Hello everybody and welcome to another edition of the Carlat Webinar series. Today's title is Insomnia Treatment Update. We're going to go over the latest and greatest treatments in the world of sleep disorders. Let's go ahead and jump right into the presentation. I'm going to be your presenter today. My name is Dr. Garrett Rossi. I am an adult psychiatrist at Atlanticare Regional Medical Center in Pomona, New Jersey, and I do not have any conflicts of interest of disclosures to make during this presentation.

Learning Objectives

After the webinar, clinicians should: 

1. Understand why the first-line treatment for insomnia is behavioral
2. Describe current pharmacotherapy approaches for the treatment of insomnia
3. Describe the indications for the use of benzodiazepines, nonbenzodiazepines, and sedating antidepressants
4. Understand the mechanism of action and how to use orexin antagonists in clinical practice

We no longer recommend medications as first-line treatment, and that's part of what we're going to go over today. The second learning objective is to describe the current pharmacotherapy approaches for the treatment of insomnia. In the third point, we're going to describe the indications for the use of benzodiazepines, non-benzodiazepines, and sedating antidepressants, and we're going to understand the mechanism of action and how to use the newest medications, orexin antagonists.

Why Is Insomnia Important to Treat?

Many of you know this already, but we should open the discussion by saying why insomnia is important to treat. We know that chronic insomnia is highly prevalent. In fact, it affects up to 30% of the general population. It's a significant number of individuals that you will likely encounter.

Insomnia is known to increase the risk of developing anxiety and depression. We know that insomnia is a chronic comorbidity of anxiety and depressive disorders as well. Finding safe pharmacological options has also been a challenge and we're going to get into why that's a problem in the next section.

Nonpharmacological Treatments for Insomnia

For many of us, we are going to want to do is prescribe medication, because that's essentially what our role has become in the world of mental health, but we must keep in mind That the American Academy of Sleep Medicine recommends Cognitive Behavioral Therapy for Insomnia, also known as CBT-I, as a first-line treatment with strong evidence base. We often don't see many guidelines providing a strong evidence base when they recommend a particular treatment, so this is one that has a very strong evidence base behind it, and it's recommended as first-line treatment by most guidelines.

Behavioral, and psychological interventions can address the other aspects of insomnia that medication cannot. We want to look at the psychological and social mechanisms of chronic insomnia, and that's what CBT-I is designed to do. What's great about this treatment is that it can be delivered in as little as four to eight sessions, which is the average number that's required. The effects are also maintained long term. Essentially you are teaching people ways of dealing with the psychological and social mechanisms associated with chronic insomnia, not just addressing the pharmacotherapy aspect of insomnia. These treatments tend to be maintained over longer periods of time, and they're better tolerated than medications. With medications, side effects and risk for Physiological dependence and withdrawal syndromes are possible.

Pharmacological Treatment of Insomnia

There are FDA-approved medications for insomnia, but they're only intended for short-term use. If read the package inserts, what you'll find is that a lot of these medications are not tested on a long-term basis. The safety and efficacy data only extends out a few months, and the quality of data beyond that is poor.

Medications do have some benefits, they are easily accessible, and are a way of providing short term relief. It’s easy for us to make an assessment clinically and say this person meets criteria for insomnia and start medication. Patients want something that will have a rapid onset of action and is going to relieve symptoms rather quickly. Medication checks those boxes. The risks of medication include things like daytime sleepiness, cognitive dysfunction, physiological dependence, and the risk for falls in older adults. The main point I wanted to continue to hammer home here is that medications do not address the behavioral, psychological, or environmental factors associated with insomnia.

Benzodiazepine Hypnotics 

There are different classes of medications available for insomnia treatment. Benzodiazepine use for insomnia is less favorable because there's a significant risk for physiological dependence and the dangers associated with the combined use of benzodiazepines with alcohol or opiates.

Benzodiazepines bind to alpha 1, alpha 2, alpha 3, and alpha 5 subunits of the GABA A receptor. Essentially these are GABA A receptor modulators. The alpha subunit expression differs throughout the brain, so that's something to keep in mind when prescribing these medications. The hypnotic activity at different subunits will induce effects that are slightly different. In addition to sedation, there can also be anxiolytic effects, anti-pain, and tolerance. There's a high risk with these medications for tolerance and withdrawal compared to the non-benzodiazepine hypnotics.

Although the point is somewhat debatable, some would say that the non-benzodiazepine hypnotics also pose a similar risk. It's also important to remember that many of the common benzodiazepines that are prescribed for anxiety, are not approved for the treatment of insomnia. We might be thinking about clonazepam, alprazolam, and lorazepam as commonly prescribed medications that we see all the time for insomnia. These medications are not FDA approved.

Nonbenzodiazepone Hypnotics

The differences here are that they bind selectively, again, to the alpha subunits of GABA A receptors. They're specifically selective for the alpha 2 and alpha 3 subunits but may have some additional benefits besides sedation for treatment for insomnia. You might also get anxiolytic effects. You might get antidepressant effects and possibly anti-pain effects as well, although that's not fully teased out in the literature.

Due to next-morning impairment, the FDA now recommends lower doses for all these medications at bedtime. Starting with eszopiclone, we are selective for the Alpha 2 and Alpha 3 subunits, and this is the only hypnotic that's approved for use over 35 days. The recommended bedtime doses have now been reduced from 3 mg to 1mg.

Zaleplon is a selective Alpha 1 subunit medication. It has a very short half-life. What's interesting about this medication is that it can be used for awakenings at night without the risk for residual daytime sleepiness. If somebody wakes up and needs to take a medication to get back to sleep, this medication may serve that purpose.

And the final one, Zolpidem, is a selective alpha 1 medication. There is also a sublingual form approved for nighttime awakenings. The dose here has been reduced to from 10 mg to 5 mg for the immediate release formulations and from 12. 5 mg to 6. 25 mg for the extended-release formulations.

Sedating Antidepressants

Let's move the discussion ahead and talk about sedating antidepressants because sedating antidepressants are one of the most common medications that we prescribe for sleep disturbances in psychiatry. Sedating antidepressants are primarily acting as antihistamines. They're going to block H1 receptors and that's going to lead to increased sedation and hopefully the person becoming tired enough to fall asleep.

The medications that we commonly think about are Trazodone, Doxepin, and Mirtazapine. Let's start with Trazodone. It's important to note that Trazodone is not FDA approved for the treatment of insomnia. When you're using Trazodone for sleep, there is a dose response. For the hypnotic doses, it's significantly lower than those for antidepressant purposes. Hypnotic doses will be anywhere from 25 mg to 150 mg.

Doxepin has a hypnotic dose of anywhere from 1 milligram to 6 milligrams. Typically, patients level out anywhere from three to six milligrams, and this is a histamine H1 receptor antagonist. This is the only medication listed here that is FDA approved for insomnia.

We can consider mirtazapine when somebody has comorbid depression. It's not necessarily a good medication to prescribe if you're only treating insomnia as it’s off label. This medication is commonly prescribed in clinical practice for sleep, and when we think about the dosing for this medication lower doses tend to be more sedating. You end up getting much more norepinephrine effect at higher doses, which can be more activating and less sedating.

Melatonin Agonist Ramelteon

An often forgotten but equally important medication is the melatonin agonist ramelteon. This was the first melatonin agonist approved for insomnia. It's a very good medication but clinically I don't see this prescribed very often. It's a full agonist at the melatonin 1 and melatonin 2 receptors.

The dosage is simply 8 mg at bedtime; there is no titration required. Common side effects we see with this medication include things like sedation, dizziness, fatigue, and headaches. We should be mindful of a potential interaction with fluvoxamine so it should not be used with fluvoxamine. It should be avoided in those with severe liver disease, and you should check the person's liver function tests before prescribing.

New Kid on the Block

Over the past several years, orexin antagonists have become popular treatment options for insomnia. We are now considering them to be safer than the hypnotics and sedating antidepressants, increasing their recent popularity.

How Do Orexin Antagonists Work?

What we know is that orexin neurons are located in the hypothalamus, and these orexin neurons produce orexin A and orexin B. We have these neurons located in the hypothalamus that are producing orexin A and B, and orexin A and B will bind to the orexin 1 and 2 receptors. When orexin A and B bind to those receptors, they promote wakefulness by regulating monoamine neurotransmitters.

Dual Orexin Antagonists (DORAs)

Currently the DORAs are only FDA approved for the treatment of insomnia. Narcolepsy is the only absolute contraindication to using orexin antagonists. What we know from the randomized controlled trials, when you pool the data together, all of the DORAs reduce time to sleep onset, reduce awake time after sleep onset, and increase total sleep time.

These benefits do not come without potential side effects, so the ones that we may see are things like somnolence, fatigue, complex sleep behaviors, sleep paralysis, hypnagogic and hypnopompic hallucinations, and worsening depression and suicidal ideation.

Suvorexant

I want to talk about each one individually, starting with Suvorexant. Suvorexant was FDA approved for insomnia in 2014. The starting dose is typically 10 mg and it will be taken 30 minutes prior to sleep. It can be titrated to a maximum dose of 20 mg once per night. The onset of action is rapid, within 30 minutes.

The half-life is 10 to 22 hours. And it's primarily metabolized by the cytochrome P450 system 3A4 and 2C19.

Lemborexant 

We can then move on to Lemborexant. So Lemborexant was FDA approved in 2019. The starting dose is 5 mg. 30 minutes prior to sleep and can be titrated to a maximum dose of 10 mg at bedtime.

The onset of action is less than 30 minutes, so an onset of action is going to be relatively quick for this medication. The half-life is 17 to 19 hours and it's metabolized primarily by the cytochrome p450 3a4 and 3a5.

Daridorexant

This was FDA approved. This is the most recent FDA approval in 2022. The starting dose is 25 mg, 30 minutes prior to sleep, and can be titrated to a maximum dose of 50 mg at bedtime. The onset is less than 30 minutes, and the half-life is 5.6-8.5 hours. And that's an important point that I want to make.

If you look at the half-life, it's consistent with a typical sleeping pattern. If someone is sleeping 6 to 8 hours, the half-life matches that time frame. It's metabolized by the CYP P450 system, specifically 3A4.

Transitioning to DORAs From Z-Hypnotics or Benzodiazepines 

One question that has been coming up is transitioning to DORAs from z-hypnotics or benzodiazepines. There is very limited data on this at this time. It's not recommended to combine or cross-taper DORA medication with benzodiazepines or z-hypnotics.

The one study I was able to review showed increased sedation when Suvorexant was added to existing benzodiazepine treatment. So as of now, we should avoid this practice.

Summary

In conclusion, insomnia is prevalent and characterized by hyperarousal and insufficient homeostatic sleep drive. The first-line treatment for insomnia is nonpharmacological—specifically CBT-I and if we do find ourselves in a position where we need to prescribe, there are several pharmacological approaches including benzodiazepines, non-benzodiazepines, sedating antidepressants, melatonin agonists, and the new orexin antagonists.

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