REVIEW ARTICLE J Korean Sleep Res Soc 2010;7:25-31 ISSN X The Efficacy and Safety of Long-Term Use of Hypnotics Kwang Ik Yang 1 and Young Hwan

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1 REVIEW ARTICLE J Korean Sleep Res Soc 2010;7:25-31 ISSN X The Efficacy and Safety of Long-Term Use of Hypnotics Kwang Ik Yang 1 and Young Hwangbo 2 1 Department of Neurology, College of Medicine, Soonchunyhang University, Cheonan Hospital, Cheonan, 2 Department of Preventive Medicine, College of Medicine, Soonchunyhang University, Cheonan, Korea 수면제장기복용의유효성및안전성 양광익 1, 황보영 2 순천향대학교의과대학천안병원신경과학교실, 1 순천향대학교의과대학예방의학교실 2 Received November 30, 2010 Revised December 13, 2010 Accepted December 13, 2010 Address for correspondence Kwang Ik Yang, MD Department of Neurology, College of Medicine, Soonchunhyang University, Cheonan Hospital, Bongmyeong-dong, Cheonan , Korea Tel: Fax: kiyang@sch.ac.kr Insomnia may present with a variety of complaint and etiology, making the evaluation and management of chronic insomnia demanding on a clinician s time. Long-term use of hypnotics and sedatives has been discouraged for a number of reasons, including tolerance, abuse liability, and the belief that insomnia is a symptom that remit with treatment of the underlying medical or psychiatric disorder. Moreover, pharmacotherapy produces only moderate improvement during drug administration and returns toward baseline after discontinuation. Although efficacy and safety have been established for benzodiazepine receptor agonists when used for short-duration therapy, there are few data that establish their continued efficacy and safety in long-term use. Benzodiazepine hypnotics have been implicated as a cause of numerous adverse events, including dependency, withdrawal, rebound symptom, daytime sedation, fall, and hip fracture, especially in older people. In order to use hypnotic properly, correct diagnosis of the underlying causes of sleep disturbance is acquired at first and extreme caution of hypnotics use to primary sleep disorders is needed, especially in sleep related breathing disorders. Physicians and patients should be cautioned about the potential adverse effects and using of hypnotics. After initial treatment, clinical efficacy and side effect should be observed regularly. Easy accessibility of cognitive behavior therapy for patient can be also a coping with long-term use of hypnotics. J Korean Sleep Res Soc 2010;7:25-31 Key Words: Insomnia, Hypnotics, Safety. 서론 불면증은아주흔한수면장애중하나이며원인에따라일차성 (primary insomnia) 과이차성 (secondary or comorbid insomnia) 으로구분한다. 불면증자체가질환일수있지만다양한원인질환에의한증상일수있다. 그렇기때문에적절한치료를위해서는우선진단이정확히이루어져야하며원인질환의감별이우선시되어야한다. 불면증치료는크게인지-행동치료 (Cognitive and Behavioral Therapy, CBT), 약물치료 (Pharmacological Treatment), CBT와약물치료의조합으로나눌수있다. 불면증의치료목적은수면의질과양을향상시키고불면증과관련된주간생활의영향을감소시켜삶의질을향상시키는것이다 (Table 1). 1 그런데불면증을하나의감기증상처럼여겨서쉽 게수면제를처방, 복용하는것은바람직하지않다. 불면증은체계적으로접근해야하며비약물요법, 수면제이외의약물요법등다양한치료방법의적응증, 효과및안전성을고려하여환자에게적용하여야한다. 이중약물요법은각각수면제의작용시간및약물상호작용 (Table 2), 안전성을충분히이해하고특히, 장기간수면제복용의문제점들을인식하여처방하여야한다. 단기간의벤조다이아제핀계열 (benzodiazepines, BzDs) 의수면제복용의유효성과안전성에관한연구는비교적잘이루어져왔지만, 장기복용에관한연구는제대로이루어지지않고있다. 물론수면제복용을 drug-seeking behavior라기보다는 therapy-seeking behavior라고생각할수있지만 2 경험적으로대부분의사들은수면제장기복용이약물의존성, 남용에대한염려및불면증은하나의증상으 Copyright 2010 Korean Sleep Research Society 25

2 Efficacy and Safety of Hypnotics Table 1. The goal of treatment in patients with insomnia 1. Primary goals Improvement in sleep quality and/or quantity Improvement of insomnia related daytime impairments such as improvement of energy, attention or memory difficulties, cognitive dysfunction, fatigue, or somatic symptoms 2. Other goals Improvement in an insomnia symptom SOL <30 minutes WASO <30 minutes Decreased frequency of awakenings or other sleep complaints TST >6 hours and/or sleep efficiency >80% to 85% Formation of a positive and clear association between the bed and sleeping Improvement in sleep related psychological distress SOL: sleep onset latency, WASO: wake after sleep onset, TST: total sleep time Table 2. FDA approved pharmacologic treatment for insomnia Drug Dosage form Recommended dosage Half life (hours) Benzodiazepine receptor agonistic modulators Benzodiazepines Estazolam 1, 2 mg/t 1-2 mg 10~ mg in elderly Temazepam 7.5, 15, 30 mg/c mg mg in elderly Triazolam 0.125, 0.25 mg/t 0.25 mg; max 0.5 mg mg in elderly; max 0.25 mg Flurazepam 15, 30 mg/c mg mg in elderly Non-benzodiazepines Eszopiclone 1, 2, 3 mg/t 2-3 mg mg in elderly; max 2 mg Zolpidem 5, 10 mg/t 10 mg; max 10 mg mg in elderly Zolpidem CR* 6.25, 12.5 mg/t 12.5 mg mg in elderly Zaleplon 5, 10 mg/c 10 mg; max 20 mg mg in elderly Melatonin receptor agonist Ramelteon 8 mg/t 8 mg 2-5 *CR: not divided, crushed or chewed. T: tablet, C: capsule, CR: controlled release 로서원인질환이해결되면해소될수있다고생각하기때문에장기처방을꺼리고있다. 1987년부터 1996년까지미국 National Disease and Therapeutic Index Data에의하면수면제처방은 53.7% 로감소한반면항우울제처방은 146% 로증가하였다. 3 특히 triazolam 및 zolpidem 의처방이늘었다. 새로운비벤조다이아제핀계열 (non-benzodiazepines, NBzDs) 의수면제가개발되고임상에사용되고있으나만성불면증환자에게서초기치료에수면제를고려할것인지, 4 말것인지 5 에대한논쟁이있으며장기복용의적응증및남용등에대한안전성에대한연구및평가가필요한상황이다. 특히국내에서는 2010년 1월부터건강보험심사평가원에의해최면진정제처방을 1회 30일로제한하고있 26

3 Yang KI et al. 다. 이에저자는문헌고찰을통해만성불면증환자치료에있어서 CBT 비교와함께수면제장기복용에대한유효성과안전성에대해다루고자한다. 본론 만성불면증치료에있어서수면제사용에대한고찰수면제와 CBT 특성 : 수면제의장점 VS. CBT의단점수면제는효과가빨리나타나복용첫날부터효과를볼수있으나 CBT는 3~4주이후부터효과를볼수있다. 6 치료접근성에있어서약물치료는용이하다. 하지만 CBT는치료자의전문성및훈련이필요하며, 환자입장에서는규칙적인수면계획및수면제한등행동조절이필요한치료초기에오히려주간졸음등증상이악화됨으로써 CBT 효과에대한불확실성및환자의적극적인의지결여등으로치료를포기할수있다. 또한성공적인 CBT를위해서는비록효과를얻지못한다하더라도일정치료기간동안환자의지속적인인내가필요한데불면증과동반하고있는여러요소들이행동조절이나치료의지를방해할수있다. 예를들면, 우울증은환자들의치료에대한동기심및활력을저하시키고행동조절이불안을야기시킬수있으며이러한불안이행동조절의어려움이될수있다. 또한정신분열증, 치매, 지적장애와같은 CBT에대한이해및수행에있어협조가부족한경우에는 CBT 치료의어려움이있어이런환자들에게서는수면제사용이고려된다. 어떤불면증환자는규칙적인수면습관및비교적좋은수면위생을갖고있어인지- 행동조절에뚜렷한초점을맞추기어려운경우가있을수있는데이런경우에서도수면제사용이고려된다. 때때로불면증은동반된질환과독립되어나타날수있고원인이될만한질환에대한치료에도불구하고효과가없는경우에는수면제복용이도움이된다. 한예로선택적세로토닌재흡수억제제로치료중인우울증환자에게서보이는불면증을 zolpidem 복용으로효과를보인연구가있었다. 7 수면제와 CBT 효과의지속성 CBT는대략 4~6주간의치료기간이필요하며 6개월및 1년추적관찰하였을때지속적인효과를보였다 반면에약물은복용중단이후불면증을다시경험하게되며만성불면증환자에게서는 4주이상의수면제복용이필요하다. 11 하지만일반적으로 3~4주이상의수면제복용은피하도록되어있으며장기수면제복용은의존성, 내성, 금단증상에대한우려를갖고있다. 아직까지장기복용에대해미 국 FDA에승인된수면제는없으며, 4주이내의단기처방을하도록되어있다. 단, eszopiclone 은복용기간에대해특별히명시된바는없다. 하지만저자는이약물이장기복용되어도무방하다는뜻은아닐것이라고생각한다. 수면제장기복용에대한위험도-효과비교장기수면제복용은의존성, 내성, 금단증상에대한우려를갖고있다. 초기 BzDs 수면제는그러한문제점을보여주었지만최근새로이개발된 NBzDs 수면제의장기복용에대한위험도-효과비교에서양호함을보여주는몇몇연구가있다. 6개월간 Placebo-Controlled Trial(PCT) 기간을포함한 1년간 Eszopiclone 복용연구, 12,13 1년간 open-label을통한 zaleplon 복용연구, 14 3개월간간헐적인 zolpidem 복용연구 15 등에서입면잠복기 (sleep-onset latency, SOL), 입면후각성 (wake after sleep onset, WASO) 에효과가있었으며장기복용에도용량증량, 내성및금단증상과연관된의존성, 복용중단후복용전에비해더불면증이악화되는반동성불면증 (rebound insomnia) 발생에대한증거는없었다. 6개월간 zolpidem extended-release 12.5 mg 복용과위약 (placebo therapy, PT) 에대한효과및안정성에대한연구에서의미있는입면, 수면유지, 낮시간집중력, 아침졸음감소에대한효과를보였고 6개월복용중단후설문지를통한총수면시간 (total sleep time, TST), WASO, 반동성불면증에대한조사에서복용중단첫날은 PT군에비해 TST 감소, WASO 증가를보였으나, 2~3일째는차이가없었다. 부작용측면에서는두통, 불안, 졸음, 어지럼증, 피로등미미한것들이었다. 16 Randomized-Controlled Trial(RCT) 에대한메타분석에서 BzDs 및 NBzDs 치료는경미한부작용은있을수있지만, 만성불면증에효과적임을보여주었다. 17 만성불면증치료에있어서수면제제한에대한고찰수면제와 CBT 특성 : 수면제의단점 VS. CBT의장점 CBT는수면제와같은약물치료에비해의존성, 남용을포함한약물에의한부작용위험이없으며, 치료효과가약물치료에비해오랫동안지속하는장점이있다. 일차성 (primary) 불면증뿐만아니라, 동반성내지이차성 (comorbid or secondary) 불면증에서도효과를보인다. 18,19 이는불면증이일단만성화가되면인지적요인이 perpetuation 요소로작용하기때문에인지및행동적요인에대한조절이결국이차성불면증에도효과적으로작용한다는것이다. 정신생리불면증환자들에서개인적차이는있겠으나약물치 27

4 Efficacy and Safety of Hypnotics 료보다는비약물치료를선호하는경우가두배로높았다. 20 이는환자들이약물에의한부작용을염려하는경향때문이라고생각될수있다. 치료비용측면에서도약물치료가단기간에는 CBT에비해저렴할수있으나장기적측면에서는 1년간약물복용 (zolpidem-100$/30 tablets) 과 6주간의 CBT( 첫주두시간-240$, 주당한시간씩총 5주-600$) 를비교하였을경우, CBT가약물치료보다훨씬저렴하였다. 5,21 수면제와 CBT 효과의지속성 CBT에대한 RCT에서는 CBT가 SOL 감소및수면의효율성 (sleep efficiency, SE) 증가에유의한것으로나타났다. 8,9 수면유지가어려운만성불면증환자 75명을대상으로 6주간매주 30분내지 60분간 CBT를시행한군과이완요법 (relaxation therapy, RT) 을시행한군, PT군을수면다원검사를통해비교하였을때, CBT군에서의미있는 WASO의감소, SE 및 TST의증가, 주관적인수면의질등이향상되는소견을보였으며, 6개월이지난후추적관찰에서도이런효과들은지속되었다. 5 입면이어려운만성불면증환자 63명을대상으로 6주간매주 30분간의 CBT를시행한군, zolpidem 6주간복용한군 ( 처음 4주간매일 10 mg 5주째매일 5 mg, 6주째격일간격으로 5 mg), CBT와 zolpidem 조합한군, PT군을수면일지, 안검및두부움직임에대한 2채널모니터링을통해비교하였을때 CBT군에서의미있는 SOL의감소, SE의향상을보여주었다. 이런효과는 1년후추적관찰에서도지속되었다. CBT와 zolpidem의조합군이 CBT 단독치료군보다우월한효과를보이지는않았다. Zolpidem 치료군은 CBT 치료군보다효과가미치지는못하였으나, SOL 및 SE의향상을보여주었다. 하지만 6주치료기간이끝난이후에는이전상태로돌아가는경향을보였다. 6 CBT는장기적효과뿐아니라단기효과에서도약물치료에비해우수하다는연구가있다. 만성불면증환자 46명을대상으로 6주간매주 50분간의 CBT 를시행한군, 매일 zopiclone 7.5 mg 복용한군, PT군을수면다원검사를통해 WASO, TST, SE, 서파수면의양등을비교한연구에서 6주및 6개월후추적검사를비교하였을때, zopiclon 복용한군은 PT군에비해차이가없었으며, CBT군에서는 6주치료후 SE가 88.9%, 6개월째 90.1% 로서치료전 81.4% 에비해향상된반면, zolpiclon 군은 82.3% ( 치료전 ) 에서 81.5%(6 주후 ), 81.9%(6 개월후 ) 로약물을복용중임에도 SE가떨어졌다. 10 CBT군에서서파수면이많이나타났으며 WASO가감소하였다. Zolpidem 과비교한연구에서도 3, 4, 8주추적관찰에서 CBT가약물에비해우수내지는동등한효과를보였다. 6 정신생리불면증환자들에서 도약물치료와 CBT는단기효과면에있어서대등할것이며, 장기효과에대해선 CBT가훨씬우월할것이라고생각되었다. 20 수면제장기복용에대한위험도-효과비교위에서언급한바와같이 NBzDs 수면제로서 eszopiclone, zaleplon, zolpidem 에대해비교적안전하다는연구들이있지만 일반적으로최면진정효과가있는수면제는진정효과, 인지기능저하, 정신활동장애등의위험성이있다. 22,23 또한이런약물들은의존성및약물중단에따른반동성불면증에대한위험성이나타날수있다. 19,24 반면에 CBT 부작용은초기에수면제한 (sleep restriction) 요법이적용되는시기에주간졸음외에는특이한부작용이없다. BzDs 약물들이일반인에게서는 13% 미만으로처방이되는반면노인에게서는 50% 가량이처방된다. 25 NBzDs 인 zaleplon의경우, 노인들에게서단기및장기복용에대한연구에서두통, 감염, 요통, 어지럼증에대한경미한부작용을보이며비교적안전하고불면증에효과적인연구 26,27 가있지만 BzDs 계열의약물들은위에서언급한의존성, 내성, 금단증상및반동성불면증외에, 주간진정효과, 혼돈, 인지기능저하, 운동실조, 구음장애, 어지럼증, 낙상및골절에대한위험성을가지고있다. 특히대퇴골골절은노인에게있어서심각한삶의질의저하 28 및건강상의문제를야기시키며조기사망률을높인다. 29 BzDs 약물은지속시간, 약물의용량, 복용기간에관계없이대퇴부골절의빈도를높였다. 물론용량이많을수록위험성은높았고 (adjusted odds ratio, AOR=1.8), 복용첫한달이내 (AOR=5.6) 및반감기가짧은경우 (AOR=1.8) 에서위험성이더높았다. 30 NBzDs인 zolpidem은짧은반감기 (~2시간), 효과및안전성을고려하였을때널리사용되는수면제이지만임상적연구를통해노인들에게서안전성을입증할만한증거는없었다. 한연구에서는 zolpidem 복용노인에게서대퇴부골절의위험성이대조군보다 2배가량높음을보여주었다. 31 미국 FDA에서는벤조다이아제핀수용체작용제인수면제들은 sleepwalking, eating, driving, sexual behavior 등수면과관련된행동장애가있음을경고하고있다. 수면제약물연구의문제점현재대부분수면질환과관련된약물, 특히수면제관련된연구들은제약회사의후원으로이루어지고있다. 32 한예로 56개의 RCT 중에서제약회사후원으로이루어지지않은것은단 5개에불과하였다. 17 이들제약회사후원으로이루어진연구들에서제시한교차비 (odds ratio) 는그렇지않 28

5 Yang KI et al. Table 3. General comment about sedative/hypnotics for insomnia Begin with a correct diagnosis of the underlying causes of sleep disturbance Choose a drug with the proper pharmacokinetic profile Use the lowest effective dose, and monitoring side effects Aim for short-term, intermittent use Consider long-term intermittent or continuous use for recurrent insomnia with substantial morbidity Administration on an empty stomach is advised to maximize effectiveness Not recommended during pregnancy or nursing Caution is advised if signs and symptoms of depression, compromised respiratory function (ex, sleep apnea, asthma, COPD), or hepatic, heart failure are present Caution and downward dosage adjustment is advised in the elderly Safety and effectiveness in patient <18 years not established Additive effect on psychomotor performance with concomitant CNS depressants and/or alcohol use Rapid dose decrease or abrupt discontinuance of BzDs can produce withdrawal symptoms including rebound insomnia COPD: chronic obstructive pulmonary disease, BzDs: benzodiazepines 은연구에비해 3.6배높은데, 이는후원회사의영향으로연구디자인및데이터분석에있어서 bias가개입되었을가능성이있음을나타낸다고할수있다. 또한연구결과가불만족스러운경우라면마케팅차원에서출판되지않는경우가있을수있다. 33 이런연구들은대부분이 PCT들로서약물의효과적측면을보여주지만다른불면증치료 (CBT, 비수면제약물-항우울제, 항히스타민제 ) 에비해우월하다는것은보여주지않았다. 또한약물복용없이불면증이호전되는경향을보여주었는데이런경우는자발적호전, 호전에대한암시 (suggestion) 내지희망, 규칙적인수면생활및위생등불면증을호전시킬수있는요소들이반영되었을가능성이있다. 매우미약한효과에대해서통계적의미를부여함으로써효과를과장하는경향이있으며, 수면다원검사와같은객관적검사를통한 TST, WASO, SE 호전을보여주는연구는없었다. 이렇듯제약회사후원에의한연구들에있어서는다양한편견및한계점이있을수있기때문에, 향후이해관계에서독립적일수있는기관이주관이되는연구, 비약물적치료인 CBT 및비수면제약물로서멜라토닌, 항우울제등과의비교, 객관적검사를통한연구가필요하리라사료된다. 불면증환자들이갖는다양한신체화증상의호전및만족도에대한연구는이루어지지않고있다. 수면제복용이위험도-효과에대한메타분석에서적어도노인에게서는득보다는실이더많음을보여주었다. 34 새로개발된 NBzDs 수면제의부작용은중추신경계와관련된혼돈, 인지기능저하, 운동실조, 어지럼증및낙상등이며, 그외에는소화기, 호흡기계에대한것에국한된경향을보임으로서부작용에관련된내용들이다소경미한사항들이라할수있겠다. 향후수천명단위의대단위대상을통한주간수행능력을포함한삶의질, 감염, 암발생, 사망률등이포함된주요부작용, 효과와안전성에대한비교연구가이루어질필요성이있겠다. 수면제복용시고려해야할사항일반적으로최면진정효과가있는수면제를복용할경우에는우선불면증의정확한진단및원인에대한치료가우선적으로이루어져야한다. 불면증의원인이될수있는수면장애를감별해야하며약물남용의가능성을고려해서단기및간헐적으로사용할필요가있다. 약물은적응증및약동학적특성을고려해서선택한다. 복용할때는효과를극대화하기위해공복시복용하며임신및수유기에는피하도록한다. 특히천식및만성폐쇄성폐질환같은호흡기질환, 수면무호흡, 심부전환자에서는상당한주의가필요하다. 노인에게는감량및용량조절이필요하며주의가요한다. 18세미만의안전성과효과에대해서는입증된바가없다. 알코올및중추신경계억제제와같이사용하는경우에는정신행동수행에있어서부가적효과를고려해야한다. 수면제복용, 특히 BzDs 계열을갑작스럽게중단할경우에는금단증상및반동성불면증이발생할수있다 (Table 3). 1,2 이상적인수면제는빨리흡수되며빠른수면유도, 정상적수면패턴을유지할수있고적절한작용시간을가져효과적인수면유지가이루질수있도록작용시간이길어야하지만정상적일상생활을하는각성기간에는의미있는혈중농도에도달하지않을정도의작용시간이어야한다. 고로주간에영향을미치지말아야하며호흡감소, 에탄올과상호작용, 내성및의존성, 반동성불면증의원인이되지않 29

6 Efficacy and Safety of Hypnotics 는약물이라할수있겠다. 2 결 론 일반적으로장기수면제복용은인지기능저하, 주간졸음, 어지럼증, 약물의존성, 금단증상의문제를야기시킬수있 으며, 특히노인에게서낙상및그로인한골절의위험성을 증가시킨다. 특히수면제는천식, 만성폐쇄성호흡장애및 코골이등수면호흡장애를악화시키기때문에주의가필요 하며약물의존성이높은환자, 여러약물을복용하여약물 상호작용이문제가될수있는노인들에게있어주의가요 하는데에도불구하고쉽게처방및복용되는측면이있다. 새로개발되는벤조다이아제핀수용체에작용하는수면 제들은유효성과안전성측면에서이전의수면제에비해효 과및안전성에서우수하다고할수있지만, 장기복용에관 한안전성에대해서는여전히고려해야할문제점이있다. 임상적연구에서도본론에서언급하였다시피후원회사의 이해관계로부터독립적일수있는기관에서수면다원검사 와같은객관적검사를통하여각불면증치료법 ( 수면제이 외의 CBT, 비수면제약물등 ) 에따른삶의질및사망률의 차이에관한연구, 각치료법에따른치료의유효성과안전 성에관한비교연구가필요하리라사료된다. 또한국내에서 CBT 를담당할수있는전문적인력양성및환자들에게쉽 게접근할수있는사회적제도및여건이갖추어져야할 필요성이있다고하겠다. 더불어불면증을단순한증상으로 서가볍게여기는풍조에대한사회적재인식이필요하며, 가장흔한치료법인수면제복용에있어서그남용의문제 를인식할필요가있다. 현재국내수면제복용, 특히장기 복용시발생하는국민의건강및사회적비용등에대한연 구, 특히수면제장기복용의사회적이슈에보다많은관심 이필요하리라사료된다. REFERENCES 1. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4: Mendelson WB, Roth T, Cassella J, et al. 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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R