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The Science of Sleep Medication

Updated: Mar 18, 2023

When it comes to sleep, some of us yearn for a magical pill; one that provides us with a blissful, dream-filled sleep and helps us feel refreshed, restored and alert upon awakening. If only that were a possibility. The reality is that, whilst there are numerous ‘sleep tablets’ available over-the-counter and on prescription, the magic of sending us off into a perfect slumber is far from reality.


Sleep is orchestrated by a number of different brain systems, all regulated by a concoction of brain chemicals and neurotransmitters. This means it is unlikely that any single pill (which usually act on one brain chemical system at a time) ever has the potential to control sleep in the same way that the brain does.


Think of the brain as a conductor conducting a complex symphony – the music being the wonderful cycles of natural sleep and dreams. The conductor gracefully and skilfully guides each member of the orchestra, telling them when to come in, when to slow down, when to fire up to a crescendo, leaving the listener satisfied and energised at the final note. This is like the richness of the sleep cycles and dreams that we long for, night after night.



If we apply this analogy to our sleeping pill, we could say that it is a conductor who only guides a single violinist within the orchestra. You may get a feel for the piece of music, but the richness and dynamics of the piece are somewhat lost, and the listener is left feeling as if something was missing and wanting more. That’s not to say the single violinist hasn’t done their job well, just that the conductor needs to be able to manage and monitor all instrumentalists in order to get the best results.


The point is that a single sleep medication only acts on one chemical pathway, and whilst these individual pathways are likely to have downstream effects on other relevant sleep pathways, they cannot individually provide the rich orchestration that the brain requires. But that does NOT mean we should reach for multiple sleep pills. In fact, whilst the focus of this article is on sleep medication, research has repeatedly shown that non-pharmacological therapies, such as Cognitive Behavioural Therapy for insomnia (CBT-I) have greater effectiveness at treating insomnia than any pill. So let's turn to the evidence.



So why do so many of us have trouble sleeping?


It is precisely because sleep is controlled by multiple mechanisms that our brains and our bodies are so vulnerable to sleep disruption. Difficulty in any one of those pathways can make sleep hard to catch. In fact, there are over 53 sleep disorders documented in the International Classification of Sleep Disorders, each with their own symptomatology, risk factors, causes and treatments. One person’s sleep problem is possibly very different to the next persons. 

That said, the most common sleep problem, and the focus of this article, is insomnia.


Insomnia is characterised by difficulty getting to sleep, staying asleep, or waking up earlier than desired. It occurs in around 10% of the adult population at disorder level (occurring at least 3 times per week, for oat least 3 months, and associated with significant daytime impairments in various areas of daily functioning). But around 30% of the adult population will experience symptoms of insomnia to some degree. That’s a lot of people!


Quite often, difficulty sleeping occurs as a result of stress or around the time of major life transitions (such as job-related stress, home stresses or responsibilities, changes in routine and even excitement). When these challenges are short lived, quite often our sleep returns to normal once the stressor has passed. But for some individuals, the period of stress can be prolonged, or the sleep problem that occurred can stick around. But sleep problems can also be a side effect of many other medications for different health conditions; they can be a symptom of another disorder; or they can be the result of hyperarousal at night.


It’s when the sleep problem becomes a demon night after night that we long for that sleeping pill, that conductor of the orchestra, to play the music of sleep to us once again. 


Identifying the cause and symptoms of insomnia (i.e. difficulty getting to sleep, or staying asleep, or awakening too early in the morning) are key to knowing what the best approach is to get sleep back on track.


So let’s look at what the options for insomnia are, and what the evidence is for their efficacy and safety. 


Sleep medications for insomnia are numerous and act on different sleep pathways, including antihistamines, herbal preparations, benzodiazepines and non-benzodiazepine receptor agonists, melatonin, and a new generation of sleep medications that have recently received approval for use in the UK, the dual orexin receptor antagonists (DORAs). Let’s look at each of these in turn.



Antihistamines and other over-the-counter sleep aids

Histamine is a naturally occurring neurotransmitter which acts as part of the arousal system. That means it keeps us alert during the day, while levels tail off during the night to allow our arousal systems to get some shuteye. Antihistamines, therefore, block or reduce histamine – theoretically quietening the arousal system, and hence making us drowsy.


Antihistamines, such as diphenhydramine, are typically used by the lay public to self-manage difficulties sleeping. While antihistamines may make it a little easier to fall asleep in the short term, they are not formally recommended as sleep aids for insomnia due to a lack of strong evidence for their effectiveness. Similarly, herbal remedies (such as lavender, camomile, valerian to name a few) also have little scientific support. But if you find relief from them, then there may be other, psychological or physiological mechanisms at play. Though you should be cautioned about the possibility of residual drowsiness the following morning.


Benzodiazepines

Historically, insomnia has been treated using benzodiazepines. These are a particularly strong class of ‘hypnotic’ medication often used to treat anxiety and depression, as well as insomnia. Benzodiazepines work on the neurotransmitter, GABA (gamma-aminobutyric acid). GABA is an inhibitory neurotransmitter in the brain, and one of its functions it to control the switching on and off of the arousal system. By enhancing its effects, as benzodiazepines do, GABA switches off the wake-promoting pathway of the brain, sending us off to sleep.  

However, whilst they are potent at sending us off to sleep, prolonged use over consecutive nights reduces the effects of these medicines, meaning that an individual will need a stronger and stronger dose to reach the required sleep-inducing effects (this is known as tolerance). Benzodiazepines also relax our muscles, and so should not be used in people who have lung or respiratory difficulties, or sleep apnoea (as they can make the muscles that are important for the normal control of breathing relax).


They are also not recommended during pregnancy or several other medical and psychiatric conditions. Benzodiazepines can also trigger rebound insomnia (counterintuitive right?!), daytime sleepiness that can make it difficult to arise feeling refreshed in the morning, and increase the risk of falls in the elderly. For these safety concerns they are not routinely considered as an option for the treatment of insomnia nowadays.


Non-Benzodiazepine Receptor Agonists

However, the newer class of non-benzodiazepine receptor agonists (which act on the same GABA pathway), called the Z-drugs (zolpidem, zopiclone and zaleplon), are frequently prescribed for short-term management of insomnia. Whilst these are considered to have fewer residual side effects than the traditional benzodiazepines, they are still only indicated for short term use (usually only for one week, and up to a maximum of two weeks) and infrequently (so not to be used on a nightly basis). This is because they do also result in tolerance – that is, the need for a stronger dose after continued nightly use to achieve the desired effect; addiction potential; and effects on daytime sleepiness.


The nature of a sleep problem is critical when doctors consider whether to prescribe a Z-drug. Each Z-drug has a different half-life. The half-life is the time it takes for the drug’s effects to reduce by half.


Zopiclone has the longest half-life of the Z-drugs, of around 6 hours, making it useful for difficulties getting to sleep and staying asleep throughout the night. However, residual daytime sleepiness often occurs, and so patients with caring responsibilities or needing to drive or operate machinery in the morning should be cautioned about the potential carryover effects into the morning.


Zolpidem and Zaleplon have shorter half-lives (between 1-3 hours) and may only be useful for difficulties getting off to sleep, but less effective for individuals who typically have trouble staying asleep. So while these drugs may seem like a nice quick fix for an intermittent sleep problem, they should not be used in the long term as they are addictive and require stronger doses to exert their sleep inducing effects, as well as coming with some other residual side effects (one of which is a bitter taste in the mouth – so really can be considered a bitter pill to swallow!).


Additionally, taken at high doses, the Z drugs may reduce Rapid Eye Movement (REM) sleep – a sleep stage important for emotional regulation (see our blog on the Role of Sleep in Mental Health here).


Anti-depressants

Other medications (often antidepressants) are sometimes prescribed to treat insomnia that occurs alongside depression. That said, some antidepressants can disrupt sleep as a common side effect.


In such cases, patients should be advised of alternative treatments, or consider carefully when to take their antidepressants (for example, taking an antidepressant in the morning may be helpful if it makes sleeping difficult). Advice from a medical practitioner should always be sought before making changes to medication use.

 

Melatonin

You may have heard the word ‘melatonin’ talked about a lot when it comes to sleep aids. Melatonin is a naturally occurring hormone secreted in the few hours prior to your normal bedtime. It isn’t a soporific as such, but it is a signal from your biological clock that it is nearly time for sleep. It is secreted when light levels in your ambient environment get darker, and it tells your brain to initiate the wind-down process in readiness for sleep.


While melatonin is available over-the-counter as a sleep aid in lots of countries worldwide, it is only available on prescription in the UK, and only indicated for adults aged over 55 years for insomnia, or for children with neurodevelopmental disorders such as Autism or ADHD. The reason that it is not available in the UK over-the-counter for insomnia is that it is regulated as a medication rather than as a food supplement (as in other countries such as the USA).

For the most part, studies have only investigated its use as a sleep aid in adults over aged 55 years (and levels of naturally occurring melatonin seem to decline as we age). But for healthy, younger adults, who have normal levels of melatonin, it is likely that melatonin will only be of benefit under certain circumstances. For example, melatonin may be useful when your insomnia is due to your biological clock being out-of-sync with the external world. This may occur when you travel across the globe and experience jet-jag; if you are a shift worker and work nights; or if you have a poorly managed circadian rhythm.


Melatonin timed correctly and used in accordance with prescribed sleep scheduling and light exposure programmes, may be helpful in managing difficulties with sleep due to this mismatch in circadian timing (a topic I’ll be exploring in more detail in future blog posts).

 

Dual Orexin Receptor Antagonists (DORAs)

Finally, a new avenue of research has focused on yet another sleep–wake pathway – orexin. Orexin is a neuropeptide involved in the switch between sleep and wake, as well as the transitions between REM and NREM sleep. Orexin sends wake-promoting signals to the arousal system to keep us alert and awake during the day.


A new class of drugs, called Dual-Orexin Receptor Antagonists (DORAs) reduce the action of orexin, quietening the arousal system and making us drowsy. DORAs (in particular, Daridorexant) can be highly soporific, and clinical trials have demonstrated good efficacy and safety profiles, improving the time it takes to fall asleep, reducing awakening during the night, and improving daytime functioning, making them a promising new option for insomnia.

Furthermore, clinical trials have demonstrated DORAs to have no detrimental effects on sleep, no tolerance or withdrawal effects and no evidence of rebound insomnia if stopped abruptly. The Medicines and Healthcare products Regulatory Agency (MHRA) has recently approved the use of Daridorexant for insomnia and it is likely to become available on prescription in 2023.

 

Non-Pharmacological Therapies are the First-Line Treatment for Insomnia

Whilst this article has focused on sleep medications, it is important to mention that the NICE guidelines, and evidence base, actually suggest non-pharmacological therapies to be the first-line treatment for short-term and chronic insomnia. In the first instance of insomnia, patients should be guided on maintaining good sleep hygiene, and only offered a Z-drug for a short time.

Chronic insomnia should be managed with Cognitive Behavioural Therapy for Insomnia (CBT-I) which has been shown by multiple researchers to be more effective in the long term than sleep medications at treating insomnia, and is recommended by the American Academy of Sleep Medicine (AASM) for the first-line treatment of chronic insomnia in adults.


As a final note and a disclaimer, I am NOT a medical professional but a scientific researcher. In this article I attempt to provide the reader with an insight into the academic research on the topic of sleep medication, but this does not constitute medical advice. You should always seek the advice of a medical professional when starting or stopping any sleep medications.


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