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1 종설 J Kor Sleep Soc / Volume 5 / December, 2008 가천의과학대학교길병원신경과학교실 Practical Management of Sleep Problem in Dementia Kee Hyung Park, M.D. Department of Neurology, Gachon University of Medicine and Science, Gil Medical Center Patients with dementias, such as Alzheimer s disease (AD), often have sleep disturbances. Clinically, this may present as agitation during the nighttime, we often have been called sundowning. Sleep disturbance in AD may be multifactorial, for example, sleep-disordered breathing, restless leg syndrome, and disrupted chronobiology, which often caused by excessive daytime napping. So we carefully consider these secondary cause of insomnia, especially in elderly demented patients. Unfortunately, there have been no randomized clinical trials of sedative-hypnotic medications specifically targeted at AD patients with sleep problems. Evidence suggests that sedative-hypnotics, such as benzodiazepine site-specific agonists, may have a role in some cases, whereas atypical antipsychotics or specific antidepressants may be necessary in other cases. There are also reports of successful interventions with nonpharmacologic options (eg, exercise, illumination). The utility of melatonin as a hypnotic in this population appears equivocal. Key Words : Alzhiemer's disease, Sleep problem, Intervention 사람들은나이가들수록여러가지건강상의문제로괴로움을당하고고민하게된다. 그중에서도편안한잠을이루지못해서겪는고통은다른중한질병과다르지않다. 미국에서실시한 Established Populations for Epidemiologic Studies of the Elderly(EPESE) 의결과를보면 65세이상건강한노인 9,000 명중 28% 가잠이들기어렵고너무일찍일어나게된다고했고, 29% 는지속적으로잠을청하기어렵다고했으며, 18% 는너무일찍일어난다고호소했다. 단지 12% 만이잠을자는데문제가없다고하였다. 1 치매환자에서도수면장애는매우흔하게관찰되는데, 활동양이적어짐으로인해서빛에대한노출이적어지고, * Address of correspondence Kee Hyung Park, M.D. Department of Neurology, Gachon University of Medicine and Science, Gil Medical Center, 1198, Gu Wal dong, Namdong-gu, Inchun, , Korea Tel: Fax: khpark@gachon.ac.kr 수면의중요한호르몬인멜라토닌의리듬이감소하며, 수면의일주기를담당하는 suprachiasmatic nucleus 뿐아니라아세틸콜린의분비에중요한 Nucleus of Maynert 등의퇴화로인하여수면의효율이감소하고, 잦은각성이일어나며, 램수면과서파수면이감소하는등의수면구조의변화가일어나게된다. 2 이러한결과로, 잦은각성, 낮은수면효율, 과도한낮잠등이야기되는데, 치매환자를대상으로조사한보고를살펴보면 205명의알쯔하이머치매환자중 40% 가과수면증, 31% 는아침에조기기상, 그리고 24% 는잦은각성을보인다고하였다. 3 치매환자에게서보이는수면장애는 Sundowning 이라고알려진야간의흥분 (agitation) 과불안등의정신행동증상을동반한배회현상을보이게되며, 이는보호자를가장힘들게하는행동증상중의하나로환자들이시설에입소하게되는가장중요한원인이다. 또한수면무호흡이나하지불안증후군의발병빈도가증가함으로써이차적인불면증으로인한수면장 Vol.5, No.2 / December,

2 애또한감별해야하는데, 알쯔하이머치매의중요한원인인자중의하나인 apolipoprotein E ε4가수면무호흡과연관이있다. 4,5 수면장애는결과적으로치매환자의우울증상을악화시키고공격적인행동증상을야기하며, 인지기능의저하를유발함으로써환자자신뿐아니라환자를돌보는간병인의삶의질에중대한악영향을미치는결과를초래하게된다. 6 치매환자의수면장애의치료치매환자의수면장애를치료하기위해서는수면장애의형태, 일차성불면증, 하지불안증후군, 수면중하지운동장애, 램수면행동장애등에대한객관적인평가가선행되어야한다. 비교적간단하고쉽게평가할수있는방법으로는수면설문과수면일기등이있고, Actigraphy, 수면다원화검사 (Polysomnography) 와같이특수화된기기를이용하는방법이있다. 또한치매환자들은내과적인질환들, 예를들어통증을유발할수있는여러가지상황들이나, 위식도역류등과같은위장장애, 심혈관질환, 만성폐쇄성호흡기질환뿐아니라우울증, 불안등의정신과적인질환을함께가지고있는경우가많고, 이에따라여러약제를한꺼번에복용하고있을가능성이높으므로, 정확한문진과병력파악이선행되어야하며, 병발한질환에따른개개인에맞는치료전략이필요하다. 치료방법은크게약물치료와비약물적인치료로나눌수있다. 비약물적치료비약물적인치료는약물치료이전에선행되어야하는데, 실제환자를치료함에있어서반드시고려해야한다. 효과적인치료로제안되는것을살펴보면, 식이교정, 낮잠의횟수와시간을제한하는방법, 그리고밤에졸릴시에만잠자리에가게하고일정시간일어나게하는것을포함한 (stimulus control) 수면환경의개선과낮동안에육체적, 사회적활동량을증가하는생활습관개선, 그리고낮동안밝은빛에대한노출을증가시키는환경개선등의방법이 제안되고있다. 최근 36명의알쯔하이머치매환자를대상으로한수면교육의효과를 6개월간관찰한이중맹검연구에의하면, 야간각성횟수와낮잠의횟수가현저히감소했다고보고하고있다. 7 특히밝은빛에대한노출을증가시키는것은생체일주기리듬을안정화시키는데중요한역할을하며, 노년기불면증환자의치료에효과적인방법이다. 8 노년기에보이는불면증은입면장애보다는수면의유지곤란에연관이있으며, 일찍잠이들어서일찍깨어나는특징으로보인다. 이것은수면의일주기로보면수면위상이전진되어서나타나는현상으로, 1만룩스의밝은빛을저녁시간 ( 오후 5시 ~7시사이 ) 에비추면위상지연이일어나일주기리듬이교정되면서수면개선효과를기대할수있다. 광치료를치매환자의치료에적용할수있는데, 수면과행동장애에대한효과에대해서일치된결론을내리지는못하고있다 그러므로가장효율적인치료효과를얻기위해어느정도의빛의강도를어느정도기간으로환자에게노출시켜야할지에대한추가적인연구가필요한실정이다. 약물치료치매환자의수면에대한약물치료는몇가지점에서주의를기울여야한다. 가장중요한것은앞서언급한내과적인질환들, 예를들어통증을유발할수있는여러가지상황들이나, 위식도역류등과같은위장장애, 심혈관질환, 만성폐쇄성호흡기질환, 그리고우울증과불안증등을포함한정신적인문제는없는지먼저살펴야한다. 또한수면무호흡증은, 잦은각성뿐아니라뇌졸중, 고혈압, 당뇨등을유발하는질환으로, 노인의경우에는젊은연령보다많게는 5배까지빈도가증가해서 4명중에한명은수면무호흡환자이므로코골이가심하거나과체중인경우반드시살펴서교정해야한다. 15 특히, 비선택적벤조디아제핀수용체에작용하는수면유도제의경우, 호흡근까지마비할수있으므로주의를요한다. 그리고하지불안증후군의경우도일반적인빈도의두배가넘는약 25% 에서가지고있으므로반드시적절한검사를통해확인하고치료해야한다. 16 또한방광염이나전립선비대증등의비뇨기문제로인한수면장애도흔하므로수면제등의약물을쓰기전에 56 수면

3 먼저고려해야한다. 벤조디아제핀계와비벤조디아제핀계수면제를비롯하여, 항우울제, 앙정신병약물, 그리고멜라토닌이수면장애를보이는치매환자에게사용할수있다 (Table 1, 2) 벤조디아제핀계수면제는수면시간을연장시키고, 수면효율을좋게할수있지만작용시간이긴수면제는낮동안의졸음을유발하여인지기능의저하와낙상의위험을증가시킬수있고, 작용시간이짧은수면제는역으로불면증을악화 시킬수있다. 벤조디아제핀계약물은장기간사용하는것은정신적, 그리고신체적으로약물의존을유발할수있으므로피해야한다. 비벤조디아제핀계약물은최근에개발된약물로효과는이전의약물과비슷하면서부작용을줄이고약물의존성을줄일수있는장점이있다. 20 삼환계항우울제가사용되는경우가있다. 진정작용을가지는항우울제중가장대표적인것은 trazodone, amitriptilline, mirtazapine 등이있으며, 이중 trazodone 은부작용이적 Table 1. The of Alzheimer s disease medications on sleep Drug class Benzodiazepine and non-benzodiazepine hypnotics Typical and atypical antipsychotics Melatonin Acetylcholinesterase inhibitors N-methy-D-aspartate receptor (NMDA) antagonst, i.e., memantine Effects on sleep Positive on sleep Risk of falling, agitation, drowsiness Effects on psychotic symptoms and nocturnal agitation Slight on nocturnal agitation and total sleep time Shorted REM latency, increased REM density in healthy controls and in patients with AD Increased risk of insomnia with donepezil Absence of negative effect on sleep with galantamine or rivastigmine Effect on sleep unknown AD=Alzheimer s disease Table 2. Hypnotics in sleep disorder Rapid elimination Dose (mg)* Elimination Half-life (h) + Tmax (h) + Active metabilic Indications and Comments Zolpidem ʃ 5/ No Zaleplon ʃ 5/ No Zopiclone ʃ 3.75/ * Triazolam ʃ 0.125/ No Mainly for sleep onset and possibly sleep maintenance; less accumulation of drug over time possibly more rebound insomnia, anterograde, anterograde amnesia, untoward drug reactions descrubed with triazolam Intermediate elimination Temazepam ʃ Lorazepam 15/30 0.5/ No No Possibly sleep onset, may be preferred for sleep maintenance; less accumulation compared with longer-acting agents Slow elimination Flurazepam ʃ 15/30 Quazepam ʃ 7.5/ (n-desalkyl flurazepam) (n-desalky flurazepam) 1.0 Yes 2.0 Yes Possibly sleep onset but more typically for sleep maintenance; higher risk for daytime sedation and related complications due to drug accumulation, especially in elderly people or those with delayed metabolism *Recommended starting dose in elderly and medically ill patients/usual recommended dose. elimination half-life and Tmax represent estimated averages for healthy adults. # All benzodiazepines carry potential for dose escalation and for psychological and physical dependence. ʃ US Food and Drug Administration approved hypnotic. Not available in norway or the UK *Active metabolic Vol.5, No.2 / December,

4 Table 3. Antipsychotic medications in patients with Alzheimer s disease Medication Brand name Initial dosage in AD patients 1 Dosage range in AD patients 1 mg/day Sedation Hypotensive Adverse Anti-cholonergic Extra-pyramidal Risperidone Risperdal /- + Olanzapine Zyprexa /- Quetiapine Seroquel /- - Ziparasidone Geodon 20 mg b.i.d /- +/- Aripiprazole Ability /- - Clozapine Clizaril Haloperidol Haldol Perphenazine Trilafon 고수면효과가뛰어나므로미국에서는수면을위해가장널리사용되는약물이다. 21 트라조돈은우울증이없는일차불면증환자에투여했을때전체수면시간을증가시키고수면의질을향상시키며수면중의각성을감소시킨다. 22 하지만트라조돈이외의항우울제는비교적부작용이흔하므로우울증이동반되었을때권장되며, 트라조돈역시기립성저혈압, 허약감등이나타날수있고드물지만심장흥분전도이상 (Cardiac conduction abnormalities) 가나타날수있어심장질환이있는경우주의를요한다. 23 행동장애가동반되는경우수면작용이있는항정신병약물이사용되는데, 특히최근에개발된비전형적항우울제 (atypical antipsychotics) 는이전의약물에비해부작용이적어서저용량으로사용할경우좋은효과를기대할 있다. 특히최근에미국에서이루어진 actigraphy 를이용하여평가한다기관이중맹검연구결과를보면 157 명의수면장애를가진알쯔하이머치매환자를대상으로 melatonin 2.5 mg과 10 mg을투여하였을때위약군과비교하여유의한차이가없다고보고하고있어추가적인연구가필요한상황이다. 28 치매환자에서의수면장애매우흔하다는것은이미주지의사실이며, 환자뿐아니라가족들의삶의질에미치는영향이지대하므로더욱관심을가지고치료해야하는증상의하나이다. 특히여러약물을복용하고있는치매환자에게는약물적인치료보다는비약물적인치료가선행되어야하므로, 이에대한가족들의이해와교육이절실히필요하다고할것이다. 수있다. ( 표 ) olanzapine 24, quetiapine 25, risperidone 26 에대한연구가있었는데, 이중맹검연구에서 olanzapine 5, 10 mg으로알쯔하이머치매환자의행동장애를안정시켰으며, 위약군에비해 5배이상의수면효과를보았다고보고하였다. Quetiapine 은치료군의 1/3에서수면효과가있다고보고했으며, risperidone 은 0.5 mg에서는치료군의 10%, 1.0 mg에서는 17%, 2.0 mg에서는 28% 에서수면효과가있다고보고하였다. 하지만동물연구에서심전도상 QT prolongation 현상이보고되어심장질환이있는치매환자에게서는주의를요한다. 27 Melatonin 은작용시간이매우짧고부작용이없어서치매환자들의수면장애를치료하는데상용되어왔다. 하지만이에대한연구결과는아직확실한결론을내리지못하고 REFERENCES 1. Foley, D. J., Monjan, A. A., Brown, S. L., Simonsick, E. M., Wallace, R. B., & Blazer, D. G. (1995). Sleep complaints among elderly persons: An epidemiologic study of three communities. Sleep, 18, Bliwise DL. Sleep disorders in Alzheimer s disease and other dementias. Clin Cornerstone. 2004;6 Suppl 1A:S McCurry, S. M., Logsdon, R. G., Teri, L., Gibbons, L. E., Kukull, W. A., Bowen, J. D., McCormick, W. C., & Larson, E. B. (1999). Characteristics of sleep disturbance in community-dwelling Alzheimer s disease patients. Journal of Geriatric Psychiatry & Neurology, 12, Yesavage J, Friedman L, Kraemer H, Tinklenberg J, Salehi A, Noda A, et al. Sleep/wake disruption in Alzheimer s disease: APOE status 58 수면

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<The natural sleep cycle of a healthy adult: Life Enhancement Magazine September 1999> (2) 수면단계에 영향을 주는 요소 (1) 연령 수면단계 분포에 영향을 주는 가장 중요한 요소는 연령이다. 신생아

<The natural sleep cycle of a healthy adult: Life Enhancement Magazine September 1999> (2) 수면단계에 영향을 주는 요소 (1) 연령 수면단계 분포에 영향을 주는 가장 중요한 요소는 연령이다. 신생아 수면장애(1) 주경미 데일리팜 부사장 약학정보원 학술자문위원 개요 사람은 일생의 약 1/3을 잠을 자며 보낸다. 충분한 잠은 지친 뇌와 신체를 회복시켜 기억력, 학습 능력, 감정 조절, 성장 발달, 면역력, 심혈관계 기능, 성기능 등을 건강하게 한다. 산업의 발전으로 24시간 사회 가 되면서 활동시간과 수면을 취하는 시간의 변화로 뇌 속 생체시계가 교란되고