Sleeplessness and Circadian Rhythm Disorder Medication
- Author: Mary E Cataletto, MD; Chief Editor: Selim R Benbadis, MD more...
Short-acting benzodiazepines are often prescribed in the early treatment of sleep-onset insomnia, while long-acting agents are often used to treat long-standing insomnia with sleep maintenance, as well as sleep-onset, insomnia.
Nonbenzodiazepine hypnotics have come into increased use because they do not significantly affect sleep architecture and, unlike benzodiazepines, are not associated with a rebound phenomenon.
Melatonin reportedly is effective against jet lag, as well as in the treatment of sleep-onset insomnia in elderly patients who are melatonin deficient. Melatonin agonists can be prescribed for insomnia characterized by difficulty with sleep onset.
These agents are recommended in preference to barbiturates because of their low toxicity and clinical efficacy. They have a rapid onset of action. Concerns remain with regard to rebound insomnia, residual daytime effects, and addictive potential.
Short-acting benzodiazepines are often chosen in the early treatment of sleep-onset insomnia and are used in conjunction with behavioral therapy. Long-standing insomnia with sleep maintenance, as well as sleep-onset, insomnia often requires long-acting agents.
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.
For patients with sleep maintenance insomnia, a benzodiazepine with an intermediate half-life (eg, estazolam [ProSom]) or a long half-life (eg, quazepam) may be considered.
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. 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.
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 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 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.
These agents are gaining popularity because they do not have a significant effect on sleep architecture and are not associated with the rebound phenomenon seen with benzodiazepines.
Zolpidem is a nonbenzodiazepine hypnotic of the imidazopyridine class. It is rapidly absorbed, has an elimination half-life of 2.5 hours, and is a good short-term option for patients with sleep-onset insomnia who require pharmacologic support. The extended-release product (Ambien CR) consists of a coated, 2-layer tablet and is useful for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The first layer releases drug content immediately to induce sleep; the second layer gradually releases additional drug to provide continuous sleep.
Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. Its precise mechanism of action is unknown, but the drug is believed to interact with the gamma-aminobutyric acid (GABA) receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. It is indicated for insomnia, to decrease sleep latency and improve sleep maintenance. It has a short half-life of 6 hours.
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.
Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. It has a chemical structure unrelated to benzodiazepines, barbiturates, or other hypnotic drugs but interacts with the GABA-benzodiazepine receptor complex. It binds selectively to the omega-1 receptor situated on the alpha subunit of the GABAA receptor complex in the brain. Zaleplon potentiates t-butyl-bicyclophosphorothionate (TBPS) binding and has preferential binding to the omega-1 receptor of the GABA receptor family.
Melatonin Receptor Agonists
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.
Melatonin (herbal/alternative) has been reported to be useful in the treatment of jet lag and in the treatment of sleep-onset insomnia in elderly patients who are melatonin deficient. Recommendations regarding melatonin are based on the extensive literature review from the Cochrane Library.
However, because of the phenomenon of publication bias, studies showing efficacy are more likely to be available for review than those that do not show efficacy. Furthermore, potential users of melatonin should be cautioned that variations in quality, purity, and quantity of active ingredient in natural pharmaceuticals make interpretation of studies difficult and raises concerns about interactions and contaminants.
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 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 the maintenance of circadian rhythm and the normal sleep-wake cycle.
Melatonin is available as an over-the-counter (OTC) preparation. It is used to enhance the natural sleep process and for resetting the body's internal time clock when an individual is traveling through different time zones. It has also been used for the treatment of circadian rhythm sleep disorders in blind people with no light perception.
No recommended daily allowance (RDA) of melatonin has been approved by the US Food and Drug Administration (FDA), nor is FDA-approved prescribing information available for any of the doses discussed here. Individual patients may or may not experience the reported benefits of melatonin.
Physicians and patients should consider the risks and benefits of each therapeutic option. Slow-release products are reported to be less effective. Melatonin is believed to be effective in persons crossing 5 or more time zones and is less effective in individuals traveling in a westward direction.
Orexin Receptor Antagonists
Orexin promotes wakefulness. Antagonism of the orexin receptor suppresses this action by orexin.
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.
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