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1 Insomnia in patients with diabetes 신원철 강동경희대병원신경과, 수면센터

2 수면장애, 얼마나발생하는가? 전인구의 20-30% 가앓고있다 수면장애진단율 : <5% 잠재적수면장애환자 : 600만 1천만명 수면장애의진료건수 : 급격한상승 노인인구의증가.26.2 만 28.8 만 41.5만 35.8만

3 Today talks 1. 수면부족의결과 2. 불면증이인체에미치는영향 3. 당뇨환자에서불면증 4. 불면증관리.

4 수면부족이미치는영향

5 스페이스셔틀챌린저호

6 스페이스셔틀챌린저호

7 스페이스셔틀챌린저호

8 Glucose and cortisol change in sleep loss 수면부족 next day after 4-h sleep 6nights 수면보충 next day after 12-h sleep 6nights 140 혈당 혈당 (mmol / L) recover 80

9 Glucose and cortisol change in sleep loss 수면부족 next day after 4-h sleep 6nights 수면보충 next day after 12-h sleep 6nights 140 혈당 혈당 (mmol / L) recover 80

10 수면부족 : 수면부채와인지기능 sleep debt affect Vs neuro-cogniitve performance 시간수면박탈시실수와동일 시간수면박탈후와동일 Sleep 03:26(2);117

11 odds rations 수면시간 versus 당뇨병발생 DM( 당뇨병 ) IGT < 5 6 7~8 9 Sleep length (53~93 y.o. N=1, 486) (male:722, female:764) DM: diabetes mellitus IGT: impaired glucose tolerance (Gottlieb DJ, et al:arch Intern Med 165, 2005) 수면睡眠不足と心臓疾患のリスク시간 versus 관상동맥질환 ( 米国 ) relative risks sleep time (CHD: coronary heart disease) Mean CES-D Score 수면年齢別の睡眠時間と시간 versus CES-D 우울증 scaleの関連발생 ( うつ評価 ) (N=32,700) ~5 5~6 6~7 7~8 8~9 9~10 10~ Sleep length (Kaneita Y, et al:j Clin Psychiatry 67,2006)

odds rations 수면시간 versus 당뇨병발생 3.0 2.5 2.0 1.5 1.0 0.5 DM( 당뇨병 ) IGT < 5 6 7~8 9 Sleep length (53~93 y.o. N=1, 486) (male:722, female:764) DM: diabetes mellitus IGT: impaired glucose tolerance (Gottlieb DJ, et al:arch Intern Med 165, 2005) 수면睡眠不足と心臓疾患のリスク시간 versus 관상동맥질환 ( 米国 ) relative risks 1.

12 odds rations 수면시간 versus 당뇨병발생 DM( 당뇨병 ) IGT < 5 6 7~8 9 Sleep length (53~93 y.o. N=1, 486) (male:722, female:764) DM: diabetes mellitus IGT: impaired glucose tolerance (Gottlieb DJ, et al:arch Intern Med 165, 2005) 수면睡眠不足と心臓疾患のリスク시간 versus 관상동맥질환 ( 米国 ) relative risks sleep time (CHD: coronary heart disease) Mean CES-D Score 수면年齢別の睡眠時間と시간 versus CES-D 우울증 scaleの関連발생 ( うつ評価 ) (N=32,700) ~5 5~6 6~7 7~8 8~9 9~10 10~ Sleep length (Kaneita Y, et al:j Clin Psychiatry 67,2006)

13 Leptin in sleep loss

14 Obesity in sleep deprivation 비만지수(BMI) 수면시간과비만지수 (BMI) (230) (347) (121) (507) (623) 수면시간 (hour) (Tahrei et al; PLOS, 2004)

15 잠을못자면? Sympathetic over activity High cortisol level Decreased glucose intolerance High blood pressure

16 불면증이인체에미치는영향

17 Chin Med J 2015;128:3292-7

18 Insomnia with objective short sleep duration is associated with a high risk for type 2 diabetes Population based study (n=1,741) found increased risk for diabetes in those with insomnia and < 5h sleep p duration (OR 2.95; 95% CI ) Vgontzas AN et al., Diabetes Care (2009) 32:

Insomnia with objective short sleep duration is associated with increased risk for hypertension Cross sectional study, n=1,741 Sleep duration assessed by polysomnography All

19 Insomnia with objective short sleep duration is associated with increased risk for hypertension Cross sectional study, n=1,741 Sleep duration assessed by polysomnography All data adjusted for age race, age, race, sex, BMI, diabetes, smoking status, alcohol consumption, depression, SDB, and sampling weight. Vgontzas AN et al., SLEEP (2009) 32:

20 불면증과심혈관질환및관상동맥질환발생위험도 Hoevenaar-Blom, et al., Sleep,2011: 34 (11) Cohort study N = 20,432, Age Y MORGEN Study : sleep duration and insomnia Vs CVD & CHD Cardiovascular disease Coronary heart disease 79% % increased risk % 23% 22% 33% 63% Normal sleepers Short sleep duration Poor quality sleep Short + poor Quality sleep Insomnia is a risk factor for cardiovascular incidents - Short sleepers, especially those with poor sleep quality, have an increased risk of total CVD and CHD incidence

21 Insomnia Vs DM and CVD

22 Insomnia Vs DM and CVD

role for SWS in the maintenance of normal glucose homeostasis Ref.

23 Slow-wave sleep & risk of DM type II Decrease in insulin sensitivity was strongly correlated with the magnitude of the reduction in SWS A clear role for SWS in the maintenance of normal glucose homeostasis Ref. Tasali et al. Slow-wave sleep and the risk of type 2 diabetes in humans., PNAS.2007

24 Add-on Circadin Improves Sleep in Patients with Insomnia and Diabetes Comorbidities Actigaphy derived sleep parameters (Mean+SD) following 3 weeks of administration of Circadin or placebo (crossover): Parameter Placebo PRM Order ef fect P value Treatment by order P value Treatment effect P value Sleep Efficiency (%) <0.04 Sleep Latency (Minut es) Wake After Sleep On set (Minutes) Total Sleep Time (Mi nutes) Number of Awakenin gs < <0.003 Garfinkel et al, 2011

25 Add-on Circadin Improves Glycemic Control (HbA1c) in Diabetic Patients with Insomnia Garfinkel et al, 2011 HbA1c levels (%,Mean +SEM) Baseline p=0.005 * 5 months treatment Long-term administration of PR melatonin 2 mg/day was associated with a significant reduction in HbA1c in type 2 diabetic patients. Mean±SD reduction in %HbA1c was 0.66% ± 1.15% which is both statistically significant and of clinical importance.

혈압일주기리듬 & CV Risk Facotr Noctural Dip in BP regulation Circadian Rhythm in BP is essential for Cardiovascular health BP falls during sleep and rises rapidly just before awakening (option-use a

26 혈압일주기리듬 & CV Risk Facotr Noctural Dip in BP regulation Circadian Rhythm in BP is essential for Cardiovascular health BP falls during sleep and rises rapidly just before awakening (option-use a separate figure) If BP when asleep drops by less than 10% from wake BP, the patient is a non-dipper In patients with insomnia the circadian rhythm of BP is blunted Stage 1 or 2 NREM: 5~9% BP SWS NREM: 8~14% BP Twenty-four SBP and DBP in insomniacs (circular symbols and continuous black lines) and controls (triangular symbols and dashed lines). Data at each hour represent the mean and standard error of hourly SBP and DBP calculated from beat-to-beat BP in each subject Lanfranchi et al., 2009, Marchiando & Elston, 2003 ; Pasqualini, Foroni, Salvioli, & Mussi, 2004

SWS( 깊은수면 ) 과고혈압위험도 SWS(Slow Wave Sleep) and HTN

012 % with incident hypertension 45-40 - 35-30 -

2 26 1 ( least ) 2 3 4 Median % Time in SWS

27 SWS( 깊은수면 ) 과고혈압위험도 SWS(Slow Wave Sleep) and HTN P = % with incident hypertension ( least ) Median % Time in SWS (Quartile of dataset) Odds ratio: 1.81 [95% CI: 1.18 to 2.80]) FUNG, M., et al, Hypertension,, 2011; 58:

drug 수면위생, 불면증인지행동치료수면리듬분석에따른, 수면스케줄조정동반또는이차성불면증에고려 British Association

29 Current Insomnia Treatment Flow Diagnosis Good sleep practices and prov en behavioral strategies If Failed GABA receptor enhancers Pharmacological treatment Non-GABAergic drug 수면위생, 불면증인지행동치료수면리듬분석에따른, 수면스케줄조정동반또는이차성불면증에고려 British Association Psychopharmacology consensus statement - Wilson et al, 2010 over-the-counter m edications, antihista mines

30 Tip 1. 수면습관을확인하라. Essential Sleep history 언제부터 Sleep-Wake Schedule (average, variability): - 몇시에눕는가? - 몇시에자는가? - 잠드는데얼마나걸리나? - 몇시에깨나? 언제일어나나? - 중간에몇번깨나? 왜? 다시잠드는데얼마나걸리나? - 총수면시간은? - 자고나면개운한가? 낮에피곤한가? Nocturnal Symptoms: - Respiratory, Motor, Other medical, Behavioral and psychological Daytime Activities and Function ; 낮잠?

31 Tip 2. 수면리듬을확인하라. Sleep dairy, Actigraphy

32 Tip 2. 수면리듬을확인하라. Sleep dairy, Actigraphy

33 Tip 2. 수면리듬을확인하라. Sleep dairy, Actigraphy

34 Tip 3. 수면설문지를활용하라. 수면장애불면증과수면증하지불안증후군수면무호흡증 설문지종류 - Insomnia Severity Index - Pittsburgh Sleep Quality Index (PSQI) - Epworth Sleepiness Scale - Standford Sleepiness Scale - 4 Questionnare - International RLS rating scale - Berlin Questionnare

35 Tip 4. 노인들의수면변화를이해하라. 1, 총수면시간감소 Same sleep need per 24 hour (naps) 2. 수면중에자주깬다. Age, Pain, medication, medical disorders, sleep disorder 3. 서파수면 (3-4 단계, 깊은잠 ) 감소 4. 렘수면은조금감소 5. 수면위상이빨라진다. 6. 하루밤잠중에수면사이클의수가적어진다. 7. 수면효율이떨어진다.

36 Tip 5. 짧고명확한지침 ; 수면위생, 수면인지행동치료 1. 기상시간을일정하게유지한다. 2. 오전에햇빛을충분하게쬐십시오. 3. 매일규칙적으로운동하십시오. 4. 잠자리는조용하고어둡게만듭니다. 5. 침실의온도는너무덥지않도록합니다.

37 6. 잠자리에들때배가너무고프거나너무부르지않도록합니다. 7. 커피, 차, 담배, 카페인이든탄산음료, 초콜릿과같은카페인섭취를제 한하십시오. 8. 술을수면유도목적으로사용하지마십시오. 9. 수면제는가급적사용하지마시기바라며, 필요하다면전문의의처방에 따라사용하십시오. 10. [30분규칙 ] 잠자리에들어 30분이내잠이오지않는다면, 잠자리에서일어나가벼운독서, TV 시청등을하면서이완하고있다가다시졸리면다시잠자리에들도록하십시오. 이후다시잠이안오면이러한과정을잠들때까지계속반복하십시오

38 불면증인지행동치료 (Cognitive Behavioral Therapy in Insomnia) 1. 부적응적인수면습관교정 : 행동치료 수면위생 : 수면을돕는습관익히기 자극통제 : 침대와침실을잠이잘오는장소로만들기 수면제한 : 침대에있는시간을제한하여수면의질을향상 이완요법 : 각성과불안을감소 2. 수면에대한걱정, 두려움 : 인지치료 수면을방해하는생각과믿음을교정 인지행동치료 : 위의열거한행동적, 인지적기법을통합하여시행하는치료.

39 Tip 6. 불면증을일으킬수있는원인들을고려하라. 일주기수면리듬장애 (Circadian Rhythm Disorders) 다른수면장애 : 수면무호흡증, 하지불안증후군, 주기적하지운동증 내과적질환 복용약물 정신과적질환 육체활동제한

40 Causes of Chronic Insomnia: 복용약물 CNS stimulants - Pemoline (Cylert), dextroamphetamine (Dexedrine), Methylphenidate (Ritalin, Concerta), mixed Amphetamine salts (Adderall) Antihypertensives - Beta-blockers, alpha-blockers, methyldopa, reserpine β-blocker - Increase REM latency, reduce REM - Increase number of awakenings, total wake time, stage 1 - Deplete endogenous melatonin (sleep hormone) - associated with nightmares Respiratory medications Theophylline, albuterol chemotherapy Decongestants Pseudoephedrine (Novafed), phenylephrine (Neo-Synephrine), Phenylpropanolamine (Entex) Homones ; Corticosteroids; thyroid Psychotropics ; SSRIs, atypical antidepressants, MAO inhibitors

tolerance and addiction More effective treatments for insomnia in the

41 Key Clinical Unmet Needs in Insomnia Ideal hypnotics Reduction in residual daytime sedation Increasing level of importance Lack of potential for tolerance and addiction More effective treatments for insomnia in the elderly Improvement in sleep maintenance More effective treatments for pediatric insomnia

Commonly used hypnotics Medication 1,2 Dosage 2,3 (mg) Tmax 1 (hr) Half-life 1 (hr) Indication 1,3 Benzodiazepine Estazolam Flurazepam Temazepam Triazolam Quazepam 1-2 15-30 15-30 0.125-0.25 15-20 1.

42 Commonly used hypnotics Medication 1,2 Dosage 2,3 (mg) Tmax 1 (hr) Half-life 1 (hr) Indication 1,3 Benzodiazepine Estazolam Flurazepam Temazepam Triazolam Quazepam Sleep maintenance Sleep maintenance Sleep maintenance Sleep onset Sleep maintenance Non-benzodiazepine Eszopiclone Zaleplon Zolpidem Zolpidem CR Sleep onset/maintenance Sleep onset Sleep onset Sleep onset/maintenance Melatonin receptor agonist Ramelteon Melatonin sustained release Sleep onset(only FDA approved) Sleep onset Histamine Receptor antagonists Doxepin Sleep maintenance Unapproved use by the US Food and Drug Administration Antidepressants, sedating Anticonvulsants Atypical antipsychotics KR.ZOL

43 Natural Sleep Architecture 보존 1. Luthringer R et al. Int Clin Pscychopharmacol Trachsel L et al. Neuropharmacol Brunner D et al. Psychopharmacol 1991.

44 잠을못잔다. 문진 : 수면패턴, 다른수면장애유무 (OSA, PLM, RLS, CRD), 복용하고있는약물, 동반질환, 술, 커피, 담배 수면일기, 수면관련설문지 (ISI, PSQI, RLSQ) Actigraphy 수면다원검사 1 달이상불면증치료를하였는데도증상호전되지않는다면 불면증 급성, 만성불면증확인 수면위생 약물치료 : short acting, less dependent, Less tolerance 수면인지행동치료다른수면장애 수면위생 OSA ; Wt control, postional therapy, CPAP CRD : 노인, 젊은사람에서의만성불면증- 광치료, 수면위생 RLS & PLMD : dopamine agonist, iron therapy, aggravating factor 내과적문제와복용약물 수면위생 불면증유발요인제거 치료약제중불면증유발약제배재, 수면유도약물이용

45 Take Home Message 1. 불면증은증상이지진단이아니다. 2. 급성불면증과만성불면증의원인과치료는다르다. - 급성 ; acute stressor - 만성불면증 ; hyperarousal 3. 1 달이상불면증치료를하였는데도증상이호전되지않으면, 다른원인을생각하여야한다. ; OSA, circadian rhythm disorder, other combined medical & psychological disorder, medication 4. 불면증치료는개개인의원인에따라다르게결정하여야한다. ; Selective BZD receptor agonist, sleep hygiene, Cognitive- Behavioral therapy

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