All Publications


  • Solriamfetol for the treatment of daytime sleepiness in obstructive sleep apnea. Expert review of respiratory medicine Abad, V. C., Guilleminault, C. 2018

    Abstract

    INTRODUCTION: Obstructive sleep apnea (OSA) is highly prevalent and constitutes a major health hazard. Current pharmacotherapy is ineffective in correcting sleep-disordered breathing and is used adjunctively to address residual sleepiness. A new drug, solriamfetol, a selective norepinephrine-dopamine reuptake inhibitor, is the first drug of its class that is being considered by the US Food and Drug Administration (FDA) to treat excessive sleepiness in OSA and narcolepsy patients. Areas Covered: This review covers drug chemistry, pharmacodynamics, pharmacokinetics, and metabolism of solriamfetol. Results of three Phase 3 trials, Treatment of OSA and Narcolepsy Excessive Sleepiness (TONES 3, 4, 5), relevant to OSA patients are summarized. Published abstracts/articles and a 2017 Jazz Investor Presentation provided data. Databases searched included PubMed, Google Scholar, Lexi-Comp, Scopus, Science, and Ovid. Expert Commentary: Solriamfetol shows promise as adjunctive therapy in OSA. It is well tolerated and effective in reducing sleepiness and is an alternative to modafinil or armodafinil. Unlike stimulants like methylphenidate or dextroamphetamine, it does not have cardiac effects, rebound hypersomnia, or withdrawal effects.

    View details for DOI 10.1080/17476348.2018.1541742

    View details for PubMedID 30365900

  • Insomnia in Elderly Patients: Recommendations for Pharmacological Management. Drugs & aging Abad, V. C., Guilleminault, C. 2018

    Abstract

    Chronic insomnia affects 57% of the elderly in the United States, with impairment of quality of life, function, and health. Chronic insomnia burdens society with billions of dollars in direct and indirect costs of care. The main modalities in the treatment of insomnia in the elderly are psychological/behavioral therapies, pharmacological treatment, or a combination of both. Various specialty societies view psychological/behavioral therapies as the initial treatment intervention. Pharmacotherapy plays an adjunctive role when insomnia symptoms persist or when patients are unable to pursue cognitive behavioral therapies. Current drugs for insomnia fall into different classes: orexin agonists, histamine receptor antagonists, non-benzodiazepine gamma aminobutyric acid receptor agonists, and benzodiazepines. This review focuses on Food and Drug Administration (FDA)-approved drugs for insomnia, including suvorexant, low-dose doxepin, Z-drugs (eszopiclone, zolpidem, zaleplon), benzodiazepines (triazolam, temazepam), and ramelteon. We review the indications, dosing, efficacy, benefits, and harms of these drugs in the elderly, and discuss data on drugs that are commonly used off-label to treat insomnia, and those that are in clinical development. The choice of a hypnotic agent in the elderly is symptom-based. Ramelteon or short-acting Z-drugs can treat sleep-onset insomnia. Suvorexant or low-dose doxepin can improve sleep maintenance. Eszopiclone or zolpidem extended release can be utilized for both sleep onset and sleep maintenance. Low-dose zolpidem sublingual tablets or zaleplon can alleviate middle-of-the-night awakenings. Benzodiazepines should not be used routinely. Trazodone, a commonly used off-label drug for insomnia, improves sleep quality and sleep continuity but carries significant risks. Tiagabine, sometimes used off-label for insomnia, is not effective and should not be utilized. Non-FDA-approved hypnotic agents that are commonly used include melatonin, diphenhydramine, tryptophan, and valerian, despite limited data on benefits and harms. Melatonin slightly improves sleep onset and sleep duration, but product quality and efficacy may vary. Tryptophan decreases sleep onset in adults, but data in the elderly are not available. Valerian is relatively safe but has equivocal benefits on sleep quality. Phase II studies of dual orexin receptor antagonists (almorexant, lemborexant, and filorexant) have shown some improvement in sleep maintenance and sleep continuity. Piromelatine may improve sleep maintenance. Histamine receptor inverse agonists (APD-125, eplivanserin, and LY2624803) improve slow-wave sleep but, for various reasons, the drug companies withdrew their products.

    View details for DOI 10.1007/s40266-018-0569-8

    View details for PubMedID 30058034

  • New developments in the management of narcolepsy. Nature and science of sleep Abad, V. C., Guilleminault, C. 2017; 9: 39-57

    Abstract

    Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%-0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy's strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABAB agonists (baclofen), melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed.

    View details for DOI 10.2147/NSS.S103467

    View details for PubMedID 28424564

  • Missing teeth and pediatric obstructive sleep apnea SLEEP AND BREATHING Guilleminault, C., Abad, V. C., Chiu, H., Peters, B., Quo, S. 2016; 20 (2): 561-568

    Abstract

    Missing teeth in early childhood can result in abnormal facial morphology with narrow upper airway. The potential association between dental agenesis or early dental extractions and the presence of obstructive sleep apnea (OSA) was investigated.We reviewed clinical data, results of polysomnographic sleep studies, and orthodontic imaging studies of children with dental agenesis (n = 32) or early extraction of permanent teeth (n = 11) seen during the past 5 years and compared their findings to those of age-, gender-, and body mass index-matched children with normal teeth development but tonsilloadenoid (T&A) hypertrophy and symptoms of OSA (n = 64).The 31 children with dental agenesis and 11 children with early dental extractions had at least 2 permanent teeth missing. All children with missing teeth (n = 43) had clinical complaints and signs evoking OSA. There was a significant difference in mean apnea-hypopnea indices (AHI) in the three dental agenesis, dental extraction, and T&A studied groups (p < 0.001), with mean abnormal AHI lowest in the pediatric dental agenesis group. In the children with missing teeth (n = 43), aging was associated with the presence of a higher AHI (R (2) = 0.71, p < 0.0001).Alveolar bone growth is dependent on the presence of the teeth that it supports. The dental agenesis in the studied children was not part of a syndrome and was an isolated finding. Our children with permanent teeth missing due to congenital agenesis or permanent teeth extraction had a smaller oral cavity, known to predispose to the collapse of the upper airway during sleep, and presented with OSA recognized at a later age. Due to the low-grade initial symptomatology, sleep-disordered breathing may be left untreated for a prolonged period with progressive worsening of symptoms over time.

    View details for DOI 10.1007/s11325-015-1238-3

    View details for Web of Science ID 000375434400014

    View details for PubMedID 26330227

  • Pharmacological treatment of sleep disorders and its relationship with neuroplasticity. Current topics in behavioral neurosciences Abad, V. C., Guilleminault, C. 2015; 25: 503-553

    Abstract

    Sleep and wakefulness are regulated by complex brain circuits located in the brain stem, thalamus, subthalamus, hypothalamus, basal forebrain, and cerebral cortex. Wakefulness and NREM and REM sleep are modulated by the interactions between neurotransmitters that promote arousal and neurotransmitters that promote sleep. Various lines of evidence suggest that sleep disorders may negatively affect neuronal plasticity and cognitive function. Pharmacological treatments may alleviate these effects but may also have adverse side effects by themselves. This chapter discusses the relationship between sleep disorders, pharmacological treatments, and brain plasticity, including the treatment of insomnia, hypersomnias such as narcolepsy, restless legs syndrome (RLS), obstructive sleep apnea (OSA), and parasomnias.

    View details for DOI 10.1007/7854_2014_365

    View details for PubMedID 25585962

  • Pharmacologic Therapy for Obstructive Sleep Apnea SLEEP MEDICINE CLINICS Abad, V. C. 2013; 8 (4): 527–42
  • Pharmacological Treatment of Obstructive Sleep Apnea CURRENT PHARMACEUTICAL DESIGN Abad, V. C., Guilleminault, C. 2011; 17 (15): 1418-1429

    Abstract

    Obstructive sleep apnea (OSA) is a growing public health hazard fueled by the obesity epidemic and an aging population. Untreated sleep apnea can result in significant consequences both in the short-term and long-term. We need to educate the public to recognize the symptoms of sleep apnea and to publicize that effective treatments are available. Positive airway pressure therapy remains the gold standard currently in treating OSA. Alternative treatments include an oral appliance or surgical options. This paper discusses the pharmacologic treatment of sleep apnea: goals include medications to address the ventilatory control of breathing, treat co-morbid diseases, treat associated health problems/complaints, address special issues, such as anesthetic precautions, and propose future targets.

    View details for Web of Science ID 000295455800002

    View details for PubMedID 21476959

  • Treatment options for obstructive sleep apnea CURRENT TREATMENT OPTIONS IN NEUROLOGY Abad, V. C., Guilleminault, C. 2009; 11 (5): 358-367

    Abstract

    Sleep apnea is a major public health problem that afflicts 9% of women and 24% of men 30 to 60 years of age. It is highly treatable, but when untreated, it has been associated with (but not necessarily linked to) increased probability of cerebral and coronary vascular disease, congestive heart failure, metabolic dysfunction, cognitive dysfunction, excessive daytime sleepiness, motor vehicle accidents, reduced productivity, and decreased quality of life. The gold standard for treatment in adults is positive airway pressure (PAP) therapy: continuous PAP (CPAP), bilevel PAP, autotitrating CPAP, or autotitrating bilevel PAP. Measures to increase compliance with PAP therapy include medical or surgical treatment of any underlying nasal obstruction, setting appropriate pressure level and airflow, mask selection and fitting, heated humidification, desensitization for claustrophobia, patient and partner education, regular follow-up with monitoring of compliance software, and attendance of support groups (eg, AWAKE). Adjunctive treatment modalities include lifestyle or behavioral measures and pharmacologic therapy. Patients with significant upper airway obstruction who are unwilling or unable to tolerate PAP therapy may benefit from surgery. Multilevel surgery of the upper airway addresses obstruction of the nose, oropharynx, and hypopharynx. A systematic approach may combine surgery of the nose, pharynx, and hypopharynx in phase 1, whereas skeletal midface advancement or tracheotomy constitutes phase 2. Clinical outcomes are reassessed through attended diagnostic polysomnogram performed 3 to 6 months after surgery. Oral appliances can be used for patients with symptomatic mild or moderate sleep apnea who prefer them to PAP therapy or for whom PAP therapy has failed or cannot be tolerated. Oral appliances also may be used for patients with severe obstructive sleep apnea who are unable or unwilling to undertake PAP therapy or surgery. For children, the main treatment modality is tonsillectomy and adenoidectomy, with or without turbinate surgery. Children with craniofacial abnormalities resulting in maxillary or mandibular insufficiency may benefit from palatal expansion or maxillary/mandibular surgery. PAP therapy may be used for children who are not surgical candidates or if surgery fails.

    View details for DOI 10.1007/s11940-009-0040-6

    View details for Web of Science ID 000268871400005

    View details for PubMedID 19744402

  • Sleep and psychiatry ZHURNAL NEVROLOGII I PSIKHIATRII IMENI S S KORSAKOVA Abad, V. C., Guilleminault, C. 2009; 109 (9): 102-?

    View details for Web of Science ID 000270866800022

    View details for PubMedID 19908413

  • Sleep and rheumatologic disorders SLEEP MEDICINE REVIEWS Abad, V. C., Sarinas, P. S., Guilleminault, C. 2008; 12 (3): 211-228

    Abstract

    Arthritis is the leading cause of chronic illness in the United States. Seventy-two percent of the adults aged 55 years and older with arthritis report sleep difficulties. This review discusses sleep disorders associated with rheumatoid arthritis, juvenile rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, scleroderma, Behcet's disease, seronegative spondyloarthropathies, osteoarthritis, sarcoidosis, and fibromyalgia. We describe the inter-relationship between sleep complaints, disease activity, depression, sleep deprivation, and cytokines. An algorithm for evaluation and treatment of sleep disorders associated with rheumatologic diseases is proposed.

    View details for DOI 10.1016/j.smrv.2007.09.001

    View details for Web of Science ID 000257451500005

    View details for PubMedID 18486034

  • The effect of CNS activation versus EEG arousal during sleep on heart rate response and daytime tests CLINICAL NEUROPHYSIOLOGY Guilleminault, C., Abad, V. C., Philip, P., Stoohs, R. 2006; 117 (4): 731-739

    Abstract

    To induce a heart rate change in normal subjects using auditory stimulation without inducing EEG arousals and to assess the effects on daytime functioning and compare results to auditory stimulation leading to short EEG arousals.Six normal young men initially randomized into two groups (A and B) underwent 4 nights of nocturnal polysomnography (normal sleep on night 1, auditory stimulation without EEG arousal or normal sleep on nights 2 and 3 using Latin square design, and auditory stimulation with EEG arousal on night 4). MSLT and PVT were performed during days following nights 2-4.MSLT and PVT results showed significant differences after EEG arousal compared to stimulation without EEG arousal and to normal sleep; there were no significant differences after normal sleep compared to stimulation without EEG arousal. RR interval showed significant differences during undisturbed sleep compared to stimulation without EEG arousal and to stimulation with EEG arousal; RR interval without EEG arousal also differed significantly from RR interval with EEG arousal.Activation of the brain-stem can lead to autonomic nervous system (ANS) response without objective consequences the next day.ANS responses induced by auditory stimulation during sleep without EEG arousal do not have the same effects on daytime sleepiness and performance as sleep fragmentation associated with EEG arousals.

    View details for DOI 10.1016/j.clinph.2005.08.035

    View details for Web of Science ID 000236663800005

    View details for PubMedID 16458068

  • Pharmacological management of sleep apnoea EXPERT OPINION ON PHARMACOTHERAPY Abad, V. C., Guilleminault, C. 2006; 7 (1): 11-23

    Abstract

    Obstructive sleep apnoea poses a significant health hazard that is associated with leading causes of mortality and morbidity. Nasal continuous positive airway pressure is the primary treatment modality, with surgical treatments as alternatives. Oral appliances and pharmacological therapy remain adjunctive modalities. Non-specific treatments include weight loss, postural therapy and behavioural measures. Pharmacotherapy goals include the reduction of risk factors for sleep apnoea; correction of underlying predisposing metabolic diseases, such as hypothyroidism or acromegaly; treatment of associated symptoms, including excessive daytime sleepiness; and prevention of apnoeas/hypopnoeas. This paper reviews data supporting the treatment of sleep apnoea with various pharmacological agents, including intranasal corticosteroids, decongestant sprays, nicotine therapy, opiate antagonists, methylxanthine derivatives, oestrogen and progesterone, testosterone, thyroid hormone, growth hormone therapy for acromegaly, beta-blockers, alpha-adrenergic agonists, angiotensin-converting enzyme inhibitors, glutamate antagonists, acetazolamide, selective serotonin re-uptake inhibitors, tricyclic antidepressants, physostigmine, modafinil and TNF-alpha antagonists, in addition to supplemental oxygen, and carbon dioxide inhalation. Some of these drugs have received very little testing and are the subject of few research articles.

    View details for DOI 10.1517/14656566.7.1.11

    View details for Web of Science ID 000234420300002

    View details for PubMedID 16370918

  • Sleep and psychiatry. Dialogues in clinical neuroscience Abad, V. C., Guilleminault, C. 2005; 7 (4): 291-303

    Abstract

    Psychiatric disorders constitute 15.4% of the disease burden in established market economies. Many psychiatric disorders are associated with sleep disturbances, and the relationship is often bidirectional. This paper reviews the prevalence of various psychiatric disorders, their clinical presentation, and their association with sleep disorders. Among the psychiatric disorders reviewed are affective disorders, psychosis, anxiety disorders (including posttraumatic stress disorder), substance abuse disorders, eating disorders, and attention deficit/hyperactivity disorders. The spectrum of associated sleep disorders includes insomnia, hypersomnia, nocturnal panic, sleep paralysis, hypnagogic hallucinations, restless legs/periodic limb movements of sleep, obstructive sleep apnea, and parasomnias. The effects on sleep of various psychotropic medications utilized to treat the above psychiatric disorders are summarized.

    View details for PubMedID 16416705

    View details for PubMedCentralID PMC3181745

  • Neurological perspective on obstructive and nonobstructive sleep apnea SEMINARS IN NEUROLOGY Abad, V. C., Guilleminault, C. 2004; 24 (3): 261-269

    Abstract

    One of every 15 adults in the United States has at least moderate sleep apnea. The true prevalence is higher, as approximately 0.3 to 5% of adults with sleep apnea are undiagnosed. Sleep apnea has major health consequences; therefore, neurologists must recognize and treat sleep apnea syndromes appropriately. There are three main categories of sleep apnea: obstructive sleep apnea (OSA), central sleep apnea (CSA), and mixed sleep apnea. OSA results from upper airway obstruction, and CSA is due to lack of inspiratory muscle effort; mixed apnea results from a combination of these factors. Sleep apnea syndromes can present within the spectrum of "typical" neurological complaints, including forgetfulness, headaches, sleepiness, fatigability, seizures, and muscle and nerve weakness. A good sleep history, a nocturnal polysomnogram, and multiple sleep latency test are important in elucidating the diagnosis and validating the complaints of sleepiness. The gold standard for treatment of OSA is positive airway pressure, although some patients may benefit from surgical interventions designed to bypass the site of airway obstruction. With CSA, treatment is directed toward the underlying disorder. Patients with CSA may also benefit from several types of nasal positive airway pressure treatment, while some require mechanical ventilation.

    View details for Web of Science ID 000224248200006

    View details for PubMedID 15449219

  • Obstructive Sleep Apnea. Current treatment options in neurology Guilleminault, C., Abad, V. C. 2004; 6 (4): 309-317

    Abstract

    Obstructive sleep apnea (OSA) is a major public health problem in the US that afflicts at least 2% to 4% of middle-aged Americans and incurs an estimated annual cost of 3.4 billion dollars. At Stanford, we utilize a multispecialty team approach combining the expertise of sleep medicine specialists (adult and pediatric), maxillofacial and ear, nose, and throat surgeons, and orthodontists to determine the most appropriate therapy for complicated OSA patients. The major treatment modality for children with OSA is tonsillectomy and adenoidectomy with or without radiofrequency treatment of the nasal inferior turbinate. Children with craniofacial anomalies resulting in maxillary or mandibular insufficiency may benefit from palatal expansion or more invasive maxillary/mandibular surgery. Continuous positive airway pressure (PAP) therapy is used in children with OSA who are not surgical candidates or have failed surgery. As a last resort, tracheotomy may be used in patients with persistent or severe OSA who do not respond to other measures. The cornerstone of treatment in adults utilizes PAP: continuous PAP, bilevel PAP, or auto PAP. Treatment of nasal obstruction, appropriate titration, attention to mask-fit issues, desensitization for claustrophobia, use of heated humidification for nasal dryness and nasal pain with continuous PAP, patient education, regular follow-up, use of compliance software (in selected individuals), and referral to support groups (AWAKE) are measures that can improve patient compliance. Adjunctive treatment modalities include lifestyle/behavioral/pharmacologic measures. Oral appliances can be used in patients with symptomatic mild sleep apnea or upper airway resistance syndrome. Patients who are unwilling or unable to tolerate continuous PAP or who have obvious upper airway obstruction may benefit from surgery. Surgical success depends on appropriate patient selection, the procedure performed, and the experience of the surgeon. Phase I surgeries have a success rate of 50% to 60%, whereas phase II surgeries have a success rate greater than 90%.

    View details for PubMedID 15157408

  • Obstructive sleep apnea syndromes MEDICAL CLINICS OF NORTH AMERICA Guillerminault, C., Abad, V. C. 2004; 88 (3): 611-?

    View details for DOI 10.1016/j.mcna.2004.01.002

    View details for Web of Science ID 000221049600005

    View details for PubMedID 15087207

  • Review of rapid eye movement behavior sleep disorders. Current neurology and neuroscience reports Abad, V. C., Guilleminault, C. 2004; 4 (2): 157-163

    Abstract

    The spectrum of rapid eye movement behavior disorders (RBD) spans various age groups, with the greatest prevalence in elderly men. Major diagnostic features include harmful or potentially harmful sleep behaviors that disrupt sleep continuity and dream enactment during rapid eye movement sleep. In RBD patients, the polysomnogram during rapid eye movement sleep demonstrates excessive augmentation of chin electromyogram or excessive chin or limb phasic electromyogram twitching. RBD may be associated with various neurodegenerative disorders, such as multiple system atrophy, Parkinson's disease, and dementia with Lewy bodies. Other co-morbid conditions may include narcolepsy, agrypnia excitata, sleepwalking, and sleep terrors. RBD is hypothesized to be caused by primary dysfunction of the pedunculo-pontine nucleus or other key brainstem structures associated with basal ganglia pathology or, alternatively, from abnormal afferent signals in the basal ganglia leading to dysfunction in the midbrain extrapyramidal area/ pedunculo-pontine nucleus regions.

    View details for PubMedID 14984689

  • C-reactive protein in non-obese and obese obstructive sleep apnea subjects 18th Annual Meeting of the Associated-Professional-Sleep-Societies Kirisoglu, C., Abad, V., Guilleminault, C. AMER ACAD SLEEP MEDICINE. 2004: 193–193
  • Effects of CNS activation on arousal and autonomic nervous system 18th Annual Meeting of the Associated-Professional-Sleep-Societies Guilleminault, C., Abad, V., Stoohs, R. AMER ACAD SLEEP MEDICINE. 2004: 40–40
  • Fatigue and sleepiness associated with OSAS and UARS 18th Annual Meeting of the Associated-Professional-Sleep-Societies Kirisoglu, C., Abad, V., Guilleminault, C. AMER ACAD SLEEP MEDICINE. 2004: 192–193
  • Diagnosis and treatment of sleep disorders: a brief review for clinicians. Dialogues in clinical neuroscience Abad, V. C., Guilleminault, C. 2003; 5 (4): 371-388

    Abstract

    Sleep disorders encompass a wide spectrum of diseases with significant individual health consequences and high economic costs to society. To facilitate the diagnosis and treatment of sleep disorders, this review provides a framework using the International Classification of Sleep Disorders, Primary and secondary insomnia are differentiated, and pharmacological and nonpharmacological treatments are discussed. Common circadian rhythm disorders are described in conjunction with interventions, including chronotherapy and light therapy. The diagnosis and treatment of restless legs syndrome/periodic limb movement disorder is addressed. Attention is focused on obstructive sleep apnea and upper airway resistance syndrome, and their treatment. The constellation of symptoms and findings in narcolepsy are reviewed together with diagnostic testing and therapy, Parasomnias, including sleep terrors, somnambulism, and rapid eye movement (REM) behavior sleep disorders are described, together with associated laboratory testing results and treatment.

    View details for PubMedID 22033666

    View details for PubMedCentralID PMC3181779