Pitolisant, a new medicine for excessive sleepiness in narcolepsy

Pitolisant is a new medicine approved by the FDA for treatment of excessive sleepiness in narcolepsy. It is an H3 reverse agonist. That means that it reduces activity at the Histamine 3 receptor in the brain. Histamine is one of the brain chemicals that helps us stay more awake and alert. The H3 receptor is an auto-receptor. That means it responds to histamine levels between cells in the brain. When activated, it reduces histamine release from nerve cells. Reducing its activity causes release of more histamine. Reducing its activity also causes release of norepinephrine and dopamine. These chemicals also make us more awake and alert.

So far, most medicines approved for use in excessive sleepiness (or used off-label) cause release of dopamine and norepinephrine. Therefore, they are called stimulants or wake promoting agents. Such medicines include methylphenidate (Ritalin^R, Concerta^R, etc.), amphetamines (Adderall^R, Dexedrine^R, etc.), modafinil and armodafinil (Provigil^R, Nuvigil^R), solriamfetol (Sunosi^R), and the off-label use of bupropion (Wellbutrin^R) and benzphetamine (Didrex^R). Amphetamines (Adderall^R, Dexedrine^R, etc.) also cause release of dopamine, which makes them more addicting and more likely to be abused. The exception has been sodium oxybate (Xyrem^R) which makes us very sleepy (and is also known as the date rape drug) but reduces next day sleepiness when taken at night.

Pitolisant, then, is the first in a new class of medicines for daytime sleepiness. Wakix^R is its trade name in the USA. Like sodium oxybate, it is very expensive. Most medicines for daytime sleepiness are now generic and cost about $1 a pill. If your insurance charges you more, you can always find it at that price on GoodRx.com. Solriamfetol is about $20 a pill. Sodium oxybate is only available through special pharmacy programs and is more than $100 a dose. Pitolisant costs about $200 a pill. A cost-benefit analysis might suggest that pitolisant should be used as a last resort, not as one of the first agents to try.

Like most other medicines for excessive sleepiness, pitolisant’s side effects may include insomnia, headaches, anxiety, decreased appetite, increased heart rate. Unlike the other FDA approved treatments for excessive sleepiness, pitolisant is not a controlled substance. It does not significantly affect dopamine levels (unlike stimulants and wake-promoting agents). It does not cause sleepiness and confusion (like sodium oxybate). Therefore, it is not likely to be addictive or abused.

Other new medicines for excessive sleepiness

Companies are currently doing research on other medicines for excessive sleepiness. We recently finished a research study on pentetrazol for excessive sleepiness in idiopathic hypersomnia. We are now starting a study on mixed oxybate salts for excessive sleepiness in idiopathic hypersomnia. We are also about to start a study on SUVN-G3031 (an H3 reverse agonist) for narcolepsy.

In conclusion, pitolisant is a new medicine for treatment of excessive sleepiness in narcolepsy. It is the first of a new class (H3 reverse agonist) of medicines for excessive sleepiness. It is extremely expensive.