Unmet Needs in Treating Insomnia - Episode 12

Managing Insomnia: An Overview of Pharmacologic Agents

January 31, 2022
Michael J. Thorpy, MD

Karl Doghramji, MD

Erinn E. Beagin, MD

Nathaniel Fletcher Watson, MD


Shared insight on the pharmacologic treatment landscape of insomnia, with a focus on mainstay drug classes.


Michael J. Thorpy, MD:Vikas, there are quite a number of different medications that are FDA [Food and Drug Administration] approved for the treatment of insomnia. Would you like to give us a little rundown on what the approved medications are, what groups are there?

Vikas Jain, MD, FAASM, FAAFP, CCSH, CPE: Sure. There’s a variety of groups that exist. Traditionally, we’ve had our benzodiazepine medication hypnotics, medications like estazolam [Prosom], lorazepam [Ativan], diazepam [Valium], triazolam [Halcion], and clonazepam [Klonopin]. And then there were newer agents introduced that worked on the benzodiazepine receptor more specific to the alpha-1 receptor, which tends to drive sleepiness, and those are what many patients are familiar with—zolpidem, or Ambien, Silenor [doxepin], or Sonata [zaleplon], and eszopiclone, or Lunesta. There are also some other agents that have been used, like low-dose doxepin, ramelteon [Rozerem], is a medication that works on melatonin receptor agonists. And then we also have some newer agents with dual orexin receptor antagonists. We definitely have a wide variety of choices to pick from, especially when we’re considering BZRas [benzodiazepine receptor agonists], and benzodiazepines, many of them have a pretty quick onset of action. Generally, for sleep latency, many of these medications can be helpful, but it’s really for sleep maintenance where these medications have a varying half-life. And that’s where it can be important in weighing the pros and cons of trying to use something to help with sleep maintenance, while also trying to minimize that sort of hangover effect into the day.

Michael J. Thorpy, MD:Yes. Is there much rationality these days in using the more traditional benzodiazepines versus the newer ones? We have these Z drugs that you mentioned, are they really the main form of benzodiazepine type agent that we would use there, or is there still a place for the older benzodiazepines?

Vikas Jain, MD, FAASM, FAAFP, CCSH, CPE: I personally don’t tend to use benzodiazepines as often as I use BZRAs these days. Why? I mean, at least, when you look at risk for tolerance, risk for withdrawal symptoms, difficulty in getting off of these medications when used chronically, there can be definitely some difficulty in patients who have been put on traditional benzodiazepines for long, long periods of time, several years, they’re on these medications. Whereas at least with many of the BZRAs, we don’t necessarily see as much of that. I’ve traditionally used more BZRAs in my own practice, more so than benzodiazepines.

Michael J. Thorpy, MD:OK. Nate, with regards to the low-dose doxepin and ramelteon, these are medications that a lot of physicians are not that familiar with. I mean, how useful have you found these agents? And if you’re going to prescribe a medication to a patient then, who might you give those to?

Nathaniel Fletcher Watson, MD: Well, the low-dose doxepin is effective for people with sleep maintenance insomnia, so they’re waking up in the middle of the night and having difficulty falling back asleep. It doesn’t seem to have any anticholinergic side effects, and it’s fairly safe. That would be a consideration in that particular type of insomnia. Ramelteon, when it originally came out was quite attractive because it’s a melatonin MT1 and MT2 receptor agonist. It was kind of utilizing what we might consider to be the more natural process of falling asleep, at least in the way that endogenous melatonin or melatonin that our pineal gland secretes works within our bodies. However, clinical trials have found it to be perhaps not as effective as some of these other medications and certainly in some of the patients that have trialed it in, I’ve had mixed results as far as success. But I would think about the sleep onset insomnia patient with that, and maybe in one that had a circadian rhythm sleep disorder. It’s, for instance, Karl mentioned earlier delayed sleep phase syndrome. If you had somebody with insomnia that ramelteon might be a good choice there. Doxepin is a tricyclic antidepressant, getting back to that. Thus, to the extent that there may be some kind of effect on mood as well, you might consider it in the patient that has mood and insomnia-related issues.

Michael J. Thorpy, MD:All right. Now, Karl, there are some newer hypnotics that are available to us now, and they tend to affect the orexin system. Can you tell us a little bit what’s the orexin system and what are these drugs and why are they effective?

Karl Doghramji, MD: The orexin system is a neurotransmitter system localized to the brain, which is important we think in the maintenance of arousal or wakefulness and also important for the coordination of a number of the other arousal systems, like epinephrine, or norepinephrine, cholinergic systems in the brain. Its lack or its difficulties with the orexin system highlighted a disease called narcolepsy, which we’re not talking very much about today. But some hypnotic agents have been developed to antagonize the orexin system, and thereby producing sleep. And the 2 that are available currently are lemborexant [Dayvigo] and suvorexant [Belsomra]. Suvorexant was the first to be introduced. Both of these are indicated for sleep initiation and maintenance difficulties, [eg] sleep problems falling asleep and staying asleep. And they’ve been developed in various ways. For example, lemborexant was developed in a study which compared the knowledge of placebo, but also to interest these open and extended release, showing that, and this is one of the very few had had studies with hypnotic agents, showing that it has some superiority, knowledge to placebo, but also to zolpidem in terms of sleep maintenance issues. This was a polysomnographic or a sleep laboratory study. But both of these agents have been said, over a long period of time, showing a lack of development of tolerance and maintain efficacy for many, many months of treatment.

Michael J. Thorpy, MD: Yes. There’s some recent evidence, I think, with regards to suvorexant, indicating that it may be helpful in people with Alzheimer’s disease. What are some of the problems in using hypnotics in elderly people and people with Alzheimer’s?

Karl Doghramji, MD: Well, as you know, Michael, the American Geriatric Society has warned us against using benzodiazepine at nights in particular, as well as the antipsychotics in elderly patients as primary treatments for insomnia. Because of the obvious difficulties with falls, hip fractures, cognitive difficulties, and so on. And interestingly, this agent was utilized with a group of patients with Alzheimer’s, where insomnia is very, very common, showing improvement in sleep measures in this population with minimal side effects in terms of daytime, memory decrement, amnesia, motor abnormalities, and so on. Thus, this is an interesting agent, which really has some usefulness it seems in this population.

Transcript edited for clarity.