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1 대한내과학회지 : 제 89 권제 3 호 특집 (Special Review) - 당뇨병성만성합병증의최신지견 당뇨병성말초신경병증치료 세종병원내과 강명신 김종화 Management of Diabetic Peripheral Neuropathy Myung Shin Kang and Chong Hwa Kim Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. The prevalence of neuropathic pain is estimated to occur in about 30-50% of all diabetic patients. Clinical symptoms vary depending on the nerves affected, and may include both positive and negative symptoms. Many patients with DPN experience pain or discomfort, anxiety, depression, and limitations in activity, which can significantly impact their physical, emotional, and social well-being. Early diagnosis is essential for the successful management of DPN. Routine management consists of glucose and risk factor control, and symptomatic relief, along with therapies designed to target the underlying disease pathology. Pharmacological treatment of DPN includes tricyclic compounds, serotonin noradrenalin reuptake inhibitors, the antioxidant α-lipoic acid, anticonvulsants, opiates, membrane stabilizers, topical capsaicin, and other drugs. Management of DPN must be tailored to each individual, and depends on a variety of factors, including disease severity and response to treatment. (Korean J Med 2015;89: ) Keywords: Diabetes; Diabetic neuropathy; Treatment 서론당뇨병성신경병증은미세혈관합병증중가장흔한만성합병증으로, 통증이있는증상 (positive symptoms) 은 아프다, 감각이이상하다, 화끈거린다, 시리다, 전기가오는것같다, 칼로자르는듯하다, 쥐어짜는듯하다 고호소하며, 통증이없는증상 (negative symptoms) 으로는저린감, 무감각, 쥐가나며 [1], 우리나라의유병률은여러연구에서 30-50% 를보고하고있다 [2,3]. 다양한임상양상으로나타나며, 삶의질저하와함께질병의이환율, 사망률증가와같은중대한임상 적의미를지닌다 [4,5]. 신경병증중가장흔한형태는만성감각운동성원위부대칭성다발성신경병증과자율신경병증이다 [1]. 원위부대칭성다발성신경병증은다른원인을배제한후진단될수있고 (diagnosis of exclusion), 진단은환자의증상과추가적인검사인침통각 (pin prick test), 진동지각 (vibration perception, 128-Hz 소리굽쇠 [turning fork] 이용 ), 양쪽엄지발가락의원위부발바닥쪽과중족골관절에 10-g 단섬유압각 (10 g monofilament test), 그리고발목반사검사 (ankle reflex) 를이용하여진단할수있고, 비전형적인경우를제외하고는전기생리학적검사는시행 Correspondence to Chong Hwa Kim, M.D., Ph.D. Department of Internal Medicine, Sejong General Hospital, 28 Hohyeon-ro 489beon-gil, Sosa-gu, Bucheon 14754, Korea Tel: , Fax: , drangelkr@hanmail.net Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

- The Korean Journal of Medicine: Vol. 89, No. 3, 2015 - 하지않는다 [6,7]. 당뇨병성말초신경병증의조기진단과치료는중요하며, 현재까지치료는혈당조절이외에근본적인신경손상에대한특별한치료는현재가능하지않으며, 혈당조절을통해신경손상의진행은늦출수있지만되돌릴수는없다 [8].

통증성신경병증을포함한당뇨병성말초신경병증의치료는실제임상의사에게중요하며매우어려운문제중에하나임에틀림없다. 이와관련한다양한임상과들의협진이필요하며, 환자에대한교육또한무척중요하다. 당뇨병성말초신경병증의치료의주요목적은신경의퇴축을막고재생을도와삶의질을높이고심각한합병증을예방하여의료비의부담을감소시키는것에있다 [8-10].

혈당조절및위험인자조절혈당조절은당뇨병성신경병증의 1차적예방효과뿐만아니라증세를완화시키고진행을막을수있다. 고혈당뿐만아니라혈당변동 (glucose fluctuation) 도증상악화에영향을주는것으로알려져있다 [14].

2 - The Korean Journal of Medicine: Vol. 89, No. 3, 하지않는다 [6,7]. 당뇨병성말초신경병증의조기진단과치료는중요하며, 현재까지치료는혈당조절이외에근본적인신경손상에대한특별한치료는현재가능하지않으며, 혈당조절을통해신경손상의진행은늦출수있지만되돌릴수는없다 [8]. 하지만몇가지형태의원위부대칭성다발성신경병증과자율신경병증에대해효과적인증상치료를할수있다 [9,10]. 본고에서는당뇨병성말초신경병증에대한치료를알아보겠다. 본론당뇨병성말초신경병증은환자에따라무증상에서부터일상생활에지장을초래할만큼의극심한통증을호소하거나족부궤양을초래하는경우까지다양하다 [11-13]. 통증성신경병증을포함한당뇨병성말초신경병증의치료는실제임상의사에게중요하며매우어려운문제중에하나임에틀림없다. 이와관련한다양한임상과들의협진이필요하며, 환자에대한교육또한무척중요하다. 당뇨병성말초신경병증의치료의주요목적은신경의퇴축을막고재생을도와삶의질을높이고심각한합병증을예방하여의료비의부담을감소시키는것에있다 [8-10]. 이런당뇨병성말초신경병증치료에는크게 3가지로나눌수있다 (Fig. 1). 첫째, 당뇨병성신경병증의근본적원인에해당하는혈당조절및위험인자를관리하는치료 ; 둘째, 당뇨병성신경병증의발병에대한병인론적연구에기초를둔치료 ; 셋째, 당뇨병성말초신경병증으로인한통증과관련하여증상에대한치료등으로나눌수있다. 혈당조절및위험인자조절혈당조절은당뇨병성신경병증의 1차적예방효과뿐만아니라증세를완화시키고진행을막을수있다. 고혈당뿐만아니라혈당변동 (glucose fluctuation) 도증상악화에영향을주는것으로알려져있다 [14]. 유럽에서진행된대규모역학연구 (EURODIAB IDDM Complications Study) 에따르면 [14] 당뇨병성신경병증의발생기전에흡연, 심혈관질환의과거력, 고혈압그리고고지혈증등과같은혈관성위험인자가주요하게관여하고있음을제시하고있다. 당뇨병성말초신경병증의치료에서무엇보다신경병증의근본원인인혈당을적극적으로조절하는것이중요하다. 전향적혹은후향적연구들에서고혈당과당뇨병성말초신경병증의중증도는서로밀접한상관관계가있으며적극적인혈당조절이치료에중요한요소가된다는사실을보여주고있다 [15,16]. 다만, 적극적인혈당조절에대한효과는제1형당뇨병환자에서는뚜렷하여제1형당뇨병환자들대상으로한 Diabetes Control and Complications Trial 연구에서적극적인혈당조절은당뇨병성신경병증의이환율을 50% 까지감소시킨바있다 [15]. 제2형당뇨병환자를대상으로한몇몇연구에서도혈당조절이당뇨병성신경병증과자율신경을예방하는데도움이되는것으로보고하고있다 [17,18]. 최근제2형당뇨병에서만성합병증예방과사망률감소를위해환자개개인이갖고있는특성에따라혈당조절목표를개별화하여관리할것을권고하고있다 [19]. 당뇨병성말초신경병증의예방과치료에있어혈당조절의목표치는정립된바없으나당뇨병치료목표와크게다르지않다. 병인론적치료 Figure 1. Optimal treatment regimens for diabetic peripheral neuropathy. α-lipoic acid, thioctic acid; γ-linoleic acid, evoprim; TCA, tricyclic antidepressants; α 2-δ ligands, gabapentin, pregablain; SNRI, serotonin norepinephrine reuptake inhibitors. SNRI: Duloxetine; Opioids: Tramadol, oxycodone. 당뇨병성신경병증의병인론적기전에기인한치료를통해당뇨병성신경병증의잠정적인이상을교정하기위한여러약제들이개발되어왔고 [20-23] 국내에서는알파지방산, 감마리놀렌산등을고려할수있다 (Table 1). 알파지방산은항산화제로서자유기에의한산화스트레스를감소시켜신경조직에대한보호효과를나타낸다. 정맥주사시통증, 이상감각, 무감각의호전이보고된바있으며오심, 구토, 설사가발생할수있다 [20-22]. 경구용치옥타시드 (thioctic acid) 는 200 mg 3회 / 일또는 600 mg ( 서방정 ) 1회 / 일식전에씹지말고물과복용한다. 정맥주사제는 600 mg을식염수 100 ml에섞어 12 분이상에걸쳐투여한다. 감마리놀렌산 (r-linolenic acid) 은필수지방산으로서신경막인지질의중요한구성요소이며신경혈류유지에관여하는프로스타그란딘 E 생성에중요한기질

3 - Myung Shin Kang et al. Management of DPN - Table 1. Pharmacological agents for diabetic peripheral neuropathy Approach Compounds Dose per day NNT Pathogenetically oriented treatment α-lipoic acid, (thioctic acid) 600 mg i.v. infusion ,800 mg orally γ-linoleic acid, evoprim mg orally 4-5 First-line symptomatic treatments TCAs Amitriptyline (10-) mg 2.1 Desipramine (10-) mg Imipramine (10-) mg Clomipramine (10-) mg 2.1 Nortriptyline (10-) mg 1.2 Selective serotonin norepinephrine reuptake inhibitors Duloxetine (30-) mg Venlafaxine mg α 2-δ ligands Pregabalin (50-) mg Gabapentin (300-)1,800-3,600 mg Second-line symptomatic treatments Local treatment Capsaicin (0.025%) cream q.i.d. topically Weak opioids Tramado mg Strong opioids Oxycodone mg 2.6 NNT, number needed to treat; TCA, tricyclic antidepressants. 로작용한다 [23]. 감각이상과무감각증의호전이보고된바있고오심, 구토, 설사가발생할수있다 [23]. 경구로 mg 을하루 2회복용한다. 대증적증상치료통증성당뇨병성신경병증은전체당뇨병환자의 10-20% 에서관찰되고, 당뇨병성신경병증환자의 40-50% 에서관찰되는것으로알려져있다 [1]. 통증성당뇨병성신경병증은손상을받은말초신경에의해기능및구조의변화가일어나며, 이런변화가중추신경에전달되어중추신경에도기능과구조적변화를일으켜통증이발생하는것으로알려져있다 [9]. 이러한신경병성통증은수면, 우울증, 불안및식욕저하와같은다양하고심각한증상을유발하여당뇨병환자에게서큰삶의질의저하를일으키기때문에조기에적극적인치료를필요로한다 [2,3]. 대증적증상치료는통증의조절이주된과제로, 약물치료와비약물치료가있다 [5,9,10]. 통증성당뇨병성신경병증은말초신경의손상과함께중추신경의반응이복합적으로작용하여자극이없어도통증이병적으로지속되는상황이며, 증상이다양하고기전이복잡하여치료에대한반응도다양하다 [4,5,8-10]. 통증성당뇨병성신경병증의치료목표는최대 한통증을완화시키고, 신체의기능을유지하도록노력하여삶의질을향상시키는데있다 [5,9,10]. 약물치료에는항우울제, 항경련제, 아편유사체, 국소도포제가있고 (Table 1) 비약물치료에는침술, 전기척수자극, 경피전극신경자극, 레이저치료, 심리치료등이시도되고있으며주로약물치료가만족스럽지못할때고려한다 [4,5,8-10]. 첫째, 항우울제는삼환계항우울제 (tricyclic antidepressants, TCA), 선택적세로토닌재흡수억제제 (selective serotonin reuptake inhibitor, SSRI), 세로토닌 / 노르아드레날린재흡수억제제 (serotonin norepinephrine reuptake inhibitor, SNRI) 등이있는데, 통증성당뇨병성신경병증의증상을조절하는데사용하며주된기전은신경세포접합부에서노르아드레날린이나세로토닌의재흡수차단이며약제에따라선택성의차이가있어효과와부작용에서차이가난다 [4,5,8-10]. TCA는통각과민및이질통, SNRI 는지속통및난자통에좋은진통효과를보이며 SSRI 는구강건조, 변비, 배뇨장애, 시각장애와같은항콜린성부작용이덜하다. TCA는 amitriptyline, imipramine, nortriptyline, desipramine 등이포함되며, 구강건조, 졸음, 시각장애, 두통, 배뇨장애, 안압항진, 심계항진, 부정맥, 실신등의부작용은 amitriptyline이가장심하고순서대로부작용이적다. 급성심근경색, 부정맥, 녹내장, 배뇨장애환자에서는금기이고고령

4 - 대한내과학회지 : 제 89 권제 3 호통권제 661 호 의환자에서도주의를요한다 [24]. 초기에저용량으로시작하여서서히증량한다. SNRI 는 duloxetine 이통증성당뇨병성신경병증치료제로 FDA 승인을받았으며오심, 졸림, 어지러움, 변비, 구강건조, 식욕감퇴, 고혈압등의부작용이있고간질환환자에서는사용을제한한다. 갑작스럽게약을중단하면금단증상이있어점진적인감량이필요하다. SSRI 는 paroxetine, citalopram 등이포함되며금기나부작용으로 TCA를사용하지못하는환자에서대체약물로사용한다. 둘째, 항경련제는 α 2-δ ligands인 gabapentin, pregabalin이통증성당뇨병성신경병증치료에사용된다 [25-27]. 이들은신경접합부위 Ca2+ 통로의 α 2-δ 부위에결합함으로써통증에관여하는신경전달물질의분비를억제하여진통효과를나타낸다. 오심, 구토, 설사가발생할수있으며신기능장애시감량이필요하다. Gabapentin은하루 1,800 mg 이상투여시에신경병증통증조절효과를보이는것으로보고되며초기기본용량 (100 mg 하루 3회 ) 으로시작하여서서히증량 (1-7일마다 mg씩 ) 한다 [25,26]. Pregabalin은용량조절이필요없으며기본용량 (75 mg 하루 2회 ) 으로도치료효과가나타난다 [27]. 효과가충분치않다면 7일간격으로 1일최대 600 mg까지증량가능하다 [28]. 셋째, 아편유사제 (opioids) 는아편유사제수용체를통해통증경감효과를나타내며이질통에특히효과를보인다. 변비, 오심, 구토, 어지럼증, 졸림, 약물의존성이발생할수있다 [29]. Tramadol을 mg/ 일사용하며평균 210 mg/ 일에서유효하다. Acetaminophen + tramadol 병용시하루 4회, 최대 8 T까지사용한다. Oxycodone CR은 mg 하루 2회복용하며평균 40 mg/ 일에서유효하다 [30]. 넷째, 국소도포제에는캡사이신이있다. 이는 capsaicin 수용체 (TRPV1) 를지속적으로자극하여신경전달물질을고갈시켜진통효과를나타낸다 [31]. 작열통과감각부전, 칼로베는듯한통증등전형적인 C섬유병증에사용한다. 일시적인국소통이발생할수있으며장기간사용시도포부위신경손상을유발할수있어주의를요한다 [32]. 결론당뇨병성신경병증은미세혈관합병증중가장흔한만성합병증으로다양한임상양상으로나타나며, 삶의질저하와함께질병의이환율, 사망률증가와같은중대한임상적의미를지닌다. 당뇨병성말초신경병증의조기진단과치료는중요하며, 현재까지치료는당뇨병성신경병증의근본적원인 에해당하는혈당조절및위험인자를관리, 당뇨병성신경병증의발병에대한병인론적치료그리고신경병증으로인한통증과관련된증상에대한치료방법등이있다. 당뇨병성말초신경병증에대한약물치료는 1차선택약제에있어동반질환, 정신적문제, 육체적문제등을고려해야한다. 일차치료에도불구하고통증조절이불량한경우에는다른기전의일차약제를병합하는것을고려할수있다. 병합요법으로도통증조절이부적절한경우에는아편유사체를추가해볼수있다. 향후약제의장기간치료에대한효과및안정성에대한연구, 병합요법에대한연구그리고통증발생의원인에입각한기존약제와다른기전의새로운약제개발등이필요할것이다. 중심단어 : 당뇨병 ; 당뇨병성말초신경병증 ; 약물치료 감사의글 당뇨병성신경병증에대한많은가르침과조언을주신대한당뇨병학회신경병증연구회회장님및회원분들께감사의글을드린다. REFERENCES 1. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study. Neurology 1993;43: Candrilli SD, Davis KL, Kan HJ, Lucero MA, Rousculp MD. Prevalence and the associated burden of illness of symptoms of diabetic peripheral neuropathy and diabetic retinopathy. J Diabetes Complications 2007;21: Kim SS, Won JC, Kwon HS, et al. Prevalence and clinical implications of painful diabetic peripheral neuropathy in type 2 diabetes: results from a nationwide hospital-based study of diabetic neuropathy in Korea. Diabetes Res Clin Pract 2014;103: Boulton AJ, Vinik AI, Arezzo JC, et al.; American Diabetes Association. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28: Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia 2000;43: Dyck PJ, Overland CJ, Low PA, et al. Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial. Muscle Nerve

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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