Original painting by Jermane Krshnan

Sleep Meds – Suvorexant (Belsomra)

FIrst approved in 2014, suvorexant (Belsomra) is a relatively new medication for insomnia, the first of its kind in a novel pharmaceutical class of sleeping medications. This unique new class of  medications works by a different mechanism than other sleep meds which offers many advantages over other currently available insomnia medications.

 

Please note that a second new medication in the same class as suvorexant was approved in the U.S. in 2019, lemborexant (Dayvigo). At this time, lemborexant appears to offer the same clinical profile as suvorexant. As more information is available, the differences will be explored on this page.

 

See also:

Insomnia – CAM Treatment Options

Sleep Apnea

 

And:

Benzodiazepines

Gabapentin (Neurontin) & Lyrica

Melatonin

Cognitive Behavior Therapy (CBT)

Hypnosis

Meditation & Mindful Exercises

Yoga & Tai Chi

 

Also:

Anxiety

Depression

 

 

Key to Links:

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Suvorexant (Belsomra)

Studies show that suvorexant (Belsomra) is effective at:

  1. Shortening the time it takes to fall asleep
  2. Reducing awakening after sleep onset
  3. Lengthening the duration of sleep.

 

In studies, the frequency of side effects leading to the discontinuation of treatment with suvorexant was not significantly different from placebo.

 

Advantages of Suvorexant

Because suvorexant works differently from other sleeping meds, it is not associated with a higher risk of falls or respiratory depression at standard doses or risks for physical or psychological dependence. Dose adjustment is not needed for advanced age, kidney impairment, or mild-to-moderate liver impairment. Suvorexant has a long half-life of 12 hours on average but its sedation is considered mild to moderate only with little impact of next day sedation.

 

Wake vs Sleep

Wake/sleep signaling in the brain is driven by two competing sets of brain circuitry: one set of nerve pathways that promotes sleep and another set that promotes wakefulness. Transitions between sleep and wake states depend on the relative strengths of the two opposing sets of circuits, much like a flip-flop switch.

Traditionally, the most common pharmacologic approach to  treat insomnia has been to increase the sleep signal, such as with medications like the benzodiazepines ( such as Valium, Xanax and Klonopin) and the Z-drugs (Ambien, Lunesta and Sonata) that target the γ-aminobutyric acid (GABA)-A receptor. 

This may not be the best approach physiologically if the insomnia is due to excessive wake signaling occurring at the time when the individual is expected to fall asleep and remain asleep. Decreasing the excessive wake signal with suvorexant may be a better treatment option by blocking orexin, a key central promotor of wakefulness (see below for how suvorexant works).

  

Dosing of Suvorexant

Suvorexant comes in 5 mg, 10 mg, 15 mg, and 20 mg tablets. The lowest effective dose should be used, with a recommended initial dose for most adults of 5-10 mg, increasing up to 20 mg (the maximum recommended dose) if the lower dose is is well-tolerated but ineffective.

 

Suvorexant should be taken within 30 minutes of bedtime and should not be taken with or shortly after a meal which causes a delay in onset of action. Its peak effect occurs around 2 hours on average, with a range of 30 minutes to 6 hours.

 

Caution should be used in increasing the dose in obese women, as women and people with body mass index BMI >30 have higher peak levels and clear the drug more slowly than men and normal-weight women.

 

Changing from Another Sleep Medication to Suvorexant

Abrupt changes in treatment with older-generation sleep medications can lead to rebound insomnia with worsened sleep. This is of practical concern because commonly a person with chronic insomnia whose medication treatment is no longer effective because of the devel- opment of physiological tolerance is rotated to a new sleeping medication.

 

A new medication such as an suvorexant may be prescribed, but the new medication may fail if the old one is abruptly discontinued because there is no cross-tolerance between the older medications (such as benzodiazepines and  Z-drugs) and suvorexant. This failure may be misinterpreted as a medication failure due to ineffectiveness of the new medication instead of it actually being the result of abrupt discontinuation of the prior medication leading to rebound insomnia. A gradual tapering off of the old medication may help to avoid rebound insomnia, particularly when the older medication was taken frequently for months or years.

 

Sleep Apnea and Suvorexant

Suvorexant is reported to not affect respiratory events during sleep or oxygenation in patients with mild- to-moderate OSA. In a randomized placebo-controlled crossover study in patients with mild to moderate obstructive sleep apnea (OSA), neither a single dose (up to 40 mg) of suvoxerant nor multiple doses resulted in clinically meaningful respiratory effects during sleep.

 

A study completed in 2019 evaluated the use of single 15mg dose suvorexant to facilitate sleep when performing sleep studies (polysomnograms – PSGs) in patients with OSA. In this study, no adverse event was observed in any of the patients and the authors concluded that suvorexant has potential as a safe and effective (but mild) hypnotic during overnight PSG for patients with suspected OSA.

 

However, effects of suvorexant in patients with severe OSA have not been studied so until further studies are completed, suvoxerant should be used cautiously and at lower doses in patients with OSA. Furthermore, suvorexant has not been studied in patients with OSA taking opioids

 

Side Effects with Suvorexant

Notable side effects are dose-related and reported to be mild. Headaches, abnormal dreams and dry mouth, have been reported in healthy volunteers, although doses of 10 and 20 mg showed adverse events similar to those of the placebo group. Doses of 40 mg and higher have a higher prevalence of adverse effects such as dizziness, sleep paralysis, and suicidal ideation.

 

Even after continued use for 4 weeks, suvorexant is not associated with complex sleep-related behaviors (sleep walking) or next-day hangover effects such as cognitive or motor impairments, anterograde amnesia or rebound insomnia.

 

Abnormal Dreams

Abnormal dreams are potential side effects of suvorexant. Rare hallucinations have been reported upon falling asleep or awakening.

 

Isolated Sleep Paralysis (ISP)

Isolated sleep paralysis (ISP) has been reported in <1% of study participants. Sleep paralysis is not dangerous and is limited in duration but can be very frightening if not anticipated. ISP is actually more common in the general population, reportedly experienced by almost 8% of the general population, 28% of college students, and 35% of people with panic disorder diagnoses reporting experiencing it at least once.

 

ISP is more prevalent in African Americans, with almost 40% of blacks without psychiatric conditions reporting experiencing an ISP experience at least once (ever), 14% at least once a year, and more than 5% at least once a month, and with more than 5% of blacks seeking mental health care experiencing ISP at least once a week.

 

Suicidal Ideation

Suicidal ideation was reported in study trials, occuring in 0%–1.6% of subjects taking 10–20 mg per night and in 3.4%–8.2% of subjects taking 40–80 mg per night – which is why higher doses of >20mg were not approved by the FDA and are not recommended. Patients with depression should use caution if taking this medication.

 

Of note, recent studies support an association between suicide risk and other sleeping medications including a link between increased suicide risk and insomnia treatment using benzodiazepine and the Z-drug hypnotics (ie, zolpidem, zaleplon and eszopiclone).

In fact, chronic insomnia can also have direct adverse effects on mood and behavior, including risk for depression and anxiety, as well as a strong link with suicidal ideation.

 

 

Drug Interactions with Suvorexant

Usual cautions should be taken regarding taking suvorexant with medications that are sedating such as alcohol, benzodiazepines, opioids and other sleeping medications.

 

Suvorexant is metabolized by the liver CYP3A enzymes so one should avoid taking suvorexant in combination with foods or medications that are moderate-strong CYP3A inhibitors including:

 

  1. Grapefruit juice
  2. Star Fruit
  3. Erythromycin
  4. Ciprofloxacin (Cipro)
  5. Diltiazem (Cardizem)
  6. Verapamil (Calan)
  7. Fluconazole (Diflucan)

 

Mechanisms of Action for Suvorexant

Suvorexant blocks both orexin receptors, type 1 and 2, and is therefore termed a “dual orexin receptor antagonist (DORA). There are two neurochemically distinct forms of orexin, orexin A and orexin B. Orexin A and B neuropeptides (also referred to as hypocretins) are exclusively synthesized by orexiner- gic neurons located in the lateral and posterior hypothalamus.

 

The orexin system is crucial to maintaining wakefulness and suppressing both sleep and muscle atonia. Orexins maintain wakefulness through continuous action in the wake-promoting brain nuclei as part of the sleep-wake cycle. The sleep-wake cycle is a complex system composed of reciprocally regulating neural systems operating under a feedback loop (the “flip-flop” cycle), which allows for stable transitions between states of wakefulness and sleep, when one state is active, the other is inactive.

 

Comparing Suvorexant with Other Sedative Sleep Meds

Benzodiazepines and non-BzRAs such as the Z-drugs (Ambien, Lunesta etc), enhance the functioning of the brain’s primary inhibitory neurotransmitter, GABA, at higher levels in the limbic system and the cortex.  This inhibitory activity contributes to their side effects, including impaired motor coordination, lethargy, slurred speech, dizziness, intense mood swings, palpitations, fatigue and, importantly, respiratory depression. Prolonged use of benzodiazepines leads to adaptations of GABA receptors, resulting in tolerance and withdrawal symptoms. Long-term use of traditional sedative hypnotics is associated with dose tolerance, tachyphylaxis, and dependence for sleeping.

 

DORAs offer an alternative approach in promoting and maintaining sleep by targeting the orexin system. The scope of orexin signaling in the brain is much more targeted that that of the whole-brain population of GABA neurons, which may result in a more favorable side-effect profile. Suvorexant has  shown to have a more balanced sleep architecture profile due to its promotion of both REM and NREM sleep.

 

 

Future Thoughts

Orexin signaling has also been implicated in other physiological functions such as memory, emotions, motivation, attention, autonomic control, feeding, and energy homeostasis. Orexin is not only involved in the regulation of eating, the sleep–wake cycle, and energy metabolism, but also closely associated with various physiological functions, such as cardiovascular control, reproduction, stress, reward, addiction, and the modulation of pain transmission.

 

A growing number of patents for orexin receptor antagonists has emerged for use not only in the areas of sleep disorders, but also pain, addiction, anxiety, panic and depression disorders.

 

Pain Regulation

Orexin and its receptors are closely associated with pain regulation. Although the number of hypothalamic orexin neurons is extremely limited, they also project to many pain-related brain regions, including the thalamus, limbic system, dorsal raphe nucleus (DR), locus coeru- leus (LC), periaqueductal gray (PAG) matter, dorsal hippocampus, reticular formation, and trigeminal caudate nucleus.

 

Animal studies indicate that injection of exogenous orexin into the spinal cord and supraspinal sites that are associated with the descending pain regulatory circuits can significantly reduce nociceptive responses. An interesting subsequent study was published in 2021. It turns out that a 5‐minute exposure to linalool odor induces significant analgesic effects in mice. Linalool is an aromatic terpene found in both lavender and many marijuana strains that is believed to offer anti-inflammatory and analgesic benefits with human exposure. The use of orexin blockers in mice blocks this analgesic benefit, suggesting the future potential of orexin antagonist medications for treating pain.

 

 

Further study of the analgesic mechanisms of orexins may provides a means for the development of new pain medications.

 

Addiction

Significant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment adherence, under scoring the importance of normalizing sleep when treating SUDs.

 

The orexin neuropeptides exclusively produced by neurons in the posterior hypothalamus also regulate not only sleep but also various behavioral and physiological processes, including motivated drug taking.

 

Preclinical lab and animal studies indicate that orexin neurons are critically involved in translating motivational states into action (i.e., bottom-up processes).  Additionally, blockade of the orexin system may also reduce drug craving via improvement of sleep outcomes and executive functioning in SUD patients (i.e., “top-down” processes). There is growing evidence implicating the orexin system in these two separate addiction mechanisms. Orexins may play a role in maintaining dopamine levels in the nucleus accumbens, a key brain region related to addiction.

 

 

Psychiatric Disorders

Studies have identified the dysregulation of orexin function in various psychiatric disorders and the orexin system is involved in the pathophysiology of psychiatric disorders, including anxiety and depression. Orexins modulate neuronal circuitry that is implicated in the expression and extinction of conditioned fear, suggesting that it may be a promising target for the treatment of anxiety disorders. Preclinical studies also suggest orexins are involved with depression.

 

Alzheimers Dementia (AD)

The orexin system has a role in Alzheimers Dementia (AD) and there is a bidirectional relationship between disturbed sleep and AD progression. DORAs such as suvorexant may also offer a mechanism for not only enhancing sleep but also reducing amyloid (Aβ) plaque formation which is also involved in the progression of the AD.

 

Future use of DORAs such as suvorexant may offer an effective treatment of comorbid insomnia in patients with AD. Additionally, the treatment of insomnia in patients with mild cognitive impairment in the early stages of AD may not only treat the insomnia, but could also reduce the cognitive deficits of the disease progression via their effect on Aβ reduction.

 

 

 

 

 

 

 

References

Sleep – Overviews

  1. Mayo Clinic Discusses Healthy Sleeping Habits for Older Adults – 2019
  2. Healthy Sleep
  3. Sleep complaints: Whenever possible, avoid the use of sleeping pills. – PubMed – NCBI

Sleep – Why is Sleep Needed?

  1. Brain Basics: Understanding Sleep : National Institute of Neurological Disorders and Stroke (NINDS)
  2. Sleep
  3. Sleep Drives Metabolite Clearance from the Adult Brain – 2013
  4. Dopaminergic Neurogenetics of Sleep Disorders in Reward Deficiency Syndrome (RDS) – 2014

 

Sleep – Deficiency

  1. Sleep Deprivation and Deficiency
  2. Are you getting enough sleep

 

Sleep – Strategies for Sleep

  1. Seven Strategies for Sleep
  2. Ten Mistaken Beliefs About Sleep
  3. Sleep Restriction Therapy instructions

 

Sleep – Circadian rhythm sleep disorders, Shift Work

  1. Circadian rhythm sleep disorders
  2. Shift work: Improving daytime sleep – Mayo Clinic

 

Sleep – Insomnia

  1. Insomnia
  2. Pain-related Insomnia Versus Primary Insomnia
  3. Sleep disorders and depression
  4. Problem-Solving Therapy Compared to Cognitive Therapy for the Treatment of Insomnia
  5. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults – An American Academy of Sleep Medicine Clinical Practice Guideline – 2017

Sleep – Nightmares

  1. Nightmare disorder – Mayo Clinic
  2. Sleep terrors (night terrors) – Mayo Clinic
  3. Imagery rehearsal therapy – An emerging treatment for posttraumatic nightmares in veterans
  4.  Putative dopamine agonist (KB220Z) attenuates lucid nightmares in PTSD patients – Role of enhanced brain reward functional connectivity and homeostasis redeeming joy – 2015

 

Sleep – Pain

  1. Sleep Disturbance and Chronic Pain
  2. Relationship among Chronic Pain, Opiates, and Sleep -Thesis
  3. sleep deprivation in patients with chronic neck and back pain
  4. The Effects of Sleep Deprivation on Pain Inhibition and Spontaneous Pain in Women
  5. Pain-related Insomnia Versus Primary Insomnia
  6. Sleep, Chronic Pain, and Inflammation- Integrative Approaches

 

Sleep – Sleep Studies (Polysomnograms – PSG)

  1. Sleep Studies
  2. Polysomnography (sleep study) – Mayo Clinic

Sleep – Opioids Effect on Sleep

  1. Relationship among Chronic Pain, Opiates, and Sleep -Thesis
  2. Sleep-Disordered Breathing and Chronic Opioid Therapy
  3. Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics. – PubMed – NCBI
  4. the-effect-of-opioids-on-sleep-architecture-2007

Sleep – Natural and Herbal Preparations for Sleep

Natural and Herbal Preparations – Overview

  1. Updates on Nutraceutical Sleep Therapeutics and Investigational Research – 2015
  2. Herbal Insomnia Medications that Target GABAergic Systems – A Review of the Psychopharmacological Evidence – 2014
  3. Herbal triple combination: An effective alternative to benzodiazepines
  4. Efficacy and safety of a polyherbal sedative-hypnotic formulation compared to Ambien

Natural and Herbal Preparations – Melatonin

  1. Melatonin for the Treatment of Primary Sleep Disorders – 2013
  2. The effectiveness of melatonin for promoting healthy sleep – a rapid evidence assessment of the literature – 2014
  3. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. – 2007
  4. Ramelteon: MedlinePlus Drug Information
  5. Melatonin hypothesizing-that-putative-dopaminergic-melatonin-benzodiazepine-reward-circuitry-receptors – 2013
  6. Melatonin therapy in fibromyalgia. – PubMed – NCBI

Natural and Herbal Preparations – Valerian

  1. Valerian-HealthProfessional
  2. Valerian | University of Maryland Medical Center
  3. Valerian – No Evidence for Clinically Relevant Interactions 2014
  4. Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? – PubMed – NCBI
  5. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. – PubMed – NCBI
  6. Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. – 2007

Sleep – Prescription Medications for Sleep

  1. Understanding the relationships of medications on sleep
  2. Hypnotics-MedlinePlus

Rx Sleep Medications – Benzodiazepines

  1. Chronic benzodiazepine usage and withdrawal in insomnia patients. – PubMed – NCBI
  2. Correlates of benzodiazepine use in individuals with insomnia. – PubMed – NCBI
  3. Efficacy of two interventions on the discontinuation of benzodiazepines in long-term users: 36-month follow-up of a cluster randomised trial in pri… – PubMed – NCBI
  4. Benzodiazepine use and risk of Alzheimer’s disease – case-control study

Rx Sleep Medications – Doxepin

  1. Treatment-resistant insomnia treated with pregabalinEfficacy and Safety of Doxepin 3 and 6 mg in a 35-day Sleep Laboratory Trial in Adults with Chronic Primary Insomnia
  2. Doxepin – up-to-date – a review of its pharmacological properties and therapeutic efficacy with particular reference to depression
  3. Doxepin for insomnia: a systematic review of randomized placebo-controlled trials. – PubMed – NCBI

Rx Sleep Medications – Gabapentin (Neurontin)

  1. Gabapentin increases slow-wave sleep in normal adults – 2002
  2. Gabapentin improves sleep in the presence of alcohol. – PubMed – NCBI
  3. A Randomized, Double-Blind, Single-Dose, Placebo-Controlled, Multicenter, Polysomnographic Study of Gabapentin in Transient Insomnia Induced by Sleep Phase Advance – 2014
  4. Treatment effects of gabapentin for primary insomnia. – PubMed – NCBI
  5. An Open Pilot Study of Gabapentin vs. Trazodone to Treat Insomnia in Alcoholic Outpatients – 2003

   

Rx Sleep Medications – Pregabalin (Lyrica)

  1. Treatment-resistant insomnia treated with pregabalin

 

Rx Sleep Medications – Suvorexant (Belsomra)

  1. Belsomra Prescribing Information
  2. Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
  3. Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders – 2020
  4. An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics – 2018
  5. single-use suvorexant for treating insomnia during overnight polysomnography in patients with suspected obstructive sleep apnea – a single-center experience – 2019
  6. Sleep disorders in the elderly – Diagnosis and management – 2016
  7. Adverse reaction with suvorexant for insomnia – acute worsening of depression with emergence of suicidal thoughts – 2017
  8. Insomnia in the Elderly – A Review – 2018
  9. Advances in the Treatment of Chronic Insomnia A Narrative Review of New Nonpharmacologic and Pharmacologic Therapies – 2021
  10. Suvorexant in insomnia – efficacy, safety and place in therapy – 2015
  11. Neurophysiologic-evidence-for-a-central-sensitization-in-patients-with-fibromyalgia-2003
  12. Lifetime Prevalence Rates of Sleep Paralysis – A Systematic Review
  13. Profile of suvorexant in the management of insomnia – 2015
  14. Migraine and sleep disorders -a systematic review – 2020
  15. Research progress on the mechanism of orexin in pain regulation in different brain regions – 2020
  16. Orexinergic descending inhibitory pathway mediates linalool odor‐induced analgesia in mice – 2021
  17. The Insomnia-Addiction Positive Feedback Loop – Role of the Orexin System – 2021

 

Rx Sleep Medications – Lemborexant (Dayvigo)

  1. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder – 2017

 

Rx Sleep Medications – Mirtazapine (Remeron)

  1. The Use of Mirtazapine in a Patient with Chronic PainThe effect of mirtazapine in patients with chronic pain and concomitant depression. – 2006
  2. Efficacy of mirtazapine for the treatment of fibromyalgia without concomitant depression – 2016
  3. Mirtazapine for fibromyalgia in adults – 2018
  4. A Review of Therapeutic Uses of Mirtazapine in Psychiatric and Medical Conditions – 2013
  5. Mirtazapine: A Newer Antidepressant – American Family Physician – 1999

 

 

Rx Sleep Medications – Remaelton (Rozerem)

  1. Rozerem Package Insert

 

 

Rx Sleep Medications – Trazadone

  1. Trazodone: a review of its pharmacological properties … [Drugs. 1981] – PubMed – NCBI
  2. Cognitive, psychomotor and polysomnographic effects of trazodone in primary insomniacs
  3. An Open Pilot Study of Gabapentin vs. Trazodone to Treat Insomnia in Alcoholic Outpatients – 2003

 

Sleep Medications – “Z-Drugs”

  1. Hypnotic hazards – adverse effects of zolpidem and other z-drugs – 2008
  2. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration – 2012

 

Sleep Medications – Zolpidem (Ambien)

  1. Zolpidem-Induced Sleepwalking, Sleep Related Eating Disorder
  2. Two Cases of Zolpidem-Associated Homicide
  3. Ambien (Zolpidem) Associated Homicide
  4. Ambien (Zolpidem)-Induced Sleepwalking, Sleep Related Eating Disorder

  

Sleep – Sleep Disorders

 

Sleep Apnea

(see Sleep Apnea)

 

Periodic Limb Movement Disorder

  1. Periodic Limb Movement Disorder
  2. Periodic Limb Movement Disorder Causes and Treatments on MedicineNet.com

 

Restless Leg Syndrome

  1. Restless Legs Syndrome:Periodic Limb Movement Disorder : National Sleep Disorders Research Plan, 2003

 

Sleep Walking

  1. Sleepwalking – Mayo Clinic
  2. Seroquel (Quetiapine)-induced Sleep-related Eating Disorder-like Behavior

 

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

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