Published April 22, 2020
Revised October 12, 2021
Complete Review/Update August 12, 2021
Vetted by Our Medical Advisory Board
What Treatments Are Available?
In August 2021, low-sodium oxybate (Xywav) became the first U.S. FDA-approved treatment for idiopathic hypersomnia (IH). There are also several treatments approved by the FDA (and similar international agencies) for use in narcolepsy and other sleep disorders, and it is common practice to use medications that are known to be effective in people with narcolepsy and other neurologic/sleep disorders to treat the sleepiness associated with IH (this is called “off-label” use).
Many of these off-label treatments have not been studied extensively in person(s) with IH (PWIH). Response to these medications can vary, and some PWIH do not achieve adequate control of symptoms with these medications. In some cases, these medications may stop working over time and/or have bothersome side effects. These medications may sometimes be used in combination, especially in people who have treatment-resistant IH. The Idiopathic Hypersomnia Severity Scale (IHSS) is a validated tool that can help to measure treatment response. (Get it free HERE.)
Researchers continue to test medications approved for other disorders, as well as novel treatments, for IH. It is also important to consider how IH and its treatment may affect anesthesia/hospitalization, parenthood & pregnancy, etc.
In addition, some PWIH have found that nonpharmacologic treatments can be beneficial. For example, behavioral approaches, including cognitive behavioral therapy (CBT), can be helpful to learn coping skills. It is also important to consider how IH and its treatment may affect finances, work, school, self-care, etc.
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)
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, mood and behavior changes, 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 placebo-controlled trials that included PWIH and has been shown to help with sleepiness in people with this disorder. (See HF’s journal article summary: Does Modafinil Improve Sleepiness in People With IH Without Long Sleep Time? See also Inoue 2021 and Maski 2021.) However, modafinil and armodafinil can interact with hormonal birth control to make it less effective (for further details, including birth control options, see Birth Control, Menstruation & Menopause: Considerations for People Who Have Hypersomnias) 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 (e.g., Sunosi)—was approved in March 2019 by the U.S. FDA and January 2020 by the European Commission 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). For more information on pharmacology, benefits, and side effects, see this 2021 journal article.
Another new non-stimulant wake-promoting medication—pitolisant (e.g., Wakix)—was approved in August 2019 by the U.S. FDA and approved in Europe in 2016 for the treatment of narcolepsy. 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 PWIH whose symptoms did not respond well to other medications. Of note, pitolisant can interact with hormonal birth control to make it less effective (for further details, including birth control options, see Birth Control, Menstruation & Menopause: Considerations for People Who Have Hypersomnias).
Sodium oxybate (e.g., 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 paper (see also HF’s summary) reported that sodium oxybate improved daytime sleepiness in people with IH treated in clinic to the same degree as in people with narcolepsy type 1 (NT1). The medication also improved severe sleep inertia in 71% of people with IH. Although most PWIH experience the night as a blackout, with no dreams or recall of what has elapsed from sleep onset to the morning, about 20% of PWIH on the contrary complain of “dreaming too much” and feel this experience contributes to a non-restorative night. Xyrem has been reported to be helpful for the latter group, possibly because it has the property to reduce dream recall (Chabani, 2020). For other ways to help manage disrupted sleep, see Nonpharmacologic Treatments.
Calcium, magnesium, potassium, and sodium oxybates (e.g., Xywav) is a modified formulation of oxybate that has 92% less sodium. The article “Xywav or Xyrem: What’s the Difference?” by Sleep Review Magazine describes the benefits of the low-sodium formulation and considerations for switching from Xyrem to Xywav. In July 2020, the U.S. FDA approved Xywav as a treatment for cataplexy or excessive daytime sleepiness in people 7 years and older with narcolepsy, and in August 2021, the FDA approved Xywav to treat idiopathic hypersomnia in adults.
Medications Sometimes Used for Severe Sleep Inertia
There are currently no medications specifically approved for the treatment of severe sleep inertia (sleep drunkenness). However, as discussed above, Xyrem has been reported to improve severe sleep inertia in 71% of people with IH. Bupropion (also discussed further below) and long-acting methylphenidate were also reported in a small 2021 case series to help with severe sleep inertia. In another small case series, which used a dose of 2 mg slow-release melatonin at bedtime, 50% of PWIH had “shortened nocturnal sleep duration, decreased sleep drunkenness and relieved daytime sleepiness” (Montplaisir et al, 2001).
Medications Not FDA-Approved for Sleepiness But Sometimes Used for Sleepiness in People Who Have Narcolepsy and Other Hypersomnias
Clarithromycin (e.g., 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 it is derived from erythromycin. It works as an antibiotic by stopping the growth of bacteria, and it 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 medication (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 reported to reduce sleepiness in PWIH 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 any other CNS (central nervous system-related; neurologic) 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 who have IH or related disorders. See HF’s FAQs About Flumazenil Access. (NOTE: HF has also 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 sleepiness in idiopathic hypersomnia. However, one antidepressant—bupropion (e.g., 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. Protriptyline may also be helpful for sleepiness and can be a good option for people who also have depression (and/or cataplexy in NT1).
Selegiline (e.g., 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, especially if one doesn’t follow the low-tyramine diet that is needed to prevent tyramine toxicity while taking MAO inhibitors. (Read more HERE.)
Carnitine supplementation has been shown to reduce daytime napping, although not other measures of sleepiness, in people with narcolepsy. 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 dozing time in the daytime.
Levothyroxine (e.g., 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). A small case series 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 was reported to reduce excessive daytime sleepiness and mean sleep time in PWIH treated clinically, 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. One small case series, which used a dose of 2 mg slow-release melatonin at bedtime, found that 50% of PWIH had “shortened nocturnal sleep duration, decreased sleep drunkenness and relieved daytime sleepiness” (Montplaisir et al, 2001). Other studies have shown that melatonin synchronizes the circadian rhythms, and improves the onset, duration and quality of sleep in conditions other than IH. (Read more about circadian rhythms and IH HERE.)
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 who have IH or narcolepsy, many people who have 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 selectively increasing norepinephrine. 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.
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 (which bind to the orexin receptor and activate a response from that receptor) in people with NT1, 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 a 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 could also be of benefit to PWIH. As of 2021, research studies in both PWIH and PWN (person[s] with narcolepsy) are currently ongoing.
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. Note that in 2021, mazindol (Quilience®, NLS pharma) has also been shown to stimulate the orexin/hypocretin receptor (OXR2) in mice, and to have almost no effect in mice without this receptor (read more HERE).
In addition to medications, behavioral approaches are sometimes recommended in an attempt to minimize sleep disturbances and optimize functioning during the daytime. During the day, regular exercise and meditation have been found to improve sleep quality in some people with sleep disturbances. There is currently no evidence that these improve sleep in PWH (person[s] with hypersomnias). However, these may help improve general well-being and ability to cope with chronic disease in general. A good resource for meditation is Jon Kabat Zinn’s book, Full Catastrophe Living, which details the 8-week meditation program pioneered at UMass medical center. Local programs based on this work are often available, as are some online programs (such as this one).
Sleep compression/restriction has not been studied in PWIH, and it could lead to worsening of their EDS and other symptoms. PWIH who see a relationship between their sleep duration and sleep inertia could work carefully with their sleep doctors to try to find their optimal individual sleep duration to minimize sleep inertia. However, sleep duration should be at least 8 hours, to avoid the known harms of sleep deprivation. (See also the above section on Medications Sometimes Used for Severe Sleep Inertia.)
Short, planned naps can be helpful for sleepiness in people with narcolepsy. Unfortunately, for many PWIH, naps may not be as helpful; they tend to be long and unrefreshing, and it can be extremely difficult to awaken from them (due to severe sleep inertia/sleep drunkenness). There is some preliminary evidence that establishing a daily schedule for activity and rest can help improve daytime functioning in PWH, including PWIH (Ong et al, 2020).
For those who have difficulty sleeping at night (e.g., disrupted sleep), regulating sleep behaviors, such as maintaining consistent sleep and wake times, can promote sleep quality and quantity. Avoiding bright light exposure at night and working/eating in bed can improve the sleep environment and reduce the likelihood of experiencing sleep disturbance. These behaviors are included in “sleep hygiene”, which has unfortunately become a catch-all phrase that often includes other behavioral techniques (e.g., sleep restriction, stimulus control) that were not part of the original sleep hygiene instructions (see Stepanski et al, 2003). It is important to note that sleep hygiene alone is not an empirically-supported treatment for insomnia, and there is also not current research evidence to indicate that a sleep hygiene intervention is effective in reducing sleep disturbance in PWN or PWIH. However, medications (such as oxybates, discussed above) have been reported to help reduce sleep disturbances).
Although behavioral approaches have not been shown to improve EDS (excessive daytime sleepiness) in PWIH, different types of therapy may help people learn to cope with this chronic disease. For example, CBT (cognitive behavioral therapy) is a type of psychotherapy that provides strategies and techniques that can help PWH learn to reduce their negative emotional responses (e.g. frustration, anger, depression) to their disease symptoms, improve self-efficacy, and reduce symptoms of depression and anxiety. Psychotherapy can help people learn coping skills and adjust to the limitations and lifestyle changes brought on by symptoms. (For further information, see our SomnusNooze articles about Emotional Well-Being and Sleep Review Mag’s article “Taking Back Control in Hypersomnia Disorders”.)
Diet and Nutrition
Diet and nutrition may affect sleep. For example, a variety of whole foods and a low-glycemic diet may be helpful in improving sleep quality; Meditteranean or ketogenic type diets may also be helpful. For a brief overview, check out Sleep Review Mag’s article “How Does Nutrition Impact Sleep Disorders?”
Educating About IH
Because symptoms of IH can affect school, work, and relationships, educating those who might regularly interact with PWIH about IH should be part of the treatment plan. Since some PWIH 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 the school and/or employer about what IH is and how the symptoms affect people. Similarly, spouses, partners, parents/family 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. (See Tips for Supporters.)
Insurance and Disability Support
PWH may also need support related to health and disability insurance. See our Disability and Health Insurance web pages for help with finding insurance, filing claims, and treatment access and affordability.
Professionally trained service animals have been reported to be able to assist PWH. A service animal may be trained to wake their owner in response to an alarm, or wake them if they are falling asleep in public. For example, a PWH could condition their cat or dog to receive food when the alarm clock rings, such that the animal makes noise and/or physically interacts with insistence until the PWH awakens and gives them food.
Service animals may help with many other tasks, including that they may help make sure their owner gets to a safe place when the owner is overwhelmed with sleep. Of course, owning and caring for any animal is a major commitment and expense. Thorough research and careful thought on the advantages, challenges, costs and responsibilities of owning a service animal are essential. For further information, see our two part series on Service and Therapy Animals and Sleep Review Magazine’s “Dogs and Their Promising Roles in Sleep Disorders Therapy.”
3) For Help With Accessing Medications That Are Not Yet Approved in Your Country, CLICK HERE.
4) Free Full Text Journal Articles:
- Treatment of Central Disorders of Hypersomnolence: An American Academy of Sleep Medicine Clinical Practice Guideline by Maski et al. Journal of Clinical Sleep Medicine (2021). See also Sleep Review Magazine’s article and AASM’s podcast (Season 3, Episode 13, featuring Dr. Maski discussing how the guideline was developed, how it should be used, and more).
- A Practical Guide to the Therapy of Narcolepsy and Hypersomnia Syndromes by Mignot et al. Neurotherapeutics (2012).
- Idiopathic Hypersomnia by Trotti et al. Sleep Med Clin (2017).
- Update on the Treatment of Idiopathic Hypersomnia by Schinkelshoek et al. Current Sleep Medicine Reports (2019).
- European Guideline and Expert Statements on the Management of Narcolepsy in Adults and Children by Bassetti et al. European Journal of Neurology (2021).
- Living With Narcolepsy: Current Management Strategies, Future Prospects, and Overlooked Real-Life Concerns by Barker et al. Nature and Science of Sleep (2020).
- Recently Approved and Upcoming Treatments for Narcolepsy by Thorpy. CNS Drugs (2020).
- Pitolisant, a Wake-Promoting Agent Devoid of Psychostimulant Properties: Preclinical Comparison With Amphetamine, Modafinil, and Solriamfetol by Krief et al. Pharmacology Research & Perspectives (2021).
- And more… See references below.
- Inoue, Yuichi, et al. “Efficacy and Safety of Modafinil in Patients With Idiopathic Hypersomnia Without Long Sleep Time: a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Comparison Study.” Sleep Medicine, vol. 80, 2021, pp. 315–321. doi:10.1016/j.sleep.2021.01.018. Abstract & Request Full Text.