sleep

As many as 40 million people in the U.S. experience some form of insomnia, making it the most common sleeping disorder. Sufferers can have trouble falling asleep, staying asleep, or returning to sleep after waking in the middle of the night, and can experience persistent drowsiness, irritability, anxiety, difficulty learning and remembering the next day. When chronic, insomnia can impede daily functions and increase the risk of cardiovascular disease.

Insomnia is two types: Acute Insomnia and Chronic Insomnia. The difference between the both types is that acute insomnia lasts for a short time for example before an important exam or in case of a job loss, while chronic insomniais when someonedoes not sleep well at least three nights a week for three months. 

To treat acute insomnia, doctors often turn to drugs, such as zolpidem. For chronic insomnia, sleep experts recommend combining a drug, to take the edge off initially, with cognitive behavioral therapy for insomnia (CBT-I), which focuses on relaxation training, sleep hygiene (e.g., limiting caffeine before bed), stimulus control, cognitive therapy (changing beliefs and habits to promote sleep), and limiting the amount of time spent in bed not sleeping.

David Cunnington, a physician and director of the Melbourne Sleep Disorders Centre in Australia, and colleagues found in a recent meta-analysis that CBT-I is effective; patients treated with CBT-I took an average of 19 fewer minutes to fall asleep and slept for an extra 26 minutes.But CBT-I can be expensive and difficult to access, and can require as many as eight sessions with a certified physician.

Still, the easiest form of insomnia treatment (at least in the short term) is a drug, Benzodiazepines discovered in 1955, were the first class of drugs used as sleeping pills. These agents, of which temazepam (Restoril) is now the most commonly prescribed for insomnia, bind to GABA receptors to enhance the sedative effects of the neurotransmitter. No study of benzos has shown improvements in daytime functioning, even though they increase sleep length.

A newer class of GABA receptor agonists, the so-called Z-drugs, was approved for insomnia in the 1990s. These agents, including zolpidem, zaleplon, and eszopiclone, are chemically different from benzos: they tend to be more readily absorbed for faster sleep onset, and they have a shorter half-life that decreases next-day grogginess. Like benzos, Z-drugs are effective for some insomniacs, but for others they decrease the amount of certain stages of sleep and can lead to a lack of concentration as well as memory impairment. Other agents approved as sleep medications include melatonin receptor agonists, antihistamines, and antidepressants, but these have limited efficacy, according to most sleep experts.

They are trying to invent a new sleeping pill…

In 2014, the Food and Drug Administration (FDA) approved the first orexin receptor antagonist, Merck’s suvorexant, and at least two more drugs of this class are currently in clinical trials. Previous sleep medications acted as sedatives, targeting GABA receptors to facilitate brain inactivity. Suvorexant, on the other hand, decreases wakefulness by blocking the brain’s orexin receptors.

“The orexin system is a super candidate as a target for insomnia treatment,” says Michael Perlis, director of the Behavioral Sleep Medicine Program at the University of Pennsylvania. “There are lots of reasons to believe some people with insomnia are hypersecretors of orexin, which is why they can’t sleep. Toning down orexin is a brilliant idea.”

In a long-term study, 521 patients who received 40 mg of the drug nightly (30 mg for those older than 65) for 12 months took less time to fall asleep and stayed asleep throughout the night. According to the company’s clinical trial data, there were no signs ofeffects such as cataplexy or narcolepsy in the trial participants. As a result, the FDA approved administration of the drug only at the two lowest (15 milligrams and 20 milligrams) of the four doses tested in the Phase 3 trials, and, subsequently, at two doses that are even lower (5 mg and 10 mg).

At least two other orexin receptor–targeting drugs are now in development. Tokyo-based Eisai and Connecticut-based Purdue Pharma are set to begin a global Phase 3 trial with a DORA called lemborexant. And Belgium-based Janssen Pharmaceutica NV, a Johnson & Johnson company, is teaming up with Massachusetts-based Minerva Neurosciences an orexin-2 single receptor antagonist (2-SORA). Also known as MIN-202, the drug is being evaluated for insomnia in a Phase 1 trial of patients who also have major depressive disorder as well as in a Phase 2 study of insomnia patients without comorbidities.

Even as more orexin-targeting sleep drugs make it to market, a fundamental challenge to treating insomnia remains: the risk of psychological addiction. Most clinicians prescribe insomnia pills to be used sparingly, only a few times per week. But this is a disaster because on the nights the patient doesn’t take the pill, he expects to sleep poorly, and learns that he can’t sleep without a pill,” says the University of Pennsylvania’s Perlis.

In a recent pilot study of 55 individuals, Perlis and his colleagues found that those who took a placebo on nights they would have skipped a dose maintained the effect of the sleeping drug and felt more rested.On nights without a pill, those who followed the standard intermittent dosing slept more poorly and had next-day insomnia symptoms.

The results point to the need for smarter approaches to insomnia treatments that tap into what is known about human behavior and psychology. “Insomnia is complex and heterogeneous, and patients have different degrees of response to interventions” says Herring.

Even with the new class of orexin-targeting drugs, doctors who work with sleep-disorder patients still think that:“None of the available sleeping pills are curative, and therapy with hypnotics is considered a form of palliative care” says Perlis. “Only CBT-I appears to confer durable results lasting months and years after treatment is discontinued.”

References:

  • http://www.the-scientist.com/?articles.view/articleNo/45356/title/Desperately-Seeking-Shut-Eye/
  • JAMA, 301:2005-15, 2009
  • Ann Intern Med, 163:191-204, 2015
  • Lancet Neurol, 13:461-71, 2014
  • Sleep Med, 16:1160-68, 2015