Naveh Tov MD PhD Internal Pulmonary Sleep medicine Bnai-Zion Medical Center Clinic: Yigal Alon 29,...

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Transcript of Naveh Tov MD PhD Internal Pulmonary Sleep medicine Bnai-Zion Medical Center Clinic: Yigal Alon 29,...

Regional cerebral metabolism during NREM sleep in idiopathic insomnia. Nofzinger et al. found increased regional metabolism (18FDG PET) from waking to NREM sleep in patients with idiopathic insomnia. Smith et al. found reduced regional cerebral blood flow (SPECT) in the basal ganglia in insomniacs. 1 = anterior cingulate, 2 = thalamus, 3 = hypothalamus, 4 = ascending reticular activating system, 5 = insula, 6 = medial temporal, 7 = basal ganglia.

Insomnia UpdateNaveh Tov MD PhDInternal Pulmonary Sleep medicineBnai-Zion Medical CenterClinic: Yigal Alon 29, Haifa, Ramat Yam 12, Herzelia, 04-8268826 www.navehmed.comPresentation OverviewSleep introductionInsomniaDefinition Epidemiology PathophysiologyTreatment How to treatSummary 2SMEI21/10/2015 23:31Optional Slides2CORE

Sleep definitionSleep is defined as a sustained quiescent period, spent in a species-specific characteristic, posture or site, and during which the threshold for response to stimuli is raised, although a stimulus of sufficient strength will rapidly reverse the state.

3Why Do We Sleep?

How Much do we sleep?

5Sleep stages

66Sleep is Cyclical 90 min

7Sleep occurs in stages. There are 4 stages of NREM or Non-Rapid Eye Movement sleep and one stage of REM or Rapid-Eye Movement sleep. NREM Stage 1 sleep is the onset of sleep with Stages 2, 3 and 4 becoming progressively deeper. REM sleep, also known as dream sleep, first occurs about 90 minutes after sleep onset. The eyes dart back and forth during REM sleep, thus, the name rapid eye movement sleep. Brain waves, which can be measured by an overnight sleep study, alter during each stage. Most of the deep sleep occurs in the first third of the night and most of the REM sleep is experienced in the last third of the night. All stages of sleep are important.Sleeping throughout these stages is important because this is when tissue growth and repair occur, energy is restored, and learning or memory is consolidated.

Opponent Process - model of sleep regulation Edgar, J Neurosci, 1993

99Sleep/Wake Neurotransmitters and Modulators: Targets for Pharmacologic DevelopmentWakeNorepinephrineSerotoninAcetylcholineHistamine Orexin/hypocretinSleepAdenosine-aminobutyric acid (GABA)GalaninMelatonin10SMEI22/10/2015 02:18Optional Slides10OPTIONAL

Consequences of sleep loss

Classification of Sleep DisordersDisorders of Excessive Sleepiness (DOES)Disorders of Initiating and Maintaining Sleep (DIMS)ParasomniasDisorders of circadian rhythmInsomnia

Insomnia definitioninsomnia is defined by difficulties in falling asleep, maintaining sleep, and early morning awakening, and is coupled with daytime consequences such as fatigue, attention deficits, and mood instability.14Symptoms

Insomnia typesshort-term (< 3 months duration)chronic (symptoms occur 3 times/week for at least 3 months) and not related to inadequate opportunity for sleep or another sleep disorder16Epidemiology

Sleep Problems- prevalenceInsomnia is the most common sleep disorder,prevalence of 10 to 15% Primary vs Comorbid InsomniaOhayon MM. Sleep Med Rev. 2002;6:97-111.

Psychiatric Disorders44%Primary Insomnia16%Other Illnesses, Medications, etc11%Other Sleep Disorders5%No DSM-IV Diagnosis24%19SMEI21/10/2015 23:31Optional Slides19CORE

Insomnia Prevalence by AgeLichstein KL et al. In: Epidemiology of Sleep: Age, Gender, and Ethnicity. Mahwah, NJ: Erlbaum; 2004.Type (%)Lower Boundary of Age Decade20SMEI22/10/2015 01:02Optional Slides20OPTIONAL

Insomnia - Costs Direct economic costs of insomnia in the US ~ $14 billionOhayon, Sleep Med Rev, 200222Pathophysiology

Schematic representation of the gamma-aminobutyric acid (GABAA)-benzodiazepine (BDZ) receptor complex.

Am J Psychiatr 1991;48:162-173. Copyright 199124Reduced Brain GABA in Primary Insomnia

Winkelman JW et al. SLEEP 2008;31(11):1499-1506. The first evidence of a neurochemical difference in the brains of those with PI compared to normal sleeping controls. Our finding of a global reduction in daytime GABA levels in non-medicated individuals with PI is preliminary, and must be replicated. However, 1H-MRS is a valuable tool to assess GABA in vivo, and with use of alternate acquisition protocols that allow better anatomical resolution, may shed further light on the neurobiology of insomnia. 2526


Predisposing FactorsNot well understoodHypothetical factorsIncreased tendency to hyperarousalIncreased cortisol, heart rate responsivity, metabolic rate, catecholamines, EEGDecreased homeostatic sleep driveProne toWorryDepression, anxietySignificant night-type/morning-typeFamilial vulnerabilityEEG = electroencephalogram.29SMEI22/10/2015 02:24Optional Slides29OPTIONAL

Genes implicated in the neurobiology of insomnia

Lancet Neurol 2015; 14: 54758Precipitating FactorsThese factors are the focus of the nosologic system (eg, stress, pain/illness, depression/anxiety, shift work, etc.)A specific precipitant is often hard to identify with certaintyFamily (24%)Marital, childPhysical health (23%)Pain, illnessWork, school (17%)Stress, shift workMental health (12%)DepressionUndetermined (22%)Bastien CH et al. Behav Sleep Med. 2004;2:50-62.31SMEI22/10/2015 02:24Optional Slides31OPTIONAL

Perpetuating FactorsBehavioralIrregular sleep-wake scheduleExcessive time in bedExcessive caffeine useStimulating activities close to bedtime, or in the middle of the nightClock watching during the nightCognitiveWorry throughout the day about sleepFear of not sleepingIrrational beliefs concerning consequences of poor sleep32SMEI22/10/2015 02:24Optional Slides32OPTIONAL

TreatmentInsomnia Treatment CBT takes longer to help, but the gains are maintained for up to 2 years laterPharmacologic treatment provides immediate benefitOthers (milder effect than CBT, may improve medication effect):Tai Chi, Chi Gong, YogaAcupuncture, AcupressureHerbsHypnosis, meditation

CBT = Cognitive Behavior Therapy.34SMEI21/10/2015 23:31Optional Slides34OPTIONAL

Unrealistic sleep expectationsMisconceptions about sleepSleep anticipatory anxietyPoor coping skillsExcessive time in bedIrregular sleep schedulesSleep incompatible activitiesHyperarousalInadequate sleep hygienePsychological / Behavioral Treatments (Treatment Targets)CognitiveCognitive TherapyBehavioralStimulus ControlSleep RestrictionRelaxationEducationalSleep HygieneEducation35SMEI21/10/2015 23:31Optional Slides35CORE

Components of Cognitive Behavioral Therapy for Insomnia

Non pharmacological treatments37

Pharmacologic TherapyBenzodiazepine Brotizolam, etc.Non-Benzodiazepine Zolpidem,Antidepressants- Trazadone,Mirtazapine, Amitryptyline , Doxepin, Melatonin- Meltonin, Circadin, RamelteonAntihistaminesAntipsychoticsMiscellaneous- Valerian Diphenhydramine38Medications Commonly Used for Insomnia

Benzodiazepine Receptor Agonists: General StatementsEfficacious in insomniaSide effects are usually an extension of desired effectsSedationAmnesiaFallsAccidentsDuration of action about 2 to 3 times T1/2ToleranceReboundAddictionNewer designer drugs

Nowell PD, Mazumdar S, Buysse DJ, et al. JAMA. 1997;278(24):2170-2177.4040Efficacy: TST, Sleep efficiency, SOL, subjective too. Rebound: insomnia worse than before starting meds. Addiction: withdrawal of BZA is mild and last 2 weeks (NEJM article). Not a problem is one doesnt exceed max dose recommendations. Designer drugs: quick onset action, BZA1 receptor activity, low receptor affinity, short T1/2.Sedative hypnotics in older people with insomnia: risks >>>> benefits24 studies (involving 2417 participants) Sedative use compared with placeboSleep quality improved (effect size 0.14, P < 0.05), Total sleep time increased (mean 25.2 minutes, P < 0.001), Number of night time awakenings decreased (0.63, P < 0.001). Adverse events were more common with sedatives than with placebo: adverse cognitive events were 4.78 times more common (95% confidence interval 1.47 to 15.47, P < 0.01); adverse psychomotor events were 2.61times more common (1.12 to 6.09, P > 0.05), daytime fatigue were 3.82 times more common (1.88 to 7.80, P < 0.001) BMJ 2005In people over 60, the benefits of these drugs may not justify the increased risk, particularly if the patient has additional risk factors for cognitive or psychomotoradverse events.

How to treat?Suggested Treatment in InsomniaTransientRecurringChronicGoodSleeperHypnotic


PoorSleeperCBTConsiderhypnoticCBT Consider hypnoticCBTConsider hypnoticCBT, cognitive behavioral therapyHypnotics Circadin, Antidepressant , Z-drugs, BZD44What would you recommend for treatment?55 year-old woman with primary insomnia and difficulty initiating sleepCognitive Behavior Therapyand Pharmacotherapy for Insomnia46

Arch Intern Med. 2004;164:1888-1896What would you recommend for treatment?63 year-old man with COPD CHF complains of repeated awakenings throughout the nightMedicina (B Aires) 1996;56(5 Pt. 1):4728.Drug Saf 1992;7(2):1528.Respiration 1988;54(4):23540Int Clin Psychopharmacol 1990;5(Suppl. 2):94-85.congress of the American Association for respiratory care 2007 December J Clin Psychiatry 2004;65(6):7525Secondary Insomnia suggested treatment Melatonin, AntidepressantReffRespirationSleepEffectDrug1-3Vt, Pco2 sensLatency, Arousals-BZDApneaSEF+4Vt, Pco2 sensLatency, Arousals-Non-BZDApneaSEF+5No effectLatency-MelatoninSEF+6Unknown-TrazodoneSEF+48Improved Sleep Efficiency in People with a Secondary Sleep Disorder

49What would you recommend for treatment?65 year-old woman with insomnia , ask your help to stop BZD treatmentBenzodiazepine Discontinuation CBTCircadinAntidepressant

Am J Psychiatry 2004; 161:332342Arch intern Med. 1999;159:2456-2460

51Insomnia SummaryProlonged insomnia is asso