Naveh Tov MD PhD Internal Pulmonary Sleep medicine Bnai-Zion Medical Center Clinic: Yigal Alon 29, Haifa, Ramat Yam 12, Herzelia,

1.Sleep introduction 2.Insomnia a.Definition b.Epidemiology c.Pathophysiology d.Treatment e.How to treat f.Summary 2

Sleep 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. 1 Reduced awareness of and interaction with the external environmen 2 Reduced motility and muscular activity 3 Partial or complete cessation of voluntary behavior and self- consciousne

ESSENTIAL TO OVERALL HEALTH & WELL-BEING Key to our health, performance, safety Essential to perform cognitive & physical tasks Key to our quality of life Essential component such as nutrition & exercise

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Wake  Norepinephrine  Serotonin  Acetylcholine  Histamine  Orexin/hypocretin Sleep  Adenosine   -aminobutyric acid (GABA)  Galanin  Melatonin 10

Disorders of Excessive Sleepiness (DOES) Disorders of Initiating and Maintaining Sleep (DIMS) Parasomnias Disorders of circadian rhythm

Insomnia

Insomnia definition insomnia 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. 14

Insomnia types  short-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 disorder 16

Epidemiology

Insomnia is the most common sleep disorder, prevalence of 10 to 15%

Primary vs Comorbid Insomnia Ohayon MM. Sleep Med Rev. 2002;6: Psychiatric Disorders 44% Primary Insomnia 16% Other Illnesses, Medications, etc 11% Other Sleep Disorders 5% No DSM-IV Diagnosis 24% 19

Lichstein KL et al. In: Epidemiology of Sleep: Age, Gender, and Ethnicity. Mahwah, NJ: Erlbaum; Type (%) Lower Boundary of Age Decade 20

Insomnia symptoms -Overall prevalence 30-48% -Often or always: 16-21% -Moderate to extreme: 10-28% Insomnia symptoms + daytime consequences 9-15% Insomnia diagnosis 6% Direct economic costs of insomnia in the US ~ $14 billion Ohayon, Sleep Med Rev, 2002

Pathophysiology

Am J Psychiatr 1991;48: Copyright 1991

Winkelman JW et al. SLEEP 2008;31(11):

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 Not well understood  Hypothetical factors  Increased tendency to hyperarousal  Increased cortisol, heart rate responsivity, metabolic rate, catecholamines, EEG  Decreased homeostatic sleep drive  Prone to  Worry  Depression, anxiety  Significant night-type/morning-type  Familial vulnerability EEG = electroencephalogram. 29

Lancet Neurol 2015; 14: 547–58

 These 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 certainty  Family (24%)  Marital, child  Physical health (23%)  Pain, illness  Work, school (17%)  Stress, shift work  Mental health (12%)  Depression  Undetermined (22%) Bastien CH et al. Behav Sleep Med. 2004;2:

 Behavioral  Irregular sleep-wake schedule  Excessive time in bed  Excessive caffeine use  Stimulating activities close to bedtime, or in the middle of the night  Clock watching during the night  Cognitive  Worry throughout the day about sleep  Fear of not sleeping  Irrational beliefs concerning consequences of poor sleep 32

Treatment

 CBT takes longer to help, but the gains are maintained for up to 2 years later  Pharmacologic treatment provides immediate benefit  Others (milder effect than CBT, may improve medication effect) :  Tai Chi, Chi Gong, Yoga  Acupuncture, Acupressure  Herbs  Hypnosis, meditation CBT = Cognitive Behavior Therapy. 34

Unrealistic sleep expectations Misconceptions about sleep Sleep anticipatory anxiety Poor coping skills Excessive time in bed Irregular sleep schedules Sleep incompatible activities Hyperarousal Inadequate sleep hygiene Cognitive Cognitive Therapy Behavioral Stimulus Control Sleep Restriction Relaxation Educational Sleep Hygiene Education 35

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 Benzodiazepine – Brotizolam, etc.  Non-Benzodiazepine – Zolpidem,  Antidepressants- Trazadone,Mirtazapine, Amitryptyline, Doxepin,  Melatonin- Meltonin, Circadin, Ramelteon  Antihistamines  Antipsychotics  Miscellaneous- Valerian Diphenhydramine 38

 Efficacious in insomnia  Side effects are usually an extension of desired effects  Sedation  Amnesia  Falls  Accidents  Duration of action about 2 to 3 times T1/2  Tolerance  Rebound  Addiction Newer “designer” drugs Nowell PD, Mazumdar S, Buysse DJ, et al. JAMA. 1997;278(24):

 24 studies (involving 2417 participants)  Sedative use compared with placebo  Sleep 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 2005 In 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 psychomotor adverse events.

How to treat?

TransientRecurringChronic Good Sleeper Hypnotic CBT Hypnotics Poor Sleeper CBT Consider hypnotic CBT Consider hypnotic CBT Consider hypnotic CBT, cognitive behavioral therapy Hypnotics – Circadin, Antidepressant, Z-drugs, BZD

 55 year-old woman with primary insomnia and difficulty initiating sleep

46 Arch Intern Med. 2004;164:

 63 year-old man with COPD CHF complains of repeated awakenings throughout the night

1.Medicina (B Aires) 1996;56(5 Pt. 1):472–8. 2.Drug Saf 1992;7(2):152–8. 3.Respiration 1988;54(4):235–40 4.Int Clin Psychopharmacol 1990;5(Suppl. 2): congress of the American Association for respiratory care 2007 December 6.J Clin Psychiatry 2004;65(6):752–5 ReffRespirationSleepEffectDrug 1-3Vt, Pco2 sensLatency, Arousals-BZD ApneaSEF+ 4Vt, Pco2 sensLatency, Arousals-Non-BZD ApneaSEF+ 5No effectLatency-Melatonin SEF+ 6Unknown-Trazodone SEF+

 65 year-old woman with insomnia, ask your help to stop BZD treatment

Benzodiazepine Discontinuation  CBT  Circadin  Antidepressant Am J Psychiatry 2004; 161:332–342

 Prolonged insomnia is associated with an increased risk of new-onset major depression.  It may be an independent risk factor for heart disease, hypertension, and diabetes, especially when combined with sleep times of less than 6 hours per night.  Evaluation should include a complete medical and psychiatric history and a detailed assessment of sleep-related behaviors and symptoms.  Cognitive behavioral therapy is the first line therapy for insomnia (setting realistic goals for sleep, limiting time spent in bed, addressing maladaptive beliefs about sleeplessness, practicing relaxation techniques).  In acute insomnia due to a defined precipitant, use of approved hypnotic medications is indicated.  Severe insomnia - long-term use medication should be considered in patients that is unresponsive to other approaches ( benzodiazepine-receptor agonists, low-dose antidepressants, melatonin agonists, or an orexin antagonist  CBT combined with other methods 52

Thanks Clinic: Yigal Alon 29, Haifa, Ramat Yam 12, Herzelia,