The Treatment of Narcolepsy With Amphetamine-Based Stimulant Medications: A Call for Better Understanding

摘要

It is possible for a clinician not specializing in sleep medicine to work an entire career and never come across a patient with narcolepsy. In the United States narcolepsy has an incidence of approximately 1:2,000 individuals,1 which according to the 2010 census yields approximately 154,350 Americans with the disorder. Narcolepsy is then considered a rare disease according to the Rare Diseases Act of 2002, which defines as rare any disease affecting fewer than 200,000 Americans.Given that rarity and the fact that the disorder is not well understood even by a significant number of sleep medicine clinicians,2 the unintentional withholding of adequate treatment from patients with narcolepsy is a common occurrence. In this letter the disorder will be discussed first, and then practical clinical considerations will be outlined.The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, respectively), are produced in a small population of neurons in the lateral hypothalamus.3 Initially identified in 1998, the orexins were originally understood to be regulators of feeding behavior and energy storage and expenditure.4,5 Soon it became clear that the orexins also play a substantial role in the regulation of sleep/wake states6 and that the loss of orexinergic signaling (regardless of the cause, which was yet unknown) causes narcolepsy.7,8 Later work painted a much larger picture: taking inputs from internal and external sensors, orexin neurons formulate and execute appropriate responses to changing conditions through regulating or modulating emotion,9,10 the reward response,1013 homeostasis,14 cognition and executive function, thermogenesis, olfactory function, intestinal motility, reproductive drive, motivated behaviors, and many other functions of the autonomic nervous system.15 Excitatory orexin neurons quickly direct other proteins, neurotransmitters, hormones, and various other neurochemicals to perform their functions.The four main symptoms of narcolepsy are excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, and hypnopompic/hypnagogic hallucinations. Experienced sleep medicine clinicians understand that not all patients with narcolepsy experience all symptoms and that the manner in which any patient with narcolepsy experiences his or her symptoms changes over time.16 They also understand that the loss of orexinergic signaling that is the cause of those symptoms is also the cause of the dysregulation of other autonomic functions, as mentioned previously.17 A primary care provider faced with a patient with narcolepsy (diagnosed or otherwise) presenting with an odd assortment of apparently unrelated symptoms, unsure of a reason for or even of the validity of the patient's claims, would not be faulted for making a diagnosis of dysautonomia. Strictly speaking, that is what it may well be, but it is likely that what they have been looking at is all part of the package that includes narcolepsy.We feel that the broad range of pathologies resulting from lost orexinergic signaling, both directly and as a result of cascading failures of dependent systems, and including the specific group of symptoms called narcolepsy, should fall under a single all-inclusive disorder that we propose to name Hypocretin/Orexin Signaling Disorder, or HOSiD.One of the most bothersome and disabling symptoms of narcolepsy is EDS. There are several ways of treating EDS. Of those, one of the more common is to prescribe amphetamine-based stimulants. In a 2007 article by the Standards of Practice Committee of the American Academy of Sleep Medicine appearing in the journal Sleep, the authors state, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are effective for treatment of daytime sleepiness due to narcolepsy.18The literature contains considerable research demonstrating that the administration of an orexin receptor antagonist to an individual addicted to alcohol or cocaine completely or substantially extinguishes the reward response and therefore the craving for the drug.1922 Having few or no orexin neurons, the brains of people with narcolepsy produce this same result. To the best of our knowledge, no formal studies have been done to conclusively determine or even document the fact that people with narcolepsy are inherently resistant to drug addiction, although there are passing mentions of this in the literature. For example, in their 2013 article entitled The physiological role of orexin/hypocretin neurons in the regulation of sleep/ wakefulness and neuroendocrine functions, Inutsuka and Yamanaka say, psychostimulants such as amphetamine or methylphenidate are often given to narcolepsy patients. Interestingly, drug addiction hardly occurs in these patients. This finding suggests that the orexin system mediates the establishment of drug addiction.Regarding amphetamine-based stimulants, the authors of the aforementioned article in Sleep18 state, These medications have a long history of