Traditional Treatments for Narcolepsy

Stimulants are often considered the first-line treatment for narcolepsy due to their effectiveness in managing the condition's most prevalent symptom–excessive daytime sleepiness. Patient regimens commonly include medications such as Modafinil (Provigil), Armodafinil (Nuvigil), and Solriamfetol (Sunosi). These act by inhibiting the breakdown of catecholamines, mainly dopamine, adrenaline, and noradrenaline, to help individuals with narcolepsy stay awake and alert throughout the day (Gowda, 2014).

In patients where these are not effective, physicians will prescribe stronger stimulants as their second-line treatment, as these medications have a less favorable safety profile and greater potential for abuse and negative side effects.These stimulants, including methylphenidate (Ritalin, Concerta) and amphetamines (Adderall XR 10, Dexedrine), while stronger, increase the risk of dependency and habituation (habit-formation). These stimulants work by increasing alertness and reducing the overwhelming urge to fall asleep during the day, by once again increasing the levels of catecholamines in the brain and blocking their reuptake, allowing individuals with narcolepsy to maintain a closer to normal daily routine. However, it's important to note that stimulant medications do not address all aspects of narcolepsy, and their long-term use may come with potential side effects, including tolerance and dependency.

While stimulants are the first-line treatment for combating excessive daytime sleepiness (EDS), antidepressants can be prescribed to combat the associated cataplexy and muscle weakness. These are further categorized into two segments: tricyclics (Imipramine, Desipramine, Clomipramine, and Protriptyline) and selective serotonin reuptake inhibitors (Venlafaxine, Fluoxetine, and Atomoxetine). These medications help patients modulate their own moods by reducing the triggers for cataplexy, empowering/giving patients more control over their symptoms (“Narcolepsy,” n.d.).

Sodium oxybate and related oxybate salts are central nervous system depressants that are likewise prescribed to treat cataplexy and daytime sleepiness. While our understanding of these medications’ complete mechanisms is not comprehensive, they have been shown to increase slow-wave sleep duration, delta power, and improve sleep quality overall in narcoleptic patients. It is theorized that these therapeutic effects are a result of GABA-B agonist activity, which enhances inhibitory signals in the brain, stabilizes sleep patterns, and reduces the frequency and severity of cataplectic episodes, ultimately leading to better symptom management in narcolepsy patients (Dominguez, 2023).

With the FDA approval of Pitolisant in 2020, histamine-3 receptor (H3R) antagonists are now recognized as an effective treatment for both T1N and T12 (narcolepsy with and without cataplexy, respectively). By antagonizing the H3 receptor, Pitolisant blocks calcium channels, thereby increasing synthesis and release of neurotransmitters histamine, dopamine, acetylcholine, and others. The increased release of histamine enables better patient management of EDS symptoms, as well as improved cognitive function. These medications are recognized as having less potential for abuse and show similar efficacy to Modafinil for EDS, and superior efficacy for cataplexy control. As a result, research into other H3R antagonists is ongoing and has much potential to transform narcolepsy treatment, with the possibility of such medications replacing stimulants as the first-line therapy (Harwell, 2020).

Narcolepsy remains a chronic, life-long condition with no known cure. While behavioral changes may be recommended by physicians, over 90% of patients still require some form of pharmacotherapy to combat their symptoms. Stimulants, which are commonly used to manage excessive daytime sleepiness, come with their own set of limitations and negative side effects. For instance, they may cause an increase in heart rate, insomnia, and dependency, which can make long-term use challenging for some individuals. Antidepressants used for cataplexy management also come with their own set of side effects including weight gain and sexual dysfunction and may also not be effective for everyone. Lastly, while some newer medications like sodium oxybate offer promising therapeutic effects, access to them remains limited by high costs and associated insurance reimbursement policies along with prescribing guidelines. There are also risks associated with taking these medications during pregnancy and breastfeeding. Even though medications have not been shown to be teratogenic when used in therapeutic doses, concerns exist from animal studies regarding potential embryotoxicity; therefore, most clinicians advocate for cessation of drug therapy during conception, pregnancy, and breastfeeding (Wozniak, 2015). Ongoing research into treatments for narcolepsy aims to overcome these challenges and develop more effective, easily tolerated options for individuals affected by this complex sleep disorder.

References

• Gowda, C., & Lundt, L. (2014). Mechanism of action of narcolepsy medications. CNS Spectrums, 19(S1), 25-34. doi:10.1017/S1092852914000583

• “Narcolepsy.” National Institute of Neurological Disorders and Stroke, https://www.ninds.nih.gov/health-information/disorders/narcolepsy. Accessed 29 Aug. 2023. Dominguez A, Soca Gallego L, Parmar M. Sodium Oxybate. [Updated 2023 Jan 17]. In:

• StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562283/

• Harwell V, Fasinu PS. Pitolisant and Other Histamine-3 Receptor Antagonists-An Update on Therapeutic Potentials and Clinical Prospects. Medicines (Basel). 2020 Sep 1;7(9):55. doi: 10.3390/medicines7090055. PMID: 32882898; PMCID: PMC7554886.

• Wozniak DR, Quinnell TG. Unmet needs of patients with narcolepsy: perspectives on emerging treatment options. Nat Sci Sleep. 2015 May 22;7:51-61. doi: 10.2147/NSS.S56077. PMID: 26045680; PMCID: PMC4447169.