Insomnia can be divided into two categories: difficulty initiating sleep and/or difficulty maintaining sleep. Approximately 30 percent of the adult population is affected by insomnia at some point, thus creating a major risk factor for anxiety, depression and/or substance abuse. Current pharmacologic therapy options for insomnia include benzodiazepines and non-benzodiazepine gamma-amino butyric acid (GABA) acting hypnotics such as zolpidem and eszopiclone. Other options include antihistamines, sedating antidepressants and melatonin agonists.
Orexin, a neurotransmitter (also known as hypocretin) was discovered in 1998. There are approximately 15,000 orexin neurons in the brain, primarily located in the perifornical lateral hypothalamus. Hypocretin deficiency is associated with decreased levels of epinephrine and histamine, important chemicals in promoting arousal, alertness and wakefulness. Ninety percent of patients with narcolepsy have been found to have decreased levels of orexin in their cerebrospinal fluid. Cataplexy, (the most common form of narcolepsy) causes sudden, transient episodes of muscle weakness triggered by emotions (such as crying or laughing). Seventy percent of narcoleptics have cataplexy, which is caused by the autoimmune destruction of orexin.
The FDA recently approved suvorexant, a duel orexin receptor antagonist, as the first in a new class of pharmacologic agents for the treatment of insomnia. This new medication blocks both 0X1R and OX2R, has been shown to improve both sleep onset as well as sleep maintenance. One major advantage of suvorexant is its low potential for addiction or rebound.
In gaining FDA approval, three Phase III studies were conducted. Two of these studies lasted three months and the largest evaluated more than 1200 elderly and non-elderly subjects for safety and efficacy. Plasma concentrations were unchanged in patients with moderate hepatic or renal dysfunction. However, suvorexant should be avoided in individuals with severe hepatic impairment. At doses of 15-20 mg, Suvorexant reduced latency to persistent sleep by about 10 minutes as compared to placebo. By the third month of therapy this was down to 5 minutes. Wakefulness after sleep onset (WASO) was about 35 minutes less than placebo (verified by polysomnography) at the 15-20 mg dose. This effect also lessens over time to a 23 minute improvement in WASO (versus placebo) by month three. Suvorexant may cause daytime sleepiness as well as some daytime confusion. The daytime sleepiness is dose dependent. There is also a potential for next day driving impairment at the higher doses. Suvorexant should be used cautiously in the setting of other moderate CYP3A medications and is contraindicated with severe CYP3A inhibitors. It is recommended that this medication be taken within 30 minutes of going to bed and by those ready to stay in bed for at least seven hours.
Many of the studies that led to the FDA approval of suvorexant looked at higher doses than were eventually approved. This fact should be kept in mind when interpreting these clinical studies. Suvorexant is now available under the brand name Belsomra® in 5, 10, 15, and 20 mg tablets. Suvorexant is a controlled substance (Schedule lV) and is contraindicated in narcolepsy. In addition to pharmacologic therapy for insomnia, it is important to remind patients about cognitive behavioral therapy, sleep hygiene, and other non-pharmaceutical treatments of insomnia (such as avoidance of caffeine, nicotine, alcohol, etc.). Perhaps in the future, there will be an orexin agonist available to treat excessive daytime sleepiness, as this is currently an active area of clinical research.
By Daniel T. Layish, MD and Kathleen Summo RN, MSN
Daniel Layish, MD, graduated magna cum laude from Boston University Medical School in 1990. He then completed an Internal Medicine Residency at Barnes Hospital (Washington University) in St.Louis, Missouri and a Pulmonary/Critical Care/Sleep Medicine Fellowship at Duke University in Durham, North Carolina. Since 1997, he has been a member of the Central Florida Pulmonary Group in Orlando. He serves as Co-director of the Adult Cystic Fibrosis Program in Orlando. Dr. Layish may be contacted at 407-841-1100 or by visiting www.cfpulmonary.com.
Kathleen Summo RN, MSN, CCP is the Clinical Director of Research and Cystic Fibrosis at the Central Florida Pulmonary Group, PA. She has a Masters degree in Nursing with a minor in Clinical Research and fifteen years of experience conducting clinical trials.