Article In Brief
Although a myriad of options are now available to help treat sleep disorders, neurologists told Neurology Today that the biggest change is the increased awareness of just how important sleep is not only for a person's overall health, but for their neurologic health as well. That change has prompted more people to seek treatment.
Neurologists who treat sleep disorders have a broader range of therapeutic options to choose from in recent years, including a half dozen new drugs approved by the US Food and Drug Administration (FDA) and more devices to assist with breathing. But none have changed the landscape dramatically, they said in interviews with Neurology Today.
The main change has been that people are more aware that sleep disorders exist, and are open to accepting treatment, whether that involves a continuous positive airway pressure (CPAP) machine for obstructive sleep apnea or cognitive behavioral therapy for insomnia (CBT-I). And they said one major shift in the field is the awareness that sleep disorders have an impact on other mental and medical conditions.
Daniel A. Barone, MD, FAASM, FANA, associate medical director at the Weill Cornell Center for Sleep Medicine and associate professor of clinical neurology at New York Presbyterian Hospital, said that just a few decades ago, doctors were unaware that a condition such as sleep apnea could increase the risk of having a stroke, for example, or that sleep issues could potentially affect the risk for having dementia.
“Compared to 20 to 25 years ago, people didn't realize how much sleep disorders could impact overall health, but especially neurologic health,” said Dr. Barone. With the amount of research that's been done, he said, sleep specialists now know that quite well. From a neurologic perspective, poor sleep can affect chronic headaches and seizures as well as pain management, not to mention anxiety and depression, Dr. Barone said. “So, the fact that we see the connections, and people are paying attention to those factors, I think that's been the biggest change,” he added.
One of the sleep disorders that the public is more aware of is sleep apnea, which is mostly treated with CPAP machines. While the air-pressure machines have been used for more than 30 years, doctors said they have become much smaller and lighter, with a variety of masks shapes and sizes to personalize them for patients.
Dr. Barone said BPAP machines, which work similarly to CPAP machines, are another option; these devices provide a higher pressure when patients inhale and a lower one when they exhale. Some patients find them to be more tolerable than CPAP, which provides a continuous pressure through inhalation and exhalation.
Mandibular advancement devices (MAD), which are oral appliances that push the lower jaw forward to help maintain an open airway, have been around nearly as long as CPAP machines. And if patients don't respond well to PAP machines or oral appliances, surgery might be an option. While several sleep apnea surgeries exist, one of the newest and fastest growing surgical treatments for sleep apnea is the hypoglossal nerve stimulator, which was FDA approved in 2014. The stimulator is surgically implanted in the chest where it monitors chest movement with each breath, sending an electric pulse timed with inhalation to an electrode adjacent to the hypoglossal nerve to stimulate the tongue to move forward thereby opening the airway.
Which treatment people receive depends on the issue they have, how severe it is, and what they have tried before, said Dr. Barone. In general, patients are first treated with CPAP machines, and if they can't tolerate those after trying different masks, doctors will often recommend a MAD or BPAP, but most people adapt to CPAP fairly well, he said. Even with newer options available, one of the earliest treatments for obstructive sleep apnea remains the standard therapy.
Several new therapies for excessive sleepiness have been approved in the last few years. Specialists said they based their treatment on symptom severity and patient comorbidities, but sometimes face challenges in getting prior authorization from insurance companies, which require patients to try older medications first, even if they are expected to be less successful.
The traditional way of treating hypersomnia was to prescribe amphetamine-based stimulants such as dextroamphetamine, or methylphenidate, which, because they are older, are readily available and usually covered by insurance, but they also can be addictive or cause side effects such as anxiety, said Andrew Spector, MD, FAASM, associate professor of neurology at Duke University. So, the first line treatment is typically modafinil (approved in 1998) or armodafinil (approved in 2007), which also work as stimulants to the central nervous system but tend to be better tolerated and still very effective for patients. The prices of modafinil and armodafinil have come down dramatically since they became available as generics.
In 2019, two new agents were approved by the FDA to treat hypersomnia. The first was solriamfetol, which is indicated for the sleepiness associated with either narcolepsy or obstructive sleep apnea. It is classified as a dopamine and norepinephrine reuptake inhibitor, increasing the same neurotransmitters as existing stimulants. Shortly thereafter the novel oral histamine-H3 receptor inverse agonist, pitolisant, was released. The drug was approved in 2016 in Europe and works by increasing histamine levels in the brain thereby promoting wakefulness, said Alon Y. Avidan, MD, MPH, FAAN, FAASM, director of the UCLA Sleep Disorders Center and professor of neurology at the David Geffen School of Medicine at UCLA.
In addition to treating excessive sleepiness, pitolisant also improves cataplexy in patients with type 1 narcolepsy. Until pitolisant was released, though, sodium oxybate (Xyrem) was the only medication approved for both excessive daytime sleepiness and cataplexy associated with type 1 narcolepsy. Those interviewed said sodium oxybate is highly effective but may have some challenges since the drug, which is a metabolite of gamma aminobutyric acid (GHB), can produce deep sedative, hypnotic and amnesic effects and over-dosage can result in respiratory depression, coma, and death
At first, Dr. Avidan said specialists were reluctant to prescribe the medication because GHB is colloquially referred to as the “date rape” drug and diversion may have forensic implications. In the US, pharmaceutical GHB used for therapeutic purposes is labeled as a schedule III drug as sodium oxybate through a single central pharmacy with a risk management program. The high sodium content, up to 9 grams, may have potential implications for patients who have significant cardiovascular and renal comorbidities, and in July of 2020, the US FDA approved a new calcium, magnesium, potassium, and sodium oxybates with lower sodium content.
“It's not necessarily a game-changer but may provide a different formulation for patients in whom sodium metabolism might confer a potential risk down the road,” said Dr. Avidan.
Dr. Spector agreed, pointing out that the change did not lead to a clinically meaningful difference from the original version with higher sodium. He also noted that insurance companies may not always cover the lower-sodium version, even if patients prefer it.
“It makes it a lot better for people with heart problems or high blood pressure. Although it is generally considered to be the equivalent of the original, there is some evidence to say that the sodium is beneficial for absorption, so it might be slightly less effective for some people,” Dr. Spector said.
Drugs for insomnia have expanded greatly over the last 20 years, but the neurologists interviewed here disagreed about which drug they preferred as a first-line therapy.
In the 1980s, doctors used to prescribe triazolam (sold under the brand name Halcion), for insomnia. It was taken off the market in Britain because of side effects including memory loss and violent behavior, but the FDA voted not to ban the drug saying it was safe at low doses.
In the early 1990s, “Z” drugs—eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien)—came on the market, which worked by slowing down activity in the brain. However, several neurologists interviewed said that major adverse outcomes from these drugs, including sometimes fatal behaviors such as driving while asleep, made them reluctant to prescribe them to patients.
In 2014, the FDA approved dual orexin receptor antagonists (DORAs), the first new class of insomnia medications in over a decade. Suvorexant (Belsomra) was first, followed by lemborexant (Dayvigo) in 2019, and daridorexant (Quviviq) in 2022. These drugs work by blocking orexin, a neuropeptide with widespread effects throughout the brain to maintain wakefulness.
Dr. Barone said that the DORAs looked promising, but that his patients have not had much success with them.
“We're looking to help patients get to sleep or stay asleep, and they just don't seem to help with either, as much as we would like,” he said. Instead, Dr. Barone said he tends to stay with some older medications, such as trazodone, which was approved by the FDA as an antidepressant in 1981 and can help with both the lack of sleep and any associated anxiety or depression. But the 2021 guidelines from the American Academy of Sleep Medicine for the pharmacological management of chronic insomnia recommended against trazodone because of the lack of research supporting its benefits.
Despite this, Dr. Barone said he felt it was an effective choice because it is not physically addictive compared with other medicines like benzodiazepines. He said it is a better option long term, especially when combined with approaches such as cognitive behavioral therapy for insomnia.
Dr. Spector avoids prescribing trazodone. His experience is that either the dose is too low to help people sleep through the night or the dose is high enough that they can sleep but then wake up feeling groggy; it's hard to find a happy middle that works well enough to help people stay asleep without causing a hangover due to the long half-life. He usually sees patients for whom other therapies have not worked, and tends to prescribe eszopiclone, zaleplon, doxepin, or mirtazapine, depending on the clinical scenario.
For instance, eszopiclone works to help with both sleep initiation and sleep maintenance, but it also has a long half-life and can cause hangovers. Zaleplon has a much shorter half-life, which makes it good for people who need helping falling back asleep when they wake up in the middle of the night. Doxepin tends to be less sedating than the others, which can be beneficial for patients who are very sensitive to medications. And mirtazapine has benefits for conditions such as migraine as well, so the effects on comorbid conditions can be factored into treatment choices.
He also likes one of the new DORAs, lemborexant (Dayvigo), but it is expensive and not always covered by insurance. Some of his patients who were refractory to older hypnotic medications benefitted greatly from lemborexant. He has found suvorexant, the original DORA to be less effective, which could be related to the dosing guidelines that prevent prescribing it at the doses that were effective in the clinical trials.
Dr. Spector said he strongly recommends CBT-I for most of his patients with insomnia in concert with any sleep medications. “If you want an actual treatment so you don't have to rely on sleeping pills the rest of your life, you have to go through CBT-I. That's a must,” Dr. Spector said. The biggest limitation to CBT-I is access, as it can be both expensive and hard to find providers who perform this therapy. However, CBT-I can improve sleep for many people with insomnia without the need for long-term pharmacotherapy.
Sleep-related Movement Disorders
Sleep-related movement disorders, like restless leg syndrome (RLS), have not seen much expansion in treatment, neurologists said. Patients with RLS who describe an irresistible urge/need or a compulsion to move their legs are usually prescribed medications that work on the brain's dopamine system, often rotigotine, pramipexole, or ropinirole, which help to control the uncomfortable sensations, or alpha 2 delta ligands (gabapentin enacaril). Particular attention to iron deficiency is of paramount importance, requiring all patients with RLS to undergo regular evaluation of their iron stores by evaluating ferritin levels, and iron replacement therapy should be initiated if stores are low.
But over the last 10 to 15 years, research has found that patients who use dopamine medication chronically may develop a phenomenon called augmentation characterized by worsening symptoms earlier in the day and to previously unaffected body parts, said Dr. Avidan, who also commented that this condition might be confused with worsening of RLS symptoms. Other doctors point to the concern about impulse control behaviors (ICB) from dopamine agonists as a reason to avoid them.
In addition to the oral dopamine agonists, rotigotine is a transdermal patch allowing for the slow release of dopamine that is helpful for patients with significant RLS throughout the day, but it might not always be approved by insurance. As a pro-drug, gabapentin enacarbil can also be used once a day and has a better bioavailability when compared with regular gabapentin. It is taken once a day at 5PM and is a good alternative for patients who experience augmentation and for those with a history of obsessive-compulsive behavior or ICB.
Gabapentin may occasionally be prescribed but has proven challenging because patients often have to take it three or four times a day, and absorption levels can vary significantly among patients, making the once-a-day gabapentin enacarbil an ideal solution.
One key challenge with managing RLS with oral dopamine agonists is the timing (one to two hours) required to take these agents in before the onset of the RLS symptoms, he said.
Gabapentin enacarbil and all alpha 2 delta ligands may not be recommended for people with depression, however, because some studies found that it increased depression and suicidal thoughts, particularly for younger patients. However, it is often effective for people who experience anxiety and insomnia in the setting of RLS.
Dr. Avidan said he would choose a dopamine medication if patients have problems with excessive sleepiness, gait instability, or if they have issues with obesity, because gabapentin may cause sedation and weight gain. People with refractory RLS would benefit from opioids, particularly when symptoms persist despite the use of a combination of therapies (dopamine agonist with α 2 δ ligands) .
“While physicians and patients may raise concerns about using opioids, these agents are very effective in the medical therapy of refractory RLS and can improve quality of life,” Dr. Avidan said. “Under close and regular follow-up by their physician and with proper screening for the development of side effects, opioids should not be precluded due to fear of abuse or dependence.”
Looking at the range of options available to treat sleep disorders, not one has made a dramatic change, said Alberto Rafael Ramos, MD, MS, FAASM, FAAN, an associate professor of clinical neurology at the Miller School of Medicine at the University of Miami.
“A host of medications that have improved things for patients, particularly for insomnia, and there have been behavioral treatments that make a difference for patients,” said Dr. Ramos. “The field has evolved, and we understand more about brain mechanisms across the board.”