Ramelteon for insomnia

The introduction of ramelteon to the market in 2005 was a significant advance in insomnia medication.  Ramelteon is a truly different type of drug from older sleep aids.  It works through a different neurochemical pathway and having it available expands the treatment options for doctors and patients.

Ramelteon works by mimicking melatonin; it is called a melatonin receptor agonist  http://www.ncbi.nlm.nih.gov/pubmed/20136385. In practical therapy, it is actually weaker (patients don’t feel as drugged) than other prescription medicines such as the Z-drugs, but the lower side effects and difference in sleep architecture upsets make ramelteon a preferred medicine for many.

The suprachiasmatic nucleus is the master clock in the brain.  The activity of the SCN is an important circadian signal,keeping us awake during the day and allowing us to sleep at night.  Melatonin effectively dampens the SCN neuronal firing. Because it mimics melatonin and can shift the timing of at least part of the circadian processes in the body, Ramelteon may find use in treatment of circadian disorders such as DSPS and ASPS. Researchers have found administration of ramelteon results in the reduction of body temperature, - something that normally happens when the body falls asleep.

Ramelteon binds to the melatonin receptors in the brain cells that have these receptors. Scientifically, it’s called a selective MT-1 receptor agonist. Recent research found it also binds to the MT-2 receptor, also, but not to the MT-3 receptor. Affinity for MT-1 is approximately 1000 times affinity for MT-2.   It has no real effect on the other neurotransmitter systems that are important in sleep: GABA, histamine, opiate, or benzodiazepine.
(http://www.scopemed.org/fulltextpdf.php?mno=6160) And from the point of view of the drug designer, that’s good.  You want a drug that is as specific as possible.

Ramelteon has no affinity for benzodiazepine, dopamine, and opiate receptors and therefore little risk for dependence. There is also less risk for impairment due to feeling loopy the way some sleeping aids do. Clinical tests show that treatment with ramelteon significantly shortened latency to sleep onset and somewhat increased total duration of sleep. Even after one week of use, sleep quality was improved.


Ramelteon may prove a particular boon to the problem of insomnia in older people. As we age, our bodies lose the ability to respond to zeitgebers and tend to fall out of sync with environmental cues. This is why melatonin finds use with older patients and why ramelteon may be particularly effective.

Alzheimer's Disease researchers have also been investigating ramelteon for use as part of dementia treatment. More on this.

On the Market

Ramelteon is sold under the brand name Rozerem in the US.. The chemical name is (S)-N-[2-(1, 6, 7, 8tetrahydro-2H-indeno-[5, 4-b]furan-8-yl)ethyl]propionamide and the formula is C16H21NO2. Patients take it before bed, every night. A typical dose is one 8 mg pill, but your doctor will give you specific instructions about your needs.

There is no generic form available. However, the cost is not excessive and appears to be under $100 for a month's supply.

Side Effects

Side effects are relatively minor compared to other insomnia drugs, with headaches being the most common complaint. Ramelteon is known to interact with commonly used prescription drugs. Drug interaction is always a concern when you take more than one drug, but particularly in this case, so be sure your doctor knows about ALL medicines you are taking, including over-the-counter ones.

Rebound insomnia does not appear to be as big a problem with ramelteon as with some drugs, and in sharp contrast to benzodiazepines, withdrawal effects are minimal.  Patients say ramelteon does not feel like a sedative when they take it, unlike older sleep aids. When taken by pill, ramelteon reaches a peak serum concentration in an hour.  It’s metabolized in the liver and the half-life is such that in the doses administered, sleep time is about right.  Like pretty much all drugs, the half-life is longer in elderly people, but this drug has actually found great success in the elderly, in particular.  It appears to really help old people with chronic insomnia. http://ajpregu.physiology.org/content/280/5/R1582.full

Will ramelteon prove as effective and popular as the Z-drugs? Most likely, it will be another tool in the doctor's arsenal. It will work for some patients, but not for others. The fact that it has low side effects and doesn't seem to cause dependence (based on tests with monkeys) means it will be appealing to some. And many people don't need much help to sleep, only a little. Ramelteon, even if it is weaker, could still be valuable.

The Japanese corporation Takeda makes Ramelteon.

Is ramelteon better than melatonin that you can buy over-the-counter much cheaper?  We cannot find any data of controlled comparisons of the two.


Ramelteon for the treatment of insomnia in adults: a systematic review and meta-analysis

Pharmacology of Ramelteon, a Selective MT1/MT2 Receptor Agonist: A Novel Therapeutic Drug for Sleep Disorders

An efficacy, safety, and dose–response study of Ramelteon in patients with chronic primary insomnia

Melatonin and sleep in aging population.


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