untitled

Transcription

1 Korean J Gastroenterol Vol. 57 No. 2, DOI: /kjg SPECIAL REVIEW 기능성소화불량증치료에관한임상진료지침 지삼룡, 정혜경 1, 민병훈 2, 최기돈 3, 이풍렬 2, 강영우 4, 이상인 5, 대한소화기기능성질환ㆍ운동학회 인제대학교의과대학내과학교실, 이화여자대학교의학전문대학원내과학교실 1, 성균관대학교의과대학내과학교실 2, 울산대학교의과대학내과학교실 3, 건양대학교의과대학내과학교실 4, 연세대학교의과대학내과학교실 5 Guidelines for the Treatment of Functional Dyspepsia Sam Ryong Jee, Hye-Kyung Jung 1, Byung Hoon Min 2, Kee Don Choi 3, Poong-Lyul Rhee 2, Young Woo Kang 4, Sang In Lee 5 and The Korean Society of Neurogastroenterology and Motility Department of Internal Medicine, Inje University College of Medicine, Busan, Ewha Womans University School of Medicine 1, Sungkyunkwan University School of Medicine 2, University of Ulsan College of Medicine 3, Seoul, Konyang University College of Medicine 4, Daejeon, Yonsei University College of Medicine 5, Seoul, Korea Functional dyspepsia (FD) is defined as the presence of symptoms thought to originate in the gastroduodenal area, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms. Based on the available evidence and consensus opinion, thirteen consensus statements for the treatment of FD were developed using the modified Delphi approach. Proton pump inhibitor, prokinetics, and histamine 2 receptor antagonists are effective for the treatment of FD. Mucosal protecting agents, fundus relaxant, and drugs for visceral hypersensitivity can improve symptoms in FD. Antacids and antidepressants may help improving symptoms in FD. Comparing endoscopy with test and treat of Helicobacter pylori, endoscopy may be more effective initial strategy for managing patients with FD in Korea given high incidence of gastric cancer and low cost of endoscopy. Helicobacter pylori eradication can be one of the therapeutic options for patients with FD. Psychotherapy is effective for those who have severe symptoms and refractoriness. Further studies are strongly needed to develop better treatment strategies for Korean patients with FD. (Korean J Gastroenterol 2011;57:67-81) Key Words: Functional; Dyspepsia; Treatment; Guideline CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 이풍렬, , 서울시강남구일원동 50, 성균관대학교의과대학삼성서울병원소화기내과 Correspondence to: Poong-Lyul Rhee, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-dong, Gangnam-gu, Seoul , Korea. Tel: , Fax: , plrhee@skku.edu Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 57 No. 2, February

2 68 지삼룡등. 기능성소화불량증치료에관한임상진료지침 개요 소화불량 이란용어는널리사용되지만의료인혹은일반인에게모두아주다양한의미로해석된다. 그정의는물론이며, 소화불량증의범주조차도애매모호할수있다. 기능성소화불량증 (functional dyspepsia) 은내시경검사, 방사선검사, 병리검사등에서기질적이상이없는 증상 을근거한진단이며, 병태생리가비교적균일한집단을포함하는것을목적으로하여그진단기준이수차례에걸쳐바뀌어져왔다. 1-3 대한소화기기능성질환ㆍ운동학회에서는최근한국에맞는기능성소화불량증의진단을위하여이에대한체계적인문헌고찰을대한소화기학회지에발표한바있다. 4 기능성소화불량증은상복부통증, 상복부팽만감, 조기만복감, 포만감, 오심, 구토, 트림등의상복부에일어나는다양한증상들로구성되며, 여러가지병태생리가관여하는이질적인모임의집합체이다. 5 병태생리가다양하고병태생리와증상이일치하지않아병태생리에근거한치료적접근이어렵다. 또한높은위약효과를월등히능가하는기능성소화불량증치료제가드물어대부분의치료는증상완화를목적으로다양한약제들을병합투여한다. 전술한바와같이기능성소화불량증은다양한병태생리로인한질환이므로이러한병태생리와증상과의연관성, 증상과연계된병태생리를교정하는효과적인약물의선택이치료에있어중요하다. 아시아-태평양소화불량증연구모임, 6 미국소화기학회, 7 영국북부소화불량증가이드라인모임, 8 캐나다소화불량증연구모임, 9 스코틀랜드대학연합가이드라인모임 10 등에서각단체나국가에맞는기능성소화불량증의치료지침에대해발표한바있다. 국내에서도 2005년기능성소화불량증에대한치료지침이발표된바있는데, 11 이번원고에서는체계적인국내외문헌고찰을시행하고국내여건에맞는치료지침을제시하고자했는데, 이번가이드라인은국내전문가의의견과일선에서진료하는일차의료기관의사들의의견을모두반영하였다. 1. 목적본기능성소화불량증임상진료지침은기능성소화불량증환자에서위산분비억제제와위장관운동촉진제로대표되는위장관약물, 정신과약물, 헬리코박터검사및제균치료, 내시경검사및생활습관개선등이전반적증상호전및개개의증상호전에미치는효과에관해현재까지알려진국내외자료를체계적으로문헌고찰한후국내전문가의의견을수렴하여우리나라의료실정에맞는기능성소화불량증임상진료지침을마련하고자한다. 이진료지침은진료를직접담당하는의료진에게양질의진료를제공하는데있어도움이되고, 동시에치료를받는환 자에게도적절하고균형잡힌정보를제공하는것을목적으로한다. 2. 필요성기능성소화불량증은매우흔하고증상의호전과악화가반복되는만성적인질환으로삶의질을떨어뜨리고의료이용자체뿐아니라신체적정신적기능저하를유발하여사회경제적으로손실을초래한다. 그러므로적절한기능성소화불량증의치료지침개발은현재의제한적의료자원의효과적이용뿐만아니라환자의호전으로인해사회경제적이득이높다고기대된다. 3. 국내기능성소화불량증진료지침현황 2005년대한소화기기능성질환ㆍ운동학회에서기능성위장질환진단및치료가이드라인이발표되었고기능성소화불량증에대한치료지침이발표된바있다. 11 문헌에근거한전문가의견을중심으로일반적인치료, 위산분비억제제, 히스타민수용체길항제, 위저부이완제, 내장과감각억제제등의약물치료, 정신적치료법등으로기술되어실제임상진료에활용되어왔다. 또한 2010년에대한소화기기능성질환ㆍ운동학회주관으로기능성소화불량증진단을위한체계적인문헌고찰을대한소화기학회지에발표하여현재사용중에있다 기능성소화불량증임상진료지침의한계국내의기능성소화불량증임상진료지침을만드는데있어가장큰문제점은국내자료가매우제한적이고, 국외의자료는우리나라기능성소화불량증과그역학적특성, 임상양상등이다른북미와유럽의연구자료가대부분이라는점이다. 약제자체에대한반응은인종간의차이가적어국외에서진행된연구결과를국내에적용할수있을것으로기대된다. 이러한국내자료의제한점을극복하기위하여국내외문헌검색에근거하여진료지침초안을만들고델파이방법을이용하여임상전문가들의합의도출과정을거쳤다. 또한이렇게만든최종안에대해일선진료현장에서가장많이진료지침을사용하게될 1, 2차진료의에게전자우편으로의견을구하여임상진료지침에반영하였다. 이번기능성소화불량증임상진료지침에다양한치료자가사용하는모든치료를다룰수없기때문에흔히사용되고보편적으로진료상황에서인정되는치료를진료지침에포함시켰다. 또한개발은되었으나국내에도입되지않은약물이나치료기법에대해서도국외에서사용중인것들은가급적포함시키고자했다. 이는기존의기능성소화불량증치료약물이장기적인증상개선효과가높지않아새로운약물이 The Korean Journal of Gastroenterology

3 Jee SR, et al. Guidelines for the Treatment of Functional Dyspepsia 69 필요한상황이기때문이다. 본진료지침의내용은현재개발을진행하는시점에서의권고안으로향후새로운임상자료에기반하여지속적으로 2년마다개정을시행할예정이다. 5. 기능성소화불량증진료지침의제작진과제작과정진료지침제작진은세군으로구성되었다. 대한소화기기능성질환ㆍ운동학회에진료지침위원회를구성하여위원장이광재 ( 아주대학교의과대학 ) 와간사정혜경 ( 이화여자대학교의학전문대학원 ) 및위원 7명으로구성하여 2010년 1월 1차모임을통해진료지침개발의원칙, 개발일정및진료지침의범위를결정하였다. 또한진료지침의대상이되는위식도역류질환, 기능성소화불량증, 과민성장증후군및변비의 4대질환에대한운용팀 (working team) 을구성하였다. 기능성소화불량증운용팀의책임자는이풍렬 ( 성균관대학교의과대학 ) 로하였고, 이상인 ( 연세대학교의과대학 ), 강영우 ( 건양대학교의과대학 ), 지삼룡 ( 인제대학교의과대학 ), 정혜경 ( 이화여자대학교의학전문대학원 ), 민병훈 ( 성균관대학교의과대학 ), 최기돈 ( 울산대학교의과대학 ) 을위원으로구성하였다. 2010년 2월에 4대질환의운용팀과학회임원진이참석한임상진료지침개발의구체적방법론에관한워크숍을실시하였다. 2010년 4월대한소화기기능성질환ㆍ운동학회춘계학술대회에서외부임상진료지침전문가인안형식교수 ( 고려대학교의과대학 ) 를초빙하여진료지침개발에관한강의를들은후진료지침개발의세부사항에대한질의응답시간을가졌다. 4대질환운용팀에서핵심질문을선정하고문헌검색에근거하여일차진료지침핵심문구를작성하였고, 델파이방법에근거하여전문가집단을대상으로 1차전자우편투표를실시하였다. 전문가집단은대한소화기기능성질환ㆍ운동학회의전 현직임원과현재학술위원등을포함하였고지역적안배를고려하여구성하였다. 각문구에대해 5 리커트척도의질문중전적으로동의함, 대체적으로동의함, 일부동의함을찬성으로판단하여 50% 이상의찬성을받은경우적절한진료지침문구로선정하였다. 50% 미만의경우운용팀에서적절히문구를수정하여이차안을작성하였다. 2010년 7월외부임상진료지침전문가에게근거평가에관한강의를듣고제한된국내자료를근거로임상진료지침을만들때의제한점에관해토의하였다. 이어서합의도출전문가군에게각진료지침문구에대한전자우편투표결과를보여주고토의한후 2차투표를실시하였다. 키패드방식을이용하여결과를투표와동시에알수있도록하고전문가군의질의와토의를통해합의안을도출한후에운용팀에서최종초안을작성하였다. 1,2차의료기관에근무하는소화기세부전문의 500인에게전자우편으로권장문을보여주고동의여부에대한설문조사를실시하였으며, 이렇게만들어진권장문을 361명의전문의들 이참가한 2010년 11월 6일대한소화기기능성질환ㆍ운동학회연수강좌에서발표하고최종의견을수렴하였다. 또한김광하 ( 부산대학교의과대학 ), 조윤주 ( 을지대학교의과대학 ), 홍수진 ( 순천향대학교의과대학 ), 남수연 ( 국립암센터 ), 강정묵 ( 서울대학교강남건강증진센터 ), 안형식 ( 고려대학교의과대학 ) 으로검토위원회를구성하여최종권고안의보완사항등을검토하게하였다. 이번연구지침개발은외부재정지원없이이루어졌으며, 진료지침개발과정에참여한모든구성원은이해상충의문제가없었다. 6. 임상진료지침의보급및실행개발된임상진료지침은대한소화기학회지, 관련된학회의홈페이지, 페이스북 (facebook), 혹은트위터 (twitter) 등의컴퓨터프로그램을이용하여널리알리고보급할예정이다. 본론 1. 연구방법 1) 기능성소화불량증의정의기능성소화불량증은소화성궤양, 위장관악성종양, 위식도역류질환, 담도질환등그인과관계가뚜렷한기질적질환이없으면서만성적이며반복적인위장관증상이상부위장관에주로발생하는증상군을일컫는다. 12 소화불량증은흔한질환으로, 일차의료기관에방문하는환자전체의 5% 정도를차지하며, 국내에서일차의료기관에서 3차의료기관으로의뢰된소화불량증환자중약 8-20% 에서기질적질환이발견되고 70-92% 에서는기능성소화불량증인것으로알려져있다. 13, 년각국의소화기질환전문가들이모여기능성소화불량증을포함한다양한기능성위장관질환에대해로마기준 I 이라불리는진단기준을만들었으며, 이후 1999년, 2006년 2, 3차개정이이뤄져현재에이르고있다. 하지만개정된로마진단기준도임상적으로적합하지않을뿐만아니라일관성이적어연구목적으로적합하지않다는주장도있어아직많은문제점을갖고있다. 15 저자들은로마기준 I, II, III를바탕으로연구를시행한논문을모두포함하여문헌고찰을시행하였다. 2) 문헌검색문헌검색은 2010년 5월 1일부터 6월 5일까지실시하였다. 국외문헌검색은 1995년부터 2010년 2월사이에기능성소화불량증치료에대한무작위통제연구로제한하여 Cochrane Library와 MEDLINE 검색엔진을이용하여검색하였고, 국내문헌검색은최근 10년동안의국내문헌을 KoreaMed ( 와한국의학논문데 Vol. 57 No. 2, February 2011

4 70 지삼룡등. 기능성소화불량증치료에관한임상진료지침 이터베이스 ( 를이용하여검색하였다. 검색논문대상으로기능성소화불량증의치료에대한임상실험 (clinical trial), 비교연구 (comparative study), 무작위통제연구 (randomized controlled trial), 메타분석 (meta-analysis), 진료지침 (practice guideline) 으로하였다. 영문검색에사용한주제어는 MeSH 용어인 dyspepsia와다음에기술하는기능성소화불량증의치료법과약제를주제어로결과내에서재검색하였다 : proton pump inhibitor (PPI), antacid, prokinetics, histamine 2 receptor antagonists, antidepressants, endoscopy, Helicobacter pylori eradication, mucosal protecting agents, fundus relaxant, visceral hypersensitivity, psychotherapy. 국내문헌검색에서사용한주제어는 소화불량증, 소화불량, 소화불량, dyspepsia 로검색되는모든문헌을조사하였다. 1차검색에서검색된문헌은국외문헌 1,885건, 국내문헌 487건이었다. 이중중복검색된문헌을배제하고선택된문헌은국외 1,580건, 국내 363건이었다. 이를논문제목이나초록전문을보고국외문헌 1,335건, 국내 342건을배제하여국외 245건, 국내 21건을선택하였다. 초록과논문전문을검토하여최종적으로자료의적합성을판단한후국외 139건, 국내 6건을배제하여국외논문 106건, 국내논문 15건의논 문을선정하였다 (Fig. 1). 3) 증거수준및권고등급기능성소화불량증운용팀에서일차진료지침핵심문구를선정하고, 최종선정된문헌의증거수준 (levels of evidence) 과권고등급 (grades of recommendation) 을평가하기위해 2008년미국흉부학회에서발표한항혈전제의임상진료가이드라인논문에서사용한권고등급의판정기준을이용하였다 (Table 1). 16 문헌근거수준은무작위통제연구이거나상대위험도 (relative risk, RR) 가 5를초과하거나 0.2 미만으로치료효과가매우크다고판단되는관찰연구를높은근거수준, 무작위통제연구이지만결과나연구방법등에서제한점을가진경우혹은 RR이높은근거수준의기준보다는낮지만치료효과가크다고판단되는관찰연구를중간근거수준, 중대한제한점이있는무작위통제연구이거나일반적인관찰연구는낮은근거수준으로분류하였다. 또한근거가부족하여전문가의견을반영한경우에는낮은근거수준으로분류하였다. 권고수준은좋은효과가나쁜효과보다확실히더크다고판단되거나권고대로했을때대부분효과가있는경우에는강한권고, 좋은효과가나쁜효과보다약간더클가능성이있을때나권고대로했을때일부에서만효과적인경우라고판단되면약한권고로판정하였다. 강한권고수준을보이는경우문헌근거수준에따라권고등급을 1A, 1B, 1C로분류하였으며, 약한권고수준을보이는경우에도문헌근거수준에따라권고등급을 2A, 2B, 2C로분류하였다. 앞에서전술한바와같이델파이방법에근거하여전문가집단을대상으로한일차전자우편투표를실시한후핵심문구를수정하였다. 이후전문가군을대상으로 2차합의도출을실시하였다. 핵심문구에대한권고등급은전문가의견이전적으로동의함, 대체로동의함및일부동의함이 50% 가안되는경우권고등급을변경하고자하였다. 이후 1, 2차의료기관에근무하는소화기세부전문의 500인에게전자우편을통해동의여부에대한설문조사를실시하였으며, 2010년 11월 6일대한소화기기능성질환ㆍ운동학회연수강좌에서발표하고최종의견수렴을하였다. 또한외부전문가를포함한검토위원회의자문을받고최종권고안을완성하였다. Fig. 1. Flow chart for searching strategy. 2. 기능성소화불량증의임상진료지침 1) 기능성소화불량증치료의개요기능성소화불량증은여러가지병태생리가관여되어다양한증상양상을보이는이질적인질환군이며증상을유발할수있는기저병태생리를추정하여이를교정해주는약물들을조합하는치료가효과적이다. (Grade 1B, 권고수준 : 높음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (89%), 대체로동의함 (11%), The Korean Journal of Gastroenterology

5 Jee SR, et al. Guidelines for the Treatment of Functional Dyspepsia 71 Table 1. Grading Recommendations 16 Grade of recommendation / description Benefit vs. risk and burdens Methodological quality of supporting evidence Implications 1A. Strong recommendation, high-quality evidence Benefits clearly outweigh risk and burden, or vice versa RCTs without important limitations or overwhelming evidence from observational studies Strong recommendation, can apply to most patients in most circumstances. Further evidence is unlikely to change our confidence in the estimate of effect 1B. Strong recommendation, moderate-quality evidence Benefits clearly outweigh risk and burden, or vice versa RCTs with important limitations (inconsistent results, methodological flaws, indirect, or imprecise) or exceptionally strong evidence from observational studies Strong recommendation, can apply to most patients in most circumstances. Higher quality evidence may well change our confidence in the estimate of effect 1C. Strong recommendation, low-quality or very low-quality evidence Benefits clearly outweigh risk and burden, or vice versa Observational studies or case series 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. 일부동의함 (0%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 기능성소화불량증은여러가지다양한증상을보이며그병태생리가한가지로설명할수없는이질적인집단이모인질환군일가능성이높다. 5 실제로유전적인요소, 가족환경, 정신사회적요소, 위장관의운동이상, 내장과민성, 염증효과, 세균등의다양한병태생리기전들이논의되어져왔고, 다양한병태생리로인하여기능성소화불량증에적합한치료약제를선택하는데어려움이있다. 따라서여러가지증상에관련된기저병태생리를이해하고이를교정하는데효과적인약제들을조합하여사용하는것이바람직하다. 2) 생활습관및식이생활습관의개선및식이요법은기능성소화불량증의증상호전에도움을줄수있다. (Grade 2C, 권고수준 : 낮음, 증거 수준 : 낮음 ) 전문가의견 : 전적으로동의함 (39%), 대체로동의함 (61%), 일부동의함 (0%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 기능성소화불량증환자들에있어생활습관을교정하거나식이요법의치료효과에대한문헌자료는부족하다. 일반적으로증상을유발하는음식을피하는것이바람직하다. 커피나매운음식, 고지방식을피하는것이좋다 과음과흡연을삼가며규칙적인생활과적당한운동을권장한다. 식이요법의원칙은어떤음식이좋고어느음식은해가된다는것이아니라환자개개인마다자기에게잘맞는음식과섭취하면불편해지는음식이있으므로일부러남들이좋다는음식을억지로섭취하지말고자기에게맞는음식을먹고, 맞지않는음식은금하는것이좋다. 과일이나기호식품도불편 Vol. 57 No. 2, February 2011

6 72 지삼룡등. 기능성소화불량증치료에관한임상진료지침 을느낄경우에는금한다. 21 3) 프로톤펌프억제제기능성소화불량증환자에서프로톤펌프억제제는치료에효과적이다. (Grade 1A, 권고수준 : 높음, 증거수준 : 높음 ) 전문가의견 : 전적으로동의함 (22%), 대체로동의함 (67%), 일부동의함 (11%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 기능성소화불량증의대표적인증상이궤양과유사한증상이므로항궤양치료에준하는위산분비억제제가사용된다. 실제연구에서통증을주증상으로하는소화불량증환자에서프로톤펌프억제제가효과가있다. 22,23 기능성소화불량증환자에서프로톤펌프억제제효과에대한메타분석은위약과표준용량의프로톤펌프억제제, 유지용량의프로톤펌프억제제등세군을비교하였다. 8 7개의무작위통제연구 3,031명을대상으로한메타분석에서프로톤펌프억제제를 2-8주투약후소화불량증의증상을줄이는데두용량모두위약보다효과적이었다. 10개의무작위통제연구에서 3,347명을대상으로한분석에서는프로톤펌프억제제를 2-8주투약후소화불량증에대한효과가 34% 로위약 (25%) 보다효과적이었다 (Table 2). 22,24-32 기능성소화불량증환자에서프로톤펌프억제제와히스타민수용체길항제를비교한무작위대조군연구에서프로톤펌프억제제가히스타민수용체길항제에비해더좋은경향을보였으나통계적차이는없었다. 25 프로톤펌프억제제와제산제를비교한연구에서는프로톤펌프억제제가제산제보다소화불량증의전반적증상경감에대해효과적이었다. 33,34 흔한부작용은두통, 설사, 구역, 복통등이며, 저염산증, 고가스트린혈증, 유암종, 공동체에서얻은폐렴, 다른약물과의상호작용등이문제가될수있다. 4) 제산제제산제는기능성소화불량증증상의치료에도움을줄수있다. (Grade 2C, 권고수준 : 낮음, 증거수준 : 낮음 ) 전문가의견 : 전적으로동의함 (18%), 대체로동의함 (75%), 일부동의함 (7%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 기능성소화불량증의증상호전면에서제산제는위약과비슷한효과를보였다. 35,36 109명의환자를대상으로 5주동안의연구에서위약은 38%, 제산제는 37% 에서효과가있었다 명의환자를대상으로한다른연구에서통증지표의감소가위약에서는 31%, 제산제에서는 36% 로제산제의효과가높았으나통계적차이는없었다. 36 그러나, 위약과의비교연구에서보듯기능성소화불량증환자에서제산제투여로 37% 에서증상호전을보이고간헐적증상완화에효과적이므로경증환자에서일차치료로고려할수있다. 흔한부작용은전해질불균형이며, 알루미늄포함약제는변비와인산결핍이생길수있고, 마그네슘포함약제는묽은변이발생할수있다. 5) 위장관운동촉진제위장관운동촉진제는기능성소화불량증의치료에효과적이다. (Grade 1B, 권고수준 : 높음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (39%), 대체로동의함 (57%), 일부동의함 (4%), 대체로동의하지않음 (0%), 전적으로동의 Table 2. Randomized Controlled Trials of Proton Pump Inhibitors for Functional Dyspepsia Author Study design and ITT population Treatment Key findings Blum et al wk, multicenter, double-blind -controlled, 792 patients with normal endoscopy, Rome for dyspepsia. Ranitidine 150 mg od in the evening or omeprazole 10 mg od or 20 mg od in the morning vs. Omeprazole 20 mg per day improved dyspeptic symptoms in patients infected with H. pylori to a greater extent than in those who were H. pylori negative. Talley et al wk, double blind, controlled, 1262 patients Omeprazole 10 mg od or 20 mg od vs. Statistical improvement in GSRS between omeprazole 20 mg and but not 10 mg and. Wong et al wk, double blind, controlled, 453 patients Lansoprazole 30 mg od vs. lansoprazole 15 mg od vs. Proton pump inhibitor was not superior to for the management of functional dyspepsia in Chinese patients. Peura et al wk, double blind, controlled, 921 patients Lansoprazole 30 mg od vs. lansoprazole 15 mg od vs. Lansoprazole 15 mg or 30 mg was better than in reducing symptoms of upper abdominal discomfort accompanied by at least some symptoms of heartburn. Veldhuyzen et 8-wk, -controlled, 502 al. 32 patients Esomeprazole 40 mg od vs. Esomeprazole was significantly more effective than for symptom relief at 4 wk. ITT, intention to treat; H. pylori, Helicobacter pylori; GSRS, gastrointestinal symptom rating scale. The Korean Journal of Gastroenterology

7 Jee SR, et al. Guidelines for the Treatment of Functional Dyspepsia 73 하지않음 (0%). 14개연구 1,053명을대상으로한메타분석에서위장관운동촉진제는위약에비해 2-8주투여후증상호전에효과적이었다. 8 19개의무작위통제연구에서 3,178명을대상으로하였을때위장관운동촉진제의효과 (57%) 가위약 (47%) 에비해유의하게높았다 (Table 3). 24,37-55 그러나, 메타분석에사용한대부분의약제는현재부작용으로시판되고있지않은 cisapride에대한연구가대부분이었고, 최근국내에서많이사용하는 mosapride, itopride에대한연구가적어, 보다많은연구가요구되는실정이다. 위장관운동촉진제는그약제기전에따라도파민 D 2 수용체길항제, 5-HT 4 수용체작용제, 모틸린수용체작용제등으로분류된다. 도파민 D 2 수용체길항제중 domperidone은메타분석에서 2-4주간사용했을때위약에비해증상호전에효과적이었다. 56 Itopride는 2상연구에서는위약에비해증상호전에효과적이었다. 48 3상연구에서는위약과차이가없다고보고되었으나, 북미외의유럽에서는증상호전을보였다 HT 4 수용체작용제중대표적인약제는 cisapride와 tegaserod이지만부정맥과심혈관질환유발가능성이각각보고되어두약물모두현재는시장에서퇴출된상태이다. 5-HT 4 수용체작용제중 mosapride는부정맥유발과같은부작용은보고되지않으며, 증상과함께삶의질을개선시킨다는보고도있다. 44,58 모틸린수용체작용제인 erythromycin은초기연구에서는증상호전에효과적이라고보고되었으나최근시행된무작위비교연구에서는위약과차이가없다고보고되었다. 59,60 증상조절이잘되지않는기능성소화불량증환자의경우위장관운동촉진제의용량을증가시킬수있으며두종류의운동촉진제를병합하여사용하는것도효과가있었다. 61,62 증상조절이잘되지않는경우 metoclopramide나 domperidone의용량을증가시킬수있으며위장관운동촉진제의조합도가능하다. 61 Cisapride와 domperidone을병합하여사용하는것이 cisapride 단독투여시보다증상완화에더효과적이었다. 62 6) 히스타민수용체길항제히스타민수용체길항제는기능성소화불량증의치료에효과적이다. (Grade 1B, 권고수준 : 높음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (15%), 대체로동의함 (74%), 일부동의함 (11%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 히스타민수용체길항제는위산분비억제제이므로프로톤펌프억제제에서전술한바와같이기능성소화불량증의증상완화에효과적이다. 12개의연구에근거한 2,183명을대상으로한메타분석결과, 히스타민수용체길항제는 2-6주간투여후위약에비해증상개선효과가있었다 (Table 4). 24,25,35,46,63-71 Table 3. Randomized Controlled Trials of Prokinetics for Functional Dyspepsia Author Study design and ITT population Treatment Key findings al-quorain et al wk, randomized double blind, 89 FD Cisapride 10 mg t.d.s. vs. Reduced postprandial bloating, epigastric pain, early satiety, epigastric burning (p< 0.05) Bekhti et al wk, randomized double blind, 40 FD Domperidone 10 mg t.d.s. vs. Reduced FD symptoms (p<0.05) Chung 40 4-wk, randomized double blind, 29 FD Cisapride 10 mg t.d.s. vs. Reduced bloating and epigastric discomfort (p<0.05); improved global symptoms (p<0.05) de Groot et al wk, randomized double blind, 121 FD Cisapride 10 mg t.d.s. vs. Not superior to in overall symptoms improvement Halleback et al wk, randomized double blind, 606 FD Mosapride 7.5 mg t.d.s. vs. Not superior to in overall symptoms improvement Holtmann et al wk, randomized double blind Itopride 200 mg t.d.s. vs. Talley et al wk, randomized double blind ABT mg b.d.s. vs. Talley et al wk, randomized double blind Itopride 100 mg t.d.s. vs. Arts et al. 60 Randomized double blind Erythromycin 200 mg iv vs. Reduced pain and fullness (p<0.05); improved global symptoms (p<0.05) Not superior to in upper abdominal discomfort improvement Not superior to in overall symptoms improvement Not superior to in overall symptoms improvement FD, functional dyspepsia. Vol. 57 No. 2, February 2011

8 74 지삼룡등. 기능성소화불량증치료에관한임상진료지침 Table 4. Randomized Controlled Trials of Histamine 2 Receptor Antagonists for Functional Dyspepsia Author Study design and ITT population Treatment Key findings Gotthard et al wk, randomized double blind; Rome criteria not used Cimetidine 400 mg b.i.d., antacid 10 ml q.i.d., vs. Cimetidine was superior in relieving pain and nausea (p<0.01), bloating (NS) Hansen et al wk, randomized, double blind; Rome criteria not used Nizatidine 300 mg q.d., cisapride 10 mg t.i.d., vs. Global symptoms: nizatidine was not superior to. Kato et al. 65 Muller et al wk, randomized double blind, crossover; Rome II criteria 4-wk, randomized, double blind; Rome criteria not used Famotidine 20 mg b.i.d., vs. Reduced pain (p<0.01), indigestion, reflux symptom (p<0.05) Ranitidine 150 mg b.i.d., vs. Disappearance of all dyspeptic symptoms: ranitidine was superior to (p<0.05) Singal et al wk, randomized, double blind; Rome criteria not used Cimetidine 400 mg b.i.d., vs. Cimetidine was superior in relieving abdominal pain (p<0.05) 위약에서는 40% 에서효과를보였으나히스타민수용체길항제는 54% 에서증상개선효과가있었으며, 여러소화불량증상중상복부통증, 식후팽만감이히스타민수용체길항제투여로효과가있었다. 일부기능성소화불량증환자에서십이지장내의산노출이증가되어있는경우가있으며, 이러한경우위배출의지연, 위팽창에대한예민도증가, 위저부이완억제등이보고되었다. 72,73 따라서위식도역류질환이동반된기능성소화불량증환자와, 십이지장내의산노출이증가되어있는환자들에게히스타민수용체길항제와같은위산분비억제제가증상의호전에도움을줄수있다. Cimetidine은항안드로겐효과가있어여성형유방, 발기부전이생길수있고다른약물과의상호작용이있을수있다. 드물게착란, 간기능저하, 혈구감소증이생긴다. Famotidine과 nizatidine은다른약물과의상호작용이적은것으로알려져있다. 7) 항우울제항우울제는일부기능성소화불량증환자의치료에도움을준다. (Grade 2B, 권고수준 : 낮음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (19%), 대체로동의함 (74%), 일부동의함 (7%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 다양한정신사회적요소들이기능성소화불량증과밀접하게연관되어있다 기능성소화불량증환자에서가장흔한정신과질환은불안장애, 우울증, 신체형장애이다 주로삼환계항우울제 (tricyclic antidepressants, TCA) 와선택적세로토닌재흡수억제제 (selective serotonin reuptake inhibitors, SSRI) 에대한연구가많다. 13개의연구에근거한 1,717명의환자를대상으로한메타분석에서항우울제는기능성소화불량증의치료에효과적이었다 개의연구에근거한다른메타분석에서도항우울제치료는기능성소화불량 증의치료에효과적이었다. 포함된 11개의연구중대부분은과민성대장증후군환자를대상으로하였고, 두개의연구만이기능성소화불량증환자를대상으로한연구였다. 82 하지만이러한임상적효과와위배출능이나위저부적응등과의연관성은적었다. 8) 내시경검사와기능성소화불량증국내에서는기능성소화불량증의진단및치료를위한초기접근방법으로위내시경검사가헬리코박터검사후제균치료보다효과적이다. (Grade 1C, 권고수준 : 높음, 증거수준 : 낮음 ) 전문가의견 : 전적으로동의함 (54%), 대체로동의함 (46%), 일부동의함 (0%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 서구의경우소화불량증환자에서 Helicobacter pylori 제균치료혹은프로톤펌프억제제투여후반응이없거나재발한경우상부위장관내시경을권하고있고, 경고증상이있거나일정연령이초과한경우는바로상부위장관내시경을권하고있다. 7,83 기준되는연령은미국의경우 55세, 유럽은 45세이다. 무작위연구에기반한메타분석결과, 헬리코박터검사후치료 (test and treat) 와내시경검사를비교하면증상호전에대하여유의한차이가없었다. 84,85 아시아는서구에비해위암이흔하고발병연령이낮으며, 특히우리나라는내시경비용이저렴하여소화불량증환자의초기진단법으로내시경을권장할만하다. 유럽에서실시된연구에서소화불량증에서초기검사로민감도와특이도가높은요소호기검사를실시한결과, 헬리코박터음성군에서소화성궤양이 5% 였으나헬리코박터양성군에서는소화성궤양이 45% 로, 헬리코박터는소화불량증으로내원한환자에서소화성궤양을감별하는진단적가치가높았다. 86 또한헬리코박터검사의부가적인장점은양성인경우제균치료로증상을호전시킬수있다는점이다. 헬리코박터 The Korean Journal of Gastroenterology

9 Jee SR, et al. Guidelines for the Treatment of Functional Dyspepsia 75 를 검사및치료 (test and treat) 하는방법은경험적위산분비억제제투여와비교할때 1년후증상호전이뛰어나 (60% vs. 47%) 영국, 스코틀랜드, 캐나다및미국의소화불량증진료지침에서초기진단으로헬리코박터검사를시행하여양성인경우제균치료를하도록권장한다. 7-10,83 우리나라와위암이나헬리코박터의역학분포가유사한중국에서 14,101명을대상으로경고증상, 헬리코박터검사및상부위장관내시경을검사하였는데, 전체환자중 1.4% (202 명 ) 에서위, 식도및십이지장악성종양이발견되었고, 이중 18.9% 는 45세미만이었고, 이중 27.8% 에서만경고증상이있었으며, 헬리코박터는 72% 에서양성이었다. 87 저자들은헬리코박터검사후치료방법을 45세미만에서적용하는경우위암의 72.2% 를진단하지못했고, 헬리코박터검사후내시경을시행하는경우 16.7% 에서위암을진단하지못했기때문에소화불량증의초치료로헬리코박터검사가적절하지않다고시사하였다. 87 국내의자료를살펴보면, 3차병원에서소화불량증으로상부위장관내시경을실시한환자에서소화성궤양에서 86.7%, 위암에서 77.8%, 비궤양성소화불량증에서 54.2% 에서헬리코박터양성이었다. 88,89 최근종합검진수진자를대상으로로마기준 II에합당한기능성소화불량증환자 793명을대상으로한연구에서기능성소화불량증의 62.5%, 대조군의 58.2% 에서헬리코박터양성으로양군간의유의한차이가없었다. 이러한자료에근거하여소화성궤양의 85%, 위암의 80%, 기능성소화불량증의 60% 에서헬리코박터양성으로가정하고민감도가 90% 가넘는헬리코박터진단방법으로검사할경우, 소화성궤양이나위암을진단하는헬리코박터검사의민감도는 85%, 특이도는 40% 내외이고양성우도비 1.4, 음성우도비 0.4로진단적가치가낮을것이예상된다. 그러나현재까지헬리코박터검사및치료를소화불량증진단에초기접근법으로전략을세우고비교한무작위대조군연구가없다. 국내 3차기관에서비궤양성소화불량증환자를대상으로내시경을시행하기전혈청헬리코박터검사의유용성을이번연구에서 40세이하 308명중에서헬리코박터양성인경우기질적질환에대한민감도 76.7%, 음성예측치 85.8% 였고, 40세초과군에서는각각 61.9%, 64.0% 였으며, 40세이하에서악성종양이없었으나 40세초과군에서는 307 명중 28명에서위암이발견되었고, 헬리코박터양성유무에따른악성종양진단율에는차이가없었다. 90 즉, 소화불량증에서헬리코박터검사는 40세이하에서는기질적질환의 85% 가소화성궤양이므로소화성궤양을진단할민감도가 75-80% 내외이고, 40세초과군에서는위암 26%, 소화성궤양 57% 가포함된기질적질환을진단할민감도가 60% 내외를의미하여, 국내에서소화불량증진단에헬리코박터검사는그진단적가치가낮을것으로추정된다. 9) 헬리코박터제균치료와기능성소화불량증헬리코박터양성인기능성소화불량증에서제균치료는일부환자에서도움을준다. (Grade 2B, 권고수준 : 낮음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (22%), 대체로동의함 (70%), 일부동의함 (4%), 대체로동의하지않음 (4%), 전적으로동의하지않음 (0%). 12개의연구에근거한 2,903명을대상으로한메타분석결과, 헬리코박터제균치료는위약에비해증상개선효과가있었다. 8,91-99 위약군에서는 36% 에서효과를보였으나헬리코박터제균치료는 43% 에서증상개선효과가있었다. 국내에서헬리코박터양성인기능성소화불량증에서헬리코박터제균치료가증상개선에미치는효과를이번연구결과는매우제한적이며서로상반되는결과를보이고있어추가연구가필요하다. 100,101 소화불량증에서헬리코박터가양성일경우제균치료와위산분비억제제를비교한연구결과를살펴보면, 위산분비억제제처방후 53% 에서 12개월후증상의재발을경험하였으나헬리코박터제균후 12개월뒤증상재발률이산분비억제제에비해 13-40% 감소하여증상이지속될상대적위험도가유의하게낮았다. 102,103 그러나이연구에서는헬리코박터음성환자가빠져있는제한점이있다. 소화불량증환자에서헬리코박터제균치료의효과로임상증상의개선을보이는국내및아시아연구자료는매우제한적이다. 1998년경주시주변 23개동주민중소화불량증증상이있는 510명을대상으로헬리코박터혈청검사를실시하여 375명이양성으로판정을받았고, 이중 304명이위내시경을실시하였다. 100 소화불량증은식후불편감, 명치팽만감및통증, 트림, 속쓰림, 위산역류, 트림의어느증상이최소 3개월이상지속된경우로정의하였고 (5-Likert scale) 어느증상이라도 5점중 1점이상좋아지면호전으로간주하였다. 신속요소분해효소검사양성은 204명 (67.1%) 였고, 이중비궤양성소화불량증이 197명이었다. 제균치료를실시하고 1년후증상호전은제균이완료된군이 62.1%, 제균이되지않은군은 59.6% 로양군간에통계적차이는없었다. 이등은 3차병원으로내원한헬리코박터파이로리양성인 203명중소화불량증환자 123명과소화성궤양 70명을대상으로제균치료후전향적으로평균 12개월까지추적관찰하였다. 101 양군간에헬리코박터제균율은차이가없었고, 기능성소화불량증군은 67.4%, 소화성궤양군은 72.5% 에서증상호전이있었고, 특히소화불량증군에서 9개월및 12개월모두헬리코박터제균치료군이제균치료실패군에비해유의한증상호전을보였다. 그러므로아직까지의연구결과로는헬리코박터양성인기능성소화불량증에서증상개선에대한효과가서로상반되는 Vol. 57 No. 2, February 2011

10 76 지삼룡등. 기능성소화불량증치료에관한임상진료지침 결과를보이고있다. 국내의기능성소화불량증에서헬리코박터양성률은 50-65% 정도로일반인구와비슷하고, 기능성소화불량증의유병률도일반인구집단의 % 로높다. 그러므로약전인구의 5% 가헬리코박터양성인기능성소화불량증을갖고있다고가정할수있어그의료비용은매우높을것으로예상된다. 또한위암의고위험군이라는이유로실패율이많은대상군에서제균치료를시행하는경우항생제내성균주가증가할수있는위험성이있다. 그러므로국내에서기능성소화불량증환자에서헬리코박터제균치료는유효성에대한근거및비용효과에대한연구결과가도출되어야하며헬리코박터제균치료의효과와위험성을모두고려한접근이필요하다. 헬리코박터제균치료와연관된주요부작용으로는항생제관련위장관이상반응이가장흔하며, 묽은변혹은설사, 구역, 구토, 복부팽만및복통등의증상이동반되기도한다. 국내자료를보면, 묽은변혹은설사는약제투여후 1주동안 41% 로높으나대부분소실되며, 장내가스, 복부팽만, 복통등이흔했다 ) 점막보호제점막보호제는일부기능성소화불량증환자의증상호전에도움을줄수있다. (Grade 2C, 권고수준 : 낮음, 증거수준 : 낮음 ) 전문가의견 : 전적으로동의함 (4%), 대체로동의함 (62%), 일부동의함 (23%), 대체로동의하지않음 (12%), 전적으로동의하지않음 (0%). 일본과서양의보고에서점막보호제는기능성소화불량증환자의일부에서증상호전을보였다. 105,106 무작위, 이중맹검법의위약과비교한보고에서 81명의기능성소화불량증환자에서 rebapamide를 4주투여후위약과비교하였을때팽만감, 트림, 통증등의일부증상에서호전을보였다. 105 외국의다기관연구에서는 rebapamide 2주투여시치료중증상이호전되는경향을보였다. 106 Ecabet sodium에대한국내연구에서는소화불량증의증상을호전시키고, cimetidine과비교시효능이뒤지지않았다. 107,108 Teprenone, eupatilin 등도미란성위염환자에서자각증상의개선을보였으나, 109,110 아직까지기능성소화불량증에대한점막보호제의연구는부족한실정이다. 11) 위저부이완제기능성소화불량증환자의일부에서위저부이완제가치료에도움을준다. (Grade 2B, 권고수준 : 낮음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (11%), 대체로동의함 (61%), 일부동의함 (29%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). Sumatriptan, buspirone, cisapride, tegaserod 등위저부이완제는위의근위부를확장시키고긴장도를조절하여기능성소화불량증환자의일부에서증상호전에도움을준다 기능성소화불량증환자의 40% 에서식후위저부의이완장애를보이며조기포만감, 체중감소가나타난다는결과가보고되어있다 HT 1 수용체작용제인 sumatriptan 을사용하면위저부의이완이유발되어조기포만감을호소하는환자들에도움이된다. 111 Buspirone 역시 5-HT 1 수용체작용제이며용량에비례하여위근위부를이완시키는것으로알려졌다 ) 내장과감각억제제내장과감각억제제가기능성소화불량증환자의치료에도움을준다. (Grade 2B, 권고수준 : 낮음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (4%), 대체로동의함 (78%), 일부동의함 (19%), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 기능성소화불량증환자는위의팽창자극에대해민감하여정상인과비교하여낮은자극에도불쾌감이유발된다. 114,116 기능성소화불량증환자의 34% 에서위팽창에대한과민성이관찰되었고, 또한식후통증, 트림, 체중감소의빈도가높았다 HT 3 수용체길항제인그라니세트론은상부및하부위장관에대한내장진통효과가있는것으로나타났으며, 오피오이드촉진제중 κ촉진제인 fedotozine은위확장시민감도를감소시켜주며기능성소화불량증환자에서통증이나팽만감을호전시켜준다. 118,119 콜레시스토키닌길항제도효과가있는것으로보고되며, 소마토스타틴유사물질인옥트레오타이드는장확장시팽창도에영향없이민감도를호전시킨다. 120,121 13) 정신치료증상이심하고, 약물치료에반응이없는기능성소화불량증환자에서정신치료가도움을준다. (Grade 2B, 권고수준 : 낮음, 증거수준 : 중등도 ) 전문가의견 : 전적으로동의함 (8%), 대체로동의함 (62%), 일부동의함 (31), 대체로동의하지않음 (0%), 전적으로동의하지않음 (0%). 정신치료중통찰치료 (insight-oriented psychotherapy), 휴식과스트레스관리훈련, 인지행동치료, biofeedback, 최면요법등이기능성소화불량증의치료에사용되어왔다. 122,123 4개의연구에근거한 404명을대상으로한메타분석에서는, 정신치료에대한보고들을분석한결과포함된개체수가적고또한탈락자의비율이높아그효용성을판단하기힘들다고하였으나, 각각의논문결과는정신치료가대증요법에비해기능성소화불량증의증상호전에도움을준다고하였다. 81, The Korean Journal of Gastroenterology

11 Jee SR, et al. Guidelines for the Treatment of Functional Dyspepsia 77 요 약 1) 기능성소화불량증은여러가지병태생리가관여되어다양한증상양상을보이는이질적인질환군이며증상을유발할수있는기저병태생리를추정하여이를교정해주는약물들을조합하는치료가효과적이다. 2) 생활습관의개선및식이요법은기능성소화불량증의증상호전에도움을줄수있다. 3) 기능성소화불량증환자에서프로톤펌프억제제는치료에효과적이다. 4) 제산제는기능성소화불량증증상의치료에도움을줄수있다. 5) 위장관운동촉진제는기능성소화불량증의치료에효과적이며, 증상조절이잘되지않는경우위장관운동촉진제의용량을증가시킬수있으며두종류의운동촉진제를병합하여사용하는것도효과가있다. 6) 히스타민수용체길항제는기능성소화불량증의치료에효과적이다. 7) 항우울제는일부기능성소화불량증환자의치료에도움을준다. 8) 국내에서는기능성소화불량증의진단및치료를위한초기접근방법으로위내시경검사가헬리코박터검사후제균치료보다효과적이다. 9) 헬리코박터양성인기능성소화불량증에서제균치료는일부환자에서도움을준다. 10) 점막보호제는일부기능성소화불량증환자의증상호전에도움을줄수있다. 11) 기능성소화불량증환자의일부에서위저부이완제가치료에도움을준다. 12) 내장과감각억제제가기능성소화불량증환자의치료에도움을준다. 13) 증상이심하고, 약물치료에반응이없는기능성소화불량증환자에서정신치료가도움을준다. REFERENCES 1. Management of dyspepsia: report of a working party. Lancet 1988;1: Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR, Tytgat GN. Functional gastroduodenal disorders. Gut 1999;45 (Suppl 2):II37-II Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006;130: Jung HK, Keum BR, Jo YJ, Jee SR, Rhee PL, Kang YW. Diagnosis of functional dyspepsia: a systematic review. Korean J Gastroenterol 2010;55: Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130: Talley NJ, Lam SK, Goh KL, Fock KM. Management guidelines for uninvestigated and functional dyspepsia in the Asia-Pacific region: First Asian Pacific Working Party on Functional Dyspepsia. J Gastroenterol Hepatol 1998;13: Talley NJ, Vakil NB, Moayyedi P. American gastroenterological association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129: National Institute for Clinical Excellence. Dyspepsia: Managing dyspepsia in adults in primary care. pdf/cg-017fullguideline.pdf, Veldhuyzen van Zanten SJ, Bradette M, Chiba N, et al. Evidence-based recommendations for short- and long-term management of uninvestigated dyspepsia in primary care: an update of the Canadian Dyspepsia Working Group (CanDys) clinical management tool. Can J Gastroenterol 2005;19: Scottish Intercollegiate Guidelines Network. Dyspepsia: A national clinical guideline. pdf, Lee KJ. Evidence based guideline for diagnosis and treatment : therapeutic guideline for functional dyspepsia. Korean J Neurogastroenterol Motil 2005;11: Jones R, Lydeard S. Prevalence of symptoms of dyspepsia in the community. BMJ 1989;298: Lieberman D, Fennerty MB, Morris CD, Holub J, Eisen G, Sonnenberg A. Endoscopic evaluation of patients with dyspepsia: results from the national endoscopic data repository. Gastroenterology 2004;127: Ryu KH, Kim YH, Son HJ, et al. Various causes of dyspepsia: to determine organic and functional cause of dyspepsia. Korean J Gastrointest Motil 1998;4: van Kerkhoven LA, Laheij RJ, Meineche-Schmidt V, Veldhuyzenvan Zanten SJ, de Wit NJ, Jansen JB. Functional dyspepsia: not all roads seem to lead to rome. J Clin Gastroenterol 2009; 43: Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schünemann HJ. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl): 123S-131S. 17. Barbera R, Feinle C, Read NW. Abnormal sensitivity to duodenal lipid in patients with functional dyspepsia. Eur J Gastroenterol Hepatol 1995;7: Barbera R, Feinle C, Read NW. Nutrient-specific modulation of gastric mechanosensitivity in patients with functional dyspepsia. Dig Dis Sci 1995;40: Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 2004;127: Boekema PJ, Samsom M, Roelofs JM, Smout AJ. Effect of coffee on motor and sensory function of proximal stomach. Dig Dis Sci 2001;46: Lee SI. Functional cyspepsia. J Korean Med Assoc 2005; Vol. 57 No. 2, February 2011

12 78 지삼룡등. 기능성소화불량증치료에관한임상진료지침 48: Talley NJ, Meineche-Schmidt V, Paré P, et al. Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, -controlled trials (the Bond and Opera studies). Aliment Pharmacol Ther 1998;12: Jones RH, Baxter G. Lansoprazole 30 mg daily versus ranitidine 150 mg b.d. in the treatment of acid-related dyspepsia in general practice. Aliment Pharmacol Ther 1997;11: Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2006;(4):CD Blum AL, Arnold R, Stolte M, Fischer M, Koelz HR. Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status. The Frosch Study Group. Gut 2000;47: Talley NJ, Lauritsen K. The potential role of acid suppression in functional dyspepsia: the BOND, OPERA, PILOT, and ENCORE studies. Gut 2002;50(Suppl 4):iv36-iv Bolling-Sternevald E, Lauritsen K, Aalykke C, et al. Effect of profound acid suppression in functional dyspepsia: a double-blind, randomized, -controlled trial. Scand J Gastroenterol 2002;37: Wong WM, Wong BC, Hung WK, et al. Double blind, randomised, controlled study of four weeks of lansoprazole for the treatment of functional dyspepsia in Chinese patients. Gut 2002;51: Farup PG, Hovde O, Torp R, Wetterhus S. Patients with functional dyspepsia responding to omeprazole have a characteristic gastro-oesophageal reflux pattern. Scand J Gastroenterol 1999;34: Gerson LB. Triadafilopoulos G. A prospective study of oesophageal 24-h ambulatory ph monitoring in patients with functional dyspepsia. Dig Liver Dis 2005;37: Peura DA, Kovacs TO, Metz DC, Siepman N, Pilmer BL, Talley NJ. Lansoprazole in the treatment of functional dyspepsia: two double-blind, randomized, -controlled trials. Am J Med 2004;116: van Zanten SV, Armstrong D, Chiba N, et al. Esomeprazole 40mg once a day in patients with functional dyspepsia: The randomized -controlled ENTER trial. Am J Gastroenterol 2006;101: Goves J, Oldring JK, Kerr D, et al. First line treatment with omeprazole provides an effective and superior alternative strategy in the management of dyspepsia compared to antacid/alginate liquid: a multicentre study in general practice. Aliment Pharmacol Ther 1998;12: Meineche-Schmidt V, Krag E. Antisecretory therapy in 1017 patients with ulcerlike or refluxlike dyspepsia in general practice. Eur J Gastroenterol Hepatol 1997;3: Gotthard R, Bodemar G, Brodin U, Jönsson KA. Treatment with cimetidine, antacid, or in patients with dyspepsia of unknown origin. Scand J Gastroenterol 1988;23: Nyrén O, Adami HO, Bates S, et al. Absence of therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. N Engl J Med 1986;314: al-quorain A, Larbi EB, al-shedoki F. A double-blind, randomized, -controlled trial of cisapride in Saudi Arabs with functional dyspepsia. Scand J Gastroenterol 1995;30: Bekhti A, Rutgeerts L. Domperidone in the treatment of functional dyspepsia in patients with delayed gastric emptying. Postgrad Med J 1979;55(Suppl 1): Champion MC, MacCannell KL, Thomson AB, et al. A double-blind randomized study of cisapride in the treatment of nonulcer dyspepsia. The Canadian Cisapride Nud Study Group. Can J Gastroenterol 1997;11: Chung JM. Cisapride in chronic dyspepsia: results of a double-blind, -controlled trial. Scand J Gastroenterol Suppl 1993;195: de Groot GH, de Both PS. Cisapride in functional dyspepsia in general practice. A -controlled, randomized, double-blind study. Aliment Pharmacol Ther 1997;11: De Nutte N, Van Ganse W, Witterhulghe M, Defrance P. Relief of epigastric pain in nonulcer dyspepsia: controlled trial of the promotility drug cisapride. Clin Ther 1989;11: Francois I, De Nutte N. Nonulcer dyspepsia: effect of the gastrointestinal prokinetic drug cisapride. Curr Ther Res 1987;41: Hallerback BI, Bommelaer G, Bredberg E, et al. Dose finding study of mosapride in functional dyspepsia: a -controlled, randomized study. Aliment Pharmacol Ther 2002;16: Hannon R. Efficacy of cisapride in patients with nonulcer dyspepsia. A -controlled study. Curr Ther Res 1987; 42: Hansen JM, Bytzer P, Schaffalitzky de Muckadell OB. Placebocontrolled trial of cisapride and nizatidine in unselected patients with functional dyspepsia. Am J Gastroenterol 1998; 93: Holtmann G, Gschossmann J, Mayr P, Talley NJ. A randomized -controlled trial of simethicone and cisapride for the treatment of patients with functional dyspepsia. Aliment Pharmacol Ther 2002;16: Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C. A -controlled trial of itopride in functional dyspepsia. N Engl J Med 2006;354: Kellow JE, Cowan H, Shuter B, et al. Efficacy of cisapride therapy in functional dyspepsia. Aliment Pharmacol Ther 1995; 9: Matsueda K, Hongo M, Sasaki D, et al. Therapeutic efficacy of novel agent (Z-338) in functional dyspespsia (FD). Gastroenterology 2005;128(Suppl 1):A Rösch W. Cisapride in non-ulcer dyspepsia. Results of a -controlled trial. Scand J Gastroenterol 1987;22: Talley NJ, Verlinden M, Snape W, et al. Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind -controlled trial. Aliment Pharmacol Ther 2000;14: Talley NJ, Van Zanten SV, Saez LR, et al. A dose-ranging, -controlled, randomized trial of alosetron in patients with functional dyspepsia. Aliment Pharmacol Ther 2001;15:525- The Korean Journal of Gastroenterology

13 Jee SR, et al. Guidelines for the Treatment of Functional Dyspepsia Wood SF, Penney SC, Cochran KM. Cisapride in functional dyspepsia: a double-blind, -controlled randomized trial in general practice patients. Scand J Gastroenterol Suppl 1993; 195: Yeoh KG, Kang JY, Tay HH, et al. Effect of cisapride on functional dyspepsia in patients with and without histological gastritis: a double-blind -controlled trial. J Gastroenterol Hepatol 1997;12: Veldhuyzen van Zanten SJ, Jones MJ, Verlinden M, Talley NJ. Efficacy of cisapride and domperidone in functional (nonulcer) dyspepsia: a meta-analysis. Am J Gastroenterol 2001;96: Talley NJ, Tack J, Ptak T, Gupta R, Giguère M. Itopride in functional dyspepsia: results of two phase III multicentre, randomised, double-blind, -controlled trials. Gut 2008;57: Cho YK, Choi MG, Kim SH, et al. The effect of mosapride on quality of life in functional dyspepsia. Korean J Gastroenterol 2004;43: Janssens J, Peeters TL, Vantrappen G, et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. Preliminary studies. N Engl J Med 1990;322: Arts J, Caenepeel P, Verbeke K, Tack J. Influence of erythromycin on gastric emptying and meal related symptoms in functional dyspepsia with delayed gastric emptying. Gut 2005;54: Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004;127: Tatsuta M, Iishi H, Nakaizumi A, Okuda S. Effect of treatment with cisapride alone or in combination with domperidone on gastric emptying and gastrointestinal symptoms in dyspeptic patients. Aliment Pharmacol Ther 1992;6: Delattre M, Malesky M, Prinzie A. Symptomatic treatment of non-ulcer dyspepsia with cimetidine. Curr Ther Res 1985;37: Hadi S. Clinical investigation of ranitidine in patients with gastritis. Clin Ther 1989;11: Kato M, Watanabe M, Konishi S, et al. Randomized, double-blind, -controlled crossover trial of famotidine in patients with functional dyspepsia. Aliment Pharmacol Ther 2005;21(Suppl 2):S27-S Kelbaek H, Linde J, Eriksen J, Mungaard S, Moesgaard F, Bonnevie O. Controlled clinical trial of treatment with cimetidine for non-ulcer dyspepsia. Acta Med Scand 1985;217: Müller P, Hotz J, Franz E, Simon B. Ranitidine in the treatment of non-ulcer dyspepsia. A -controlled study in the Federal Republic of Germany. Arzneimittelforschung 1994;44: Nesland AA, Berstad A. Effect of cimetidine in patients with non-ulcer dyspepsia and erosive prepyloric changes. Scand J Gastroenterol 1985;20: Olubuyide IO, Ayoola EA, Okubanjo AO, Atoba MA. Non-ulcer dyspepsia in Nigerians clinical and therapeutic results. Scand J Gastroenterol Suppl 1986;124: Saunders JH, Oliver RJ, Higson DL. Dyspepsia: incidence of a non-ulcer disease in a controlled trial of ranitidine in general practice. Br Med J (Clin Res Ed) 1986;292: Singal AK, Kumar A, Broor SL. Cimetidine in the treatment of non-ulcer dyspepsia: results of a randomized double-blind, -controlled study. Curr Med Res Opin 1989;11: Lee KJ, Demarchi B, Demedts I, Sifrim D, Raeymaekers P, Tack J. A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea. Am J Gastroenterol 2004;99: Lee KJ, Vos R, Janssens J, Tack J. Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans. Am J Physiol Gastrointest Liver Physiol 2004;286: G Castillo EJ, Camilleri M, Locke GR, et al. A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia. Clin Gastroenterol Hepatol 2004;2: Kim JW, Kim SY, Kim CS, et al. Role of stress in functional dyspepsia. Korean J Gastrointest Motil 2002;8: Lee S, Park M, Choi S, Nah Y, Abbey SE, Rodin G. Stress, coping, and depression in non-ulcer dyspepsia patients. J Psychosom Res 2000;49: Locke GR 3rd, Weaver AL, Melton LJ 3rd, Talley NJ. Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case-control study. Am J Gastroenterol 2004;99: Haug TT, Svebak S, Wilhelmsen I, Berstad A, Ursin H. Psychological factors and somatic symptoms in functional dyspepsia. A comparison with duodenal ulcer and healthy controls. J Psychosom Res 1994;38: Lee KT, Rhee PL, Kim JJ, et al. A study on the psychologic factors in functional dyspepsia. Korean J Med 1996;51: Magni G, di Mario F, Bernasconi G, Mastropaolo G. DSM-III diagnoses associated with dyspepsia of unknown cause. Am J Psychiatry 1987;144: Hojo M, Miwa H, Yokoyama T, et al. Treatment of functional dyspepsia with antianxiety or antidepressive agents: systematic review. J Gastroenterol 2005;40: Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med 2000;108: Rubin G, Meineche-Schmidt V, Roberts A, de Wit N. The use of consensus to develop guidelines for the management of Helicobacter pylori infection in primary care. European Society for Primary Care Gastroenterology. Fam Pract 2000;17(Suppl 2):S21-S Ford AC, Qume M, Moayyedi P, et al. Helicobacter pylori test and treat or endoscopy for managing dyspepsia: an individual patient data meta-analysis. Gastroenterology 2005;128: Heaney A, Collins JS, Watson RG, McFarland RJ, Bamford KB, Tham TC. A prospective randomised trial of a test and treat policy versus endoscopy based management in young Vol. 57 No. 2, February 2011

14 80 지삼룡등. 기능성소화불량증치료에관한임상진료지침 Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45: McColl KE, el-nujumi A, Murray L, et al. The Helicobacter pylori breath test: a surrogate marker for peptic ulcer disease in dyspeptic patients. Gut 1997;40: Li XB, Liu WZ, Ge ZZ, Chen XY, Shi Y, Xiao SD. Helicobacter pylori "test-and-treat" strategy is not suitable for the management of patients with uninvestigated dyspepsia in Shanghai. Scand J Gastroenterol 2005;40: Kim KC, Park HJ, Lee HW, et al. Relation of serum gastrin and pepsinogen levels to serologic recognition of CagA and VacA in Helicobacter pylori infection. Korean J Gastroenterol 1997;29: Park IS, Lee YC, Park HJ, et al. Helicobacter pylori Infection in Korea. Yonsei Med J 2001;42: Hwang IR, Kim JH, Lee KJ, Cho SW. Can Helicobacter pylori serology predict non-ulcer dyspepsia in young dyspeptic patients? Korean J Gastrointest Endosc 2000;21: Blum AL, Talley NJ, O'Moráin C, et al. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin effect one year after treatment (OCAY) study group. N Engl J Med 1998;339: Froehlich F, Gonvers JJ, Wietlisbach V, et al. Helicobacter pylori eradication treatment does not benefit patients with nonulcer dyspepsia. Am J Gastroenterol 2001;96: Gisbert JP, González L, Calvet X, Roqué M, Gabriel R, Pajares JM. Helicobacter pylori eradication: proton pump inhibitor vs. ranitidine bismuth citrate plus two antibiotics for 1 week-a meta-analysis of efficacy. Aliment Pharmacol Ther 2000;14: Lin CK, Hsu PI, Lai KH, et al. One-week quadruple therapy is an effective salvage regimen for Helicobacter pylori infection in patients after failure of standard triple therapy. J Clin Gastroenterol 2002;34: Koskenpato J, Farkkilä M, Sipponen P. Helicobacter pylori eradication and standardized 3-month omeprazole therapy in functional dyspepsia. Am J Gastroenterol 2001;96: Malfertheiner P, Bayerdörffer E, Diete U, et al. The GU-MACH study: the effect of 1-week omeprazole triple therapy on Helicobacter pylori infection in patients with gastric ulcer. Aliment Pharmacol Ther 1999;13: McColl KE, Murray LS, Gillen D, et al. Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H pylori testing alone in the management of dyspepsia. BMJ 2002;324: Miwa H, Nagahara A, Sato K, et al. Efficacy of 1 week omeprazole or lansoprazole-amoxycillin-clarithromycin therapy for Helicobacter pylori infection in the Japanese population. J Gastroenterol Hepatol 1999;14: Talley NJ, Janssens J, Lauritsen K, Rácz I, Bolling-Sternevald E. Eradication of Helicobacter pylori in functional dyspepsia: randomised double blind controlled trial with 12 months' follow up. The Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group. BMJ 1999;318: Kim SH, Hong DY, Kang PS, et al. Community-based Helicobacter pylori screening and its effects on eradication in patients with dyspepsia. Korean J Prev Med 2000;33: Lee EJ, Gham CW, Park TW, et al. The effect of Helicobacter pylori eradication on the improvement of the symptoms in patients with functional dyspepsia and peptic ulcer disease. Korean J Med 2006;71: Chiba N, Van Zanten SJ, Sinclair P, Ferguson RA, Escobedo S, Grace E. Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatment-helicobacter pylori positive (CADET-Hp) randomised controlled trial. BMJ 2002;324: Stevens R, Baxter G. Benefit of Helicobacter pylori eradication in the treatment of ulcer-like dyspepsia in primary care. Gastroenterology 2001;120(Suppl 1):A Kwon SB, Lee KL, Kim JS, et al. Antibiotics-associated diarrhea and other gastrointestinal abnormal responses regarding Helicobacter pylori eradication. Korean J Gastroenterol 2010;56: Miwa H, Osada T, Nagahara A, et al. Effect of a gastro-protective agent, rebamipide, on symptom improvement in patients with functional dyspepsia: a double-blind -controlled study in Japan. J Gastroenterol Hepatol 2006; 21: Talley NJ, Riff DS, Schwartz H, Marcuard SP. Double-blind -controlled multicentre studies of rebamipide, a gastroprotective drug, in the treatment of functional dyspepsia with or without Helicobacter pylori infection. Aliment Pharmacol Ther 2001;15: Yang Kim H, Hahm KB, Choi MG, et al. Prospective multi-center trial for the efficacy of ecabet sodium on the relief of dyspepsia in Korean patients with chronic gastritis. J Clin Biochem Nutr 2007;41: Lee JH, Kim JJ, Hahm KB, et al. Efficacy and safety of ecabet sodium on functional dyspepsia: a prospective, double-blinded, randomized, multi-center controlled trial. World J Gastroenterol 2006;12: Seol SY, Kim MH, Rew JS, Choi MG. A phase III clinical trial of stillen(tm) for erosive gastritis. Korean J Gastrointest Endosc 2004;28: Sakamoto C, Ogoshi K, Saigenji K, et al. Comparison of the effectiveness of geranylgeranylacetone with cimetidine in gastritis patients with dyspeptic symptoms and gastric lesions: a randomized, double-blind trial in Japan. Digestion 2007; 75: Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998;115: Tack J, Coulie B, Wilmer A, Andrioli A, Janssens J. Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut 2000;46: Van Oudenhove L, Kindt S, Vos R, Coulie B, Tack J. Influence of buspirone on gastric sensorimotor function in man. Aliment Pharmacol Ther 2008;28: The Korean Journal of Gastroenterology

15 Jee SR, et al. Guidelines for the Treatment of Functional Dyspepsia Tack J, Broeckaert D, Coulie B, Janssens J. The influence of cisapride on gastric tone and the perception of gastric distension. Aliment Pharmacol Ther 1998;12: Tack J, Vos R, Janssens J, Salter J, Jauffret S, Vandeplassche G. Influence of tegaserod on proximal gastric tone and on the perception of gastric distension. Aliment Pharmacol Ther 2003;18: Camilleri M, Coulie B, Tack JF. Visceral hypersensitivity: facts, speculations, and challenges. Gut 2001;48: Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001;121: Moss HE, Sanger GJ. The effects of granisetron, ICS and ondansetron on the visceral pain reflex induced by duodenal distension. Br J Pharmacol 1990;100: Read NW, Bardhan KD, Whorwell PJ, et al. Fedotozine in functional dyspepsia: results of a 6-week -controlled multicenter therapeutic trial. Gastroenterology 1995;108(Suppl): A Boulant J, Fioramounti J, Dapoiguy M, Bommelear G, Bueno L. Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distension in dogs. Gastroenterology 1994;107: Bradette M, Delvaux M, Stsumont G, Fioramonti J, Bueno L, Frexinos J. Octreotide increases thresholds of colonic visceral perception in IBS patients without modifying muscle tone. Dig Dis Sci 1994;39: Talley NJ, Owen BK, Boyce P, Paterson K. Psychological treatments for irritable bowel syndrome: a critique of controlled treatment trials. Am J Gastroenterol 1996;91: Calvert EL, Houghton LA, Cooper P, Morris J, Whorwell PJ. Long-term improvement in functional dyspepsia using hypnotherapy. Gastroenterology 2002;123: Soo S, Forman D, Delaney BC, Moayyedi P. A systematic review of psychological therapies for nonulcer dyspepsia. Am J Gastroenterol 2004;99: Bates S, Sjoden PO, Nyren O. Behavioral treatment of non-ulcer dyspepsia. Scand J Behav Ther 1988;17: Haug TT, Wilhelmsen I, Svebak S, Berstad A, Ursin H. Psychotherapy in functional dyspepsia. J Psychosom Res 1994; 38: Hamilton J, Guthrie E, Creed F, et al. A randomized controlled trial of psychotherapy in patients with chronic functional dyspepsia. Gastroenterology 2000;119: Calvert EL, Houghton LA, Cooper P, Morris J, Whorwell PJ. Long-term improvement in functional dyspepsia using hypnotherapy. Gastroenterology 2002;123: Vol. 57 No. 2, February 2011