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1 수면장애의약물치료 분당서울대병원신경정신과 윤인영

2 1. 불면증 2. 하지불안증후군 3. 기면병 ( 수면과다증 ) 4. 렘수면행동장애 5. 수면무호흡증

3 1. 불면증

4 정의및역학 * 정의 : 잠이불충분하거나비정상적이라고느끼는상태 : 잠이들기힘들거나, 자다가자주깨거나, 한번깨면다시잠들기힘들거나, 잠을자고개운하지않다고느끼는상태 * 역학 1) 만성불면증 (1 개월이상지속 ) : 전인구의 10% 내외 : 65 세이상노인 ; % 2) 일시적불면증 (1 개월미만 ) : 전인구의 30 50%

5 원인 * 불면증 진단명이아니라증상 : 두통이있거나열이날때무조건두통약이나해열제를복용하기전에원인을찾아야하듯불면증의경우에도어떤원인이있는것이아닌지생각해야한다. * 불면증의원인 우울증 불면증환자의최소 25% 이상수면무호흡증 노년기하지불안증후군 노년기약물남용이나금단, 통증

6 Drugs in managing insomnia Hypnotics - Benzodiazepine; triazolam (halcion ), flurazepam (dalmadorm ) - Nonbenzodiazepine; zopiclone (imovan ), zolpidem (stilnox ) zaleplon (sonata ) Antidepressants - amitriptyline, trazodone, mirtazapine (remeron ) Antihistamine - hydroxyzine, diphenhydramine Melatonin Benzodiazepines - clonazepam (rivotril ), lorazepam (ativan ), etizolam (depas )

7 Hypnotics (I) Functional 3 moieties: BZ recognition site, GABA recognition site, Cl - ionophore Molecular cloning: 5 glycoprotein subunits with multiple isoforms

8 Hypnotics (II) BZ 1 receptor: alpha 1, beta 2, gamma 2 BZ 2 receptor: alpha 3, beta 2, gamma 2 Benzodiazepines: binding to both types Non-benzodiazepines : bind to relatively greater specificity to type 1 Selective binding of non-bz : more specific pharmacologic properties (?) - sedative effects >> muscle relaxation

9 Hypnotics (III) Indications / Guidelines - transient and short-term insomnia (4 wks or less) - insomnia with comorbid conditions - lowest effective dose / a short trial (less than 1 month) Side Effects - hangover / drowsy feeling - dizziness / headache - impairment in psychomotor performance / anterograde amnesia - mild respiratory depression (long-acting BZ) - rebound insomnia on withdrawal (short-acting BZ) - delirium

10 Hypnotics (IV)

11 Antidepressants (I) Widespread use of trazodone and other antidepressants 1. concern about tolerance, dependence, and S/E of hypnotics 2. not as an antidepressants but as a hypnotic agent 3. mechanism of action: antihistaminergic 4. Considerations - Low abuse potential and helpful in BZ dependence - Little or no evidence from systematic studies that they aid sleep in insomnia (non-depressed) pts.

12 Antidepressants (II) 약물상품명배출반감기 ( 시간 ) 치료용량 (mg) 활성대사물 Flurazepam Dalmadorm Triazolam Halcion, Zolmin Zaleplon* Sonata Zolpidem Stilnox Amitriptyline Etravil, Amitriptyline Mirtazapine Remeron Trazodone Trazodone, Trittico

13 Antidepressants (III) S / E of Antidepressants 1. Trazodone : orthostatic ht, dizziness, headache, dry mouth, gastric irritation, N/V, cardiac conduction abnormalities 2. Mirtazapine : wt gain, increased appetite, dry mouth, daytime somnolence, dizziness, restless legs syndrome 3. Amitriptyline : anticholinergic S/E, and delirium and cognitive dysfunction, orthostatic ht, cardiac effects

14 Benzodiapines clonazepam (rivotril ), etizolam (depas ), lorazepam (ativan ), alprazolam (xanax ) 1. Anxiety and Insomnia 에동시에효과 2. Hypnotics 만으로효과가미흡할때 3. 항우울제에비해부작용이적다 4. 내성및의존의위험성

15 비약물치료 : 생활습관중수면에방해가되는요인을찾아내어제거하고수면에대한오해를교정하는과정 - 밤에잠자리에누워있는시간을줄이기 - 밤에잠자리에누워있는시간을줄이기 - 낮에누워있지말기 - 새벽에깨어시계를보지말기 - 매일규칙적인운동을하되저녁늦게는하지말기 - 침대에서잠자는이외의행동은하지말기 - 새벽에잠이오지않으면거실에있다가자기 - 잠자리에들어복식호흡하기

16 숨을들이쉴때

17 숨을내쉴때

18 불면증에관련된의문들 (1) * 불면증을치료하지않으면우울증혹은치매가되는가?? 불면증우울증치매 X X * 수면제는중독성이있는가? 약간의의존성이있는것은사실 : 새로운수면제는의존성이어느정도개선됨치료용량이증가되는내성도과거에비해줄어듬

19 불면증에관련된의문들 (2) * 수면제를장기복용하면해가되지않는가? : 과량을장기복용하면기억력장애, 운동기능저하, 간기능장애등이초래될수있음 : 전문의와상의하에소량을사용할경우부작용을최소화할수있음 * 수면제는끊을수있는가? : 외국의경우 40% 에서수면제를끊을수있는것으로보고됨 : 비약물적인요법을병행하면 40% 내외에서수면제를끊을수있을것으로생각됨. 이외의경우에는전문의와상의하면서수면제를소량복용하도록

20 2. 하지불안증후군

21 Definition and Prevalence * Carl Ekbom, 1945 : Unpleasant, subjective sensation in the legs, appearing only at rest, producing an irresistible need to keep the legs in motion * Prevalence 1) 5-10% of adult population : Asian countries - < 3 %? Korean adults 7.5 % (men, 6.2%; women, 8.7%) (Cho et al, 2008) 2) Increasing with age, reaching to the plateau around 40s 3) Probably occurring more in women than in men

22 성남시노인인구에서의유병율 연령남성여성전체 세 4.2% 10.5% 7.6% 세 7.4% 11.3% 10.0% 85 세이상 25.0% 4.6% 10.0% 전체 5.3% 10.4% 8.3%

23 하지불안증후군의진단기준 ( 필수항목 ) 1. 다리를움직이고싶은강한충동을느낀다. 이러한충동은다리에불편한혹은불쾌한감각과동반되어나타나는경우가흔하다. 2. 움직이고싶은충동혹은불쾌한감각이눕거나앉아있는동안, 즉휴식중이나가만히있는동안에발생하거나악화된다. 3. 움직이고싶은충동혹은불쾌한감각이걷거나다리를뻗는등의움직임에의해부분적으로혹은완전히해소되며, 최소한움직이는동안에는이러한증상의해소가지속된다. 4. 움직이고싶은충동혹은불쾌한감각이낮보다저녁혹은밤에더심하거나저녁혹은밤에만발생한다.

24 Secondary RLS 1. Patients on dialysis: 20-60% 2. Pregnant women: 20-30% 3. Iron deficiency anemia cf.) Gastric surgery and frequent donations Compromise of iron sufficiency Iron status should be evaluated by iron / ferritin / transferrin / TIBC. 4. Medications inducing or worsening RLS or PLMS : Li, TCA and other antidepressants, typical antipsychotics : Caffeine and alcohol

25 Pathophysiology * Central dopamine system dysfunction 1) Therapeutic effects of L-dopa and dopamine agonists 2) Akathisia caused by dopamine receptor-blocking agents 3) Imaging studies mixed results * Brain iron deficiency : CSF measures of ferritin and transferrin, MRI measures of regional brain iron concentrations, autopsy evaluations of brain iron status * Genetics familial aggregation of RLS * Opiate system dysfunction

26 Flow Chart for the Management of RLS (2005, Sleep Medicine)

27 Dopamine agonist * Bromocriptine: nausea, rarely used * Pergolide: semisynthetic ergot alkaloid agonist activity at D1 and D2 receptors nausea, orthostatic hypotension, pulmonary fibrosis and cardiac dysfunction * Non-ergoline derivative Ropinirole: Approved by FDA for RLS Pramipexole: Approved by FDA for RLS Effective in 70% to 100% of patients

28 Other Drugs * Benzodiazepines : diazepam, clonazepam : mild cases, to improve sleep continuity an adjunct to overcome a stimulating effect of dopaminergic agents : no substantial benefit for managing RLS : hang over and dependency * Gabapentin : a valuable alternative to dopaminergic agents : neuropathic RLS, RLS patients with pain sensation * Oxytdodone and Propoxyphene

29 Case F/65 ( ) * 주소및현병력 주소 깊은잠을못잔다 1. 20년전부터잠들기가어렵고깊은잠을못자고자다가자주깬다. 남편이복용하던수면제를간혹먹었지만효과가뚜렷하지않았다. snoring (+), apnea (+) 년전부터자기전에허벅지와무릎이화끈거린다. 걸어다니면나아진다. 낮에가만히있을때나타나고밤에더심해진다. 다리를흔들고부딪치기도한다. * Lab findings 1) NPSG: AHI 36.5, PLMS index 84.1 / hr 2) Fe / Ferritin: 76 ug% / 70.9 ng/ml - WNL * Treatment Ropinirol (Requip) 0.25mg-1.25mg

30 3. 기면병 ( 수면과다증 )

31 Narcolepsy (1) Age of onset Primary peak; 15 to 25 years Secondary, smaller peak; 35 to 45 years 역학한국청소년 : 0.053% (0.015%) 미국, 서구및홍콩 : 0.013% % 일본 : 0.16% 이스라엘 : 0.002% Tetrad excessive daytime somnolence (EDS), cataplexy, sleep paralysis, hypnogogic hallucination (pentad: tetrad + disturbed nocturnal sleep)

32 Narcolepsy (2) * EDS usually first symptom * Sleep paralysis - suddenly unable to move the limbs, to speak, or even to breathe deeply on falling asleep or awakening - fully aware of the condition and able to recall it completely afterward - brief and benign, rarely lasting longer than 10 min, ending spontaneously

33 Narcolepsy (3) * Cataplexy (1) - usually considered unique to narcolepsy - an abrupt and reversible decrease or loss of muscle tone - most frequently elicited by emotion ; laughter or anger, surprise, abrupt strain, elation - conscious; clear, memory; not impaired, respiration; grossly intact - a few second to several minutes

34 Classical Stimulants

35 Modafinil (Provigil ) A new, wake-promoting drug with minimal side effect. Low incidence of side effects - headache (13%) - nervousness, nausea, dry mouth (<10%) Fewer side effects if treatment is begun with a low dose Tolerance or difficulties during withdrawal are very rare Little potential for addiction Known as alpha1-adrenergic agonist - mechanism is only partially understood

37 Idiopathic CNS Hypersmonia Chronic sleepiness without cataplexy No nocturnal sleep disturbances such as OSA or PLMS Associated symptoms of autonomic dysfunction ; cold hands and feet, lightheadedness on standing up, orthostatic hypotension, dull headache (slightly migrainous) Treatment symptomatic; stimulants

38 4. 렘수면행동장애

39 Case M/67 Chief Complaints: 악몽을꾼다. Present Illness 1) 이년전 (2004년 7월내원 ) 부터악몽을꾸기시작했고일년전부터는자다가일어나서고함을지르기도하고발로차기도하고벽을치기도하였다. 충격으로인해통증을느끼면깨기도한다. 싸우기도하고도망갈때도있고때리기도하고뱀을피하기도하는꿈이었다. 술을마시고자면증상이좀심해지는것같다. 2) snoring: 약간, apnea (-), RLS (-) 우울감 : 경한정도, 흥미저하 (-), 기력저하 (-), 집중력저하 (-)

40 Description 1) RBD as a distinct clinical disorder by Schenck and colleagues in ) Vigorous sleep behaviors usually accompanying vivid striking dreams resulting in ecchymoses, lacerations, and fractures : Dream-enactment 3) Arousals from sleep to alertness and orientation : Usually rapid and accompanied by dream recall (cf. NREM arousal disorders) 4) Waking personality : Calm, friendly, placid, and free of behavioral alteration Epidemiology 1) M:F = 9:1 2) 0.5 % of G.P.

41 (Olson EJ, 2000)

42 RBD vs. Sleepwalking RBD Sleepwalking Onset Early 60s Childhood or adults Spontaneous Remission Rare Many cases Sleep stage REM Stage 3, 4 Dreams Most cases Rare Neurological Abnormalities Common Rare Awakening Relatively easy Difficult Treatment Clonazepam Benzodiazepine

43 Treatments 1. Clonazepam 1) Mechanism uncertain, partly related with serotonergic effect 2) Effective in nearly 90% of cases ; on sleep behaviors and nightmares within the 1 st week 3) Little evidence of tolerance or abuse 4) Dose; 0.25mg 1.5mg 5) No gross changes in the absence of atonia ; probably acting on the locomotor system 2. Other drugs Carbamazepine, clonidine, levodopa, desipramine, melatonin 3. Environmental safety

44 5. 수면무호흡증

45 Diagnosis * Definition Apnea hypopnea index (AHI, Apnea + Hypopnea / hr) 5 * Prevalence 1) Between 30 and 60 yr ; about 2% of women, 4% of men 2) Over 65 yr ; about 24% of the independently living more prevalent in inpatient and nursing home population * Risk factors Obesity (central obesity; hip-to-waist ratio or waist circumf.) Aging, Male gender, Alcohol ingestion

46 CPAP Treatment (I) 1) First described by Sullivan and colleagues in ) Mechanism of Action : A pneumatic splint to prevent collapse of the upper airway a mechanical stent of the upper airway : CPAP does not increase upper airway muscle activity by reflex mechanism. 3) Pressure Prescription: 4-14 cmh2o or more

47 CPAP Treatment (II) Awake During sleep With CPAP

48 Compliance of CPAP Acceptance : The patient s perception of CPAP and willingness to consider its use. Ranging from 72% to 91% Adherence : The patient is prescribed CPAP and reports continuing use of CPAP. At least 4 hours on at least 70% of nights only 46% of patients

49 Surgical Procedures of OSA Nasal reconstruction Uvulopalatopharyngoplasty (UPPP) / Uvulopalatal flap Genioglossus advancement (GA) Hyoid advancement (HA) or suspension Radiofrequency tongue base reduction Maxillomandibular advancement (MMA) Maxillomandibular expansion (Li, 2005)

50 UPPP

51 Factors influencing surgery outcomes Favorable Unfavorable Age Younger patients (<60 y.o.) Older patients (>60 y.o.) Body habitus OSA severity Site of obstruction Non-obese Mild to moderate (RDI<30) Oropharyngeal (with tonsils) Obese Severe (RDI>30) Hypopharyngeal (Li, 2005)

52 Oral Appliance: Lateral View

53 Oral Appliance: Frontal View

55 결론 불면증의치료시비약물요법을병행하면수면제의용량및투여기간을줄일수있다. 하지불안증후군은흔히 40 대이후에문제가되는질환으로 dopamine agonist 가선택약제이다. 주간졸림증의경우비교적부작용이적은 Modafinil 을사용할수있다. 렘수면행동장애는노년기에흔한질환으로 Clonazepam 이효과적이다. 수면무호흡증의약물치료는없는상태이며상기도양압기가대표적인치료방법이다.

Psychiatry의 분야

Psychiatry의 분야 Category of illness Cognitive impairment Mood disorders Anxiety disorders Alcohol abuse/dependence Schizophrenic disorders Somatization Personality disorder Other psychiatric disorder Distribution of Psychiatric