Sedative hypnotics, intermediate-acting benzodiazepine receptor agonists

These agents have been the hypnotics of choice for many years because of their relative safety compared with the barbiturates. By binding to specific subunits of GABA_A receptor sites, these agents appear to potentiate the effects of GABA and facilitate inhibitory GABA neurotransmission by increasing the frequency of chloride channel opening. The older sedative hypnotics have prolonged half-life with an increased risk for next day sedation, daytime psychomotor impairment, and an increased risk for abuse and dependence.

Useful in sleep-onset insomnia.

Estazolam (ProSom)

Intermediate acting with slow onset of action and long duration; good agent for sleep-maintenance insomnia.

Temazepam (Restoril)

Short to intermediate acting with longer latency to onset and half-life; may be more helpful in sleep-maintenance insomnia.

Tricyclic antidepressants

Drugs in this category are not FDA approved treatment of insomnia, and there have been no randomized placebo controlled trials demonstrating efficacy for insomnia.

Amitriptyline (Elavil)

Tricyclic antidepressant with sedative effects. Inhibits reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases concentration in CNS.

Doxepin (Adapin, Sinequan)

Increases concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. These effects are associated with a decrease in symptoms of depression.

Nortriptyline (Aventyl HCl, Pamelor)

Has demonstrated effectiveness in the treatment of chronic pain.
By inhibiting the re-uptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the CNS.
Pharmacodynamic effects such as the desensitization of adenyl cyclase and downregulation of beta-adrenergic receptors and serotonin receptors also appear to play a role in its mechanisms of action.

Non-tricyclic antidepressants

The side effect of drowsiness seen with some antidepressants can be used to benefit the patient in the treatment of sleep-maintenance insomnia or insomnia associated with depression.

Trazodone (Desyrel)

Nontricyclic antidepressant with short onset of action; consolidates sleep. Antagonist at 5-HT2 receptor and inhibits reuptake of 5-HT. Also has negligible affinity for cholinergic and histaminergic receptors.

Nefazodone (Serzone)

Withdrawn from market in May 2004 due to hepatotoxicity risk. Inhibits serotonin reuptake and is potent antagonist at type 2 serotonin (5-HT) receptor. Also has negligible affinity for cholinergic, histaminic, or alpha-adrenergic receptors.

Antidepressant, alpha-2 antagonists

This drug is not an FDA approved treatment for insomnia, and no randomized, placebo-controlled trials have demonstrated its efficacy for insomnia.

In patients with depression, the sedative properties of the drug may help with sleep-onset insomnia.

Mirtazapine (Remeron, Remeron SolTab)

Exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, shown to be superior to other SSRI drugs.

Selective melatonin agonists

Indicated for insomnia characterized by difficulty with sleep onset.

Ramelteon (Rozerem)

Melatonin receptor agonist with high selectivity for human melatonin MT₁ and MT₂ receptors. MT₁ and MT₂ are thought to promote sleep and be involved in maintenance of circadian rhythm and normal sleep-wake cycle. Stimulation of the MT1 receptor in the suprachiasmatic nucleus (SCN) inhibits neuronal firing (reduces alerting affect of the SCN) and stimulation of the MT2 receptor in the SCN affects the circadian rhythm causing a phase advance (earlier sleep time).
Ramelteon has a short half-life of 1-2.6 hours. Its active metabolite M-II has a half-life of 2-5 hours. It has a 3-5 times greater affinity for the melatonin receptor and is up to 17 times more potent than melatonin.