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Pitolisant is an Effective Treatment for Cataplexy

Individuals with narcolepsy have poor control of their sleep-wake cycles. This means that they are frequently very tired during the day. Sometimes they even have “sleep attacks” that last for seconds or minutes.

Some patients with narcolepsy also experience cataplexy. These individuals have a sudden loss of muscle tone while they are awake. During a cataplectic attack, the individual remains conscious, but loses tone, appears limp, and is unable to move. Cataplexy is typically triggered by laughter or sadness or fear. That said, many individuals experience a cataplectic attack absent an emotional trigger.

While physicians prescribe several medications to treat narcolepsy, scientists have had difficulties finding an effective treatment for cataplexy. Now, a new study published in Lancet Neurology has found that pitolisant is an effective treatment for cataplexy. Pitolisant is a first-in-class drug that acts on the histamine 3 receptor. Previous studies have shown that improves subjective daytime sleepiness in patients with narcolepsy. The new study found that, not only did pitolisant reduce excessive daytime sleepiness as determined by both subjective and objective measures, but it also decreased the number of cataplectic episodes. The study was short (only seven weeks) and should be repeated, but these first results are striking, especially given how well the patients tolerated pitolisant.

The European study included 105 patients who were randomly assigned to treatment or placebo. The investigators used a flexible dosing protocol and patients received 5 mg, 10 mg, 20 mg, or 40 mg dosages as needed. The flexible dosing approach allowed the researchers to minimize unnecessary drug exposure.

The investigators measured a weekly cataplexy rate (WCR) as their primary outcome. Patients who enrolled in the study had a WCR of 9.15. This decreased to 2.27 (75%) in the pitolisant treatment group. The placebo group also saw a decrease from a baseline of 7.31 to a final of 4.52. The high placebo effect may be related to the fact that cataplexy can be triggered by many subjective and emotional factors.

The researchers documented several adverse events in the pitolisant group: headache, irritability, anxiety, and nausea. These were described as mild or moderate. When pitolisant treatment was stopped, none of the patients exhibited signs of withdrawal. One of the patients in the placebo group, however, did show signs of withdrawal. While treatment-related adverse events were more common in the pitolisant group than in the control group, there was only one severe adverse event and it was in the pitolisant group. That individual experienced extreme nausea and dropped out of the study.

The authors remain uncertain as to why pitolisant is uniquely effective against cataplexy. They note, however, that mouse studies have shown that pitolisant decreases direct transitions from wakefulness to REM sleep episodes.

The investigators conclude in their discussion:

“In our study, once-daily treatment with pitolisant significantly improved cataplexy in patients with narcolepsy, in contrast with previous work, which only reported improvement in excessive daytime sleepiness. Our trial recruited severely affected narcoleptic patients with cataplexy who experienced a high frequency of cataplexy episodes at baseline (7–9 per week; ie, considerably higher than the minimum required for inclusion), marked daytime sleepiness (mean ESS of 17, a low score on the multiple sleep latency test, and low MWT values), and high frequency of associated symptoms such as hallucinations (in 68 [65%] all 105 patients randomised to treatment).”





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