By Alan Z. Segal, MD
Associate Professor of Clinical Neurology, Weill Cornell Medical College
Many new drugs are coming on the market to treat daytime sleepiness, as well as insomnia, as the prevalence of sleep disorders continues to grow in modern society. Neurologists should familiarize themselves with these disorders and the various ways to treat them safely.
Dauvilliers Y, Lecendreux M, Lammers GJ, et al. Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: A double-blind, randomised, placebo-controlled trial. Lancet Neurol 2023;22:303-311.
A walk down the aisle of any pharmacy provides ample evidence that antihistamines can promote sleep. Multiple sleep aids available over the counter, such as diphenhydramine (e.g., Benadryl or Tylenol/Advil PM) or doxylamine (Unisom), depend on their inhibitory effects on histamine. Among prescription drugs, the so-called GABAergic Z drugs (zolpidem [Ambien], eszopiclone [Lunesta], and zaleplon [Sonata]), dominate the market. However, prior to the arrival of these medications, trazodone, because of its effects as an antihistamine, was the most widely prescribed medication for insomnia.
On the flip side, histaminergic upregulation is known to promote wakefulness. Produced in the tuberomammillary nucleus, histamine binds to H1 receptors, which are distributed in the ventrolateral hypothalamus, as well as in the thalamus and cerebral cortex. In fact, target cells for histamine are so widespread that it has been considered to be a regulator of “whole brain” activity. The drug pitolisant (Wakix), recently added to the available pharmacopoeia for treating narcolepsy, harnesses the power of histamine to promote arousal. Pitolisant is an antagonist/inverse agonist, acting on the H3 histamine receptor. The normal role of the H3 receptor is to provide negative feedback on histamine production and, thus, pitolisant, by inhibiting H3, allows for an increase in histamine release. Furthermore, because H3 receptors also inhibit the release of other neurotransmitters (acetylcholine, dopamine, serotonin, and norepinephrine), blockage of H3 by pitolisant also may create a more widespread and multifactorial neurostimulatory boost.
In contrast to modafinil (a widely used drug for narcolepsy with no clear mechanism), pitolisant can be considered more akin to the typical stimulants historically used for narcolepsy. These drugs, such as dextroamphetamine (Adderall) and methylphenidate (Ritalin), either stimulate monoamine release from presynaptic terminals or act as a reuptake inhibitor. The result of these actions is an increase in multiple neurotransmitters, including dopamine, serotonin, and norepinephrine.
Among the challenges in narcolepsy treatment is the fact that narcolepsy itself is not a homogenous disorder. Classic narcolepsy with cataplexy (type 1) is a known consequence of loss of hypocretin (orexin) neurons in the hypothalamus, while narcolepsy without cataplexy (type 2) is a more complex disorder. Although human leukocyte antigen (HLA) type DQB1*0602 is associated with > 90% of patients with cataplexy, it is found in only 40% of people with type 2 narcolepsy (compared with rates as high as 38% in the general population).
Cataplexy treatment has evolved over the years. Once treated with tricyclic antidepressant (TCA) medications such as clomipramine and imipramine, cataplexy more recently has been treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine such as fluoxetine (Prozac) and venlafaxine (Effexor). However, the most dramatic advance in the treatment of cataplexy has been the development of sodium oxabate (Xyrem), also known as gamma-hydroxybutyrate (GHB). This drug deepens nocturnal sleep, promoting deep slow-wave (Stage 3) sleep, with the aim of promoting daytime alertness. GHB is used widely for narcolepsy as well as for idiopathic hypersomnia, but its only approved indication is narcolepsy with cataplexy.
Like GHB, pitolisant is Food and Drug Administration-approved for narcolepsy with cataplexy, but it has wider off-label indications for type 2 narcolepsy as well as excessive daytime sleepiness (idiopathic hypersomnia). In adults, two studies (Harmony 1 and Harmony CTP) have demonstrated that pitolisant promotes wakefulness, with improvements of ≥ 3 points on the Epworth Sleepiness Scale (ESS). Cataplexy rates in these studies decreased by as much as 75%. Pitolisant, investigated here, is shown to have similar benefits in children.
In this trial, children with narcolepsy, with or without cataplexy, were studied over an eight-week period. There was a significant difference in the Ullanlinna Narcolepsy Scale, with a decrease of 6.2 in treated patients (n = 72) compared with 2.6 in the placebo group (n = 38). The UNS score includes end points related to both cataplexy and sleepiness, with subscores reaching significance for both. In keeping with this, secondary end points, such as the weekly cataplexy rate and Pediatric Daytime Sleepiness Scale (PDSS) score, also showed significant benefits for pitolisant.
While the ESS includes questions for adults about activities such as being stopped in traffic or sitting in a meeting, the PDSS queries children about sleepiness in class, sleepiness while doing homework, or feeling grumpy upon being awakened in the morning by an adult. Both scores range from 0 to 24, with > 10 being considered excessively sleepy. The PDSS scores decreased by 5.5 in treated patients (from a mean of 20.3 to 14.8) compared to 2.1 with placebo (from a mean of 20.1 to 18). The magnitude of these changes was comparable to the benefits observed in the adult trials, with a majority of patients still remaining sleepy, even if improved.
Treatment-emergent adverse effects were common among the two groups, 22/72 (31%) of treated patients compared to 13/38 (34%) in the placebo group. Side effects directly attributable to the drug were more common in treated patients, with 19% of pitolisant patients complaining of headache (compared to 8% of patients in the placebo group), and insomnia in 7% compared to 3% in the placebo group. Of note, although the study included both type 1 and type 2 narcolepsy patients, 85% of treated patients had type 1 (76% among placebo-treated patients). The study also allowed for continued use of previously prescribed medications, such as other stimulants or GHB in 18% of treated patients. The authors emphasized that combination therapy had a favorable safety profile and would be indicated in severe or complex cases.
COMMENTARY
Pitolisant has a modest role in the management of narcolepsy (with comparable results in children and adults) but is hardly a game changer. Limitations include the magnitude of its effect (significant on sleepiness scales but perhaps less noticeable clinically) and significant incidence of side effects. In addition, studies of narcolepsy (particularly this one in children) are skewed by enrollment of type 1 narcolepsy (with cataplexy as a major component of outcome), limiting their generalizability. In typical practice, patients with true cataplexy are quite rare. Of the approximately 30 patients with narcolepsy that I follow, only two have cataplexy.
Despite the relative flood of designer stimulants on the market, fueled by the pharmaceutical industry (including soltamiterol [Sunosi], in addition to pitolisant), simple medications such as dextroamphetamine and methylphenidate continue to be the mainstay of treatment for both narcolepsy and attention-deficit/hyperactivity disorder. Recently, however, national shortages related to a limited generic supply chain have produced significant logistical challenges, forcing patients to search multiple pharmacies for medication.
Drugs in the amphetamine class have had a checkered history. Diet pills (Fen-Phen) containing fenfluramine were associated with potentially fatal pulmonary hypertension and cardiac valvular disease. Amphetamine-based decongestants (such as pseudoephedrine) have been cooked into crystal methamphetamine, reaching the zenith of pop culture with the success of the television show “Breaking Bad.” Methamphetamine has a legal form (marketed as Desoxyn), which can be very effective in people with narcolepsy but is not commonly stocked. Most notably, GHB has been stigmatized as a “date rape” drug or, alternatively, celebrated in movies such as “The Hangover.” Highly regulated through a single central pharmacy, Xyrem costs upward of $100,000 per year. A newer form of Xyrem, known as Xywav (which avoids a sodium load by using salts of calcium and magnesium), will extend the patent profitability of these drugs, especially since Xywav has an indication for idiopathic hypersomnia as well as narcolepsy.
