Insomnia and Dual Orexin Receptor Antagonists - Suvorexant

There has been a breakthrough in the treatment of insomnia. A new compound being tested and prepared for the market blocks a neurotransmitter receptor for orexin (hypocretin), the chemical messenger responsible for arousal and “wakefulness.” Dual orexin receptor antagonists (DORAs) have been shown to improve circadian rhythms and sleep patterns with no side effects, the first drug to do so since the beginning of research to cure insomnia.

This will be a novel treatment for insomnia and the first a brand new class of medicines.

The History of Hypnotics

With a demographic of about 15% or more suffering from worsening or chronic insomnia in the United States, the market for so-called “hypnotics” has always been big.

In the beginning, starting in about the 1950s, physicians treated rather rare cases of insomnia with sedatives, mainly barbiturates. These treated the symptoms of insomnia rather than the cause, which was unknown. As drugs such as meprobamate and chloral hydrate proved addictive or even fatal, the use of barbiturates was finally ended and medical science began its focus on the chemical biology of the brain and sleep to figure out how insomnia functioned in human neuro-pathways and how to combat it chemically.

Barbiturates were known to cause a flat result on brain scans, mimicking actual brain death. They activate a channel receptor for GABA (gamma-aminobutyric acid) which is a central inhibitory neurotransmitter.

The next drugs sold to fight insomnia were safer, but still potentially harmful or toxic. Benzodiazepine caused some respiratory issues and memory loss. Following that, drugs like zaleplon, zolpidem, and zopiclone were created and continue to be prescribed as sleep aids under strict control by the FDA, which remains concerned about the “Z-drugs” potential for addiction and abuse.

As the results of pharmacological research for the treatment of insomnia were mixed—with some success, some fatalities, and some bad side effects—medical research recently began to move in a new direction.

DORA

The dual orexin receptor antagonists (DORA) compounds actually follow in the footsteps of some research done years ago which suggested that a treatment of the orexin system, which modulates of wakefulness and arousal, may be a new path toward a final treatment of insomnia. Although this was understood as a possibility at the time, it was not undertaken until 2003.

In the trials, doses of DORA were found to have few if any side effects, although very high doses impaired human performance during the day. However, there were no incidences of memory loss and no instances of a return or exacerbation of insomnia once the compound was taken away. It often happens that after a successful treatment, insomnia will return and be worse than it was before, a phenomenon which is called “rebound cessation.”

The DORA compound did not impair cognition, attention, or working memory. All of this is very rare and exciting for the world of insomnia research. Insomnia drugs have classically come at the cost of heavy side effects and health risks.

Furthermore, the technique of blocking orexin gets closer to treating the real cause of insomnia. Other drugs effectively treated a symptom of a brain condition, whereas treating the orexin system actually treats the brain condition itself. Orexin are a small component of chemical brain activity but they control a huge number of wake-promoting signals with enormous anatomical projections throughout the brain and in large cell groups throughout the body. Stopping orexin from entering the cell body treats the chemical issue that is at the core of arousal and wakefulness-promoting conditions. This is seen as a better alternative to simply promoting a depletion of brain activity with the use of sedatives in order to attain a sleep state.

Moving Forward

Only long-term human trials will tell us if the drug is, in fact, completely safe and effective, but many of the researchers feel this treatment is more promising than others that have gone before it. Some researchers have expressed concern,however, that the drug actually worked too well, causing narcoleptic symptoms in previously insomniac patients.

Narcolepsy is not simply a bad case of sleepiness. Sufferers experience waking dream states, hallucinations, abnormal rapid eye movement, and episodes of muscle paralysis. It is actually caused by an autoimmune attack against the body’s neurons that express orexin.

Some question if it is wise to replace a large minority of insomniacs with a population of narcoleptics. Yet even so, the U.S. Food and Drug Administration is reviewing the use of DORAs for the treatment of insomnia. Clinical trials will continue for most of this year. After a schedule assessment and determination has been completed by the FDA the drug, to become known as Suvorexant, will become available in the United States and throughout the world.

Summary

The Center for Sleep Science at California’ renowned Stanford University in Palo Alto was responsible for the recent studies and for the discovery in 1998 of the critical role that orexins A and B play in sleep, wakefulness, insomnia, and narcolepsy. With the latest twelve-month and two-month trials having advanced the understanding of how DORAs can be used in a new pharmaceutical for the treatment of insomnia, focus on the orexin system has peaked. The results so far look good and the drug is making its way through FDSA approval.

The global pharmaceutical company Merck, known as MSD outside of the US and Canada, has submitted the drug to FDA approval and will be providing the new pharamceutical to markets once it receives final approval.