Exploring psychotherapeutic issues and agents in clinical practice
Insomnia, defined as difficulty initiating or maintaining sleep, is a common, important, and often chronic problem in medical and mental health settings. Behavioral therapies and pharmacotherapy are similarly effective for the short-term treatment of insomnia, although the risk of adverse effects is higher with the use of medications. In this month’s column, the use of suvorexant (Belsomra®), a pharmacologically novel drug approved by the U.S. Food and Drug Administration (FDA) in August 2014 for the treatment of insomnia, is reviewed.
What Is Suvorexant?
Suvorexant is a dual antagonist of orexin receptors OX1R and OX2R. Orexin A and B, also known as hypocretin 1 and 2, are neuropeptides that were first discovered in 1998 by two different research groups (Hoyer & Jacobson, 2013). One group named them orexins because of their putative effect on appetite (Sakurai et al., 1998). The other group called them hypocretins because they are produced in the hypothalamus and have some similarity to the gut hormone secretin (de Lecea et al., 1998).
Orexins are produced exclusively by a small cluster of neurons in the lateral hypothalamus. Orexin neurons project widely throughout the brain, thus including systems that are involved in sleep–wake regulation, feeding, and arousal; their receptors are widely distributed in the brain, including cortical, subcortical, limbic, and brainstem regions. Orexin neurons are active during wakefulness, especially during motor activity when animals actively explore their environment, and they stop firing when sleep begins (Saper, Scammell, & Lu, 2005). In human beings, orexin levels in the amygdala are maximal during times of positive emotion, social interaction, and anger (Blouin et al., 2013). The wake-promoting centers of the brain are under active control of orexin neurons. Sleep-inducing centers can inhibit the activity of orexin neurons, but orexin neurons cannot directly affect sleep-inducing centers. Therefore, orexin neurons reinforce arousal systems, and blocking orexin receptors is associated with decreased arousal and decreased wakefulness, thus resulting in beneficial effects on sleep, rather than having a direct sleep-promoting effect.
Within several years of the initial discovery of orexins, it was found that narcolepsy/cataplexy in dogs and human beings is related to defects in the orexin system (Hoyer & Jacobson, 2013). Narcolepsy/cataplexy is characterized by excessive daytime sleepiness, disturbed nocturnal sleep, abnormal sleep-onset rapid eye movement (REM) periods (i.e., dream sleep), and sudden transient episodes of muscular weakness or paralysis, which occur while fully conscious and are triggered by strong emotional reactions, especially laughter or anger (Burgess & Scammell, 2012). Dogs with narcolepsy/cataplexy have an OX2R mutation, whereas human beings with narcolepsy/cataplexy have lost all or nearly all of their orexin-producing neurons in the lateral hypothalamus.
Four drugs have been developed as dual orexin receptor antagonists (DORAs) for treating insomnia (Hoyer & Jacobson, 2013). Suvorexant, also known as MK-4305, was the first DORA approved by the FDA. Almorexant was also found to be effective for treating insomnia in Phase II trials and in a single Phase III trial; however, its development was discontinued for unspecified safety observations (Hoyer & Jacobson, 2013). The development of a third drug, referred to as SB-649868, was stopped for unknown reasons. Development of a fourth drug, Filorexant (MK-6096) (Winrow et al., 2012) has included Phase II studies for insomnia, migraine prophylaxis, and painful diabetic neuropathy (NCT01021852; NCT01513291; NCT01564459; access http://www.ClinicalTrials.gov); however, a Phase II study using this drug for antidepressant augmentation in major depression was terminated for unknown reasons (NCT01554176; access http://www.ClinicalTrials.gov).
Clinical Studies of Suvorexant for Insomnia
Final FDA approval of suvorexant for the treatment of insomnia was based on three large, randomized, double-blind, placebo-controlled, clinical trials, only one of which has been published (Michelson et al., 2014).
Two similarly designed safety and efficacy studies compared high-dose suvorexant (40 mg per day for study participants younger than 65; 30 mg per day for participants 65 and older), low-dose suvorexant (20 mg per day for younger participants; 15 mg per day for older participants), and placebo during 3 months of double-blind treatment. At the end of each study, a 1-week randomized, double-blind, placebo-controlled, discontinuation phase was conducted to evaluate whether abruptly stopping suvorexant or placebo was associated with withdrawal effects, including rebound insomnia. Raw outcome data for each study can be viewed online (NCT01097616; NCT01097629; access http://www.ClinicalTrials.gov). Both suvorexant doses were more efficacious than placebo, but high-dose was not more effective than low-dose. Drop-out rates, adverse event (AE) rates, drop-out rates due to AEs, and serious AE (SAE) rates were similar among the three groups.
The third safety and efficacy study (Michelson et al., 2014; NCT01021813, access http://www.ClinicalTrials.gov) compared suvorexant (40 mg per day for study participants younger than 65; 30 mg per day for participants 65 and older) and placebo during 12 months of double-blind treatment. At the end of the study, a 2-month, randomized, double-blind, placebo-controlled, discontinuation phase was conducted to evaluate the effects of abruptly stopping suvorexant or placebo. Suvorexant was more efficacious than placebo during the course of the study. Dropout rates, AE rates, drop-out rates due to AEs, and SAE rates were similar between the two groups.
Dose-related somnolence was the most common AE in all three studies, occurring in approximately 3% of placebo-treated study participants, 5% to 8% of low-dose suvorexant participants, and 10% to 13% of high-dose participants. Headache and dry mouth were more frequently associated with suvorexant than with placebo. Withdrawal effects were not associated with suvorexant discontinuation in any study. Rebound insomnia occurred with suvorexant discontinuation at the end of the long-term study but not at the end of the short-term studies.
Clinical Use of Suvorexant
Suvorexant is available in 5-, 10-, 15-, and 20-mg tablets. The usual recommended dose is 10 mg per day. Doses higher than 20 mg per day do not have greater efficacy and are likely to be associated with more side effects, especially somnolence. The time to maximum concentration after taking the drug is 30 minutes to 6 hours, and it has an elimination half-life of approximately 12 hours. For these reasons, it should be taken at least 8 hours before the individual expects to be up and active in the morning to minimize next-day sedation. Taking suvorexant with food can delay its absorption, which may delay its onset of action and possibly contribute to next-day sedation.
Suvorexant has not been associated with significant weight gain, although the available data from short-and long-term studies are insufficient to adequately assess this issue. One study described in the suvorexant package insert (Merck & Co., 2014) (comparing doses of 10, 20, 40, and 80 mg to placebo for 4 weeks) found a small dose-related increase in cholesterol levels compared to placebo. Orexin neurons in the hypothalamus have a significant role in regulating energy homeostasis and metabolism (Inutsuka et al., 2014). As a result, long-term experience in a broad population of patients will be necessary to determine whether adverse weight or metabolic effects occur with the chronic use of suvorexant.
Side effects of suvorexant include somnolence, headache, and dry mouth. Psychomotor performance, including reaction time and driving skills, is not prominently impaired but can be affected in some individuals. After oral administration, exposure to suvorexant (calculated as the serum concentration over time) is increased in women compared to men, as well as in obese compared with non-obese individuals. Women have higher rates of somnolence, headache, and dry mouth than men. Obese individuals might also be at higher risk of side effects. Therefore, lower doses should be considered for women and obese individuals. Suvorexant does not appear to have adverse cardiac effects. Animal and human being studies have not identified significant toxicity with high-dose use or overdoses.
All DORA drugs enhance REM sleep and shorten the latency to REM sleep onset (Hoyer & Jacobson, 2013). Potential side effects related to these effects include hypnogogic hallucinations, sleep paralysis, cataplexy-like symptoms, and complex sleep-related behaviors, but these appear to be rare with suvorexant. Because of the specific involvement of orexin systems in narcolepsy/cataplexy, these individuals should not take suvorexant. In addition, individuals with evidence of REM sleep behavior disorder should also probably not take suvorexant. REM sleep behavior disorder is characterized by a lack of normal paralysis during REM sleep, such that individuals act out their dreams (Boeve et al., 2007). This disorder has been associated with narcolepsy; it is more common in older adults and has been associated with various neurodegenerative diseases, including Parkinson’s disease and Lewy body dementia.
The REM sleep effects of DORA drugs are also similar to some of the characteristic sleep electroencephalogram features associated with depression. Both hypoactivity and hyperactivity of orexin-signaling pathways have been found to be associated with depression (Nollet & Leman, 2013). For this reason, it is possible that chronic administration of suvorexant might be a risk factor for depression (Blouin et al., 2013). It is not clear whether depressed individuals with insomnia would necessarily respond to suvorexant in the same way as individuals with primary insomnia.
Suvorexant is metabolized primarily by the cytochrome-P450 3A4 enzyme (CYP3A4), with a minor contribution from CYP2C19. Therefore, potential exists for drug–drug interactions involving drugs that inhibit or induce CYP3A4 activity. Grapefruit juice, nefazodone (Serzone®), ketoconazole (Nizoral®), erythromycin, and antiretroviral drugs used for treating HIV are all CYP3A4 inhibitors, and their use will increase serum suvorexant levels. By contrast, the concurrent use of CYP3A4 inducers, such as carbamazepine (Tegretol®) or phenytoin (Dilantin®), will decrease suvorexant’s level. Suvorexant doses should be adjusted accordingly. Suvorexant can increase serum digoxin levels but has not been shown to affect other drugs.
Suvorexant does not have active metabolites. Most of the drug is excreted through the gastrointestinal tract. It can be used without dose adjustments in individuals with renal impairment or with mild to moderate liver impairment. Its safety in individuals with severe liver impairment is not known; therefore, suvorexant use should be avoided in such patients.
Suvorexant has not been studied in children or adolescents but has been well studied in relatively healthy individuals older than 65. Side effect rates are not greatly different in younger and older individuals, but the drug can adversely affect balance in older adults who are wakened during the night. The risk of delirium is higher in older adults and is related to alterations in arousal systems (Maldonado, 2013). Because orexin signaling decreases with age, suvorexant should be avoided or monitored closely in older adults at risk for delirium. No specific data are available regarding its safety during pregnancy or breast feeding.
Suvorexant is classified as a schedule IV drug. In a study of recreational drug users, suvorexant and zolpidem (Ambien®) had similar “liking” effects, but no evidence of physiological withdrawal (Merck & Co., 2014).
Suvorexant is a pharmacologically novel DORA drug that promotes sleep by reducing arousal and wakefulness. Although its tolerability and safety profile generally appear to be good, long-term experience in a broader population will be necessary to uncover any untoward or unexpected adverse effects. In this regard, it is of concern that the development of two other DORA drugs were halted, with one discontinued for unspecified safety reasons. Nurses should be familiar with the pharmacology and clinical profile of suvorexant.
- Blouin, A.M., Fried, I., Wilson, C.L., Staba, R.J., Behnke, E.J., Lam, H.A. & Siegel, J.M. (2013). Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. Nature Communications, 4, 1547. doi:10.1038/ncomms2461 [CrossRef]
- Boeve, B.F., Silber, M.H., Saper, C.B., Ferman, T.J., Dickson, D.W., Parisi, J.E. & Braak, H. (2007). Pathophysiology of REM sleep behavior disorder and relevance to neurodegenerative disease. Brain, 130, 2770–2788. doi:10.1093/brain/awm056 [CrossRef]
- Burgess, C.R. & Scammell, T.E. (2012). Narcolepsy: Neural mechanisms of sleepiness and cataplexy. Journal of Neuroscience, 32, 12305–12311. doi:10.1523/JNEUROSCI.2630-12.2012 [CrossRef]
- de Lecea, L., Kilduff, T.S., Peyron, C., Gao, X., Foye, P.E., Danielson, P.E. & Sutcliffe, J.G. (1998). The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences of the United States of America, 95, 322–327. doi:10.1073/pnas.95.1.322 [CrossRef]
- Hoyer, D. & Jacobson, L.H. (2013). Orexin in sleep, addiction and more: Is the perfect insomnia drug at hand?Neuropeptides, 47, 477–488. doi:10.1016/j.npep.2013.10.009 [CrossRef]
- Inutsuka, A., Inui, A., Tabuchi, S., Tsunematsu, T., Lazarus, M. & Yamanka, A. (2014). Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons. Neuropharmacology, 85, 451–460. doi:10.1016/j.neuropharm.2014.06.015 [CrossRef]
- Maldonado, J.R. (2013). Neuropathogenesis of delirium: Review of current etiologic theories and common pathways. American Journal of Geriatric Psychiatry, 21, 1190–1222. doi:10.1016/j.jagp.2013.09.005 [CrossRef]
- Merck & Co. (2014). Suvorexant [package insert]. Whitehouse Station, NJ: Author.
- Michelson, D., Snyder, E., Paradis, E., Chengan-Liu, M., Snavely, D.B., Hutzelmann, J. & Herring, W.J. (2014). Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: A phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurology, 13, 461–471. doi:10.1016/S1474-4422(14)70053-5 [CrossRef]
- Nollet, M. & Leman, S. (2013). Role of orexin in the pathophysiology of depression: Potential for pharmacological intervention. CNS Drugs, 27, 411–422. doi:10.1007/s40263-013-0064-z [CrossRef]
- Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H. & Yanagisawa, M. (1998). Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92, 573–585. doi:10.1016/S0092-8674(00)80949-6 [CrossRef]
- Saper, C.B., Scammell, T.E. & Lu, J. (2005). Hypothalamic regulation of sleep and circadian rhythms. Nature, 437, 1257–1263. doi:10.1038/nature04284 [CrossRef]
- Winrow, C.J., Gotter, A.L., Cox, C.D., Tannenbaum, P.L., Garson, S.L., Doran, S.M. & Renger, J.J. (2012). Pharmacological characterization of MK-6096—A dual orexin receptor antagonist for insomnia. Neuropharmacology, 62, 978–987. doi:10.1016/j.neuropharm.2011.10.003 [CrossRef]