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1 대한내과학회지 : 제 80 권제 5 호 2011 특집 (Special Review) - 흔한하부장관의기능성질환 과민성장증후군의치료 아주대학교의과대학소화기내과학교실 이광재 Treatment of Irritable Bowel Syndrome Kwang Jae Lee Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea Irritable bowel syndrome (IBS) is a common gastrointestinal condition and its pathophysiology remains to be unestablished. Traditional symptom-based therapies of IBS are directed at the relief of individual IBS symptoms. Combinations of drugs to target bothersome symptoms are suggested as the first-line pharmacologic treatment. Exclusion diets have modest efficacy in improving symptoms in some IBS patients. Dietary fiber, bulking agents, laxatives, antispasmodics and laxatives can be used for the improvement of some individual symptoms including constipation, abdominal pain and diarrhea. 5HT 3 receptor antagonists and 5HT4 receptor agonists are effective in relief of global IBS symptoms and individual symptoms such as abdominal pain and abnormal bowel habits. A short term course of nonabsorbable antibiotics may be beneficial, particularly in patients with diarrhea-predominant IBS. Some probiotics, tricyclic antidepressants and selective serotonin reuptake inhibitors may have some benefits in relieving global IBS symptoms. The treatment strategies adequate for Korean patients with IBS are required. (Korean J Med 2011;80: ) Keywords: Irritable bowel syndrome; Treatment 서론과민성장증후군 (irritable bowel syndrome, IBS) 은복통혹은복부불쾌감, 배변후증상의완화, 배변빈도혹은대변형태의변화등의특징적인증상들이만성적으로반복되는기능성위장관질환이다. 유병률이인구의 7-10% [1-3] 로흔하며반복되는증상들로삶의질이크게떨어지므로적절한치료를통해증상을호전시키고삶의질을개선시키는것이매우중요하다. 과민성장증후군의병태생리기전으로장관의운동이상, 내장감각의과민성, 중추신경계의조절이상, 장관감염및염증, 정신사회적요인등이제시되고있으나 [4], 근본적인원인은아직잘모르는상태여서지금까지치 료들은주로증상을개선시키는데초점을맞추고있다. 그러나최근들어장관의운동, 감각, 분비기능등과관련된기전들과매개체들이밝혀지면서다양한신경전달물질및그수용체를표적으로하는치료제들이개발되고있다. 본종설에서는과민성장증후군의치료에대해서문헌근거들을중심으로정리해보고자한다. 본론식이과민성장증후군환자들은특정음식에의해장증상이발생하거나악화될수있다. 이런경우에는장증상이유발

2 - The Korean Journal of Medicine: Vol. 80, No. 5, 될수있는음식을제한하는것이과민성장증후군의증상을줄여줄수있다는보고들이많이있다. 관련된기전의하나로음식알레르기가연관되어있을가능성이제시되고있으나 [5] 아직까지특정음식을제한하는것이어떤기전을통하여효과를나타내는지는명확하지않다 [6,7]. 식이섬유나부피형성하제식이섬유나부피형성하제는대변부피를증가시키고대장운동항진, 대장통과시간단축, 대변양의증가, 대변경도완화의효과가있다. 따라서과민성장증후군의변비증상들에사용될수있다. 밀기울 (wheat bran) 또는차전자피 (psyllium) 를투여한후증상의변화를관찰한연구들이보고되어있으며, 이연구들을대상으로한메타분석결과를보면밀기울은유의한효과를보이지않았지만 [8], 차전자피는전반적인장증상의호전을보였다 [9-12]. 또한수용성섬유인차전자피와불용성섬유인밀기울을비교한무작위대조군연구결과에서도차전자피는복통및복부불편감을유의하게개선시키는효과를보였지만밀기울은유의한증상개선효과가없었다 [13]. 부피형성하제는장내세균에의한대사로장내가스를만들어서복통이나복부팽만을유발할수있으므로이에대한주의를요한다. 삼투성하제과민성장증후군환자를대상으로삼투성하제의치료효과를확인한연구는매우적다. 대부분의무작위대조군연구는만성변비환자를대상으로시행되었다. Polyethylene glycol (PEG) 은장에서흡수되지않으므로대장내의삼투압을증가시켜서체내로의물의흡수를방해하여변이부드러워지고대변양도증가하게된다. 실제로변비우세형과민성장증후군환자들을대상으로 PEG 투여전후의증상을비교해보면배변횟수는유의하게증가하지만통증은호전시키지못한다 [14]. 진경제항콜린성약물이나무스카린수용체를차단하는약물, 칼슘통로차단제, 아편수용체조절제등이진경제로사용되고있다. 이러한약물들은흥분성신경전달물질인아세틸콜린의작용을차단하며위장관평활근에직접적인작용을나타내거나, 무스카린수용체등을통해위장관의운동을조절하고복통및복부불편감을개선시키는효과를나타낸다. 12개의무작위대조군연구들을대상으로한메타분석에서도진경제가과민성장증상의치료에효과적이라고보고되어있다 [8]. 그러나과민성장증후군의증상중에전반적인증상이나배변이상에대한개선효과는아직근거가부족하다. Trimebutine, cimetropium bromide, pinaverium bromide, peppermint oil, otilonium bromide, hyoscine 등이복통이나복부불편감을호전시키는효과가있지만진경제의종류에따른효과의차이는자료가아직부족하다 [15]. 진경제와관련된심각한부작용은없으나, 입마름, 어지러움증, 시력장애등이나타날수있으며변비를유발할수있어변비형이나교대형과민성장증후군환자에게투여할때는주의가필요하다. 지사제지사제인 loperamide는오피오이드수용체를통해장관의평활근에직접적으로작용하여소장운동의감소, 장내수분및이온흡수의증가, 항문괄약근압의증가등의효과를나타낸다. 과민성장증후군환자에서 loperamide의치료효과를평가한위약대조군연구들은 [16-19] 위약에비해과민성장증후군의전반적인증상의개선은없지만설사형과민성장증후군에서배변형태를호전시키고배변횟수를줄이는데도움을준다고보고하고있다. Loperamide를포함한지사제는변비를유발할수있어변비형환자에서는투여를피해야하며, 교대형과민성장증후군환자에서도투여시주의가필요하다. Loperamide는혈액뇌장벽 (blood-brain barrier) 을통과하지않기때문에 diphenoxylate나 codeine보다부작용이적다. 세로토닌 3형수용체길항제 (5HT 3 receptor antagonist) 다양한세로토닌수용체중주로 1형, 3형및 4형수용체가위장관의운동, 감각및분비기능에관여하는것으로알려져있다. 세로토닌 3형수용체길항제는장관신경총에작용하여구강- 맹장통과시간및대장통과시간의연장, 식후위대장반사의감소, 내장감각의감소등과같은작용을나타내기때문에설사형과민성장증후군환자에서효과적인치료제로간주되고있다. Alosetron 은세로토닌 3형수용체의강력한선택적인길항제로설사형과민성장증후군여성에대한치료제로승인을받은약물이다. 여러무작위위약대조군연구들에서 alosetron 은전반적인증상의개선과복통및복부불쾌감, 대변못참

3 - Kwang Jae Lee. Treatment of irritable bowel syndrome - 음의호전율이위약에비해유의하게높았으며, 배변의빈도를줄이고변의굳기를증가시키는변화를보였다 [20-28]. 8 개의위약대조군연구를메타분석한결과에서도위약에비해과민성장증상의치료에효과적이었으며, 남성환자에서도여성과같은치료효과를보였다 [29]. 부작용으로는변비가가장흔한증상으로알려져있으며, 심한변비와허혈성대장염등의부작용이일부환자에서발생할수있어서시판을철회하였다가통상적인치료에반응이없는설사형과민성장증후군여성환자에제한적으로사용하는것으로재승인을받았다. Ramosetron 은설사형과민성장증후군의치료제로개발된새로운약제로위약대조군연구에서전반적인증상개선과복통, 배변습관의호전등이위약에비해유의하게높은결과를보였다 [30]. 위약대조군 3상연구에서전반적인증상의호전율이위약에비해유의하게높았으며, 심한부작용은보고되지않았고 [31], 최근에설사형과민성장증후군남자환자를적응증으로국내에도시판되기시작하였다. 세로토닌 4형수용체작용제 (5HT 4 receptor agonist) 세로토닌 4형수용체작용제는아세틸콜린, CGRP (calcitonin gene-related peptide) 등의신경전달물질을유리해서위장관운동및분비기능을촉진하고내장의구심성감각을조절하는효과를나타낸다. 따라서만성변비나변비형과민성장증후군환자의치료에도움이된다. 세로토닌 4형수용체의선택적부분작동제 (partial agonist) 인 tegaserod는변비형이나교대형과민성장증후군환자에서전반적인증상의호전이나치료에대한만족도, 복통, 복부불쾌감, 변비와같은증상을유의하게호전을시킨다고보고되었고 [32-38], 11개의무작위대조군연구에대한메타분석에서도이런효과가입증되어있다. 그렇지만 0.1% 의환자에서심근경색, 뇌졸중, 협심증등의심혈관계부작용이보고되어, 시판을철회하였다가 55세미만의변비형과민성장증후군여성환자혹은만성변비환자에국한해서제한적으로사용이가능하게되었으나국내에서는아직시판되고있지않다. 국내에서는세로토닌 4형수용체작용제로 mosapride 가사용되고있으나과민성장증후군환자에서의효과를본자료가부족해서향후임상연구가더필요하다. 비흡수성경구용항생제비흡수성경구용항생제인 rifaximin 은과민성장증후군 환자에서증상호전에효과적이었다는연구결과들이보고되어있다 [1]. Rifaximin 400 mg을하루세번씩 10일간투약하고, 이후 10주간추적조사한결과전반적인과민성장증상의호전이추적기간전반에걸쳐유지되었다는보고가있고 [39], rifaximin 을하루 1,200 mg 투약받은환자의 69% 에서임상양상의호전을나타내었다는후향적연구결과도있다 [40]. 특히과민성장증후군의발병기전가운데하나로간주되는소장세균과다증식이있는경우에효과가있을것으로추정되고있으며, 설사형과민성장증후군환자나복부팽만감을주소로하는경우에좋은효과를보인다. 프로바이오틱스 (probiotics) 장내세균총의이상이나변화가과민성장증상을유발할수있다는이론적배경하에과민성장증후군환자들을대상으로프로바이오틱스를사용한연구들이시행되었다. Lactobacillus 균종을이용한연구들에서는일정한결과를보이지않았으나 bifidobacterium animalis균을이용한연구들에서는위약에비해전반적인장증상, 삶의질지수와복부팽만감이유의하게호전되었다 [41,42]. Bifidobacterium 균종을포함하여두종류이상의균종들을투여한경우에는대부분의연구들에서복통이나복부팽만감등과민성장증상의호전에유의한효과가있었고, Bacillus subtilis 및 Streptococcus faecium 균을투여한경우와 Enterococcus 및 Escherichia coli 세포추출물을투여한경우에도복통이나전반적인증상의호전을보였다. 향후에과민성장증후군환자에이상적인균주의조합이나농도가제시될필요가있다. 선택적염소통로활성제 (Chloride channel activator) 장상피세포의표면세포막에존재하는 C-2 염소통로는세포막의투과도및세포용적의생리적조절을담당한다. 선택적 C-2 염소통로활성제인 lubiprostone은전신순환계로의흡수가거의없이소장세포표면에국소적으로작용하여수분분비를일으킨다. 최근에발표된자료들에의하면만성변비나변비형과민성장증후군환자에서우수한효과를나타내며특히배변형태를무르게하고복통의완화에도움이되는것으로알려져있으나아직국내에는판매되고있지않다. 항우울제삼환계항우울제와세로토닌재흡수억제제와같은항우

- 대한내과학회지 : 제 80 권제 5 호통권제 609 호 2011 - 울제는과민성장증후군의증상이장기능개선제를투여해도호전되지않는경우에사용될수가있다.

4 - 대한내과학회지 : 제 80 권제 5 호통권제 609 호 울제는과민성장증후군의증상이장기능개선제를투여해도호전되지않는경우에사용될수가있다. 삼환계항우울제혹은세로토닌재흡수억제제를과민성장증후군환자에투여한연구들에서전반적인과민성장증후군증상을호전시켰고 [43], 두약제의효과는우울증동반여부에관련이없었으며, 우울증환자에게사용하는용량보다적은용량으로도장증상이호전되었다. 이론적으로삼환계항우울제는항콜린효과가있어서장운동이증가되어있는설사우세형과민성장증후군에더좋은효과가있을것으로추정되고, 세로토닌재흡수억제제는장운동촉진효과가있기때문에설사우세형과민성장증후군보다변비우세형과민성장증후군에더효과가있을것으로추정되지만삼환계항우울제및세로토닌재흡수억제제모두과민성장증후군의전반적인증상호전이주된효과라서실제로는세가지아형모두에비슷한정도로효과가있다 [44]. 결론과민성장증후군은장관의운동, 감각과, 중추신경계, 정신사회요인, 염증, 소장세균과증식등의여러가지요인들이병태생리에영향을줄수있으므로개개인에따라관련된요인들이다를수가있고, 다양한증상들을호소하게된다. 이와같이과민성장증후군은여러가지병태생리가관여되어다양한증상을보이는이질적인질환군이므로각각의호소하는증상에대한약제를선택해서조합하는치료가일반적이다 (Fig. 1). 전반적인장증상을호전시킬수있는단일치료법이아직뚜렷하게확립되어있지않으므로환자가어떠한증상들을호소하는지를알아보고어떤기전들이증 정신과적치료 정신과적인치료는약물요법과비슷한정도로과민성장증후군환자의증상혹은삶의질을향상시킬수가있다 [43]. 그렇지만정신과적치료에대한연구들은약물과달리연구간통합비교가어렵고, 이중눈가림이어렵기때문에연구결과를직접임상에적용하기에는주의를요한다. 정신과적치료중에서인지- 행동치료와역동정신치료및병합적정신과적치료, 최면요법은일부과민성장증후군환자에서약물과비슷한치료효과를나타낼수있을것으로보이지만향후더많은임상경험과연구들이필요하다. Figure 1. IBS therapies directed at predominant symptoms. Table 1. Antispasmodic agents or 5-HT 3 receptor antagonists for the treatment of IBS Treatment Key findings Otilonium bromide vs. placebo Improved pain and bloating Otilonium bromide vs. placebo Reduced pain episodes, distension, improved well- being, global symptoms Otilonium bromide vs. placebo Higher response to treatment within 2-4 months Trimebutine vs. placebo Improved abdominal pain/distension/flatulence/constipation Cimetropium bromide vs. placebo Reduced abdominal pain and anxiety, improved global symptoms Cimetropium bromide vs. placebo Reduced abdominal pain and pain episodes, improved global symptoms Pinaverium bromide vs. placebo Improved pain duration, stool frequency and consistency Alosetron vs. placebo Greater relief of pain/discomfort, decreased urgency and stool frequency, and improved stool consistency, improved global IBS symptoms Ramosetron vs. placebo Improved global IBS symptoms, Greater relief of abdominal pain/discomfort, Improved abnormal bowel habit

5 - 이광재. 과민성장증후군의치료 - 상유발에작용하는지를추정해서이에대한치료제를선택해서사용하는것이바람직하다. 따라서과민성장증후군의치료는하제, 진경제 (Table 1), 지사제, 세로토닌 3형수용체길항제 (Table 1), 세로토닌 4형수용체작용제, 비흡수성경구용항생제, 프로바이오틱스, 선택적 C-2 염소통로활성제, 삼환계항우울제와세로토닌재흡수억제제, 정신과적치료중적합한것을선택해서치료하는것이효과적이다. 중심단어 : 과민성장증후군 ; 치료 REFERENCES 1. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidencebased position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009;104(Suppl 1):S1-S Lee SY, Lee KJ, Kim SJ, Cho SW. Prevalence and risk factors for overlaps between gastroesophageal reflux disease, dyspepsia, and irritable bowel syndrome: a population-based study. Digestion 2009;79: Park DW, Lee OY, Shim SG, et al. The differences in prevalence and Sociodemographic Characteristics of Irritable Bowel syndrome according to Rome II and Rome III. J Neurogastroenterol Motil 2010;16: Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B, Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther 2004;20(Suppl 2): S1-S9. 5. Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004;53: Drisko J, Bischoff B, Hall M, McCallum R. Treating irritable bowel syndrome with a food elimination diet followed by food challenge and probiotics. J Am Coll Nutr 2006;25: Costabile A, Klinder A, Fava F, et al. Whole-grain wheat breakfast cereal has a prebiotic effect on the human gut microbiota: a double-blind, placebo-controlled, crossover study. Br J Nutr 2008;99: Ford AC, Talley NJ, Spiegel BM, et al. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ 2008;337: a2313, doi: /bmj.a Ritchie JA, Truelove SC. Treatment of irritable bowel syndrome with lorazepam, hyoscine butylbromide, and ispaghula husk. Br Med J 1979;1: Arthurs Y, Fielding JF. Double blind trial of ispaghula/poloxamer in the irritable bowel syndrome. Ir Med J 1983;76: Nigam P, Kapoor KK, Rastog CK, Kumar A, Gupta AK. Different therapeutic regimens in irritable bowel syndrome. J Assoc Physicians India 1984;32: Jalihal A, Kurian G. Ispaghula therapy in irritable bowel syndrome: improvement in overall well-being is related to reduction in bowel dissatisfaction. J Gastroenterol Hepatol 1990; 5: Bijkerk CJ, de Wit NJ, Muris JW, Whorwell PJ, Knottnerus JA, Hoes AW. Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ 2009;339:b3154, doi: /bmj.b Khoshoo V, Armstead C, Landry L. Effect of a laxative with and without tegaserod in adolescents with constipation predominant irritable bowel syndrome. Aliment Pharmacol Ther 2006;23: Tack J, Fried M, Houghton LA, Spicak J, Fisher G. Systematic review: the efficacy of treatments for irritable bowel syndrome: a European perspective. Aliment Pharmacol Ther 2006;24: Lavö B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome: a double-blind placebo controlled study. Scand J Gastroenterol Suppl 1987;130: Hovdenak N. Loperamide treatment of the irritable bowel syndrome. Scand J Gastroenterol Suppl 1987;130: Efskind PS, Bernklev T, Vatn MH. A double-blind placebocontrolled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol 1996;31: Cann PA, Read NW, Holdsworth CD, Barends D. Role of loperamide and placebo in management of irritable bowel syndrome (IBS). Dig Dis Sci 1984;29: Bardhan KD, Bodemar G, Geldof H, et al. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2000;14: Camilleri M, Chey WY, Mayer EA, et al. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001;161: Chey WD, Chey WY, Heath AT, et al. Long-term safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2004;99: Lembo AJ, Olden KW, Ameen VZ, Gordon SL, Heath AT, Carter EG. Effect of alosetron on bowel urgency and global symptoms in women with severe, diarrhea-predominant irritable bowel syndrome: analysis of two controlled trials. Clin Gastroenterol Hepatol 2004;2: Camilleri M, Mayer EA, Drossman DA, et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT 3 receptor antagonist. Aliment Pharmacol Ther 1999;13: Chang L, Ameen VZ, Dukes GE, McSorley DJ, Carter EG, Mayer EA. A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS. Am J

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untitled Korean J Gastroenterol Vol. 57 No. 2, 82-99 DOI: 10.4166/kjg.2011.57.2.82 SPECIAL REVIEW 과민성장증후군치료에관한임상진료지침 권중구, 박경식 1, 박정호 2, 박재명 3, 박철희 4, 이광재 5, 박효진 6, 이종철 2, 대한소화기기능성질환ㆍ운동학회 대구가톨릭대학교의과대학내과학교실, 계명대학교의과대학내과학교실