Is There a Safe Effective Sleep Medication?

What Is Insomnia?

Insomnia is defined as trouble falling asleep or staying asleep severe enough to cause decreased ability to function during the day. The most common daytime problems reported by people with insomnia include fatigue, sleepiness and cognitive or emotional problems. Unrefreshing sleep is a bit different from insomnia. Virtually every patient with ME/CFS, FM, ES and long COVID reports unrefreshing sleep. Some people sleep less than needed, some more but all have in common that they wake up feeling horrible and often feel the need to rest or sleep during the day to make it through. This occurs even when people fall asleep easily and sleep 10 or more hours each night.

I recommend cognitive behavior therapy for insomnia (CBI-I) as a first line approach for insomnia and unrefreshing sleep. But sometimes careful application of CBT-I isn’t enough to improve quantity and quality of sleep. That’s when it makes sense to consider a hypnotic or sleep-inducing medication. But which ones are safe and effective?

The ideal sleep medication should:

• Improve sleep quality as measured objectively with an overnight sleep study or wearable tracker.
• Increase subjective morning refreshment.
• Be easy to stop when you want or need to do so.

The ideal sleep medication should not:

• Have any severe side effects either short-term like increased risk of car accidents or long term like increased risk of dementia. You can read a previous blog on the risks of sleep medications for more on this.
• Cause tolerance meaning needing to take more and more to be effective.
• Be used for effects other than sleep (such as anxiety) as this will lead to addiction.

Believe it or not, until very recently there were NO sleep medications on the market meeting these criteria.

The benzodiazepines, things like lorazepam, temazepam, alprazolam and others

• Decrease the quality of sleep
• Are associated with tolerance and withdrawal
• Increase the risk of falls and car accidents and
• May increase the risk dementia if used long term.

The Z-drugs (things like zopiclone, eszopiclone and zolpidem) have an improved profile compared with their cousins the benzodiazepines. They don’t worsen sleep quality, neither do they improve it. They are not associated addiction or withdrawal but in some people tolerance does develop meaning the drugs don’t work as well over time. And they do increase the risk of falls and car accidents if taken after midnight or if the person is elderly and has a slower metabolism.

Antidepressants like trazodone, amitriptyline and doxepin are safe from the standpoint of tolerance and addiction but often cause a “hangover” in the morning. And at the low doses used for sleep, there is virtually no antidepressant effect.

NEW Information Dec 30, 2023

Why Might Antidepressants Cause a Hangover?

It turns out that noradrenaline, one of the neurotransmitters implicated in depression, also plays a central role in sleep. Noradrenaline constricts the tiny blood vessels in the brain. This increases the pressure in these vessels, and the pressure pushes blood plasma out of the small vessels and into the cerebrospinal fluid. As this fluid is collected back into the lymph and into the blood, the metabolites in the brain are flushed out to the body where they can be processed by the liver and excreted by the kidneys. This process is called the glymphatic system and was discovered in 2013 by Dr. Maiken Nedergaard and colleagues at the University of Copenhagan. Glymphatic flow helps the brain get rid of many toxic molecules including beta amyloid, the misfolded protein associated with Alzheimer's disease.

Dr. Nedergaard recently spoke at the NIH ME/CFS Research Roadmap webinar on physiology. She reported on more recent research showing that the waves of noradrenaline, which create glymphatic flow during non-REM sleep, can be measured in sleep EEG studies as something called sigma power, a measure that strongly correlates with refreshing sleep.

If noradrenaline levels are too low or too high, the waves or oscillations, sigma power, and glymphatic flow are all negatively affected. Some antidepressants — such as desipramine, nortryptyline, and to a lesser extent, amitryptyline and doxepin — increase the amount of noradrenaline in the brain. Desipramine and nortriptyline are commonly used in chronic pain. Amitriptyline is used for sleep and pain, and doxepin is used for sleep especially in the elderly. Studies in mice show that desipramine inhibits the waves of noradrenaline, decreases sigma power, and impairs memory. This is another example of unanticipated and difficult to measure side effects of medications commonly prescribed for pain and sleep. The moral of this story is that, whenever possible, it is best to use lifestyle modification to manage health. It is cheaper and less risky than medication.

Using Tryptophan for Sleep

What about the amino acid L-Tryptophan? Since I wrote my manual, I had a few patients who did poorly on L-Tryptophan, and I had stopped using it. More recently, we have learned that if the breakdown of tryptophan goes astray, it may result in a dangerous buildup of tryptophan, which can impair cellular metabolism.

Two versions of the enzyme break down tryptophan called Indoleamine-pyrrole 2,3-dioxygenase or IDO. One version (IDO1) can be turned off by infections agents, such as viruses that want to use the tryptophan for their own benefit. The other (IDO2) may be mutated in many people with ME/CFS. If both versions are unable to work fully, tryptophan levels build up and cause a vicious circle or "metabolic trap" in which tryptophan levels rise, blocking the breakdown leading to ever higher levels.

Although this idea hasn’t been proven, I recommend an alternative to tryptophan called 5-hydroxytryptophan (5HTP), which can’t cause the same metabolic problems. Be aware that 5HTP can interact with antidepressants, causing a dangerous increase in serotonin levels. So, although 5HTP is available over the counter, please use it only with the knowledge of your health-care team, especially your pharmacist.

A New Sleep Medication with Promise

A new category of sleep medications came onto the world market in 2014 and one drug in this class, lemborexant (Dayvigo), made its way to Canada in 2020. Lemborexant is a dual orexin receptor antagonist (DORA). These drugs block orexin, a brain chemical responsible for wakefulness. Orexin neurons occur only in the brain – so there may be fewer side effects than when using medications with receptors throughout the body.

A review of studies of lemborexant suggests it improves total sleep time, waking after sleep onset and sleep efficiency. The amount of drug in the body decreases to about ¼ the effective dose by morning, and in the 9 studies to date, there is no evidence of impaired daytime function such as falls. In fact, people reported better morning alertness with lemborexant than with placebo – possibly because the drug improved sleep quality.

My Story

I have had severe insomnia and unrefreshing sleep since becoming ill in 1989. I required sleep medications to get any sleep at all, and for decades all attempts to wean or discontinue medications were unsuccessful. In 2015, I put myself on a CBT-I program and had significant improvement. Since then, I have been able to fall asleep almost every night without medication. However, I still wake up between 2 and 4 am and rarely fall back to sleep unaided. CBT-I made a big difference but didn’t solve my sleep problems fully.

In June 2021, some of you know I purchased an Oura ring (wearable tracker) that showed me I wasn’t getting enough REM or dreaming sleep. This made total sense since it’s been years since I remember dreaming. As an aside, REM is critical for creativity and learning skills like playing an instrument or a sport. REM should comprise about 25% of the total sleep time, and mine was usually below 10%.

Then I attended a scientific presentation on lemborexant and learned that it appears to increase both deep and REM sleep. No other medication on the market does this. So armed with this information and my tracking data, I asked my family doctor if I could try it. I am fortunate to have a collaborative family doctor who agreed. Starting from the first night and every night since then, my REM sleep has been in the low normal range of 20 – 25% of my total sleep time. I am waking more refreshed, and I don’t experience any side effects or morning hangover. Wow.

Needless to say, based on my experience I have mentioned this new drug in my practice groups and online classes. And like every other treatment, some people have benefitted and for others it has made no difference at all.

I’ve been undecided whether to talk about this in a blog post or not. I wonder whether lemborexant could work for many people or whether I was just very lucky? Then, I happened to notice a new paper by renowned meta-analysis researcher Andrea Cipriani, professor of psychiatry at Oxford University. He and his team compared all the sleep medications on the market in a comprehensive meta-analysis.

Which Sleep Drugs are the Most Effective?

Overall, eszopiclone (called Sublinox in Canada) and Lemborexant (called Dayvigo in Canada) came out on top for a combination of efficacy, acceptability, and tolerability. Antihistamines, including antidepressants with antihistamine effects like doxepin and trazodone, show efficacy for sleep but only doxepin had benefits outweighing side effects.

Eszopiclone got the nod even, although there are concerns about adverse effects including sleep behaviors (like sleep walking and eating) and next-day driving impairment. Lemborexant is relatively new to the market, and there isn’t enough safety data yet to be sure it is safe over the long term.

With this new comparison data available, I feel more confident that I am not an outlier and that many others in our community may benefit from lemborexant. If you try it, please let me know how it works for you so that I can increase my knowledge and pass it on.

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