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Belsomra®: a Novel Dual Orexin Receptor Antagonist for the Treatment of Insomnia

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Belsomra®: a Novel Dual Orexin Receptor Antagonist for the Treatment of Insomnia Pharmacy and Wellness Review Volume 7 Issue 1 Article 1 January 2016 Belsomra®: A Novel Dual Orexin Receptor Antagonist for the Treatment of Insomnia Shane Bogusz Ohio Northern University Steven Blake Ohio Northern University Michaela Wolford Ohio Northern University Victoria Cho Ohio Northern University Manoranjan D'Souza Ohio Northern University, [email protected] Follow this and additional works at: https://digitalcommons.onu.edu/paw_review Part of the Medical Pharmacology Commons, Nervous System Diseases Commons, Neurology Commons, and the Pharmaceutics and Drug Design Commons This Article is brought to you for free and open access by the ONU Journals and Publications at DigitalCommons@ONU. It has been accepted for inclusion in Pharmacy and Wellness Review by an authorized editor of DigitalCommons@ONU. For more information, please contact [email protected]. CNS Belsomra®: A Novel Dual Orexin Receptor Antagonist for the Treatment of Insomnia Shane Bogusz, Steven Blake, Michaela Wolford, Victoria Cho, Manoranjan D'Souza, M.D., Ph.D. Key Terms This knowledge-based activity is targeted for all pharmacists Belsomra®; Benzodiazepine; Dual Orexin Receptor Antago­ and is acceptable for 1.0 hour (0.1 CEU) of continuing nist; DORA, Insomnia, Insomnia Treatment, Orexin, education credit. This course requires completion Suvorexant of the program evaluation and at least a 70 percent grade on the program assessment questions. Introduction Insomnia refers to a disease state that involves persistent ACPE Universal Activity Number (UAN): 0048-0000-16-005-HOl-P difficulty falling asleep and/or frequent awakenings during sleep. Over 35 percent of the adult population exhibits one or To complete the continuing education program and receive more symptoms associated with insomnia, with 12 percent credit, please go to www.raabecollegeofpharmacy.org/PAW/. to 20 percent actually demonstrating a symptom profile suf­ Objectives ficient for diagnosis of the disorder.1 The lack of restful sleep After completion of this program, the reader should be able to: may lead to symptoms such as daytime fatigue, daytime 1. List medications currently approved for treatment of sleepiness, memory or concentration deficits, anxiety, de­ insomnia. pression, irritability, reduced energy and lack of motivation. 2. Enumerate the limitations of benzodiazepines and Furthermore, insomnia is associated with changes in mood, non-benzodiazepines for insomnia treatment. poor job performance, disturbed personal relationships and 3. Describe the mechanism of action of suvorexant. difficulty in carrying out daily activities. Ozminkowski and 4. List the major adverse effects of suvorexant. colleagues have estimated that insomnia results in an enor­ 5. Describe the role of the pharmacist in counseling and mous economic loss to society of approximately $30 billion managing patients on suvorexant therapy. per year, mostly through reduced productivity and absentee­ ism.z Thus, effective insomnia treatments could not only Abstract improve quality of life via symptom relief but also have 'Insomnia is a disease state characterized by a persistent diffi­ tremendous economic benefits to society. culty in falling asleep, and results in enormous health-related and economic costs to both the individual and society. Sever­ Several treatment options are available for the treatment of .al medications are currently available for the treatment of insomnia; however, adverse effects associated with these insomnia; however, these medications are associated with treatment options make the management of insomnia chal­ several limitations including anterograde amnesia, depend­ lenging. Recently, suvorexant (trade name Belsomra®) was ence, withdrawal symptoms upon stopping the medication approved by the U.S. Food and Drug Administration (FDA) :and rebound insomnia. The U.S. Food and Drug Administra­ on Aug. 13, 2014, as a Schedule IV drug for insomnia.3 Su­ :tion recently approved suvorexant (Belsomra®) as a treat­ vorexant is a dual orexin receptor antagonist, and is the first ment for insomnia. Suvorexant is a first-in-class dual orexin medication in this class, offering a novel mechanism for the receptor antagonist for the treatment of insomnia. This re­ treatment of insomnia. This article will discuss the role of view will first describe the Diagnostic and Statistical Manual orexin neurons in sleep, the mechanism of action of su­ of Mental Disorders (DSM-5) criteria used for diagnosing vorexant, various clinical studies that demonstrate efficacy of ·insomnia and current treatment options for insomnia and suvorexant, and finally the role of the pharmacist in dispens­ then will characterize the role of orexin neurons in the path­ ing and managing patients taking suvorexant. Additionally, ophysiology of sleep. Subsequently, pivotal clinical trials that potential challenges and unanswered questions associated evaluated the safety, efficacy and adverse effects associated with suvorexant treatment will be discussed. with suvorexant will be discussed. Finally, the review will ,delineate the role of the pharmacist in managing patients on Insomnia: Diagnosis, Current Treatment Options and suvorexant. Current available_data suggests that suvorexant Challenges With Current Treatment possesses superior efficacy compared to placebo and a better Insomnia can be broadly divided into primary and secondary :safety profile compared to alternative insomnia treatments. insomnia.I The diagnosis of primary insomnia is defined by 1Further study of suvorexant in larger and diverse popula­ the Diagnostic and Statistical Manual of Mental Disorders tions is necessary to confirm existing findings. In particular, (DSM-5) as a sleep disturbance that affects sleep quantity or ;trials with longer durations, direct comparisons with cur­ quality, causes impairment in activities of daily living, occurs !rently available sleep medications and more participants at least three nights per week for at least three months, and :would increase the confidence among prescribers and is not due to substance use, other medical conditions and 1healthcare providers and promote the use of suvorexant for other sleep-wake disorders.4 Additionally, insomnia can be ! ~r~~~ll!e_!lt of insomni<l_. secondary to other medical diseases, may exacerbate other 2 THE PHARMACY AND WELLNESS REVIEW Winter 2016 Volume 7, Issue 1 Belsomra®: a Novel Dual Orexln Receptor Antagonist for the Treatment of Insomnia CNS disease states or can even render insomniacs susceptible to Suvorexant: A Novel Medication for Treatment of Insom­ other disease states.s The prevalence of insomnia in the pop­ nia Targeting Orexin Transmission ulation is clustered among patients with one of several risk Suvorexant (Belsomra®) is a dual orexin receptor antagonist factors.1 For example, insomnia is more prevalent in di­ marketed by Merck Sharp & Dohme Corp_7.a The action of vorced patients than in those who are married or have never suvorexant is achieved through interaction with a collection been married. Insomnia is also more commonly present in of neurons known as the orexin system, which coordinates females, African-Americans and in patients with depression. the body's transition from a sleep-state to an alert-state.9 Lower socioeconomic status is also a risk factor for insomnia. There are approximately 100,000 orexinergic neurons spread across the brain, but these neurons are located princi­ There are a wide range of treatment options available for pally in the lateral hypothalamus and lower brainstem insomnia patients. The two primary treatment strategy nuclei.10 The role of orexin in the sleep-wake cycle was eluci­ groups are cognitive-behavioral therapy (CBT) and pharma­ dated by studying narcolepsy patients. Narcolepsy is a state cological therapy. These treatment options are often used characterized by excessive daytime sleepiness and intermit­ effectively in combination. Cognitive-behavioral therapy tent uncontrollable episodes of daytime sleepiness. Narco­ most commonly includes behavioral adjustments, such as lepsy patients were found to lack orexigenic neurons or have having patients maintain a sleep diary, changing specific hab­ low levels of orexin, a neuropeptide.11 This discovery eventu­ its associated with 'pre-sleep behavior, and other priority ally led to the conclusion that the death of these neurons or changes for the patient.1 Currently, most commonly used absence of these neuropeptides is a leading cause in the nar­ medications for insomnia target the inhibitory neurotrans­ colepsy-cataplexy disease state. Consistent with these find­ mitter gamma aminobutyric acid (GABA). Broadly, pharma­ ings, the knockout of orexin genes in animals resulted in the cological agents acting on the GABA receptors can be divided development of narcolepsy in animals. The effects of orexin into benzodiazepines (BZD) such as flurazepam, triazolam, released by orexigenic neurons is mediated by two recep­ estazolam, and lorazepam, and non-benzodiazepines (non­ tors: orexin Rl (OX1R) and R2 (OX2R). Both orexin receptors BZD) such as zolpidem, eszopiclone, zaleplon, and zopiclone. are G-protein-coupled receptors. Animal studies support the In addition to GABA, histamine neurotransmission has been important role of OX2R over OX1R in the regulation of the an important target for insomnia medications. Tricyclic anti­ sleep-wake cycle.12 Binding of orexin to orexin receptors ac­ depressants such as trazodone, doxepin and pivagabine, tivates the brain's "wake-promoting system."12 Suvorexant
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