Everything You Should Know About Tasimelteon Vs Ramelteon

Published 2016-07-15 18:00:00 sleep

Tasimelteon (tradename Hetlioz) and ramelteon (Rozerem) are FDA-approved prescription drugs that treat sleep disorders.

Tasimelteon vs Ramelteon Breakdown

  • Uses. Both drugs treat sleep disorders. Tasimelteon is approved for Non-24-Hour Sleep-Wake Disorder, ramelteon is approved for insomnia (difficulty falling asleep).
  • Mechanism. Both bind melatonin receptors
  • Receptor binding. Tasimelteon has 2-5x greater affinity for the melatonin receptor MT2 than MT1. Ramelteon has 10x the affinity for the melatonin receptor MT1 than MT2.
  • Half-life. The half-life of tasimelteon is about 1 hour (according to one source). The half-life of ramelteon is 1-2.6 hours.
  • Interactions. Ramelteon has drug-drug interactions with Amiodarone, Ciprofloxacin, Fluvoxamine, Ticlopidine. Since tasimelteon is metabolized by CYP1A2 and CYP3A4/5, it interactions with many drugs also metabolized by these enzymes.

Before elaborating on these differences, I'm going to cover what these drugs treat, how they work, and what you need to know to stay informed about your sleep aid.

Sleep Drugs (Somnogens): Who Cares?

Why should you care about sleep medications in the first place? If you have a recurrent sleep disorder, medication is often necessary. (It's always better to solve problems with lifestyle changes like exercise but that is not always possible).

Some sleep medications have insidious ill-health effects, whereas others are relatively benign.

Here's an example of one of the worst-offendors: seroquel. Seroquel is an atypical antipsychotic that's being prescribed off-label for insomnia. But it's diabetogenic (1/3 of patients will eventually get diabetes on it). To be clear, some severe cases of insomnia require severe interventions. But I wouldn't be surprised if this medication were prescribed inappropriately for individuals who could benefit from drugs with more tolerable side effects.

What are the key differences between tasimelteon verses remelteon? Read on.

No More Sleepless Nights

Shoddy sleep quality is the bane of my existence. Its unpleasant effects creep up on you. A few nights of bad sleep? Surviveable. But chronic, unending insomnia can result in profound unhappiness.

Sleep disorders are classified as follows:

  • Insomnias (trouble falling or staying asleep)
  • Hypersomnias (sleeping all the time - narcolepsy)
  • Breathing disorders (think sleep apnea - where you briefly stop breathing multiple times a night)
  • Circadian disorders (your biological is out of sync. You could have a circadian disorder if you're a hardcore night-owl who can't sleep before 4am. Or just a college student).
  • Parasomnias (unusual behavior when you're asleep, like sleepwalking, sleep-driving, and so forth).
  • Movement disorders (example: restless leg syndrome can interfere with a decent night's rest)

Where do tasimelteon and ramelteon come in? These prescription sleep drugs treat insomnias and circadian disorders. They mimic the effects of melatonin. Unshockingly, drug nerds call them melatonin-mimetics.

Sleep Drugs On The Market

In recent years, a slew of sleep aids - both over-the-counter and prescription - have become available. Sleep aids can be broadly classified like so:

  • Antihistamines
  • Stuff like Benadryl (diphenhydramine). These block the histamine receptor, which makes you drowsy.
  • Tricyclics
  • These are old-school antidepressants that have fallen into disfavor due to their burdensome side effects. Usually a last resort.
  • Benzodiazepines
  • Drugs like Klonopin (clonazepam). Benzos bind the GABA receptor. This is not a first-line treatment for insomnia due to the risks of substance use and cognitive problems.
  • Z-drugs
  • Think Ambien (zolpidem). Most z-drugs are short-acting drugs that, like benzodiazpeines, bind GABA. The effects? Sedation, amnesia, and (hopefully) increased sleep quality for those who need it.
  • Melatonin Mimetics
  • Both tasimelteon and ramelteon fall into this class. They bind the melatonin M1 and M2 receptors. This is the most elegant solution to the problem of insomnia - but is not the most effective.

Tasimelteon vs Ramelteon

So what's the difference between tasimelteon vs ramelteon, anyway?

Tasimelteon treats non-24-hour sleep-wake disorder. Ramelteon has broader applications: physicians prescribe it for general insomnia.

Both drugs are "melatonin mimetics." In other words, these melatonin agonists mimic the effect of melatonin. They selectively bind to melatonin receptors in the brain (MT1 and MT2).

Melatonin is a neurohormone that affects many bodily functions. But it's most well known for its role in sleep and circadian rhythym. If you're jetlagged, melatonin is probably playing a role!

What's Insomnia?

If you're not a robot, there's a good chance you've experienced insomnia. Insomnia is a common sleep disorder. About 10-15% of people self-identify as insomniacs.

Most of the time, insomnia is transient. Maybe you can't sleep the night before an exam. Or a stressful breakup impairs your sleep quality for a month.

Falling Asleep Vs Staying Asleep

To state the obvious: insomnia is the inability to fall asleep (sleep initiation) or stay asleep (sleep maintenance). These are separate processes. Some people are prone to awakening in the night; their sleep is fragmented. Other people are good to go once they fall asleep, but it takes them a long time.

Tasimelteon vs ramelteon - sleep fragmentation

Insomnia is no laughing matter. It causes significant impairment in social and occupational function and mental health.

Stressful events can trigger transient insomnia, which typically lasts for less than a month. Chronic insomnia can persist from a month to years and occurs on its own or in parallel with other medical conditions.

Why Can't I Sleep?

A primary cause of insomnia is the disruption of circadian rhythms, physical, mental and behavioral changes in the body that follow an approximately 24-hour cycle.

Sleep is a process under circadian control. What the hell does that mean?

Sleep pressure (the urge to sleep you feel at the end of the day) is regulated by the circadian clock. This clock is affected by everything from the temperature to light and other cues.

In the case of sleep onset and waking, light and dark information from the environment that is detected by the eye sent to a region of the brain called the suprachiasmatic nucleus (SCN).

The pineal gland starts to release melatonin when at the end of the day when light decreases. It's the SCN that detects this decrease in light.

Melatonin interacts with its receptors MT1 and MT2 located throughout the central nervous system. The interaction reduces the firing of a subset of neurons resulting in sleep onset. Melatonin binding to the MT2 receptor maintains circadian rhythm which helps the body shift between daytime and nighttime.

Many patients with insomnia turn to melatonin receptor agonists to retrain their circadian rhythms to achieve and improve sleep. (An agonist is just a molecule or drug that binds to and activates a receptor. So melatonin itself is an agonist at the melatonin receptor - because it activates this receptor).

The first melatonin receptor agonist approved for treatment of insomnia was ramelteon (Brand name Rozerem). Ramelteon improves entrainment of circadian rhythms to a light-dark cycle with minimal side effects.

Ramelteon is taken as one 8mg dose 30 minutes before bed for chronic insomnia and enhances sleep quality. Ramelteon decreases the time it takes for patients to fall asleep (sleep initiation), the total time spent asleep, and sleep efficiency.

Sleep Efficiency

When you're thinking about insomnia, sleep efficiency is a useful concept.

Sleep efficiency is the time spent asleep divided by the time spent in bed. If you had a 90% sleep efficiency, that would mean that you were asleep 90% of the time in bed. If you're like me and like to use your laptop in bed doing work - that will crush your sleep efficiency. (Note that it's best to separate work from sleep and specifically designate your bed as a place only for sleep and sex).

It also significantly shifts the circadian rhythm when taken at unusual hours in the day as shown by a shift in the time that melatonin secretion increased.

Many factors that still need improvement including the number of times the patient wakes up in the middle of the night and the patient's difficulty falling back to sleep. Ramelteon is also associated with mild to moderate side effects such as a headache, a strong urge to fall asleep, dizziness and fatigue.

Ramelteon works by binding to both melatonin MT1 and MT2 receptors. Compared to melatonin, Ramelteon binds 6 times strongly to MT1 and 3 times more to MT2. It's also fast acting as it is rapidly absorbed and reaches peak concentrations 45 minutes after ingestion. It also has a half-life of approximately 1 hour and 20 minutes - which while short - is longer than that of melatonin.

Recently, a new drug was added to the pharmacologist's toolkit.

Tasimelteon was approved for treatment of non-24 hour sleep-wake disorder in blind people without light perception in January 2014. People with Non-24 go through long periods of misalignment of their circadian rhythm which significantly impairs the ability of these people to work and socialize in everyday life. Approximately 70% of blind people suffer from non-24.

Tasimelteon (also known as VEC-162 or by its brand name Hetlioz), like Ramelteon, functions by activating the melatonin receptors, MT1 and MT2.

Through activation of these receptors, Tasimelteon helps synchronize the circadian system to improve sleep at night and alertness during the day. Although it does not interact as strongly with the melatonin receptors as Ramelteon (Tasimelteon's affinity for the receptors is similar to that of melatonin's), it has a much longer half-life (2 hours compared to 30 minutes). However, this may not necessarily be beneficial since lingering could result in the improper training of the circadian rhythm causing patients to oversleep or feel drowsy the next day.

A typical dose of tasimelteon is 20mg taken orally once a day at night without food. It is quickly absorbed, reaching peak concentrations between 30 min to 3 hours. Still, Tasimelteon is not without side effects. But, as is the case with its predecessor ramelteon, the effects are relatively mild. They include headaches, nightmares, and upper respiratory or urinary tract infections.

Although Tasimelteon is only approved to treat non-24 hour sleep disorder, the way it functions and is processed by the body suggests that it may be a potential candidate to treat other sleep disorders such as insomnia and other circadian rhythm irregularities.

Though inconclusive, a few clinical trials have noted the beneficial effects of tasimelteon. Tasimelteon dose-dependently improved sleep efficiency sleep efficiency compared with placebo.

Unlike Ramelteon, Tasimelteon also has a positive impact on sleep disturbances. Patients taking Tasimelteon woke up less in the middle of their sleep and took less time to fall asleep. An increase in melatonin triggered by dim light also happened sooner in those that took the medication suggesting that their circadian rhythm had shifted. The only side effects observed in these studies were a strong urge to sleep, nausea and headache.

Sleep disorders are severe conditions that affect the lives of millions of people every day. A leading cause behind these disorders is a disruption of circadian rhythms that regulate sleep. It was only in the last few decades that therapeutics targeting melatonin receptors were developed and approved for treatment of sleep disorders. Ramelteon has been a pioneer for melatonin receptor agonist and has had a significant impact on the treatment of insomnia.

The recently approved Tasimelteon has provided a treatment option for blind people with sleep disorder non-24 and shows promise for indications for insomnia and other sleep disorders. Through further development of these therapies and circadian rhythm altering medications, sleep disorders may become a thing of the past.

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