Approximately 40 million to 70 million Americans, or 20% of the population, have either chronic or intermittent sleep problems, according to the National Institutes of Health, and more and more of them are relying on sleep aids as a solution to this growing problem.

In the past 2 years, the FDA approved several new insomnia treatments, including eszopiclone (Lunesta), ramelteon (Rozerem), an extended-release version of zolpidem tartrate (Ambien CR), and other agents are in the pipeline.

New Mechanism of Action
Unlike all the other agents currently available (Table), ramelteon is the first agent that is not scheduled as a controlled substance. In addition, this new agent promotes sleep but does not involve sedation; daytime sedation is often a problem associated with drugs used to fight insomnia. The other nonbenzodiazepine (non-BZD) agents—eszopiclone, zolpidem tartrate (Ambien), and zaleplon (Sonata)—are hypnotics.

All non-BZD agents likely interact with gamma-aminobutyric acid (GABA) receptor complexes, which incorporate a BZD site. GABA receptor complexes are located throughout the central nervous system (CNS); their sedating effects are caused by CNS depression, which also accounts for their “sleeping pill hangover” effects.

In contrast, ramelteon is a melatonin receptor agonist that reinforces our natural sleep rhythm. Our sleep is related to the circadian rhythm, which, when working properly, allows us to keep awake for many hours during the day and then sleep for 8 hours at night. Our normal melatonin rhythm follows this pattern; our melatonin level is low in the day and rises in the evening. As it rises, it decreases the arousal signal that is generated through the suprachiasmatic nucleus.

Ramelteon is a selective receptor agonist for particular melatonin subtypes in the suprachiasmatic nucleus. It enhances the natural sleep-onset process by a focused mechanism that does not involve sedation.

Prescribing Considerations
Ramelteon is indicated for insomnia characterized by difficulty falling asleep. In clinical trials of 375 healthy adults aged 35 to 60 years (Sleep. 2005; 28:303-307), ramelteon-treated patients (16 or 64 mg) had a significantly shorter latency period to persistent sleep and significantly longer total sleep times compared with placebo-treated patients.

Ramelteon is contraindicated in persons with a hypersensitivity to any of its components, in patients with severe hepatic impairment, in patients with severe sleep apnea or with severe chronic obstructive pulmonary disease, and in combination with fluvoxamine maleate.

The most common side effects reported in clinical trials were headache, daytime somnolence, dizziness, and fatigue; other adverse effects included nausea, exacerbation of insomnia, and upper respiratory tract infection.

Before prescribing ramelteon, ask about use of alcohol, caffeine, and other substances; other prescribed medications with stimulating effects; depression/anxiety disorders; discomfort/pain; and medical processes that may be contributing to the insomnia.