Ramelteon: A Novel Therapy May Help Curb the Prevalence of Sleep Deprivation

Ramelteon: A Novel Therapy May Help Curb the Prevalence of Sleep Deprivation

Subhead:First Melatonin Receptor Agonist, without Daytime Sedation

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. More than 35 million prescriptions for sleeping aids were filled in 2004 in the United States, at a cost of $2.1 billion, according to a recent Medco Health Solutions Survey.

In the past 12 month, the FDA approved 2 new insomnia treatments—eszopiclone (Lunesta; Sepracor) in December 2004, and ramelteon (Rozerem; Takeda) in July 2005, as well as an extended release version of zolpidem tartrate (Ambien CR; Sanofi-Synthelabo) in September 2005—and other agents are in the pipeline. Recent surveys underscore the reasons behind the continuing development and increased use of these drugs. According to the Medco survey, adult Americans used twice as many prescription sleeping drugs in 2004 compared with 2000.

“That doesn’t surprise me at all,” observes David Neubauer, MD, associate director, Johns Hopkins Sleep Disorders Center, Baltimore, Md. “There has been a lot more education about sleep problems, and the public is much more aware.”

But not everyone is willing to embrace sleeping pills. In a recent Gallup survey of 1000 adults aged ³50 years sponsored by the International Longevity Center, 46% of respondents said they got <7 hours of sleep each night, and 1 in 4 believed they had a “sleep problem.” Yet only 9% felt that prescription sleep aids were “very safe.”

New Mechanism of Action

“Both doctors and patients have concerns about the safety of prescription sleep medications, especially with long-term use, even though the newer medications…are indicated without any short-term limitations,” Dr Neubauer notes. “Nevertheless, they are all scheduled as controlled substances, with the exception of ramelteon. I think the fact that ramelteon is not a controlled substance has a lot of appeal both for physicians and for those patients who have been wary of taking a sleeping medication in the past.”

Another important feature of ramelteon is that “it has a mechanism of action that allows the promotion of sleep, without the promotion of sedation,”he suggests.

The other nonbenzodiazepine (non-BDZ) agents (Table)—eszopiclone, zolpidem tartrate (Ambien; Sanofi-Synthelabo), and zaleplon (Sonata; King)&mdash;are hypnotics, with a likely interaction with gamma-aminobutyric acid (GABA) receptor complexes, which incorporate a BDZ 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. “We’ve known over the past several decades about the interaction of the homeostatic drive for sleep and the circadian rhythm, which, when it is working right, allows us to be awake for 16 hours or so during the daytime and evening and then be able to sleep reasonably well for 8 hours at night,” said Dr Neubauer.

Our normal melatonin rhythm follows this pattern. “Normally, throughout the daytime, melatonin is very low. In the evening…melatonin rises. As it’s rising, 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 that natural sleep-onset process by a focused mechanism that doesn’t involve sedation like the other sleeping medications do.”

Ramelteon is indicated for insomnia characterized by difficulty falling asleep. In a clinical trial 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.

Contraindications

Ramelteon is contraindicated in the following situations:

• Persons with a hypersensitivity to any of its components
• Patients with severe hepatic impairment
• Severe sleep apnea
• Severe chronic obstructive pulmonary disease
• In combination with fluvoxamine maleate.

Fluvoxamine maleate is a strong inhibitor of the cytochrome P1A2 [CYP1A2] enzyme inhibitor; it has been shown to increase serum levels of ramelteon by approximately 70-fold. When needed, prescribe ramelteon (with caution) in patients taking less potent inhibitors of the CYP1A2 enzyme system, such as rifampin (Rifadin), ketoconazole (Nizoral), or fluconazole (Diflucan).

Also advise patients not to consume alcohol when taking this or any other prescription sleep aid.

In placebo-controlled clinical trials, the most common side effects were headache (7%), daytime somnolence (5%), dizziness (5%), and fatigue (4%); other adverse effects included nausea, exacerbation of insomnia, and upper respiratory tract infection (3% for each).

Tips on Taking the History of Insomnia

Considering the multitude of medical problems, psychiatric disorders, and life circumstances that can lead to insomnia, Dr Neubauer emphasizes that patient evaluation requires a broad history, noting that “shift work, jet lag, and lifestyle choices can all undermine our ability to sleep well.”

He recommends first thinking about the relationship between the homeostatic and circadian systems in relation to the individual patient. “Homeostatically, you need to make sure that there is a sufficient sleep drive to promote sleep when the person expects to be going to sleep. For example, someone who is napping a lot during the daytime is ‘stealing’ some of that homeostatic drive that is needed to get to sleep at bedtime. So considering the timing of sleep is critical.”

In terms of the circadian system, you must ascertain whether the patient is attempting to sleep at a time that makes sense in terms of the day/night cycle and the personal predisposition. “Although a lot of people seem to be driven to sleep at about 10 or 11 at night to 6 or 7 in the morning, certainly there are those who are early birds and can’t stay up past 8 pm and then wake up in the middle of the night and those who can’t fall asleep until the middle of the night and sleep till noon.”

Be sure to ask about:

·Use of alcohol, caffeine, and other substances

·Use of prescribed medications that may have stimulating effects

·Depression or anxiety disorders

·Discomfort or pain

·Medical processes that may be contributing to the insomnia.

Treatment Options for Insomnia

In addition to the non-BDZ sleep aids, 5 old-generation BDZs are also indicated for the treatment of insomnia: estazolam (ProSom; Abbott), Flurazepam (Dalmane; Valeant), Quazepam (Doral; Wallace), Temazepam (Restoril; Mallinckrodt), and triazolam (Halcion; Upjohn). Although these are effective, “if you are looking for a medication for sleep by way of promoting sedation, I would be inclined to use one of the newer-generation hypnotics as opposed to the older traditional benzodiazepines,” Dr Neubauer says.

“It’s exciting to have new options available,” he notes. “Ramelteon is the first with a new mechanism of action, but there are some others in the pipeline that are also deeply different in terms of mechanism of action.”

He stresses that “a lot more patients have insomnia than physicians probably realize. The ones who complain about it are just the tip of the iceberg….If you can help somebody sleep better, you will also have them feeling much better. We also know that insomnia patients tend to be more expensive in terms of health care utilization. So it makes economic sense as well.”

Table. Comparing non-BDZ prescription drugsfor the treatment of insomnia

Drug Mechanism of action Dosage half life Side effects* Comment

Eszopiclone Positive allosteric modulator 2-3 mg at 6 h Headache, dyspepsia, In the elderly, reduce

(Lunesta) of GABA-A receptor bedtime nausea, dizziness starting dosageto 1 mg/d and do not exceed

2 mg/d

Ramelteon Selective melatonin receptor 8 mg 30 min before 1.0-2.6 h Headache, daytime Tell patients to avoid use after

(Rozerem) agonist bedtime somnolence, dizzinesshigh-fat meal; do not prescribe

with fluvoxamine

Zaleplon Positive allosteric modulator 5-10 mg at bedtime 1 h Headache, dizziness, In the elderly, limit dose

(Sonata) of GABA-A receptor for 7-10 d abdominal pain, to 5 mg

asthenia, daytime

somnolence

Zolpidem Positive allosteric modulator 10 mg at bedtime 2.6 h daytime somnolence, In the elderly or debilitated,

(Ambien) of GABA-A receptor for 7-10 d dizziness, diarrhea use 5 mg; should not be taken

with or immediately after a meal

Zolpidem ER Positive allosteric modulator 12.5 mg at bedtime 2.8 h Headache, somnolence, In the elderly or debilitated,

(Ambien CR) of GABA-A receptor dizziness use 6.5 mg; should not be

taken with or immediately

after a meal

*Listed in order of frequency.

BDZ = benzodiazepine; GABA-A = gamma-aminobutyric acid receptor A.