1. health and fitness
2. disorders
3. sleep disorders

04/06/2015
SLEEP DISORDERS WITH SPECIAL EMPHASIS ON INSOMNIA
Presented by
Jim Slaughter M.D.
With case reports supplied by
Little‐known British playwright,
William Shakespeare
Drugged sleep, a murder, insomnia
• Lady Macbeth: “I will with wine so convince their memory, the guardian of the brain, shall be a fume… When in swinish sleep their drenched natures lie as in a death, what cannot you and I perform upon the unguarded Duncan?”( Lady Macbeth kills the king!)
• Macbeth: I thought I heard a voice cry, “Sleep no more! Macbeth does murder sleep”, the innocent sleep, sleep that knits up a raveled sleeve of care, the death of each day’s life, sore labor’s bath, balm of hurt minds, great nature’s second course, chief nourisher of life’s feast …
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Parasomnia, insomnia, depression and obsessive compulsive disorder
• Observer: “Lo you, here comes Lady Macbeth! This is her very guise; and, upon my life, fast asleep…”
• Lady Macbeth: “Out, damned Spot! Out I say! One; two… Yet who would have thought the old man to have had so much blood in him… To bed, to bed!”
• Doctor: “Unnatural deeds do breed unnatural troubles. Infected minds to their deaf pillows will discharge their secrets. More needs Lady Macbeth the Divine than the physician.”
Insomnia, depression and despair
A sleepless Macbeth upon learning Lady Macbeth has died: “She should have died hereafter,,,” “Tomorrow, and tomorrow, and tomorrow, creeps its petty pace from day to day to the last syllable of recorded time, and all our yesterdays have lighted fools the way to dusty death. Out, out, brief candle! Life’s but a walking shadow, a poor player that struts and frets his hour upon the stage and then is heard no more. It is a tale told by an idiot, full of sound and fury, signifying nothing.” (Shakespeare, 17th century)
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STATES OF CONSCIOUSNESS • Awake: hypervigilant too drowsy
• NREM sleep: Stages 1, 2 and 3
• REM sleep: An awake brain in a paralyzed body; dreaming sleep
Polysomnography
• Sleep stages occurring during 30 second epochs: NREM (1,2,3) & REM
• EMG displaying motor activity
• EKG and chest expansion recorded
• (Rechtschaffen A & Kales A. Sleep Stages, in NIH 204,1968)
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NREM sleep
• NREM sleep is characterized by 3 stages
• Stage 1 is the transition from wakefulness to sleep with a loss of the alpha frequency
• Stage 2 is characterized by vertex sharp waves and sleep spindles (thought generated by the thalamus)
• Stays 3 is characterized by high voltage slow waves REM sleep
• It might be somewhat surprising to note that the purpose of REM sleep is not entirely clear • Dreams are only fragmentary at best during NREM sleep but typically are quite complex when patients are aroused from REM sleep
• Freud labeled dreams the royal road to the unconscious (Freud, 1900)
• More recently REM sleep has been characterized as potentially the brain’s opportunity to consolidate new learning (Hopson and McCarly, 1977; Wilson M, McNaughton B Science 265,1994) 4
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Circadian rhythm
• Circadian from the words circa = around; dias=day • The human biological clock is approximately 24 hours in duration
• This 24 hours circadian rhythm is principally under the control of the suprachiasmatic n. of the hypothalamus
• Not only is sleep and wakefulness governed by a 24 hour cycle but also other physiologic functions, such as temperature
Wakefulness and the hypothalamus
• The hypothalamus links the central nervous system to the endocrine system
• The SCN fires at a tremendously high rate to maintain wakefulness as sleep load builds during wakefulness
• The anterior hypothalamus also produces histamine to maintain wakefulness
• The lateral hypothalamus contains orexin producing neurons that increase not only wakefulness, but also hunger and thirst (more on Orexin later)
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The hypothalamus links with brainstem and limbic system
• The hypothalamus interfaces with the reticular formation of the brainstem
• The hypothalamus connects to the autonomic nervous system (e.g., decreased sympathetic activity in NREM sleep)
• Interconnects with the limbic system, particularly the amygdala and septal nuclei (? New memories)
• It connects directly to the nucleus solitarius, locus ceruleus and ventral medulla
Insomnia
• Insomnia involves difficulty initiating sleep, difficulty maintaining sleep, a combination of initiating and maintaining sleep, and none refreshing sleep lasting one month or more
• Insomnia may be considered idiosyncratic (primary insomnia) or insomnia associated with another condition, such as psychiatric
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Psychiatric causes of insomnia
• Depression, often labeled as terminal insomnia
• Anxiety‐generalized anxiety associated with difficulty initiating sleep
• Panic disorder‐nocturnal panic attacks
• Posttraumatic stress disorder‐with nightmares
• Substance induced insomnia, for example alcohol
Insomnia treatment‐
nonpharmacological interventions
• Sleep hygiene
• Sleep restriction‐the bed is for sleep and no excess time should be spent in bed awake
• Relaxation training and CBT –quite effective
• Bright light therapy‐early a.m. to assist with awakening
• Morin CM et al. (meta‐analysis) A J Psych 151,1994
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Insomnia and sleep hygiene
• Encourage patients to go to bed and get up each day at about the same time
• Try to exercise during each day
• Keep bedroom reasonably cool
• Avoid smoking; no caffeine, chocolate later
• Avoid heavy meal close to bedtime
• Avoid alcohol and excess OTCs as sleep aids
• Avoid bright light ,eg, computer screens for last hour before bedtime‐time to relax
Depression and insomnia
• Depression is often complicated by early morning awakening
• Less frequently depression is complicated by difficulty initiating sleep as well as middle insomnia
• Depression may be complicated by other psychiatric disorders such as generalized anxiety, panic disorder, posttraumatic stress disorder, and substance abuse
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Depression and insomnia
• Insomnia may be present prior to the onset of major depression and should be considered a potential risk factor for the development of depression
• Early treatment of insomnia complicating depression is often associated with earlier resolution of the depression
Depression’s effects on sleep
• A decrease in REM latency
• The first REM episode is more prolonged
• Decreased slow wave (NREM) sleep
• Note: Most antidepressants decrease REM sleep (Riemann et al. Biol Psychol,2001)
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Anxiety and insomnia
• Generalized anxiety and difficulty initiating sleep‐
? Should we be using benzodiazepines for any long‐term treatment given the potential risk of dementia
• Evidence for the potential of benzodiazepines to increase the risk of Alzheimer’s disease was presented by Billioti de Gage S et al. (BMJ,2014;349) comparing 1796 patients with Alzheimer’s disease compared to 7184 controls
Insomnia treatments
• Benzodiazepine treatments from very short acting to long acting benzodiazepines, GABA alpha1, 2, 3, 5 inhibitors
• GABA A1 inhibitors short‐acting to longer acting
• Melatonin and melatonin agonist
• Histamine blockers
• Orexin blockers
• Alpha 1 adrenergic blockade
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BMJ Study’s findings: Benzodiazepine increase the potential for Alzheimer’s
• Patients that have been treated with benzodiazepines‐ the risk of developing Alzheimer’s disease has been found to be‐
adjusted odds ratio 1.51 (interval 1.36‐1.69)
• Risk of the development of Alzheimer’s increases after 91 days or more, increasing most substantially at greater than 180 days, especially with longer acting benzodiazepines (short‐acting‐
1.43; long‐acting 1.7 adjusted odds ratio)
Insomnia and nocturnal panic attacks
• Some patients panic attacks occur during sleep in addition to daytime panic attacks
• A very few patients will have only nocturnal panic attacks
• Due to concerns about benzodiazepines and Alzheimer’s disease SSRIs are generally the treatment of choice; benzodiazepine usage considered for short‐term intervention
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Insomnia and PTSD
• PTSD is often complicated by insomnia
• PTSD patients may experience very frightening nightmares‐ reexperiencing the trauma
• Prazosin (1 to 16mg) may effectively eliminate or decrease these nightmares and daytime hyperarousal
• Raskin M at al. Am J Psych 2013; 170 (9)
• Germaine A et al. J Psychosom Res 2012; 72(2)
Insomnia and alcohol abuse
• Many patients attempt to self‐medicate with alcohol for difficulties with sleep
• Unfortunately, this use of alcohol may become quite problematic not only because of alcohol dependency issues, but also middle insomnia
• Alcohol and substance use in general should be considered in every prolonged case of insomnia
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Insomnia, hypersomnia and bipolar disorder
• Classical bipolar disorder is usually characterized as decreased sleep with an increase in racing thoughts at night
• However, bipolar disorder may at times he complicated by periods of hypersomnia
• Hypersomnia typically occurs in bipolar depression, whereas insomnia is more characteristic of hypomania or mania
Hypersomnia and sleepiness
• Classical obstructive sleep apnea (OSA) is very often complicated by daytime sleepiness
• Obstructive sleep apnea is often complicated by major depression and every sleep apnea patient should be considered potentially depressed
• The use of CPAP or BiPAP may resolve the depression as well as the OSA
• Occasionally, an OSA patient may present with a chief complaint of insomnia because of frequent awakenings during the night‐attempt to avoid as much as possible sedating an untreated OSA patient
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Benzodiazepines for sleep
• Short acting‐1.5‐5.4 hour Half‐life: triazolam (Halcion)‐
dose 0.125‐0.25 mg •
Intermediate acting‐10‐20 hour Half‐life: temazepam (Restoril)‐dose 7.5‐30 mg
• Long‐acting‐47‐100 hour half‐life: flurazepam (Dalmane)‐15‐30 mg
• Recall concern versus use of benzodiazepines and possible risk of Alzheimer’s disease GABA A1 receptor agonists often labeled “Z‐drugs” • Short acting: zolpidem/zolpidem MR (Ambien and Ambien CR) 1.4‐4.5 hour half‐life‐dosage 5‐10 mg and for CR 6.25 and 12.5 mg
• Intermediate acting: eszopiclone(Lunesta) 1,2,3mg; half‐life= 6 hour (? Plus)
• ? Concern versus Alzheimer’s disease
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Evidence for benzodiazepines and Z‐drugs
• Nowell PD et al. JAMA,1997 278(24) performed a meta‐analysis of 22 studies
• Benzodiazepines and Z drugs were effective for reducing sleep latency
• Limits of the majority of studies: The limited duration of the studies
Z‐drug specific evidence
• Huedo‐Medina et al. BMJ 2012; 345
• Effectiveness of Z‐drugs for adult insomnia: A meta‐analysis of data submitted to the FDA
• 13 studies of Z‐drug efficacy indicated a decrease in sleep latency of 22 min. (33 min. for placebo versus 11 min. for Z drugs)
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Older adults and treatment of insomnia with benzodiazepine/Z‐drugs
• Glass J et al. BMJ 2005; 331
• Meta‐analysis of risks and benefits for the use of benzodiazepines and Z‐drugs in the elderly
• 24 studies (N= 2417) revealed total sleep time increased by 25.2 min. (P < 0.001) • Adverse events: decrease in cognitive ability (P< 0.01); psychomotor ability decreased (P> 0.05) and daytime fatigue increased (P< 0.001)
Conclusions about commonly used sedative/hypnotics
• Benzodiazepines and Z‐drugs are clearly effective when used to decrease sleep latency and may well be effective in increasing total sleep time
• Benzodiazepine chronic drug usage may ultimately be shown to increase the risk of Alzheimer’s
• Z‐drugs may or may not be shown to increase the risk of Alzheimer’s
• Both classes of sedative/hypnotics possess the potential for serious side effects
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Melatonin and melatonin agonists for the treatment of insomnia
• Many of our patients take over‐the‐counter melatonin for the treatment of insomnia
• Over‐the‐counter melatonin agents are not regulated by the FDA and may or may not contain an uncontaminated level of melatonin advertised on the label
• A prolonged release melatonin (PLM= Circadin) is available in Europe and approved by their equivalent of the FDA as an effective hypnotic‐it remains to be seen whether it will come into more widespread usage
Melatonin agonist and insomnia
• Ramelteon ( Rozerem) is a tricyclic analog of melatonin that acts upon the M1 and M2 receptors in the SCM
• Ramelteon is a chronobiotic and hypnotic agent‐ possesses the ability to advance to sleep clock and cause sleepiness
• Borja N, Daniel K. Clin Therapy, 2006‐ 12 RCTs: modest but statistically significant decrease ‐‐‐in sleep latency ranging from 10‐19 min.
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Anti‐histamines and insomnia
• Most over‐the‐counter remedies for insomnia contain antihistamines with their attendant anticholinergic side effects
• Many patients report these as effective and do not appear to experience side effects unless used in excess
• Some clinicians now feel more comfortable recommending anti‐histaminergic agents secondary to concerns regarding benzodiazepines and Z‐drugs
• Small doses of some of our older antidepressants are now utilized on or off label for the treatment of insomnia, for example, doxepin and trazodone
Orexin antagonism and insomnia
• Recall that Orexin has been found to be deficient in patients with narcolepsy
• Orexin antagonism has been explored as a therapy for insomnia
• Will Orexin antagonism result in daytime symptoms resembling narcolepsy/cataplexy?
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Suvorexant for insomnia
• Mickelson D et al. safety and efficacy of suvorexant (an orexin inhibitor) during one year treatment of insomnia‐Lancet Neurology 2014; 13 (5)
• N=322 active med; N= 162 placebo for 1 yr.
• <65 years of age 40mg; >65 30 mg
• Significant improvement in subjective total sleep time and subjective time to onset of sleep
Suvorexant side‐effects
• Potential daytime sleepiness
• Potential for daytime cognitive slowing
• Potential psychomotor difficulties
• Potential parasomnias similar to benzodiazepine and Z‐drug side‐effects
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Summary
• Many agents over the years have been used for the treatment of insomnia
• Patient’s use of alcohol and over‐the‐counter medications is an important part of the patient’s history
• Alcohol and excessive use of over‐the‐counter medications is to be discouraged for treatment of insomnia
Summary
• The use of benzodiazepines may increase the risk of Alzheimer’s
• It remains to be seen whether Z‐drugs will increase the risk of Alzheimer’s; I think this less likely though with insufficient evidence to substantiate that opinion‐ stay tuned!
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Summary
• Melatonin and melatonin agonist may be prepared in a manner that sustains the release of melatonin to M1 and M2 receptors in the SCN
• Melatonin agonist may ultimately display fewer side effects than currently available sedative/hypnotics, though modest evidence to substantiate that opinion at present
Summary
• An Orexin antagonist, suvorexant, is currently available and has shown evidence of efficacy for promoting sleep in patients suffering insomnia, including elderly patients • The potential for significant side effects remains, though this agent has been utilized in a clinical trial lasting one year without significant withdrawal upon abrupt cessation
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Summary
• Currently, available evidence favors short term usage of any medication for the treatment of insomnia, particularly that insomnia associated with psychiatric conditions‐insomnia may resolve with the treatment of the underlying psychiatric disorder‐ recall the benefits of good sleep hygiene and CBT
• The use of hypnotics in the treatment of primary insomnia‐insomnia not associated with psychiatric or medical disorders‐may require prolonged usage of hypnotics. It may be prudent for primary care physicians to refer these patients to a sleep disorders clinic
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