A study from a team of Japanese researchers has revealed a new class of sleep-inducing drugs can potentially preserve a person's ability to wake quickly in response to loud threatening noises. The study suggests this new type of hypnotic drug could also reduce the "hangover effect" that commonly strikes people taking regular benzodiazepine-based sleeping aids.
"Benzodiazepines stimulate the widespread brain receptor GABA-A, which makes us sleepy but also suppresses off-target brain areas – including the "gatekeeper" that decides which sensory inputs to process," says Tomoyuki Kuwaki, senior author on the new research.
A classic study from the 1980s revealed that benzodiazepine triazolam, at a high dose, so strongly sedated the trial subjects that half the participants slept through three, minute-long loud bursts from a fire alarm. This inability to rouse subjects dosed with sleeping pills, when faced with emergency sensory input, is a serious problem that modern medicine has yet to overcome.
Over recent years a new class of drug called dual orexin receptor antagonists (DORAs) has been developed to assist with sleep difficulties. Instead of targeting the GABA brain receptors, DORAs work by more selectively influencing the brain's arousal and wakefulness pathways. This promises safety advantages over traditional sedatives, with one reported benefit a reduced "hangover effect," with the drug less likely to impact a user's driving ability the next day.
The new study set out to see if DORAs functioned as a better alternative to benzodiazepines in terms of also maintaining a person's alert responses while sleeping. Through a series of mouse trials, the researchers first revealed that an experimental version, called DORA-22, was as effective at promoting sleep as the benzodiazepine triazolam.
In several different arousal tests, however, the research revealed the animals responded quickly to threatening stimuli and sounds, suggesting the new drug doesn't inhibit or suppress the body's waking systems in the same way as traditional sedatives.
"As expected, arousal in response to these threatening stimuli was delayed significantly in the triazolam treatment, but not in the DORA-22 treatment, compared to placebo," says Kuwaki. "Even though the DORA-22-treated mice were quickly woken by a threat, they subsequently fell back asleep as quickly as with triazolam, and significantly faster than with placebo."
It is unclear at this point whether the results can be replicated in humans, but the new study offers compelling insights into how this new class of hypnotic drugs works in fundamentally different ways to the traditional sedatives we are familiar with.
A DORA by the name of suvorexant became available in the United States in 2015 for treating serious insomnia. Since the drug's approval there have been a number of safety reports suggesting it was not as effective at inducing sleep as many had hoped. More than 40 percent of the reports suggested the drug simply did not work to help induce sleep, and 20 percent claimed the drug actually had the opposite effect, resulting in anxiety and wakefulness.
The Japanese team behind this new research suggests the concerns around suvorexant's efficacy won't signal the end for DORA drug development, but certainly more work needs to be done. DORAs are currently being refined so they clear the body faster, eliminating any "hangover effect," and their unique ability to preserve the wake response makes them an important and interesting new drug deserving of further investigation.
The new study was published in the journal Frontiers in Behavioral Neuroscience.
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