Treatment

What Treatments Are Available?

At this time, there is no U.S. FDA-approved treatment for IH. However, there are several treatments approved by the FDA for use in narcolepsy, and it is common practice to use wake-promoting medications that are known to be effective in people with narcolepsy to treat the sleepiness associated with IH (this is called “off-label” use).

Most of these treatments for narcolepsy have not been studied to nearly the same extent in people with idiopathic hypersomnia, and some people with IH do not achieve adequate control of symptoms with these medications. These medications, in some cases, also may stop working over time and/or have bothersome side effects. These medications may sometimes be used in combination, especially in people who are treatment-resistant.

Researchers continue to test medications approved for other disorders, as well as novel treatments, for IH. In addition, some people with IH have found that behavioral approaches, including cognitive behavioral therapy (CBT), can be helpful for learning skills to cope with IH.

More information about treatments, including some Australian-specific information, can be found HERE.

More information about prescription medication affordability in the U.S. can be found HERE.

Medications FDA-Approved for Sleepiness

There are three major classes of medications approved for the treatment of sleepiness associated with narcolepsy: stimulant medications (i.e., derivatives of amphetamines), non-stimulant wake-promoting medications (e.g., modafinil, armodafinil, solriamfetol, and pitolisant), and sodium oxybate.

Stimulants approved for the treatment of sleepiness in narcolepsy include dextroamphetamine (e.g., Dexedrine) and methylphenidate (e.g., Ritalin). While stimulants may be effective, potential side effects include dependence, aggressive behavior, dental problems, and heart problems. (Read more about dental side effects and how to manage them.)

Non-stimulant wake-promoting medications include modafinil (e.g., Provigil) and armodafinil (e.g., Nuvigil). While it is not completely known how these medications work, they appear to influence the brain chemistry that increases wakefulness, particularly the neurotransmitter dopamine. Modafinil has been studied in two placebo-controlled trials that included people with IH and has been shown to help with sleepiness in people with this disorder. However, modafinil and armodafinil can interact with hormonal birth control to make it less effective (learn more about “Women and Hypersomnia” HERE) and can result in a life-threatening rash. In addition, modafinil and armodafinil can sometimes result in headaches, which, if severe enough, can cause a user to reduce the dosage, thereby limiting the effectiveness of the medications.

A new non-stimulant wake-promoting medication – solriamfetol (Sunosi) – was approved in March 2019 by the U.S. FDA for the treatment of sleepiness caused by narcolepsy and obstructive sleep apnea. It has different pharmacology than either the stimulants or modafinil/armodafinil (it is the first dual-acting dopamine and norepinephrine reuptake inhibitor approved to treat excessive daytime sleepiness in adults).

Another new non-stimulant wake-promoting medication – pitolisant (Wakix) – was approved in August 2019 by the U.S. FDA (anticipated to be available several months after approval) and approved in Europe in 2016. This new medication is a selective histamine 3 (H3) receptor antagonist/inverse agonist that works through a novel mechanism of action to increase the synthesis and release of histamine, a wake-promoting neurotransmitter in the brain. Pitolisant improved sleepiness in approximately ⅓ of people with IH whose symptoms did not respond well to other medications.

Sodium oxybate (Xyrem) is a medication taken at bedtime (and again during the night) that promotes deep sleep and improves daytime sleepiness in people with narcolepsy; however, its effects in those with idiopathic hypersomnia are not as well characterized. A 2016 study found that sodium oxybate improved daytime sleepiness in people with IH to the same degree as in people with narcolepsy type 1. The drug also improved severe sleep inertia in 71% of people with IH.

Medications FDA-Approved for Cataplexy

Sodium oxybate is the only FDA-approved medication for cataplexy. Antidepressants, especially serotonin and norepinephrine reuptake inhibitors, are frequently used “off-label” to treat cataplexy. Pitolisant has also been shown to treat cataplexy, although it is not FDA-approved for this indication.

Medications Not FDA-Approved for Sleepiness but Sometimes Used for Sleepiness in People with Narcolepsy and Other Hypersomnias

Clarithromycin (Biaxin) has been shown in a small, randomized trial to improve daytime sleepiness and quality of life more than a placebo, in those people with primary hypersomnias related to excess activity of the GABA system. Clarithromycin is in a class of medications called macrolide antibiotics, and is derived from erythromycin. It works as an antibiotic by stopping the growth of bacteria, and was approved by the U.S. FDA in 1991 for treating certain infections. In 2015, 20 persons, all of whom had IH, narcolepsy without cataplexy, or habitually long sleep time, participated in a 5-week, double-blind, placebo-controlled, crossover study, and were given either clarithromycin or a placebo for two weeks. Then, after a week off, the participants were given the other drug (either clarithromycin or a placebo) for another two weeks.  At the end of the study, participants reported significant reductions in sleepiness and increases in energy. The researchers concluded that while the long term use of an antibiotic “must be justified by clinical benefit that exceeds these potential risks,” clarithromycin might be considered for daytime sleepiness, “especially in cases that are otherwise treatment-refractory.” (NOTE: HF has published two journal article summaries about clarithromycin: 1) Antibiotic May Decrease EDS in GABA-Related Hypersomnia; 2) Summary of Research into Clarithromycin as a Hypersomnia Treatment).

Flumazenil is another medication which acts on the GABA system. It, too, has been shown to reduce sleepiness in people with IH whose sleepiness is not controlled with other medications. Flumazenil is a GABA receptor antagonist that was approved by the U.S. FDA in 1991 as an intravenous (IV) medication to reverse excessive or prolonged sedation suspected to be caused by benzodiazepines (such as Valium or Ambien). It is not FDA-approved for IH or other any CNS disorder of hypersomnolence. In 2012, researchers discovered that the cerebrospinal fluid from some people with hypersomnolence demonstrated potentiation (or strengthening) of GABA-A receptors that exceeded that of controls, and that flumazenil reversed those excessive levels. In 2016, researchers published a study, examining the clinical experience with 153 people taking flumazenil for their hypersomnolence that was resistant to other treatments. Of those people, 39% were found to have “sustained clinical benefit” from the flumazenil. NOTE: Since flumazenil is currently only available in liquid form for IV use, it must be formulated into a transdermal cream or lozenge (for topical or mucosal absorption, respectively) by a compounding pharmacy for use by people with IH or related disorders. See HF’s FAQs about flumazenil access. (NOTE: HF has published a journal article summary about flumazenil: Flumazenil for the Treatment of Refractory Hypersomnolence.)

Antidepressants, generally, have not been found to be helpful for treatment of idiopathic hypersomnia. However, one antidepressant – bupropion (Wellbutrin) – is known to have wake-promoting effects. Bupropion is an atypical antidepressant, in that it is not a selective serotonin reuptake inhibitor (SSRI); rather, it is a norepinephrine-dopamine reuptake inhibitor (NDRI), which means that it works by inhibiting the reabsorption of two important brain chemicals – norepinephrine and dopamine.

Selegiline (Emsam or Eldepryl) may also be useful for the treatment of IH. It is in a group of medications called monoamine oxidase type B (MAO-B) inhibitors, which means that it works by slowing the breakdown of certain substances in the brain (mostly dopamine, but also serotonin and norepinephrine). By slowing the breakdown of these substances, their activity within the brain is increased. Selegiline is used primarily for the treatment of Parkinson’s disease, especially in combination with levodopa, to help control the difficulties with movement, muscle control and balance. Although selegiline was found to suppress REM sleep and increase sleep-onset and REM-onset latencies on both the PSG and MSLT (and people taking it reported significant improvement in daytime sleepiness, reduced number of naps needed, and reduced frequency of cataplexy), this medication is not commonly prescribed for people with narcolepsy because of the high dosage required and potential for severe side effects.

Carnitine supplementation has also been shown to improve narcolepsy symptoms (including daytime sleepiness) by increasing fatty-acid oxidation. Carnitine is a substance that our bodies make in our liver and kidneys, which is then stored and later used to help turn fat into energy. While most people make enough carnitine, some people don’t make enough or their bodies can’t transport the carnitine into their tissues so it can be used. In a 2013 study involving 30 people with NT1, researchers found that oral carnitine supplementation improved sleepiness or dozing time in the daytime.

Levothyroxine (Synthroid) is an FDA-approved thyroid medication that replaces a hormone normally produced by the thyroid gland to regulate the body’s energy and metabolism. It is generally prescribed for people with hypothyroidism (an underactive thyroid gland). Some small studies have suggested levothyroxine as a possible treatment for IH, especially for people with subclinical hypothyroidism (an early, mild form of hypothyroidism, in which the serum level of thyroid stimulating hormone (TSH) from the front of the pituitary gland is a little bit above normal). However, while this treatment has been shown to reduce excessive daytime sleepiness and mean sleep time in people with IH, levothyroxine carries potential risks (especially for people without hypothyroidism or subclinical hypothyroidism), including the risk of cardiac arrhythmia.

Melatonin is a hormone that the body produces to help regulate sleep. The production and release of melatonin is connected to the time of day – increasing when it is dark outside and decreasing when it is light. Melatonin production gradually decreases with age. Melatonin is available as a supplement, usually in an oral tablet, and is often used to combat jet lag or insomnia. A few studies have suggested that melatonin might also be helpful in the treatment of IH. One small study, which used a dose of 2 mg slow-release melatonin at bedtime, found that 50% of participants had “shortened nocturnal sleep duration, decreased sleep drunkenness and relieved daytime sleepiness.” Other studies have shown that melatonin synchronizes the circadian rhythms, and improves the “onset, duration and quality of sleep.”

Caffeine is considered one of the safer non-dopaminergic wake-promoting compounds. It is widely used but can have intolerable side effects at high doses, including cardiovascular side effects.  Although it is commonly used by people with IH or narcolepsy, many people with these disorders report that it has only limited benefit on their sleepiness.

Atomoxetine (e.g., Strattera) is a medication that is approved by the U.S. FDA to treat attention-deficit hyperactivity disorder (ADHD). It belongs to the group of medicines called selective norepinephrine reuptake inhibitors (NRIs), and is believed to work by increasing norepinephrine and dopamine. It increases attention in people who are hyperactive, have problems with concentration, or are easily distracted. It  increases wakefulness, but generally less strongly than the medications which act directly on dopamine. Reboxetine (e.g., Davedex) is a similar NRI, which is approved in Europe. While it is not currently approved in the U.S., in October 2018, the U.S. FDA granted Orphan Drug Designation (ODD) status to Axsome Therapeutics’ AXS-12 (reboxetine) for the treatment of narcolepsy symptoms.

Ritanserin, a serotonin receptor antagonist, has been shown in humans to increase deep slow-wave sleep and to improve symptoms in a variety of psychiatric disorders, including OCD, acute mania, and schizophrenia. In a 2003 study of 134 people with narcolepsy, adding ritanserin to their usual narcolepsy treatment resulted in a significant increase in nocturnal slow-wave deep sleep and significantly reduced non-REM Stage 1 percentage during daytime sleep. Ritanserin is intended as an adjunct (a supplement to another main therapeutic treatment). While it is not currently available in the U.S., it is available in Europe.

Mazindol is a stimulant that works similarly to amphetamines, in that it increases alertness and central nervous system stimulation, but, unlike amphetamines, it has little or no effect on mood or the cardiovascular system. It has dopamine and adrenergic blocking properties, and has been shown to be effective for the treatment of both excessive daytime sleepiness and cataplexy in humans, and in canine narcolepsy. It was previously approved in the U.S. and Europe as a short-term treatment for obesity, but its manufacturer stopped production of Mazindol in 1999 for commercial reasons (not for safety or effectiveness reasons). While it is not currently approved in the U.S., mazindol was granted Orphan Drug Designation (ODD) status for the treatment of narcolepsy by the U.S. FDA in July 2016 (read more HERE). (The European Commission had previously granted mazindol ODD status in October 2015.)

Novel and Emerging Treatments for Sleepiness in Primary Hypersomnias

As the brain systems regulating sleepiness and wakefulness are better understood, scientists will be in a better position to design treatments that target key portions of this system. For example, based on the role of histamine in keeping people awake (and hence the common side effect of antihistamines such as diphenhydramine causing sleepiness), medications that act on histamine are under development for the treatment of excessive sleepiness (see pitolisant, as the first in this class, above). In the case of the primary hypersomnias related to excess activity of the GABA system, medications that could counteract this activity have the potential to improve sleepiness (see clarithromycin and flumazenil above).

In addition, researchers are currently testing medications called orexin receptor agonists (or drugs that bind to the orexin receptor and activate a response from that receptor) in people with type 1 narcolepsy, since NT1 is known to result from a lack of orexin in the brain due to destruction of the cells that produce it. (Orexin, also called “hypocretin,” is neuropeptide responsible for regulating arousal, wakefulness and appetite.) For example, in a 2018 study involving orexin/ataxin-3  mice, researchers in Japan found that an orexin receptor agonist called TAK-925 “significantly increased wakefulness time and also completely recovered wakefulness fragmentation and cataplexy-like episodes.” It is possible that these new orexin receptor agonist medications, if eventually approved, could also be of benefit to people with IH.

Information about clinical trials for new treatments and how to access treatments that aren’t yet available in your home country can be found HERE.

Behavioral Treatments

In addition to medications, behavioral approaches are sometimes recommended. Short, planned naps can be helpful for sleepiness in people with narcolepsy. Unfortunately, for many people with IH, planned naps are not as helpful, because they tend to be long and unrefreshing, and it can be difficult to awaken from naps.

Although behavioral approaches have not been shown to improve EDS in people with IH, different types of therapy may help people learn to cope with this chronic disease. For example, in CBT (cognitive behavioral therapy), one goal of therapy is to help people learn to reduce their negative emotional responses (e.g. frustration, anger, depression) to their disease symptoms. This and other types of therapy can help people learn coping skills and adjust to the sometimes large lifestyle changes brought on by IH symptoms. (Read more HERE.)

Finally, because symptoms of IH can affect school, work, and relationships, it is important to educate everyone who might regularly interact with people with IH about this sleep disorder. Since some people with IH require educational and/or work accommodations so they can be successful in reaching their career goals, this may require a conversation between healthcare providers and school and/or employer about what IH is and how the symptoms affect people. Similarly, spouses, partners, parents, and close friends can also benefit from learning more about IH, so they can better understand IH symptoms and how these symptoms may affect their loved one.

Revised 10/2019 by Lynn Marie Trotti, MD, MSc, Chairperson, HF Medical Advisory Board


Further Information

1) Current Treatments for Idiopathic Hypersomnia – 2018 HF Conference Video Featuring Dr. Lynn Marie Trotti.

2) Wake-Promoting Medication – SleepHub Australia.

3) Women and Hypersomnia – 2018 HF Conference Video, Transcript, and More, Featuring Dr. Isabelle Arnulf.

4) SomnusNooze Articles about Treatments, Including Novel and Emerging Treatments.

5) Participate in Research Studies, including Clinical Trials for New Medications.

6) For help with accessing medications that are not yet approved in your country, CLICK HERE.

7) Free Full Text Journal Articles:


References

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