1 example of this class of medications.
Temazepam (Restoril)
Temazepam's intermediate rate of absorption and duration of action make it useful for treating initial and middle insomnia. Because temazepam has no active metabolite, cognitive impairment and grogginess the following day are reduced. Temazepam enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Triazolam (Halcion)
Triazolam is frequently chosen as a short-term adjunct to behavioral therapy. This short-acting agent is effective in helping patients fall asleep. It is not effective in persons with sleep maintenance problems. Triazolam enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Estazolam
Estazolam is an intermediate-acting agent with a slow onset of action and a long duration. It is a good agent for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Quazepam (Doral)
Quazepam is used for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Flurazepam
Flurazepam is frequently chosen as a short-term treatment of insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.
Nonbenzodiazepine Hypnotics
Class Summary
These agents are used for the treatment of acute and short-term insomnia.
Zolpidem (Ambien, Edluar, Zolpimist, Intermezzo)
Zolpidem binds at a benzodiazepine receptor subtype (omega I). This receptor is found more in the central nervous system (CNS) than in the peripheral nervous system, which helps to account for the drug's hypnotic effect without significant muscle-relaxant properties. Unlike benzodiazepines, zolpidem does not suppress normal sleep architecture.
Zolpidem is rapidly absorbed, with a fast onset of action (20-30 min), and thus is a good drug for sleep induction. It decreases sleep latency and increases sleep duration.
Zaleplon (Sonata)
Zaleplon is not structurally related to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with the GABA-benzodiazepine receptor complex, causing sedation. It should be taken immediately before bedtime.
Zaleplon decreases the time to sleep onset. Its shorter onset of action means that peak serum concentrations are achieved within 1 hour of administration. This may account for the lower incidence of daytime grogginess and the reduced withdrawal rebound insomnia.
Eszopiclone (Lunesta)
Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. Its precise mechanism of action is unknown, but it is believed to interact with GABA receptors at binding domains close to or allosterically coupled to benzodiazepine receptors. It is indicated for treatment of insomnia by decreasing sleep latency and improving sleep maintenance. It has a short half-life (6 h).
The starting dose is 1 mg immediately before bedtime, with at least 7-8 h remaining before the planned time of awakening. The dose may be increased if clinically warranted to 2-3 mg HS in nonelderly adults, and 2 mg in elderly or debilitated patients.
Melatonin Receptor Agonists
Class Summary
Melatonin receptor agonists (tasimelteon, ramelteon) have been approved by the FDA. Tasimelteon is indicated for non–24-hour sleep-wake disorder. Ramelteon is indicated for insomnia characterized by difficulty with sleep onset.
Tasimelteon (Hetlioz)
Tasimelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors in the suprachiasmatic nucleus of the brain. MT1 and MT2 are thought to synchronize the body's melatonin and cortisol circadian rhythms with the day-night cycle in patients with non–24-hour disorder. It is indicated for non–24-hour sleep-wake disorder in the totally blind.
Ramelteon (Rozerem)
Ramelteon is a melatonin receptor agonist with high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and to be involved in maintenance of circadian rhythm and normal sleep-wake cycles. Ramelteon is indicated for insomnia characterized by difficulty with sleep onset.
Antidepressants, Other
Class Summary
Although no antidepressants have been specifically approved for use in the treatment of sleep disorders, the cyclic antidepressant trazodone is routinely used for this purpose.
Trazodone (Olepro)
Trazodone's mechanism of action is not fully understood but is believed to involve selective inhibition of serotonin uptake by brain synaptosomes and potentiation of behavioral changes induced by the serotonin precursor 5-HT. The major adverse effect of trazodone is sedation.
Orexin Receptor Antagonists
Class Summary
Orexin promotes wakefulness. Antagonism of the orexin receptor suppresses this action by orexin.
Suvorexant
Suvorexant is an orexin receptor antagonist. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R by suvorexant is thought to suppress wake drive. It is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
