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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 1, 성균관대학교의과대학내과학교실 2, 가톨릭대학교의과대학내과학교실 3, 한림대학교의과대학내과학교실 4, 아주대학교의과대학소화기내과학교실 5, 연세대학교의과대학내과학교실 6 Guidelines for the Treatment of Irritable Bowel Syndrome Joong Goo Kwon, Kyung Sik Park 1, Jung Ho Park 2, Jae Myung Park 3, Cheol Hee Park 4, Kwang Jae Lee 5, Hyo-Jin Park 6, Jong Chul Rhee 2 and The Korean Society of Neurogastroenterology and Motility Department of Internal Medicine, Catholic University of Daegu School of Medicine, Keimyung University School of Medicine 1, Daegu, Sungkyunkwan University School of Medicine 2, The Catholic University of Korea College of Medicine 3, Seoul, Hallym University College of Medicine 4, Chuncheon, Department of Gastroenterology, Ajou University School of Medicine 5, Suwon, Department of Internal Medicine, Yonsei University College of Medicine 6, Seoul, Korea Traditional symptom-based therapies of irritable bowel syndrome (IBS) are directed at the relief of individual IBS symptoms, but they are often of limited efficacy in addressing the entire symptom complex. Combinations of drugs to target bothersome symptoms are suggested as the first-line pharmacologic treatment. Increasing knowledge of the pathophysiology and molecular mechanisms of IBS has resulted in the development of several new therapeutic approaches. Thirteen consensus statements for the treatment of IBS were developed using the modified Delphi approach. Exclusion diets have modest efficacy in improving symptoms in some IBS patients. Symptom-based therapies with dietary fiber, bulking agents, laxatives, antispasmodics and laxatives are effective in the improvement of some individual symptoms, e.g. dietary fiber and bulking agents for constipation, laxatives for constipation, antispasmodics for abdominal pain and discomfort, antidiarrheals for diarrhea. 5HT 3 receptor antagonists and 5HT 4 receptor agonists are effective in the relief of global IBS symptoms and individual symptoms such as abdominal pain and abnormal bowel habits. A short term course of nonabsorbable antibiotics may improve global IBS symptoms, particularly in patients with diarrhea- predominant IBS. Some probiotics appear to have the potential benefit in improving global IBS symptoms. Selective C-2 chloride channel activator is more effective than at relieving global IBS symptoms in patients with constipation-predominant IBS. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are equally effective in relieving global IBS symptoms, and have some benefits in treating abdominal pain. Certain types of psychologic therapy may be effective in improving global symptoms in some IBS patients. Further studies are strongly needed to develop better treatment strategies for Korean patients with IBS. (Korean J Gastroenterol 2011;57:82-99) Key Words: Irritable bowel syndrome; Treatment; Guideline CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 이광재, 443-721, 경기도수원시영통구원천동산5, 아주대학교병원소화기내과 Correspondence to: Kwang Jae Lee, Department of Gastroenterology, Ajou University Hospital, San 5, Wonchon-dong, Yeongtong-gu, Suwon 443-721, Korea. Tel: +82-31-219-6939, Fax: +82-31-219-5999, E-mail: kjleemd@hotmail.com Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 57 No. 2, February 2011 www.gastrokorea.org

Kwon JG, et al. Guidelines for the Treatment of Irritable Bowel Syndrome 83 개요 과민성장증후군 (irritable bowel syndrome, IBS) 은복통혹은복부불쾌감, 배변후증상의완화, 배변빈도혹은대변형태의변화등의특징적인증상들이만성적으로반복되는대표적인기능성위장관질환이다. 서구에서매우흔한질환으로전체인구의 7-10% 에서이질환의진단기준에합당한증상을가지며, 1 국내에서도지역사회주민을대상으로한연구들에서 8-9.6% 로서구와유사한유병률을보인다. 2,3 생명을위협할수있는중한질환은아니지만반복되는증상들로인해삶의질은크게떨어지며, 4,5 SF-36을사용하여삶의질을평가하였을때당뇨병과유사한낮은삶의질점수를보인다. 6 또한많은환자들이일상생활에큰어려움을겪거나의료비의지출이현저히증가하는등의문제가발생할수있어, 7 적절한치료를통해증상을호전시키고삶의질을개선시키는것이매우중요하다. 과민성장증후군의중요한병태생리기전으로장관의운동이상, 내장감각과민성, 중추신경계의조절이상, 장관감염및염증, 정신사회적요인등이제시되고있으나, 8 근본적인원인은아직잘모르고있는실정이어서전통적인약물치료는주로증상을개선시키는데초점을맞추어왔다. 그러나최근들어장관의운동, 감각, 분비기능등과관련된기전들과매개체들이좀더자세히밝혀지면서다양한신경전달물질및그수용체를표적으로하는치료제들이개발되었고또현재연구중인상태이다. 과민성장증후군의적절한진단및치료를위해미국을비롯한서구에서는체계적인문헌고찰을통해진료지침을개발하여사용해왔으며, 1,9 우리나라를포함한아시아여러나라의소화기질환전문가들이델파이접근법을통해아시아의실정에맞는과민성장증후군의임상적특징, 병태생리, 진단및치료에대한공통된의견을 2010년제시한바있다. 10 1. 목적본과민성장증후군임상진료지침은과민성장증후군환자의치료를위해사용되고있는식이요법, 진경제를포함한다양한위장관약물, 항우울제, 정신과적치료등의다양한치료방법들이전반적증상호전및개개의증상호전에미치는효과에관해현재까지보고된국내외문헌들을체계적으로고찰하고국내전문가의의견을수렴하여우리나라의료실정에맞는과민성장증후군임상진료지침을마련하고자한다. 이진료지침은진료를직접담당하는의료진에게양질의진료를제공하는데있어도움이되고, 동시에치료를받는환자에게도적절하고균형잡힌정보를제공할수있도록하는것을목적으로한다. 2. 필요성과민성장증후군은매우흔하고증상의호전과악화가반복되는만성적인질환으로삶의질을떨어뜨리고의료이용자체뿐만아니라신체적정신적기능저하를유발하여사회경제적으로손실을초래한다. 그러므로적절한과민성장증후군의치료지침개발은현재의제한적의료자원의효과적이용뿐만아니라환자의호전으로인해사회경제적이득이높다고기대된다. 3. 국내과민성장증후군진료지침현황국내에서 2005년대한소화기기능성질환ㆍ운동학회에서기능성위장질환진단및치료가이드라인이발표되었고과민성장증후군에대한치료지침이발표된바있다. 11 문헌에근거한전문가의견을중심으로일반적인치료, 평활근이완제, 정신작용제, 세로토닌수용체관련약물, 생균제, 항생제등의약물치료, 정신과적치료법을중심으로나누어기술되어실제임상진료에활용되어왔다. 또한 2010년에대한소화기기능성질환ㆍ운동학회주관으로과민성장증후군진단을위한체계적인문헌고찰을대한소화기학회지에발표하여현재사용중에있다. 12 4. 과민성장증후군임상지료지침의한계국내의과민성장증후군임상진료지침을만드는데있어가장큰문제점은국내자료가매우제한적이고, 국외의자료는우리나라와역학적특성, 임상양상등이다른북미와유럽의연구자료가대부분이라는점이다. 그러나약제자체에대한반응은국외에서진행된연구에서도인종간의차이가적어그효과를국내에적용할수있을것으로기대된다. 또한우리나라와역학분포가비슷한아시아자료등을참고하고자하였다. 이러한국내자료의제한점을극복하기위하여국내외문헌검색에근거하여진료지침초안을만들고델파이방법을이용하여임상전문가들의합의도출과정을거쳤다. 최종안을일선진료현장에서가장많이진료지침을사용하게될 1,2차진료의에게전자우편을통하여의견을구하는과정을거쳐임상진료지침을개발하였다. 이번과민성장증후군임상진료지침에다양한치료자가사용하는모든치료를다룰수없기때문에흔히사용되고보편적으로진료상황에서인정되는치료들을진료지침에포함시켰다. 또한개발은되었으나국내에도입되지않은약물이나치료기법에대해서도국외에서사용중인것들은가급적포함시키고자했다. 이는기존의과민성장증후군치료약물이장기적인증상개선효과가높지않아새로운약물이필요한상황이기때문이다. 이번진료지침의내용은현재개발을진 Vol. 57 No. 2, February 2011

84 권중구등. 과민성장증후군치료에관한임상진료지침 행하는시점에서의권고안으로향후새로운임상자료에기반하여지속적으로 2년마다개정을시행할예정이다. 5. 과민성장증후군진료지침의제작진과제작과정진료지침제작진은세군으로구성되었다. 대한소화기기능성질환ㆍ운동학회에진료지침위원회를구성하여위원장이광재 ( 아주대학교의과대학 ) 와간사정혜경 ( 이화여대의학전문대학원 ) 및위원 7명으로구성하여 2010년 1월에 1차모임을통해진료지침개발의원칙, 개발일정및진료지침의범위를결정하였다. 또한진료지침의대상이되는위식도역류질환, 기능성소화불량증, 과민성장증후군및변비의 4대질환에대한운용팀 (working team) 을구성하였다. 과민성장증후군운용팀의책임자는이광재 ( 아주대학교의과대학, 이하호칭생략 ) 로하였고, 이종철 ( 성균관대학교의과대학 ), 박효진 ( 연세대학교의과대학 ), 권중구 ( 대구가톨릭대학교의과대학 ), 박경식 ( 계명대학교의과대학 ), 박정호 ( 성균관대학교의과대학 ), 박재명 ( 가톨릭대학교의과대학 ), 박철희 ( 한림대학교의과대학 ) 를위원으로구성하였다. 2010년 2월에 4대질환의운용팀과학회임원진이참석한임상진료지침개발의구제적방법론에관한워크숍을실시하였다. 2010년 4월대한소화기기능성질환ㆍ운동학회춘계학술대회에서외부임상진료지침전문가인안형식교수 ( 고려대학교의과대학 ) 를초빙해서진료지침개발에관한강의를들은후진료지침개발의세부사항에대한질의응답시간을가졌다. 4대질환운용팀에서핵심질문을선정하고문헌검색에근거하여일차진료지침핵심문구를작성하였고, 델파이방법에근거하여전문가집단을대상으로일차전자우편투표를실시하였다. 전문가집단은대한소화기기능성질환ㆍ운동학회의전, 현직임원과위원들을포함하였고지역적안배를고려하여 64명의합의도출전문가군을구성하였다. 각문구에대해 5 리커트척도의질문중전적으로동의함, 대체적으로동의함, 일부동의함을찬성으로판단하여 50% 이상의찬성을받은경우적절한진료지침문구로선정하였다. 50% 미만의경우운용팀에서적절히문구를수정하여 2차안을작성하였다. 2010년 7월임상진료지침워크숍에서외부임상진료지침전문가에게근거의평가에관한강의를듣고제한된국내자료를근거로임상진료지침을만들때의제한점에관해토의하였다. 이어서합의도출전문가군에게각진료지침문구에대한전자우편투표결과를보여주고토의를한후에 2차투표를실시하였다. 키패드방식을이용하여결과를투표와동시에알수있도록하고전문가군의질의와토의를통해합의안을도출한후에운용팀에서최종초안을작성하였다. 1, 2차의료기관에근무하는소화기세부전문의 500인에게전자우편으로권장문들을보여주고동의여부에대한설문조사를실시하였으며, 이렇게만들어진권 장문들을 361명의전문의들이참가한 2010년 11월 6일대한소화기기능성질환ㆍ운동학회연수강좌에서발표하고최종의견수렴을하였다. 또한김광하 ( 부산대학교의과대학 ), 조윤주 ( 을지대학교의과대학 ), 홍수진 ( 순천향대학교의과대학 ), 남수연 ( 국립암센터 ), 강정묵 ( 서울대학교강남건강검진센터 ), 안형식 ( 고려대학교의과대학 ) 으로검토위원회를구성하여최종권고안의보완사항등을검토하게하였다. 이번연구지침개발은외부재정지원없이이루어졌으며, 진료지침개발과정에참여한모든구성원은이해상충의문제가없었다. 6. 임상진료지침의보급및실행개발된임상진료지침은대한소화기학회지, 관련된학회의홈페이지, 페이스북 (facebook), 혹은트위터 (twitter) 등의컴퓨터프로그램을이용하여널리알리고보급할예정이다. 본론 1. 연구방법 1) 과민성장증후군의정의 1978년 Manning 등 13 에의해처음과민성장증후군의 Manning 기준이제시된이래, 1989년각국의소화기질환전문가들이모여과민성장증후군을포함한다양한기능성위장관질환에대해로마기준 I이라불리는진단기준을만들었으며, 이후 1999년, 2006년 2, 3차개정이이뤄져현재에이르고있다. 이번원고에서는 Manning 기준을비롯하여로마기준 I, II, III를바탕으로연구를시행한논문을모두포함하여문헌고찰을시행하였다. 2) 문헌검색문헌검색은 2010년 4월 27일부터 5월 15일까지실시하였다. 국외문헌검색은 1995년부터 2010년 2월사이에과민성장증후군치료에대한무작위통제연구로제한하여 Cochrane Library와 MEDLINE 검색엔진을이용하여검색하였다. 미국소화기학회진료지침, 영국 IBS 진료지침 (National Institute for Clinical Excellence, NICE), 영국소화기학회진료지침, 유럽일차진료소화기질환진료지침 (European Society of Primary Care Gastroenterology, 이하 ESPCG), 2005년개정된과민성장증후군에대한 Cochrane 고찰에있는문헌들을중복검색하였다. 국내문헌검색은 2000년 1월부터 2010년 3월까지한국의학논문데이터베이스, 국회도서관, KoreaMed, Korean studies Information System 을이용하여검색하였다. 과민성장증후군의치료에관한관찰연구 (observational study) 및무작위통제연구 (randomized controlled trial) 를대상으로하 The Korean Journal of Gastroenterology

Kwon JG, et al. Guidelines for the Treatment of Irritable Bowel Syndrome 85 였으며, 영문검색에사용한주제어는 Mesh 용어인 irritable bowel syndrome과과민성장증후군치료에사용되는다음과같은치료방법을주제어로결과내에서재검색하였다 : diet, dietary fiber, bulking agent, laxatives, antispasmodics, antidiarrheals, serotonin receptor agonist or antagonist, antibiotics, probiotics, chloride channel activators, antidepressant, psychologic therapy, combination therapy. 국내문헌검색에서사용한주제어는 과민성장증후군, 과민성장, irritable bowel syndrome, IBS 로검색되는모든문헌을고찰하였다. 이번체계적문헌고찰에포함된문헌선정기준은다음과같다 : 1) 성인을대상으로한연구일것, 2) 일차진료에서가능한치료법을이용한연구, 3) 과민성장증후군의정의가명시되어있는연구, 4) 치료효과의판정을위해적어도 1주이상추적관찰을시행했던연구, 5) 치료효과의판정을위해전반적인장증상혹은개별적인증상의호전유무가명시되어있거나증상점수를이용하여치료전후를비교한연구. 연구제외기준은다음과같다 : 1) 생체내혹은생체외실험실연구, 2) 국외연구중영어이외의언어로게재된문헌, 3) 학회초록, 4) 종설, 5) 연구종료점 (outcome) 이비용혹은비용효과분석인연구. 자료추출과 1차문헌선정은초록의제목혹은내용을보고선정하였으며, 독립된 2인의소화기내과전문의가각기시행하여 Endnote와 Excel 프로그램에정리하여중복된문헌을검색하여제거하였다. 1차검색에서검색된문헌은국내문헌 123건, 국외문헌 1,436건이었다. 이중중복검색된문헌을배제하고선택된문헌은국내 104건, 국외 1,112건이었다. 이를논문제목이나초록전문을보고제외기준에합당한국내문헌 53건, 국외문헌 464건을배제하였다. 1차에서선정된문헌 699건중두저자가문헌을선택할것인지에대해의견이일치되지않는경우에한해논문의전문을확인한후각각 2차선택을실시하였다. 2차에서선정된 334건의논문전문을모두재검토하여자료의적합성을판단한후최종적으로국내 2건, 국외 128건의논문을선정하였다 (Fig. 1). 3) 증거수준및권고등급과민성장증후군운용팀에서일차진료지침핵심문구를선정하고, 최종선정된문헌의증거수준 (levels of evidence) 과권고등급 (grades of recommendation) 을평가하기위해 2008년미국흉부학회에서발표한항혈전제의임상진료가이드라인논문에서사용한권고등급의판정기준을이용하였다 (Table 1). 14 문헌근거수준은무작위통제연구이거나상대위험도 (relative risk, RR) 가 5를초과하거나 0.2 미만으로치료효과가매우크다고판단되는관찰연구를높은근거수준, 무작위통제연구이지만결과나연구방법등에서제한점을가 진경우혹은 RR이높은근거수준의기준보다는낮지만치료효과가크다고판단되는관찰연구를중간근거수준, 중대한제한점이있는무작위통제연구이거나일반적인관찰연구는낮은근거수준으로분류하였다. 또한근거가부족하여전문가의견을반영한경우에는낮은근거수준으로분류하였다. 권고수준은좋은효과가나쁜효과보다확실히더크다고판단되거나권고대로했을때대부분효과가있는경우에는강한권고, 좋은효과가나쁜효과보다약간더클가능성이있을때나권고대로했을때일부에서만효과적인경우라고판단되면약한권고로판정하였다. 강한권고수준을보이는경우문헌근거수준에따라권고등급을 1A, 1B, 1C로분류하였으며, 약한권고수준을보이는경우에도문헌근거수준에따라권고등급을 2A, 2B, 2C로분류하였다. 전술한바와같이델파이방법에근거하여전문가집단을대상으로한일차전자우편투표를실시한후핵심문구를수정하였다. 이후전문가군을대상으로 2차합의도출을실시하였다. 핵심문구에대한권고등급은전문가의견이전적으로동의함, 대체로동의함및일부동의함이 50% 가안되는경우권고등급을변경하고자하였다. 이후 1, 2차의료기관에근무하는소화기세부전문의 500인에게전자우편을통해동의여부에대한설문조사를실시하였으며, 2010년 11월 6일대한소화기기능성질환ㆍ운동학회연수강좌에서발표하고최종의견수렴을하였다. 또한외부전문가를포함한검토위원회의자문을받고최종권고안을완성하였다. Fig. 1. Flow chart for searching strategy. Vol. 57 No. 2, February 2011

86 권중구등. 과민성장증후군치료에관한임상진료지침 Table 1. Grading Recommendations 14 Grade of recommendation / description Benefit vs. risk and burdens Methodological quality of supporting evidence Implications 1A. Strong recommendation, high-quality evidence 1B. Strong recommendation, moderate-quality evidence 1C. Strong recommendation, low-quality or very low-quality evidence Benefits clearly outweigh risk and burden, or vice versa Benefits clearly outweigh risk and burden, or vice versa Benefits clearly outweigh risk and burden, or vice versa RCTs without important limitations or overwhelming evidence from observational studies RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies Observational studies or case series Strong recommendation, can apply to most patients in most circumstances. Further evidence is unlikely to change our confidence in the estimate of effect Strong recommendation, can apply to most patients in most circumstances. Higher quality evidence may well change our confidence in the estimate of effect Strong recommendation, can apply to most patients in most circumstances. Higher quality evidence is very likely to change our confidence in the estimate of effect 2A. Weak recommendation, high-quality evidence Benefits closely balanced with risk and burden RCTs without important limitations or overwhelming evidence from observational studies Weak recommendation, best action may differ depending on circumstances or patients or societal values. Further evidence is unlikely to change our confidence in the estimate of effect 2B. Weak recommendation, moderate-quality evidence Benefits closely balanced with risk and burden RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies Weak recommendation, best action may differ depending on circumstances or patients or societal values. Higher quality evidence may well change our confidence in the estimate of effect 2C. Weak recommendation, low-quality or very low-quality evidence Uncertainty in the estimates of benefits, risks and burden; benefits, risk and burden may be closely balanced Observational studies or case series Very weak recommendations; other alternatives may be equally reasonable. High quality evidence is very likely to change our confidence in the estimate of effect RCT, randomized controlled trial. 2. 과민성장증후군의임상진료지침 1) 식이증상을악화시키는음식의제한은과민성장증후군의치료에도움을줄수있다. (Grade 2C, 권고수준 : 약함, 증거수준 : 낮음 ) 전문가의견 : 전적으로동의함 (44%), 대체로동의함 (52%), 일부동의함 (4%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 과민성장증후군환자는특정음식에의해장증상이발생한다고생각하는경우가많다. 15,16 장증상이발생할수있는음식을제한하는방법이과민성장증후군의증상을줄여준다는연구들도많이보고되고있다. 17-24 이연구들을종합하여평가한보고에의하면, 장증상유발가능성이있는음식을제한하는방법으로 12.5-67% 까지장증상을줄여줄수있다 고한다. 25 그기전중하나로음식알레르기가과민성장증후군과연관되어있을가능성도있다. 특정음식을섭취한후혈청 IgG 농도가증가한음식을제한하면과민성장증후군의증상을줄일수있다는보고 22 가그근거이다. 하지만그효과는그다지크지않으며, 아직까지특정음식을제한하는것이어떤기전을통하여효과를나타내는지명확하지않다. 26,27 한국에서는다수의의사들이식이요법이과민성장증후군의치료의한방법이라고인식하였다. 비록객관적인증거는없지만경험적으로환자들이호소하는증상과음식과의관련성을중요하게여긴결과라고생각된다. 요약하면장증상을유발하는음식을제한하는것은대부분효과가있다고보고되고있지만대부분의연구가대조군이없어위약효과일가능성을배제할수없다. 제한식이요법이과민성장증후군의증상호전에효과적인치료법이라는증거 The Korean Journal of Gastroenterology

Kwon JG, et al. Guidelines for the Treatment of Irritable Bowel Syndrome 87 수준은아직낮다. 향후잘계획된무작위연구를통하여제한식이요법이과민성장증후군치료의한축을담당할수있는지알아볼필요가있다. 2) 부피형성하제부피형성하제는과민성장증후군의일부증상의치료에도움을준다. (Grade 2B, 권고수준 : 약함, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (8%), 대체로동의함 (73%), 일부동의함 (19%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 식이섬유나부피형성하제는대장에서수분을함유할수있어장관내대변부피를증가시키고대장운동항진, 대장통과시간단축, 대변량증가, 대변경도완화의효과가있다. 그러므로대다수의의사들은과민성장증후군환자의장기능을조절하고환자의통증완화를위해섬유식이또는부피형성하제의사용을권장하지만이를뒷받침할만한연구는부족하다. 12개의무작위대조군연구들을검토하였을때 28-39 주로밀기울 (wheat bran) 또는차전자피 (psyllium) 를투여한후증상의변화를관찰한연구들이었으며, 대부분의연구가대상환자수가적고추적기간이짧으며진단시로마기준을따르지않았다는제한이있다. 9개연구는이중맹검연구, 두개는단일맹검연구였으며한연구는맹검법을적용하지않았다. 이연구들을대상으로메타분석을시행하였을때, 밀기울은비교위험도 1.02 (95% CI=0.82-1.27) 로대부분의연구에서유익하지않았고, 40 한가지연구에서만통증호전과배변횟수증가를보고하였다. 29 반면에차전자피를이용한연구들에서는 6개의연구중 4개의연구에서전반적인장증상의호전이있었고, 30,32,33,37 메타분석에서비교위험도 0.78 (95% CI= 0.63-0.96), number needed to treatment (NNT) 는 6으로위약에비해유의한증상개선효과를나타내었다. 40 또한 275 명의비교적많은환자를대상으로수용성섬유인차전자피와불용성섬유인밀기울을비교한무작위대조군연구결과가최근에보고되었는데, 차전자피는복통및복부불편감을유의하게개선시키는효과를보였으나밀기울은유의한증상개선효과가없었다. 41 부피형성하제는장내세균에의한대사로이산화탄소나수소와같은가스를형성하여복통이나복부팽만을유발할수있으며 42 특히복용량을갑자기늘렸을때발생할수있어복용량의적절한조절이필요하다. 요약하면밀기울은과민성장증후군증상의호전에도움이되지않지만차전자피는변비, 복통등과민성장증후군의일부증상의호전에도움이된다. 그러나부피형성하제를복용하면복부팽만감이나다량의가스를유발할수있다는점을고려하여야한다. 3) 삼투성하제변비형과민성장증후군환자에서삼투성하제는배변횟수를증가시키는데도움을줄수있다. (Grade 2C, 권고수준 : 약함, 증거수준 : 낮음 ) 전문가의견 : 전적으로동의함 (26%), 대체로동의함 (63%), 일부동의함 (7%), 대체로동의하지않음 (4%), 전적으로동의하지않음 (0%). 삼투성하제의치료효과에대한무작위대조군연구는대부분만성변비환자를대상으로시행되었고, 과민성장증후군환자를대상으로한연구는적다. Polyethylene glycol (PEG) 은장에서흡수되지않고그대로배출이되기때문에대장내의삼투압의증가로인해체내로의물의흡수를방해하여변이부드러워지고대변양도증가하여액상의형태로배설된다. 변비우세형과민성장증후군환자들을대상으로 PEG 투여전후의증상을비교한연구에서배변횟수는유의하게증가되었으나, 통증은호전시키지못하였다. 43 향후과민성장증후군환자를대상으로삼투성하제의치료효과에대한무작위대조군연구가필요하다. 요약하면변비형과민성장증후군환자에서삼투성하제는배변횟수를증가시킬수있다. 그렇지만통증등의증상은감소시키지못한다. 4) 진경제진경제는과민성장증후군환자에서복통및복부불편감의치료에효과적이다. (Grade 1B, 권고수준 : 강함, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (78%), 대체로동의함 (22%), 일부동의함 (0%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 위장관의대표적인흥분성신경전달물질인아세틸콜린의작용을차단하기위해사용되는비선택적인항콜린제제나특정무스카린수용체를차단하는약물, 칼슘통로차단제, 아편수용체조절제등과같은다양한진경제는과민성장증후군의치료제로가장흔하게사용되고있다. 이는위장관평활근에직접적인작용을나타내거나, 무스카린수용체등을통해위장관의운동능을조절하고복통및복부불편감을개선시키는효과를나타낸다. 1 12개의무작위대조군연구를메타분석한결과에서도위약에비해과민성장증상이지속될상대위험도 0.65 (95% CI=0.48-0.89), NNT는 5 (95% CI=4-9) 로장증상조절에효과적이라는보고가있었다. 40 그러나과민성장증후군의전반적인증상개선효과나배변양상의조절효과는일부연구에서만보고되어, 그효과가불분명하며근거가부족하다. 44 진경제의치료효과와관련된임상연구들은대부분연구의질이높지않고, 기능성위장관질환의로마기준을적용하기이전에시행되었으며연구방법에있어서제한점이많 Vol. 57 No. 2, February 2011

88 권중구등. 과민성장증후군치료에관한임상진료지침 Table 2. Studies of antispasmodic agents for treatment of IBS Author Study design and ITT population Treatment Key findings Baldi et al. 51 4-week, randomized double blind; Rome criteria not used Otilonium bromide 40 mg t.d.s. vs. Improved pain and bloating (p<0.02); frequency of bowel movements (NS) Battaglia et al. 52 15-week, randomized, double blind, parallel (378 IBS; subtype not specified); Rome I criteria Otilonium bromide 40 mg t.d.s. vs. Reduced pain episodes (p<0.01); distension (p<0.05); improved well- being (p<0.05); global symptoms (p<0.01) Glende et al. 53 15-week, randomized double blind (378 IBS; subtype not specified); Rome I criteria Otilonium bromide 40 mg t.d.s. vs. Higher response to treatment within 2-4 months (p=0.007) Luttecke et al. 45 Trials 1 and 2: 3-day, randomized double blind cross-over (45 IBS: subtype not specified); Rome criteria not used Trial 1: Trimebutine 200 mg t.d.s. vs. Trial 2: Trimebutine 100 mg t.d.s. vs. Trial 2: improved abdominal pain /distension/flatulence/ constipation (p<0.001) Centonze et al. 46 6-month, randomized double blind; (48 IBS); Rome criteria not used Cimetropium bromide 50 mg t.d.s. vs. Reduced abdominal pain (p<0.01) and anxiety (p<0.05); improved global symptoms (p<0.01) Dobrilla et al. 47 3-month, randomized, double blind, parallel (70 IBS); Rome criteria not used Cimetropium bromide 50 mg t.d.s. vs. Reduced abdominal pain (p<0.0005) and pain episodes (p<0.001); improved global symptoms (p=0.039) Awad et al. 48 3-week, randomized, double blind, parallel (40 IBS; all subtypes); Rome I criteria Pinaverium bromide 50 mg t.d.s. vs. Improved pain duration, stool frequency and consistency (p 0.01) Cappello et al. 50 4-week, randomized, double blind, (57 IBS); Rome II criteria Peppermint oil 2 capsules b.i.d. vs. Improved global IBS symptoms (p<0.01) Liu et al. 49 1-month, randomized, double blind, (110 IBS); Rome criteria not used Peppermint oil 187 mg 3 to 4 times vs. Improved abdominal pain, distension, stool frequency, borborygmi and flatulence, (p<0.05) IBS, irritable bowel syndrome. ITT, intention to treat. 다. 1 각약제별로과민성장증후군환자에대한치료효과를확인하여보면 trimebutine, 45 cimetropium bromide, 46,47 pinaverium bromide, 48 peppermint oil, 49,50 otilonium bromide, 51-53 hyoscine 30,33 등을단기간투여하였을때복통이나복부불편감을호전시키는효과가있었다 (Table 2). 진경제의종류에따른치료효과의차이에대한연구는부족하다. 44 진경제와관련된연구들이대부분소규모의연구이고안전성및내복성에대한정보가부족하여정확한평가는어렵다. 현재까지나온여러결과들을종합하여볼때이약제와관련된심각한부작용은없으나, 40 입마름, 어지러움증, 시력장애등이나타날수있으며변비를유발할수있어변비형이나교대형과민성장증후군환자에게투여할때는주의가필요하다. 요약하면진경제와관련된연구들은최근연구가많지않고연구의질이높지않은제한점을가지고있지만진경제가위약에비해유의하게복통및복부불쾌감의개선효과가높 으며, 약제와관련된심각한부작용은없고비교적안전한약물로생각된다. 5) 지사제지사제는과민성장증후군에서배변형태를호전시키고배변횟수를줄이는데도움을준다. (Grade 2B, 권고수준 : 약함, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (19%), 대체로동의함 (81%), 일부동의함 (0%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 설사형과민성장증후군환자의경우소장과근위부대장의통과시간이빨라져있어, 54 아편제제 (opioid) 와같은장관의통과를지연시키는약제의투여가증상을호전시킬가능성이있다. Loperamide는위약대조군연구결과를가지고있는유일한지사제로오피오이드수용체를통해장관의평활근에직접적으로작용하여소장운동의감소, 장내수분및이온 The Korean Journal of Gastroenterology

Kwon JG, et al. Guidelines for the Treatment of Irritable Bowel Syndrome 89 Table 3. Studies of antidiarrheals for treatment of IBS Author Study design and ITT population Treatment Key findings Lavo et al. 55 13-week, randomized double blind, parallel (25 IBS); Rome criteria not used Loperamide 2-8 mg q.d. vs. Improvements in stool consistency (p<0.001), pain (p<0.01), urgency (p<0.05) and overall response (p<0.03) all vs. Hovdenak et al. 56 3-week, randomized, double blind, parallel (58 IBS); Rome criteria not used Loperamide 4 mg q.d. vs. Improvements in stool frequency and consistency (p<0.01), fewer painful days (p<0.01) Efskind et al. 57 5-week, randomized double blind (69 IBS; subtype not specified); Rome criteria not used Loperamide 2-6 mg q.d. vs. Improvements in stool frequency (p<0.0001)and consistency (p<0.01) Cann et al. 58 5-week, randomized, double blind, cross-over (28 IBS); Rome criteria not used Loperamide 2-12 mg q.d. vs. Improvements in stool frequency (p<0.001) and consistency (p<0.01), diarrhea (p<0.01) and urgency (p<0.01) IBS, irritable bowel syndrome; ITT, intention to treat. 흡수의증가, 항문괄약근압의증가등의효과를나타낸다. 과민성장증후군환자에서 loperamide의치료효과를평가한위약대조군연구들은현재까지 4개의보고가있으며, 55-58 위약에비해과민성장증후군의전반적인증상의개선은없었으나, 배변형태를호전시키고배변횟수를줄이는데도움이되었다 (Table 3). 일부연구에서는위약에비해복통이나변급박감의유의한감소를보였다. 55,58 그렇지만이들연구들은연구에포함된환자의수가적고, 모두로마기준을적용하기이전에시행되었고, 연구의질이높지않으며, 대부분이 5주이내의단기간의치료효과를평가하였으며, 장기간의치료효과를평가한연구는아직없다. Loperamide를포함한지사제의안전성과내복성에대한연구는아직없으나, 변비를유발할수있어변비형환자에서는투여를피해야하며, 교대형과민성장증후군환자에서도투여시주의가필요하다. Loperamide는혈액뇌장벽 (bloodbrain barrier) 을통과하지않기때문에 diphenoxylate나 codeine보다부작용이적다. 요약하면 loperamide는위약에비해과민성장증후군의전반적인증상의개선이나복통, 복부불쾌감의유의한호전은없으나배변형태를호전시키고배변횟수를유의하게줄이는효과를보인다. 그렇지만변비를유발할수있어설사형과민성장증후군이아닌경우에는투여시주의가필요하다. 6) 세로토닌 3형수용체길항제 (5HT 3 receptor antagonist) 세로토닌 3형수용체길항제는설사형과민성장증후군의치료에도움을준다. (Grade 2A, 권고수준 : 약함, 증거수준 : 높음 ) 전문가의견 : 전적으로동의함 (12%), 대체로동의함 (77%), 일부동의함 (8%), 대체로동의하지않음 (4%), 전적으로동의하지않음 (0%). 세로토닌은위장관의주요기능에중요한역할을하는신경전달물질로작용하며, 1형에서 7형까지의다양한세로토닌수용체중주로 1형, 3형및 4형수용체가위장관의운동, 감각및분비기능에관여한다. 59 중추신경계에영향을주지않으면서위장관의세로토닌수용체에선택적으로작용하는작용제나길항제가여러기능성위장관질환의치료나위장관증상의조절에이용되고있다. 세로토닌 3형수용체길항제는장관신경총에작용하여구강-맹장통과시간및대장통과시간의연장, 식후위대장반사의감소, 내장감각의변화등과같은다양한작용을나타내며, 60,61 설사형과민성장증후군환자에서효과적인치료제로생각되고있다. Alosetron은세로토닌 3형수용체의강력한선택적인길항제로설사형과민성장증후군여성에대한치료제로승인을받은약물이다. 변비형을제외한과민성장증후군환자를대상으로로마기준을적용하고연구의질이비교적높다고판단되는여러무작위위약대조군연구들에서 alosetron은전반적인증상의개선과복통및복부불쾌감, 변급박감의호전율이위약에비해유의하게높았으며, 배변의빈도, 변의굳기등에있어서도유의한변화를나타내었다 (Table 4). 62-70 8개의위약대조군연구를메타분석한결과에서도위약에비해과민성장증상이지속될상대위험도 0.79 (95% CI=0.69-0.90), NNT는 8 (95% CI=5-17) 로장증상조절에효과적이었으며, 남성환자에서도여성과같은치료효과를보였다. 71 부작용으로는변비가가장흔한증상으로알려져있으며투여용량에따라발생빈도가증가하는경향을보인다. 1 심한변비와허혈성대장염등의부작용이일부환자에서발생할수있어, 72 시판을철회하였다가통상적인치료에반응이없는여성설사형과민성장증후군등의제한된적응증과안전성감독하에재승인을받아사용되고있다. Vol. 57 No. 2, February 2011

90 권중구등. 과민성장증후군치료에관한임상진료지침 Ramosetron은설사형과민성장증후군의치료제로개발된새로운약제로위약대조군연구에서전반적인증상개선과복통, 배변습관의호전등이위약에비해유의하게높은결과를보였다 (Table 4). 73 일본에서 539명을대상으로 12주간시행한위약대조군 3상연구에서전반적인증상의호전율이 ramosetron 투여군이 47% 로위약투여군의 27% 에비해유의하게높았으며, 심각한부작용은보고되지않았다. 74 이약제와관련되어발생한허혈성대장염은아직보고되지않았으며, 미국과유럽에서추가적인 3상연구가계획중이다. 요약하면세로토닌 3형수용체길항제는변비형을제외한과민성장증후군환자에서전반적인증상, 복통및복부불쾌 감, 배변습관등의호전에효과적인약제로생각된다. 그러나 alosetron은변비, 급성허혈성대장염등의심각한부작용을유발할수있어통상적인치료에반응이없는설사형과민성장증후군환자에제한적으로사용되고있다. Ramosetron은임상연구결과들을보면심각한부작용이없이설사형과민성장증후군의전반적인증상의호전에도움이되는것으로보인다. 7) 세로토닌 4형수용체작용제 (5HT 4 receptor agonist) 세로토닌 4형수용체작용제는변비형과민성장증후군환자의치료에도움을준다. (Grade 2A, 권고수준 : 약함, 증거수준 : 높음 ) Table 4. Studies of 5HT 3 antagonists for treatment of IBS Author Study design and ITT population Treatment Key findings Bardhan et al. 62 12-week, randomized double blind, parallel (462 IBS-D); Rome I Alosetron 0.1, 0.5, and 2 mg b.d. vs. Increased pain-free days and decreased VAS score for diarrhea (p<0.05) Hardened stools and reduced stool frequency (p<0.002) Camilleri et al. 63 12-week, randomized, double blind, parallel (626 IBS-D); Rome I Alosetron 1 mg b.d. vs. Greater relief of pain/discomfort (p<0.001), decreased urgency and stool frequency, and improved stool consistency (p<0.001) Chey et al. 64 48-week, randomized double blind, parallel (714 IBS-D); Rome I Alosetron 1 mg b.d. vs. Greater 48-week average relief (p<0.01) and urgency control (p<0.001) Lembo et al. 65 12-week, randomized, double blind, parallel (492 IBS-D); Rome II Alosetron 1 mg b.d. vs. Greater urgency control (p<0.001); improved global symptoms (p<0.001) at 4, 8, and 12 weeks Camilleri et al. 66 12-week, randomized double blind; (370 IBS-D or IBS-M); Rome I Alosetron 1, 2, 4, 8 mg b.d. vs. Females: greater relief of pain/discomfort, (p<0.05); decreased urgency and stool frequency, and improved stool consistency (p<0.05) Chang et al. 67 12-week, randomized double blind; (662 IBS-D, male); Rome I Alosetron 0.5, 1, 2 and 4 mg b.d. vs. Greater relief of pain/discomfort, (p<0.05); improved stool consistency (p<0.001) Camilleri et al. 68 12-week, randomized double blind; (647 female, IBS-D or IBS-M); Rome I and negative GI investigations within the last 5 years Alosetron 1 mg b.d. vs. Greater relief of pain/discomfort (p<0.05), decreased urgency and stool frequency, and improved stool consistency (p<0.001) Krause et al. 69 12-week, randomized double blind; (705 female, IBS-D); Rome II Alosetron 0.5 or 1 mg o.d., or 1 mg b.d. vs. Improved global IBS symptoms (p<0.02); Greater relief of pain/discomfort (p 0.038) Lembo et al. 70 12-week, randomized, double blind, (801 female, IBS-D); Rome II Alosetron 1 mg b.d. vs. Improved global IBS symptoms (p<0.001); Significant relief of bowel urgency (p<0.001) Matsueda et al. 74 12-week, randomized, double blind, parallel (539 IBS-D); Rome II Ramosetron 5 μg q.d. vs. Improved global IBS symptoms (p<0.001) Matsueda et al. 73 12-week, randomized, double blind, parallel ( 418 IBS-D); Rome II Ramosetron 1, 5, 10 μg q.d. vs. Ramosetron 10 μg; Improved global IBS symptoms (p<0.026), Greater relief of abdominal pain/discomfort (p<0.002), Improved abnormal bowel habit (p=0.038) IBS, irritable bowel syndrome; ITT, intention to treat. The Korean Journal of Gastroenterology

Kwon JG, et al. Guidelines for the Treatment of Irritable Bowel Syndrome 91 전문가의견 : 전적으로동의함 (12%), 대체로동의함 (76%), 일부동의함 (12%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 세로토닌 4형수용체작용제는아세틸콜린, calcitonin gene-related peptide (CGRP) 등의위장관운동에관여하는신경전달물질의유리를촉진함으로써위장관운동및분비기능을촉진하고내장구심성감각을조절하는효과를나타내며, 59 만성변비나변비형과민성장증후군환자의치료에도움이된다. 세로토닌 4형수용체의선택적부분작용제 (partial agonist) 인 tegaserod는변비형이나교대형과민성장증후군환자를대상으로한여러무작위대조군연구들에서전반적인증상의호전이나치료에대한만족도, 복통, 복부불쾌감, 변비와같은증상의호전이위약에비해유의하게높은것으로보고되었다 (Table 5). 75-81 11개의무작위대조군연구들을대상으로메타분석을시행하였을때 tegaserod를투여한군에서장증상이지속될비교위험도 0.85 (95% CI=0.80-0.90) 로위약에비해장증상조절에효과적이었으며, 변비형환자군 과교대형환자군을비교하였을때증상에대한상대위험도는유의한차이를보이지않았다. 71 Tegaserod에의한전체부작용의발생위험도는위약에비해유의한차이를보이지않지만, 설사가흔한부작용으로나타난다. 71 0.1% 의환자에서는심근경색, 뇌졸중, 협심증등의심혈관계부작용이보고되어, 시판을철회하였다가 55세미만의여성변비형과민성장증후군혹은만성변비환자등의제한된적응증에서사용되고있다. Renzapride는세로토닌 3형수용체길항제와세로토닌 4 형수용체작용제의작용을동시에가지고있는약물로 cisapride와매우유사한속성을가지고있다. 변비형혹은교대형과민성장증후군환자를대상으로한 4개의위약대조군연구에서전반적인증상의개선율이위약에비해유의한차이를보이지않았으며, 일부연구에서장통과시간의변화, 대변의굳기나배변빈도등에서유의한차이를보였다. 82-85 이연구들을대상으로메타분석을하였을때장증상이지속할비교위험도는 0.99 (95% CI=0.79-1.23) 로증상개선에있어 Table 5. Studies of 5HT 4 agonists for treatment of IBS Author Study design and ITT population Treatment Key findings Nyhlin et al. 75 12-week, randomized double blind, parallel (647 IBS, no IBS-D); Rome II Tegaserod 6 mg b.d. vs. Greater overall relief from IBS symptoms over weeks 1-4 (p=0.0049) and weeks 1-12 (p<0.0001) Muller-Lissner et al. 76 12-week, randomized double blind, parallel (881 IBS-C); Rome I Tegaserod 2 or 6 mg b.d. vs. Improved global IBS symptoms (p<0.005), Greater relief of abdominal pain/discomfort (p<0.05), Increased number of bowel movement (p<0.05), Decrease in stool consistency (p<0.05) Novick et al. 77 12-week, randomized double blind, (1519 IBS-C, female); Rome I Kellow et al. 78 12-week, randomized double blind, (520 IBS, no IBS-D); Rome II Tack et al. 79 10-week, randomized double blind, (2660 IBS-C, female); Rome II Tegaserod 6 mg b.d. vs. Tegaserod 6 mg b.d. vs. Tegaserod 6 mg b.d. vs. Improved global IBS symptoms (p<0.033), Greater relief of abdominal pain/discomfort (p<0.003) and bloating (p<0.05), Increased number of bowel movement (p<0.05), Decrease in stool consistency (p<0.05) Improved global IBS symptoms (p<0.0001), Greater relief of abdominal pain/discomfort (p=0.0134), Increased number of bowel movement (p=0.0002), Decrease in stool consistency (p<0.0001) Greater global symptom relief and/or abdominal pain/discomfort during initial and repeated treatment (p 0.0001), Improved bowel habit and quality of life Harish et al. 80 12-week, randomized double blind, parallel (40 male, IBS-C); Rome II and negative GI investigations Tegaserod 6 mg b.d. vs. Significant difference in colonic transit time (p<0.05), Decrease in stool consistency (p<0.05) Chey et al. 81 4-week, randomized double blind, (661 IBS, no IBS-D, female); Rome II IBS, irritable bowel syndrome; ITT, intention to treat. Tegaserod 6 mg b.d. vs. Significant improvement in satisfactory relief of IBS symptoms (p<0.001) Vol. 57 No. 2, February 2011

92 권중구등. 과민성장증후군치료에관한임상진료지침 서위약에비해유의한차이가없었다. 71 요약하면세로토닌 4형수용체작용제는설사형을제외한과민성장증후군환자에서전반적인증상의호전에도움이된다. Tegaserod는드물게발생하는심혈관계부작용으로인해현재사용이제한되어있다. Renzapride는효과검증을위해추가적인임상연구가더필요하다. 8) 비흡수성경구용항생제비흡수성경구용항생제의단기간사용은일부과민성장증후군환자의치료에도움을준다. (Grade 2B, 권고수준 : 약함, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (12%), 대체로동의함 (77%), 일부동의함 (8%), 대체로동의하지않음 (4%), 전적으로동의하지않음 (0%). 비흡수성경구용항생제와관련해서는주로 rifaximin에관한보고들이많으며과민성장증후군환자에서다양한증상들의호전에효과적이었다는이중맹검무작위위약대조군연구들과체계적문헌고찰보고가있다. 1 이번고찰에서는국외연구의경우최근 5년간발표된연구들을대상으로하였고초록만발표된경우는제외하였으므로대상논문이많지않았는데 87명을대상으로잘계획된한위약대조군연구에서 rifaximin 400 mg을하루세번씩 10일간투약하고이후 10주간추적조사한결과전반적인과민성장증상의호전이추적기간전반에걸쳐유지되었다고보고하였다. 86 또한과민성장증후군환자 98명을대상으로항생제효과를후향분석한연구에서 rifaximin을하루 1,200 mg 투약받은환자의 69% 에서임상양상의호전을나타내었다. 87 특히최근과민성장증후군의발병기전가운데하나로소장세균과다증식이제시되고있는데이점은과민성장증후군에서항생제사용을고려할수있는근거를제공한다. 88 Rifaximin 투약후추적검사로호기가스검사를시행하였던증례들을후향분석한연구에서 rifaximin에반응이있었던환자군에서반응이없었던환자군보다투약후정상호기가스검사소견을보인경우가많았다. 87 여행자설사환자에서일반적으로권장되는 rifaximin 용량이하루 400 mg인것에비해과민성장증후군환자들을대상으로한기존연구들에서는사용된 rifaximin 용량이하루 1,100-1,200mg으로고용량인경우가많았고특히설사형과민성장증후군환자나복부팽만감을주소로하는경우에우수한효과를나타내었다. 1,86-88 변비형과민성장증후군환자 39명을대상으로시행된한무작위위약대조군연구에서 neomycin 500 mg을하루 2회투약한군에서위약군에비해전반적인과민성장증상및변비의호전빈도가유의하게높았으며, 특히호기가스검사에서 methane 양성인경우 neomycin의효과가더욱우수한 것으로보고하였다. 89 비흡수성경구용항생제의장기안정성에관한보고는아직없으나위약에비해유의한부작용은없었다. 1,86,87,89 요약하면비흡수성경구용항생제인 rifaximin이나 neomycin의단기간투여는일부과민성장증후군환자에서전반적인과민성장증후군증상의호전에도움이된다. 과민성장증후군발병기전의하나로소장세균과증식이제시되고있다는점은과민성장증후군환자에서항생제사용의근거를제공한다. 9) 프로바이오틱스 (probiotics) 프로바이오틱스는일부과민성장증후군환자의치료에도움을줄수있다. (Grade 2C, 권고수준 : 약함, 증거수준 : 낮음 ) 전문가의견 : 전적으로동의함 (19%), 대체로동의함 (73%), 일부동의함 (8%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 최근다양한장질환의기전으로장내세균총의이상이나변화현상이제시되면서프로바이오틱스에대한관심이증가되고있으며이에따라과민성장증후군환자들을대상으로프로바이오틱스를사용한연구들도비교적흔하다. 이번고찰에서는 19편의연구결과들을분석하였으며 90-108 많은수의환자를대상으로잘계획된무작위위약대조군연구들이 10 편이었고 92,96-100,103-105,107 나머지연구들에서도 6편은적절한맹검과무작위배정이이루어진연구들이었다. 90,94,101,102,106,108 한종류의균종만을이용하여시행된 6편의연구들 92,96,102,103,106,107 가운데 4편에서는 Lactobacillus 균종을이용하였는데 92,102,103,106 이들가운데이중맹검이이루어지지않았던한연구에서복통과복부불편감지수가호전되었다고보고하였으나 106 각각 54명과 100명을대상으로시행된위약대조군연구들에서는효과가없었고 92,103 오히려사용후증상이악화되었다는보고도있다. 102 Bifidobacterium animalis균을이용하여 267명의변비형과민성장증후군환자들을대상으로 6주간이루어진위약대조군연구에서위약에비해전반적인삶의질지수와복부팽만감이유의하게호전되었다고보고하였으며, 96 362명의과민성장증후군환자들을대상으로 4주간 Bifidobacterium infantis 균을투여한위약대조군연구에서전반적인과민성장증상지수가유의하게호전되었다고보고하였다. 107 그외연구들은 Bifidobacterium 균종을포함한두종류이상의균종들을사용하였는데대부분의연구들에서복통이나복부팽만감등과민성장증상의호전에유의한효과가있었다. 90,91,93,95,97-100,104,105,108 다른균종에대한연구들로 40명의과민성장증후군환자들을대상으로 4주간 Bacillus subtilis 및 Streptococcus faecium 균을투여하였을때위약에비해복통의빈도와정 The Korean Journal of Gastroenterology

Kwon JG, et al. Guidelines for the Treatment of Irritable Bowel Syndrome 93 도가유의하게호전되었다는국내보고가있으며, 101 8주간 Enterococcus 및 Escherichia coli 세포추출물을투여한후전반적인증상지수가호전되었다는보고가있다. 94 그러나이러한연구들은이용된균종들이매우다양하고같은균종내에도다양한균주들을사용하고있으며사용된균의농도도매우다양하여과민성장증후군환자에이상적인제형을제시하기는어렵다. 요약하면과민성장증후군에서장내세균의역할이강조되면서프로바이오틱스에관해많은연구들이시도되고있으며, Bifidobacterium 균종이나이를포함한복합요법이위약에비해증상의호전에도움이되는것으로보인다. 10) 선택적염소통로활성제 (ClC-2, chloride channel activator) 선택적염소통로활성제는변비형과민성장증후군환자의치료에효과적이다. (Grade 1B, 권고수준 : 강함, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (12%), 대체로동의함 (73%), 일부동의함 (15%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 장상피세포의표면세포막에존재하는염소통로의활성화는 Cholera 등의예에서보듯분비성설사에있어매우중요한역할을담당한다. 염소통로들가운데 C-2 염소통로는약한강도의염소통로로아직까지이부위와관련되어발생하는질환은알려져있지않으며, 세포막의투과도및세포용적의생리적조절을담당하는것으로알려져있다. 109 Lubiprostone은현재까지개발된유일한선택적 C-2 염소통로활성제로, 전신순환계로의흡수가거의없이소장세포표면에국소적으로작용하여수분분비를일으킨다. Lubiprostone과관련된연구들은수편있으나주로초록형태의발표가많으며비교적많은변비형과민성장증후군환자들을대상으로잘계획된두편의무작위위약대조군연구들이있다. 110,111 변비형과민성장증후군환자 195명을대상으로시행된 2상임상시험에서하루 16 ug (8 ug b.d), 32 ug (16 ug b.d), 48 ug (24 ug b.d) 을 3개월간각각투약하면서매달마다추적한결과전기간에걸쳐모든용량의투약군에서위약군에비해복통및복부불편감지수의의미있는호전을나타내었으나구토및설사등의부작용을고려하여하루 16 ug (8 ug b.d) 요법을권장하였다. 110 변비형과민성장증후군환자 1,171명을대상으로시행된 3상임상시험에서위약군의 10%, lubiprostone 군의 18% 에서증상의호전을보여유의한차이를나타내었고부작용의빈도는양군간차이가없었다. 111 요약하면 lubiprostone은선택적 C-2 염소통로활성제로, 만성변비나변비형과민성장증후군환자에서우수한효과를 나타내며특히배변형태를무르게하고복통의완화에도움이된다. 11) 항우울제삼환계항우울제 (tricyclic antidepressant) 와선택적세로토닌재흡수억제제 (selective serotonin reuptake inhibitor) 는일부과민성장증후군환자의치료에도움을준다. (Grade 1A, 권고수준 : 약함, 증거수준 : 높음 ) 전문가의견 : 전적으로동의함 (30%), 대체로동의함 (52%), 일부동의함 (7%), 대체로동의하지않음 (7%), 전적으로동의하지않음 (4%). 과민성장증후군의증상이장기능개선약제로좋아지지않으면삼환계항우울제와선택적세로토닌재흡수억제제와같은항우울제를사용하는경우가있다. 항우울제는중추신경계및말초신경계에영향을줄수있어과민성장증후군발병기전으로볼때효과적인약제일가능성이있다. 112,113 실제로많은연구에서항우울제가과민성장증후군에효과적이라고보고하였다. 114-122 과민성장증후군치료제로삼환계항우울제혹은선택적세로토닌재흡수억제제를투여한무작위대조시험에서이들약제는전반적인과민성장증후군증상을호전시켰다. 123 삼환계항우울제는위약에비해우월한효과가있었으며, NNT는 4 (95% CI=3-8) 이었다. 123 선택적세로토닌재흡수억제제는증상호전효과가위약에비해 NNT 3.5 (95% CI=2-14) 로효과적인약물이었다. 123 두약제모두우울증을동반한과민성장증후군환자에게더효과적이지는않았으며, 우울증환자에게사용하는용량보다적은용량으로도장증상이호전되었다. 각아형에따른항우울제의효과차이는분명하지않다, 이론적으로항우울제는항콜린효과로장운동이증가되어있는설사우세형과민성장증후군에더좋은효과가있을것이라추정할수있지만, 114 연구결과에의하면항우울제의효과는세가지아형모두에비슷한정도로효과가있었다. 124 항우울제의종류에따른효과차이도아직분명하지않다. 세로토닌재흡수억제제는삼환계항우울제에비해내복성 (tolerability) 이우수하고장운동촉진효과도함께있기때문에설사우세형과민성장증후군보다는변비우세형과민성장증후군에서더효과가있을것이고, 삼환계항우울제는반대로설사우세형과민성장증후군에더효과가있을것으로생각해볼수있다. 125 하지만삼환계항우울제및세로토닌재흡수억제제모두과민성장증후군의전반적인증상호전이주된효과였다. 116,119 항우울제는비교적안전한약물이나부작용에대한주의를요한다. 일반적으로세로토닌재흡수억제제는삼환계항우울제에비해부작용이적다. 항우울제의안전성에관한연구에서항우울제를복용한경우부반응 (adverse effect) 의위험도 Vol. 57 No. 2, February 2011

94 권중구등. 과민성장증후군치료에관한임상진료지침 가높기는했지만통계적으로유의하지않았다. 115-117,121 항우울제는과민성장증후군환자를치료하는데비교적안전한약물로생각되나, 126 부작용에대한모니터링이필요할것이다. 요약하면과민성장증후군에서삼환계항우울제와선택적세로토닌재흡수억제제는일부과민성장증후군환자에서전반적인증상의완화에도움을줄수있는비교적안전하게사용할수있는약물로생각된다. 12) 정신과적치료인지-행동요법 (cognitive behavioral therapy), 역동정신요법 (dynamic psychotherapy), 최면요법 (hypnotherapy) 은일부과민성장증후군환자의치료에도움을준다. (Grade 2B, 권고수준 : 약함, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (7%), 대체로동의함 (54%), 일부동의함 (29%), 대체로동의하지않음 (11%), 전적으로동의하지않음 (0%). 정신과적치료에는인지-행동요법, 이완요법 (relaxation therapy), 최면요법및정신치료가포함된다. 여러무작위대조연구에서정신과적치료는과민성장증후군의증상을효과적으로경감시켰다. 114,127-140 이를종합분석한결과에따르면, 정신과적인치료는약물요법과비슷한정도로과민성장증후군환자의증상혹은삶의질을향상시켰다 (NNT=4). 123 하지만, 이들연구중 9개는한기관에서이루어졌으며, 141 전반적인연구의질이높지않았고, 약물과달리연구간통합비교가어려우며, 이중눈가림이어렵기때문에연구결과를직접임상에적용하기에는주의를요한다. 127,128,134,135,137,140 정신과적치료중에서인지-행동치료와 114,127,128,139,142 역동정신치료 131,132 및병합적정신과적치료는 130,135 모두비슷한효과가있었으나, 이완요법단독은유의한효과가없었다. 134,139 최면요법의효과는위약에비해효과적이었다. 137,138 정신과적치료에서는부작용이없었다. 요약하면정신과적치료중인지-행동요법, 역동정신요법, 최면요법은일부과민성장증후군환자에서약물과비슷한치료효과를나타낼수있을것으로보이며향후더많은임상경험과연구들이필요하다. 13) 약제의조합과민성장증후군은여러가지병태생리가관여되어다양한증상양상을보이는이질적인질환군이며각각의증상에대한약제를조합하는것이치료에효과적이다. (Grade 1B, 권고수준 : 강함, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (71%), 대체로동의함 (29%), 일부동의함 (0%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%) 과민성장증후군의병태생리기전으로장관의운동, 감각과고위중추, 정신사회요인, 염증, 소장세균과증식등의여 러가지요인들이서로혼재되어병태생리에영향을주므로개개인에따라다양한증상들을호소한다. 이와같이과민성장증후군은여러가지병태생리가관여되어다양한증상을보이는이질적인질환군이므로각각의증상에대한약제를조합하는것이치료에효과적이다. 과민성장증후군을적절하게치료하기위해서는환자개인에게어떠한기전들이작용하는지, 어떠한증상들을호소하는지를알아보고이에대한치료제를조합하여사용하는것이바람직하다. 143 요약하면과민성장증후군은여러가지병태생리가관련되어다양한증상을보이는이질적인질환군이며, 관련된병태생리나증상에대한약제를조합하는것이치료에효과적이다. 요약 1) 증상을악화시키는음식의제한은과민성장증후군의치료에도움을줄수있다. 그러나제한식이요법이효과적인치료법이라는증거수준은낮으며향후잘계획된무작위연구가필요하다. 2) 부피형성하제는변비, 복통등과민성장증후군의일부증상의치료에도움을준다. 그러나부피형성하제를복용하면복부팽만감이나가스를유발할수있다는점을고려하여야한다. 3) 변비형과민성장증후군환자에서삼투성하제는배변횟수를증가시키는데도움을줄수있다. 그렇지만통증등의증상은감소시키지못한다. 4) 진경제는과민성장증후군환자에서복통및복부불편감의치료에효과적이며, 약제와관련된심각한부작용은없고비교적안전한약물로생각된다. 5) 지사제는과민성장증후군에서배변형태를호전시키고배변횟수를줄이는데도움을준다. 그렇지만변비를유발할수있어설사형과민성장증후군이아닌경우에는투여시주의가필요하다. 6) 세로토닌 3형수용체길항제는설사형과민성장증후군환자에서전반적인증상, 복통및복부불쾌감, 배변습관등의호전에효과적인약제로생각된다. 7) 세로토닌 4형수용체작용제는변비형과민성장증후군환자에서전반적인증상의호전에도움이된다. 8) 비흡수성경구용항생제의단기간투여는일부과민성장증후군환자에서전반적인증상의호전에도움이된다. 9) 프로바이오틱스는일부과민성장증후군환자에서증상의완화에도움을줄수있다. 10) 선택적 C-2 염소통로활성제는변비형과민성장증후군환자의치료에효과적이며특히배변형태를무르게하고 The Korean Journal of Gastroenterology

Kwon JG, et al. Guidelines for the Treatment of Irritable Bowel Syndrome 95 복통의완화에도움이된다. 11) 삼환계항우울제와선택적세로토닌재흡수억제제는일부과민성장증후군환자에서전반적인증상의완화에도움을줄수있으며비교적안전하게사용할수있는약물이다. 12) 정신과적치료중인지-행동요법, 역동정신요법, 최면요법은일부과민성장증후군환자의치료에도움을준다. 13) 과민성장증후군은여러가지병태생리가관련되어다양한증상을보이는이질적인질환군이며, 관련된병태생리나증상에대한약제를조합하는것이치료에효과적이다. REFERENCES 1. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al; American College of Gastroenterology Task Force on Irritable Bowel Syndrome. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009;104(Suppl 1):S1-S35. 2. 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;79:196-201. 3. 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;16:186-193. 4. 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