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“It really provides a whole new tool to our toolkit.” Philip Gehrman, Ph.D., CBSM

Sleep or the lack of it is a serious issue in chronic fatigue syndrome and fibromyalgia. Not just your energy level but your ability to think clearly, your sensitivity to pain and your emotional well-being can be affected by the amount and depth of sleep you get.

Despite the various sleep medications present many are not getting deep, enriching sleep and insomnia remains a problem. A new sleep medication with a novel mechanism due out later this year could change that.

In fact, it and the drugs expected to follow it, could create a sea-change in how sleep issues are treated.

It all started about 15 years ago when two research teams stumbled upon a new receptor. Further research led to a fundamental re-assessment of how sleep happens (or does not happen) and, ultimately the development of a new class of sleep drugs.

The neurons that promote wakefulness (called orexin neurons) do not get turned down at night in insomniacs. Suvorexant reduces orexin neuron activity, hopefully allowing insomniacs to go to sleep.

Insomniacs on orexin fell asleep more quickly than those on placebo, and slept longer, and had fewer awakenings during sleep in the latest clinical trial. Animal studies suggest the drug affects cognitive functioning less than current sleep drugs.  The fact that all stages of sleep improved suggested the drug might have broad applications in ME/CFS where different types of sleep disturbance occur. Results can occur as quickly as the first night.

FDA Wariness

Nine clinical trials (and three phase III clinical trials) later, almost everyone is betting the FDA will approve its first new insomnia drug in over thirty years this year. In a review analysts called ‘tough’, however, the FDA expressed wariness about the daytime sleepiness some participants experienced at higher doses. After halving the dosage for Ambien in women because of sleep-walking and other issues, the FDA is keeping a close watch on sleep inducing drugs.

The potentially large number of people – from young to old, some on other drugs – taking a new drug with a new mode of action raises concerns at the FDA.

After hundreds of reports of car accidents due to Ambien, the FDA is now requiring driving tests to assess the impact sleeping drugs have on driver safety. Several participants on higher doses who swerved out of their lane too often suggested suvorexant could pose a problem for drivers the next morning.

After noting that suvorexant stays in the body 8 times longer than Ambien, and that people on the drug cannot assess their driving ability accurately, Public Citizen spoke against its approval.

The FDA panel, however, voted 10-3 that suvorexant is safe at 15/20 mgs, and 8-7 that it is not safe at 30/40 mgs.  The FDA is expected to approve the drug at lower doses.

From the Hammer to the Scalpel a New Approach to Enhancing Sleep

One of the most exciting things about suvorexant is how different it is.  According to Dr. Daryle Shoepp of Merck Labs, most sleep drugs work by turning off GABA neurotransmitters, but because they turn off GABA receptors all over the brain they essentially bludgeon the brain to sleep.

Because they turn off GABA receptors indiscriminately Ambien-like drugs can be used to prevent convulsions, to reduce anxiety, etc., and help people to fall asleep.  Benzodiazepines effectively enhance short-term sleep, and, in fact, may be more effective than suvorexant at short term sleep inducement, but problems with tolerance  and dependence have left sleep specialists clamoring for better drugs. Withdrawal from benzodiazepines can even result in increased insomnia.

hypothalamus picture

Surovexant targets the neurons in the hyopathalamus of the brain

Developed to target a key process in sleep first identified in lab animals and then in humans, suvorexant is a scalpel to GABA drugs hammer.  In contrast to the billions of neurons the current crop of sleep drugs affects, suvorexant targets about 100,000 neurons in the hypothalamus.

Studies suggest suvorexant has fewer side effects than benzodiazepines and is not addictive.  A yearlong study suggested suvorexant had good staying power and produced few side effects with about 10% reporting morning drowsiness.

Despite the availability of lower-cost alternatives analysts project sales could reach $900 million dollars in the first year.

More Applications on the Way (?)

Orexin neurons in the LHA are anatomically well placed to provide a link between the limbic system, energy homeostasis, and brain stem monoaminergic or cholinergic neurons….

These findings indicate a critical role for orexin neurons in the regulation of vigilance states, according to internal and external environments, for survival.  Yamanaka and Inutsuka

Don’t be surprised if suvorexant does not end up affecting more than sleep.  Concentrated in the hypothalamus, orexin neurons axons extend throughout the brain.

Autonomic Nervous System – The ‘always on’ orexin neuron issue, interestingly, appears to resemble a similar autonomic nervous system (ANS) issue in ME/CFS.  Programmed to always be ‘on’, the sympathetic nervous system (SNS) is only turned off when the parasympathetic nervous system (PNS) tells it to calm down. The default position, for the ANS, in other words, is to have the SNS ‘on’ so that it can quickly respond to an emergency situation that requires that we fight or flee.

The inability of the parasympathetic nervous system, including the vagus nerve, is to turn the SNS off, appears to contribute to the hypervigilance and ‘wired but tired’ feeling found in ME/CFS.

orexin neuron functions

Orexin neurons extend throughout the brain and affect many functions including the autonomic nervous system

Given that, orexin’s regulation of the ANS is intriguing. Orexin’s stimulation of the sympathetic nervous system suggests that orexin inhibitors such as suvorexant might be able to help reduce the ‘arousal’ present in ME/CFS. Propranolol’s ability to reduce orexin induced heart rate increases suggests it could be impacting that system in ME/CFS.

Knockout mice without orexin neuron functioning demonstrated reduced cardiovascular responses to an emotional stress, another issue with ANS implications, which may come to bear in ME/CFS.

Cerebral Glucose – With the evidence of reduced cerebral glucose concentrations in ME/CFS, it’ intriguing that reduced glucose triggers orexin neuron activity (and increased wakefulness). Likewise orexin’s stimulation of the histaminergic neurons of the brain is interesting given the interest in mast cell activation and histamine role in ME/CFS.

Glutamate – Then there’s the fact that glutamate, a possible player in ME/CFS and other neuroinflammatory disorders, activates orexin neurons.

Merck is also reportedly tinkering with a similar ‘molecule’ they believe may be able to affect migraines, neuropathic pain and depression.

Conclusion

Suvorexant’s expected FDA approval will bring a new class of sleep drug to ME/CFS/FM patients suffering from insomnia.  Targeting a sleep center of the brain, suvorexant may be a better fit for chronic insomniacs than the anti-hypnotics available now. The drug’s ability to down regulate sympathetic nervous system functioning suggests it could have ancillary benefits as well.

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