Treatment for Idiopathic Hypersomnia & Narcolepsy

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.” Of note, clarithromycin can also cause QT prolongation, which can potentially lead to fast, chaotic heartbeats that can trigger fainting, seizures, and even sudden death. (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 (e.g., Vivactil) 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.)

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.

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.

Carnitine (e.g., Carnitor) 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.)