Dr. Karl Doghramji Reviews Recent Developments in Prescription Sleep Aids

In this video, Sleep Disorders Section Editor Karl Doghramji, MD, reviews the neurotransmitter systems governing sleep and wakefulness, the variety of prescription medications available for sleep difficulties, and agents that have recently been approved or are in development.

Dr. Doghramji is Professor of Psychiatry, Neurology, and Medicine, Director, Jefferson Sleep Disorders Center, and Program Director, Fellowship in Sleep Medicine, at Thomas Jefferson University in Philadelphia, Pennsylvania.

Read the transcript:

Hello. I'm Dr. Karl Doghramji. I'll be discussing the topic of "What's New in the World of Sleeping Pills."

Insomnia is a very common malady, a very common complaint. About half of the US population complains of this. Fifty-four percent of the population reports at least one insomnia symptom a few nights per week or more. It's encountered by every clinical discipline in medicine.

Before we delve into the hypnotic agents, I'd like to spend a couple of minutes talking about the neurotransmitter systems governing sleep and wakefulness because hypnotics also act on these very same neurotransmitter systems.

The wakefulness neurotransmitters are serotonin, norepinephrine, dopamine, histamine, acetylcholine, and the hypocretins. These are involved in the maintenance of arousal, promotion of arousal and wakefulness. On the other hand, sleep induction is accomplished mainly by gamma aminobutyric acid and, of course, to some extent, melatonin and adenosine.

The neurotransmitter systems and the ascending fibers which are involved in the production of arousal are on the left hand of this slide. On the right side is the GABAergic system listed. The seed of the GABA, of course, is a ventrolateral preoptic nucleus. These 2 systems, sleep and arousal, are balanced with one another. A promotion of one system inhibits the other and vice versa.

The orexin system, which I talked about a couple of minutes ago, is a more recently discovered system. The peptides are localized in the dorsolateral hypothalamus. There are wide projections throughout the brain and even in the spinal column. The neurotransmitters are involved not only in the production of arousal, but locomotion, metabolism, and even blood pressure and heart rate increase.

The prescription medications that we know of are listed on this slide. The various categories are on this slide. The benzodiazepines. The nonbenzodiazepine receptor agonists, the so-called Z drugs. The melatonin receptor agonists, such as ramelteon. Tricyclic antidepressants, such as doxepin. The dual orexin receptor antagonists, suvorexant and lemborexant.

These are the prescription medications that are approved by the FDA for the treatment of insomnia.

These agents are listed on this slide with greater detail. On the left-hand side, you'll see the benzodiazepine receptor agonists. These are actually benzodiazepine molecules, estazolam, flurazepam, quazepam, temazepam, and triazolam. These have seen less usage over the course of the past few decades because of the introduction of newer drugs which seem to have a smaller array of side effects.

The benzodiazepines, because of their longer durations of action primarily, are involved in causing some daytime sedation and, because they're GABAergic agents, also have effects on the other systems which are involved in the production of side effects such as mild over-relaxation, wobbling, memory decrement, and so on and so forth.

The newer agents, the nonbenzodiazepine agents, which also act at the benzodiazepine receptor, are eszopiclone, zaleplon, and zolpidem. Eszopiclone is effective both in sleep initiation and maintenance and is therefore an all-night drug. It can help patients in terms of falling asleep and staying asleep.

Zaleplon and zolpidem, on the other hand, are sleep initiation drugs primarily. They're effective in helping patients fall asleep, but they're not that great in the form in the production of sleep maintenance. The zolpidem extended-release, a longer formulation of zolpidem, is, on the other hand, effective for both initiation and maintenance.

On the right-hand side, we see some benzodiazepine receptor agonists that were essentially reformulations of zolpidem, an oral spray and a sublingual formulation, which have the advantage over zolpidem in that they achieve Tmax much more quickly and produce sleep more rapidly for patients who want more rapid induction of sleep.

Zolpidem sublingual, a very small dose of zolpidem, as you can see, 1.75 and 3.5 mg, which is an interesting drug in the sense that it's given in the middle of the night, after patients wake up and cannot fall back to sleep, as long as they have a minimum of 4 hours ahead of them in bed.

This is a nice agent to take on an as-needed basis if patients don't take a hypnotic to begin with, wake up. Many of the other hypnotics have longer durations of action and may cause daytime sedation. With this one, the drug is metabolized rapidly out of the system, within 4 hours.

The ramelteon is a nonbenzodiazepine agent. It's effective at the melatonin receptor. It's an agonist and is involved in sleep production, primarily for sleep initiation difficulties. It's an initial drug, helpful in initiation insomnia.

Doxepin, on the other hand, low-dose doxepin, 3 to 6 mg, is helpful in sleep maintenance insomnia, patients who wake up a great deal during the course of the night. Both ramelteon and doxepin, of course, are nonscheduled agents. They do not have DEA scheduling classification and are therefore probably agents that may be considered in patients who have drug misuse difficulties.

The newest agents to be introduced, suvorexant and lemborexant, are dual orexin receptor antagonists. Recall again that the orexin system is involved in wake promotion. These antagonize that very system and therefore produce sleep by inhibiting wakefulness.

Now, let's talk a little bit about these orexin agents in greater detail since they are the most recently introduced agents. Suvorexant was approved 7 years ago. It's involved in the onset and maintenance of sleep. Many of the patients studied on this agent were above 65 years of age.

The most common side effects are the ones that you would anticipate with any hypnotic agent, such as somnolence, dry mouth, headache, and so on. The interesting thing about this drug is its lack of significant side effects upon awakening in the morning.

No morning driving performance impairment, no psychomotor performance impairment. After a period of use, there was no rebound insomnia after rapid discontinuation of the agent.

There was a recent label update for this drug because of a new study, which was a 4-week study with patients with insomnia who had mild to moderate Alzheimer's disease. Of course, in this population, this is a very common symptom, insomnia.

The drug produced significant improvements in total sleep time, wake after sleep onset, compared to placebo. There was a nonsignificant reduction in sleep latency. The most common side effects were the ones that you would anticipate with a hypnotic agent.

This drug has also demonstrated safety in some respiratory conditions. As you know, the sleeping pills may produce respiratory suppression. This agent was studied in mild to moderate obstructive sleep apnea and also mild to moderate COPD and was found to not have significant impairment above placebo.

Lemborexant is the latest orexin receptor antagonist to be introduced. It was introduced in December 2019. It's also a Schedule IV agent. It antagonizes both orexin receptors, type 1 and type 2.

The most common side effects are the ones you would anticipate, somnolence and fatigue. There was no difference in placebo with this drug as well in morning cognitive performance, driving performance, or body sway.

Body sway is a measure of, as the term suggests, the degree of sway in the body, which is something we see commonly with the benzodiazepine agents when they're active within one system. There was a lack of this side effect with this agent in the morning upon awakening. The rebound insomnia was also not present after rapid discontinuation.

The 2 trials which were involved in this agent were, number 1, a one-month trial where sleep was assessed with objective measures in patients who were elderly, primarily above 55 years of age in women and 65 years of age or greater in men.

The objective parameters that were measured were sleep efficiency, time to sleep onset, and wake after sleep onset. There was superiority to placebo in all of these measures with this agent. Interestingly, it was superior to zolpidem extended-release for wake after sleep onset in the second half of the night. The second half of the night, it was superior to zolpidem extended-release.

The second study was a six-month, placebo-controlled study, where subjective parameters of sleep were assessed. There was a decrease in the severity of insomnia on the ISI index, or the Insomnia Severity Index. There was improvement in sleep onset latency and wake after sleep onset.

This agent has also been demonstrated to have safety in patients with mild obstructive sleep apnea but has not yet been studied in COPD or mild to moderate obstructive sleep apnea.

One of the issues that we confront with sleeping pills is their use in the elderly, because they tend to be more susceptible to side effects. Many of the societies which are involved with clinical guidelines for the elderly, such as the American Geriatric Society, have recommended against the usage of some of the commonly used benzodiazepines, as well as the selective benzo receptor agonists, such zolpidem, eszopiclone, and zaleplon, in the case of the elderly because of the observation of cases of falls, delirium, and increased sensitivity in metabolism.

They also have recommended against the use of diphenhydramine and doxylamine, antihistamines. Doxepin, at the doses that we utilize for sleep, seem to be OK from the standpoint of this particular society, but above 6 mg, which is above the hypnotic dosage has not been recommended. Of course, the antipsychotics as well are not recommended in this population because of the cognitive impairment that they may produce.

Now, this brings up the question of, how can we select some of these sleeping pills now that we have such a large array of medications? Can we do so based on clinical characteristics of our patients?

Age is possibly one of those characteristics. Some of these agents have been better studied with the elderly than others. The recommendation would be to think about the agents that are nonbenzodiazepines, especially the ones that are shorter-acting, in the selection of agents for patients who are older.

Sleep-onset insomnia because of the nature of their effect on sleep initiation, ramelteon, zolpidem, and zaleplon are ideally suited for patients who have difficulty falling asleep. On the other hand, patients who only have difficulty in sleep maintenance, that is who wake up a great deal after falling asleep, doxepin low-dose is selective for that particular clinical profile.

Zolpidem low-dose also is an interesting drug because it can be administered in the middle of the night, after patients wake up, as long as they have 4 hours ahead of them in bed.

If patients have both sleep onset and maintenance difficulties, that is they have difficulty both falling asleep and staying asleep, the agents that are panacea drugs in this regard are eszopiclone, zolpidem extended-release, suvorexant, and lemborexant. The first two are, of course, selective benzo receptor agonists. The last two are orexin receptor antagonists.

If patients have comorbid respiratory disturbances, mild to moderate obstructive apnea or COPD, ramelteon and suvorexant have been studied in this regard. Lemborexant has only been studied in mild obstructive sleep apnea.

Patients who have a history of substance abuse, ramelteon and doxepin are nonscheduled agents. They've been shown to not promote drug abuse difficulties in patients who are susceptible to these types of problems. Of course, patient preference is always an issue. Naturally, insurance reimbursement, in many ways, also determines to what extent we can use one agent over the other.

In the future, we'll be seeing greater research being performed on another array of orexin receptor antagonists. Daridorexant is a dual orexin receptor antagonist with a half-life of 6 hours. It's a shorter half-life than the currently approved orexin receptor antagonist. It's currently in phase III trials.

Seltorexant, which is selective for the orexin-2 receptor, hypothesized to be more important than the type 1 receptor in insomnia. The clinical trials are ongoing. Interesting with this drug that it's being investigated for treatment of major depression adjunctive to antidepressants. This will be an interesting area. As you know, insomnia and depression so frequently coexist in clinical settings.

In conclusion, therefore, insomnia is a highly prevalent condition. It's associated with a number of negative clinical outcomes. More recently introduced hypnotic agents add an index of safety and widen the scope of available choices for us clinically.

It's now possible to match these medications, their characteristics, to the individual patient clinical profiles, hopefully improving clinical care in insomnia.

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