- Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD more...
Medications used in the treatment of insomnia include nonbenzodiazepine receptor agonists, benzodiazepine receptor agonists, the selective melatonin receptor agonist ramelteon, and sedating antidepressants. All can be considered first-line agents for insomnia; agent choice is largely dictated by past trials, cost, side-effect profile, drug interactions, and patient preference. Pharmacologic therapy is used in concert with behavioral and psychological interventions.
Sedative-hypnotics include nonbenzodiazepine receptor agonists (zaleplon, zolpidem, eszopiclone); short-acting benzodiazepine receptor agonists (triazolam); intermediate-acting benzodiazepine receptor agonists (estazolam, temazepam); and selective melatonin agonists (ramelteon).
Nonbenzodiazepine receptor agonists have a nonbenzodiazepine structure and bind more specifically to the alpha-1 subunit of the gamma-aminobutyric acid–A (GABAA) receptor, which is associated with sedation. They are excellent choices for treatment of sleep-onset insomnia.
Both eszopiclone and sustained-release zolpidem are effective for both sleep-onset and sleep-maintenance insomnia, with a reduced abuse potential and long-term efficacy of up to 6 months as compared with nonselective benzodiazepine receptor agonists.
Short-acting (eg, triazolam) and intermediate-acting (eg, estazolam, temazepam) benzodiazepine receptor agonists are useful for sleep-onset insomnia. These agents have been the hypnotics of choice for many years because of their relative safety compared with the barbiturates, as well as their low cost. By binding to specific subunits of GABAA receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission by increasing the frequency of chloride channel opening.
Benzodiazepines are on the Beer’s List of potentially inappropriate medications for older patients. They are not recommended in the elderly because of the risk of falls; if used, they should be given at the lowest effective dose for the shortest amount of time. The older sedative-hypnotics that have a prolonged half-life increase the risk for next-day sedation and daytime psychomotor impairment and pose an increased risk for abuse and dependence. Other complications of benzodiazepine use include tolerance, withdrawal, abuse, and rebound insomnia.
Selective melatonin agonists are indicated for insomnia characterized by difficulty with sleep onset, particularly for individuals who lack dim-light melatonin-onset stimulation. Melatonin itself is not regulated by the US Food and Drug Administration (FDA) and is thus not approved for treatment of insomnia. Melatonin does not appear to have obvious side effects other than sedation. Currently, ramelteon is the only melatonin receptor agonist approved by the FDA for treatment of insomnia and is available by prescription.
A sedative-hypnotic of the pyrazolopyrimidine class, zaleplon has a rapid onset of action and an ultra-short duration of action, making it a good choice for treatment of sleep-onset insomnia. A second dose can be used during the middle of the night without residual sedation in the morning (this is believed to be an advantage of this hypnotic over others).
A sedative-hypnotic of the imidazopyridine class, zolpidem has a rapid onset and short duration of action. It is a good first choice for treatment of sleep-onset insomnia and produces no significant residual sedation in the morning.
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. The higher-dose sublingual product (Edluar) is available as 5- and 10-mg tablets; an oral spray (Zolpimist) is also available for sleep-onset and/or sleep-maintenance insomnia. The low-dose sublingual product (Intermezzo) is indicated for middle-of-the-night awakening.
Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown, but this agent is believed to interact with GABA receptors 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 (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.
Triazolam depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. It is indicated for short-term insomnia. Triazolam was the first short-acting benzodiazepine for promoting sleep but fell out of favor after high-profile reports of amnesia with its use.
Estazolam is an intermediate-acting benzodiazepine with a slow onset of action and a long duration. Estazolam is a good agent for sleep-maintenance insomnia.
Temazepam is a short- to intermediate-acting benzodiazepine with longer latency to onset and half-life. Temazepam may be more helpful in sleep-maintenance insomnia than in sleep-onset insomnia.
Ramelteon is a melatonin receptor agonist that is indicated for insomnia characterized by difficulty with sleep onset. This agent has high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and to be involved in maintenance of the circadian rhythm and normal sleep-wake cycle. Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal firing (reduces alerting effect of the SCN), and stimulation of the MT2 receptor in the SCN affects the circadian rhythm, causing a phase advance (earlier sleep time).
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.
Except for low-dose doxepin (Silenor), drugs in this category are not approved for treatment of insomnia by the US Food and Drug Administration (FDA), and there have been few randomized, placebo-controlled trials demonstrating efficacy for insomnia. Nevertheless, these agents can be useful, especially in patients with comorbid depression or anxiety.
Amitriptyline is a tricyclic antidepressant (TCA) with sedative effects. It inhibits reuptake of serotonin and/or norepinephrine at the presynaptic neuronal membrane, which increases concentration in the central nervous system (CNS).
Low-dose doxepin is FDA approved for sleep-maintenance insomnia. It is available in 3- and 6-mg tablets.
Nortriptyline has demonstrated effectiveness in the treatment of chronic pain.
By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS.
The side effect of drowsiness seen with some antidepressants can be used to benefit patients in the treatment of sleep-maintenance insomnia or insomnia associated with depression.
Mirtazapine exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, it has been shown to be superior to other selective serotonin reuptake inhibitors (SSRIs). In patients with depression, the sedative properties of mirtazapine may help with sleep-onset insomnia. This drug is not an FDA-approved treatment for insomnia, and no randomized, placebo-controlled trials have demonstrated its efficacy for insomnia.
A nontricyclic antidepressant with short onset of action, trazodone consolidates sleep. It is an antagonist at the type 2 serotonin (5-HT2) receptor and inhibits reuptake of 5-HT; it also has negligible affinity for cholinergic and histaminergic receptors.
Nefazodone inhibits serotonin reuptake and is a potent antagonist at the 5-HT2 receptor. It also has negligible affinity for cholinergic, histaminic, or alpha-adrenergic receptors. The FDA has added a Black Box warning regarding rare cases of liver failure with this drug.
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