complementary and alternative therapies for functional ......complementary and alternative therapies...

Complementary and Alternative Therapies for Functional Gastrointestinal Diseases

Guest Editors Jiande D Z Chen Jieyun Yin Toku Takahashi and Xiaohua Hou

Evidence-Based Complementary and Alternative Medicine

Complementary and Alternative Therapies forFunctional Gastrointestinal Diseases



Guest Editors Jiande D Z Chen Jieyun YinToku Takahashi and Xiaohua Hou

Copyright copy 2015 Hindawi Publishing Corporation All rights reserved

This is a special issue published in ldquoEvidence-Based Complementary and Alternative Medicinerdquo All articles are open access articlesdistributed under the Creative Commons Attribution License which permits unrestricted use distribution and reproduction in anymedium provided the original work is properly cited

Editorial Board

Mona Abdel-Tawab GermanyJon Adams AustraliaGabriel A Agbor CameroonUlysses P Albuquerque BrazilSamir Lutf Aleryani USAAther Ali USAM Ali-Shtayeh PalestineGianni Allais ItalyTerje Alraek NorwayShrikant Anant USAIsabel Andjar SpainLetizia Angiolella ItalyVirginia A Aparicio SpainMakoto Arai JapanManuel Arroyo-Morales SpainHyunsu Bae Republic of KoreaGiacinto Bagetta ItalyOnesmo B Balemba USAWinfried Banzer GermanyPanos Barlas UKVernon A Barnes USASamra Bashir PakistanPurusotam Basnet NorwayJairo Kennup Bastos BrazilSujit Basu USAArpita Basu USAGeorge D Baxter New ZealandAndre-Michael Beer GermanyAlvin J Beitz USALouise Bennett AustraliaMaria Camilla Bergonzi ItalyAnna R Bilia ItalyYong C Boo Republic of KoreaMonica Borgatti ItalyFrancesca Borrelli ItalyGeoffrey Bove USAGloria Brusotti ItalyArndt Bussing GermanyRainer W Bussmann USAAndrew J Butler USAGioacchino Calapai ItalyGiuseppe Caminiti ItalyRaffaele Capasso ItalyFrancesco Cardini ItalyOpher Caspi Israel

Subrata Chakrabarti CanadaPierre Champy FranceShun-Wan Chan Hong KongIl-Moo Chang Republic of KoreaChun T Che USAKevin Chen USAEvan P Cherniack USASalvatore Chirumbolo ItalyW Chi-shing Cho Hong KongJae Youl Cho KoreaKathrine B Christensen DenmarkShuang-En Chuang TaiwanY Clement Trinidad And TobagoPaolo Coghi ItalyMarisa Colone ItalyLisa A Conboy USAKieran Cooley CanadaEdwin L Cooper USAOlivia Corcoran UKMuriel Cuendet SwitzerlandRoberto K N Cuman BrazilVincenzo De Feo ItalyRocıo De la Puerta SpainLaura De Martino ItalyNunziatina De Tommasi ItalyMartin Descarreaux USAAlexandra Deters GermanyFarzad Deyhim USAManuela Di Franco ItalyClaudia Di Giacomo ItalyAntonella Di Sotto ItalyM Dijoux-Franca FranceLuciana Dini ItalyTieraona L Dog USACaigan Du CanadaJeng-Ren Duann TaiwanNativ Dudai IsraelThomas Efferth GermanyAbir El-Alfy USATobias Esch USAGiuseppe Esposito ItalyKeturah R Faurot USAYibin Feng Hong KongNianping Feng ChinaPatricia D Fernandes Brazil

Josue Fernandez-Carnero SpainAntonella Fioravanti ItalyFabio Firenzuoli ItalyPeter Fisher UKFilippo Fratini ItalyBrett Froeliger USAMaria pia Fuggetta ItalyJoel J Gagnier CanadaSiew Hua Gan MalaysiaMary K Garcia USASusana Garcia de Arriba GermanyDolores G Gimenez SpainGabino Garrido ChileIpek Goktepe QatarMichael Goldstein USAYuewen Gong CanadaSettimio Grimaldi ItalyGloria Gronowicz USAMaruti Ram Gudavalli USAAlessandra Guerrini ItalyNarcis Gusi SpainSvein Haavik NorwaySolomon Habtemariam UKAbid Hamid IndiaMichael G Hammes GermanyKuzhuvelil B Harikumar IndiaCory S Harris CanadaJan Hartvigsen DenmarkThierry Hennebelle FranceLise Hestbaek DenmarkEleanor Holroyd AustraliaMarkus Horneber GermanyChing-Liang Hsieh TaiwanBenny T K Huat SingaporeRoman Huber GermanyHelmut Hugel AustraliaCiara Hughes UKAttila Hunyadi HungarySumiko Hyuga JapanH Stephen Injeyan CanadaChie Ishikawa JapanAngelo A Izzo ItalyChris J Branford-White UKSuresh Jadhav IndiaG K Jayaprakasha USA

Gao jianli ChinaStefanie Joos GermanyZeev L Kain USAOsamu Kanauchi JapanWenyi Kang ChinaShao-Hsuan Kao TaiwanJuntra Karbwang USAKenji Kawakita JapanDeborah A Kennedy CanadaYoun C Kim Republic of KoreaC-H Kim Republic of KoreaYoshiyuki Kimura JapanToshiaki Kogure JapanJian Kong USATetsuya Konishi JapanKarin Kraft GermanyOmer Kucuk USAVictor Kuete CameroonYiu W Kwan Hong KongKuang C Lai TaiwanIlaria Lampronti ItalyLixing Lao Hong KongChristian Lehmann CanadaMarco Leonti ItalyLawrence Leung CanadaShahar Lev-ari IsraelMin Li ChinaXiu-Min Li USAChun G Li AustraliaBi-Fong Lin TaiwanHo Lin TaiwanChristopher G Lis USAGerhard Litscher AustriaI-Min Liu TaiwanYijun Liu USAVıctor Lopez SpainThomas Lundeberg SwedenFilippo Maggi ItalyValentina Maggini ItalyGail B Mahady USAJamal Mahajna IsraelJuraj Majtan SlovakiaFrancesca Mancianti ItalyCarmen Mannucci ItalyFulvio Marzatico ItalyMarta Marzotto ItalyJames H McAuley AustraliaKristine McGrath Australia

James S McLay UKLewis Mehl-Madrona USAPeter Meiser GermanyKarin Meissner GermanyAlbert S Mellick AustraliaA Guy Mensah-Nyagan FranceAndreas Michalsen GermanyOliver Micke GermanyRoberto Miniero ItalyGiovanni Mirabella ItalyDavid Mischoulon USAFrancesca Mondello ItalyAlbert Moraska USAGiuseppe Morgia ItalyMark Moss UKYoshiharu Motoo JapanKamal D Moudgil USAYoshiki Mukudai JapanFrauke Musial GermanyMinKyun Na Republic of KoreaHajime Nakae JapanSrinivas Nammi AustraliaKrishnadas Nandakumar IndiaVitaly Napadow USAMichele Navarra ItalyIsabella Neri ItalyPratibha V Nerurkar USAKaren Nieber GermanyMenachem Oberbaum IsraelMartin Offenbaecher GermanyJunetsu Ogasawara JapanKi-Wan Oh Republic of KoreaYoshiji Ohta JapanOlumayokun A Olajide UKThomas Ostermann GermanyStacey A Page CanadaSiyaram Pandey CanadaBhushan Patwardhan IndiaBerit S Paulsen NorwayPhilip Peplow New ZealandFlorian Pfab GermanySonia Piacente ItalyAndrea Pieroni ItalyRichard Pietras USAAndrew Pipingas AustraliaJose M Prieto UKHaifa Qiao USAWaris Qidwai Pakistan

Xianqin Qu AustraliaCassandra L Quave USAE Ferreira Queiroz SwitzerlandRoja Rahimi IranKhalid Rahman UKCheppail Ramachandran USAElia Ranzato ItalyKe Ren USAMan H Rhee Republic of KoreaLuigi Ricciardiello ItalyDaniela Rigano ItalyJose L Rıos SpainPaolo Roberti di Sarsina ItalyMariangela Rondanelli ItalyOmar Said IsraelAvni Sali AustraliaMohd Z Salleh MalaysiaA Sandner-Kiesling AustriaManel Santafe SpainTadaaki Satou JapanClaudia Scherr SwitzerlandG Schmeda-Hirschmann ChileAndrew Scholey AustraliaRoland Schoop SwitzerlandSven Schroder GermanyHerbert Schwabl SwitzerlandVeronique Seidel UKSenthamil R Selvan USAFelice Senatore ItalyHongcai Shang ChinaKaren J Sherman USARonald Sherman USAKuniyoshi Shimizu JapanKan Shimpo JapanYukihiro Shoyama JapanMorry Silberstein AustraliaK N S Sirajudeen MalaysiaGraeme Smith UKChang-Gue Son KoreaRachid Soulimani FranceDidier Stien FranceCon Stough AustraliaAnnarita Stringaro ItalyShan-Yu Su TaiwanBarbara Swanson USAGiuseppe Tagarelli ItalyOrazio Taglialatela-Scafati ItalyTakashi Takeda Japan

Ghee T Tan USAHirofumi Tanaka USALay Kek Teh MalaysiaNorman Temple CanadaMayankThakur GermanyMenaka C Thounaojam USAEvelin Tiralongo AustraliaStephanie Tjen-A-Looi USAMichał Tomczyk PolandLoren Toussaint USAYew-Min Tzeng TaiwanDawn M Upchurch USAKonrad Urech SwitzerlandTakuhiro Uto JapanSandy van Vuuren South Africa

Alfredo Vannacci ItalySubramanyam Vemulpad AustraliaCarlo Ventura ItalyGiuseppe Venturella ItalyPradeep Visen CanadaAristo Vojdani USADawnWallerstedt USAShu-Ming Wang USAYong Wang USAChong-Zhi Wang USAJ L Wardle AustraliaKenji Watanabe JapanJ Wattanathorn ThailandMichael Weber GermanySilvia Wein Germany

Janelle Wheat AustraliaJenny M Wilkinson AustraliaDarren Williams Republic of KoreaChristopher Worsnop AustraliaHaruki Yamada JapanNobuo Yamaguchi JapanJunqing Yang ChinaLing Yang ChinaEun J Yang Republic of KoreaKen Yasukawa JapanAlbert S Yeung USAArmando Zarrelli ItalyChris Zaslawski AustraliaRuixin Zhang USA

Contents

Complementary and AlternativeTherapies for Functional Gastrointestinal Diseases Jiande D Z ChenJieyun Yin Toku Takahashi and Xiaohua HouVolume 2015 Article ID 138645 2 pages

ANew Strategy Using Rikkunshito to Treat Anorexia and Gastrointestinal Dysfunction Yayoi SaegusaTomohisa Hattori Miwa Nahata Chihiro Yamada and Hiroshi TakedaVolume 2015 Article ID 364260 10 pages

The Effectiveness of Electroacupuncture for Functional Constipation A Randomized ControlledClinical Trial Nili Da Xinjun Wang Hairong Liu Xiuzhu Xu Xun Jin Chaoming Chen Dan ZhuJiejing Bai Xiaoqing Zhang Yangyang Zou Guangyong Hu and Jianbin ZhangVolume 2015 Article ID 670963 5 pages

Efficacy of Adaptive Biofeedback Training in Treating Constipation-Related Symptoms Jing TangZhihui Huang Yan Tan Nina Zhang Anping Tan Jun Chen and Jianfeng ChenVolume 2015 Article ID 959734 5 pages

Ameliorating Effect of Transcutaneous Electroacupuncture on Impaired Gastric Accommodation inPatients with Postprandial Distress Syndrome-Predominant Functional Dyspepsia A Pilot StudyFeng Xu Yan Tan Zhihui Huang Nina Zhang Yuemei Xu and Jieyun YinVolume 2015 Article ID 168252 7 pages

Complementary and AlternativeTherapies for Chronic Constipation Xinjun Wang and Jieyun YinVolume 2015 Article ID 396396 11 pages

Mindfulness-BasedTherapies in the Treatment of Functional Gastrointestinal Disorders AMeta-Analysis Monique Aucoin Marie-Jasmine Lalonde-Parsi and Kieran CooleyVolume 2014 Article ID 140724 11 pages

Effects and Mechanisms of Transcutaneous Electroacupuncture on Chemotherapy-Induced Nausea andVomiting Xing Zhang Hai-feng Jin Yi-hong Fan Bin LU Li-na Meng and Jiande D Z ChenVolume 2014 Article ID 860631 6 pages

Therapeutic Effects of Biobran Modified Arabinoxylan Rice Bran in Improving Symptoms of DiarrheaPredominant or Mixed Type Irritable Bowel Syndrome A Pilot Randomized Controlled StudyTakeshi Kamiya Michiko Shikano Mamoru Tanaka Keiji Ozeki Masahide Ebi Takahito KatanoShingo Hamano Hirotaka Nishiwaki Hironobu Tsukamoto Tsutomu Mizoshita Yoshinori MoriEiji Kubota Satoshi Tanida Hiromi Kataoka Noriaki Okuda and Takashi JohVolume 2014 Article ID 828137 6 pages

Traditional Japanese Medicine Daikenchuto Improves Functional Constipation in Poststroke PatientsTakehiro Numata Shin Takayama Muneshige Tobita Shuichi Ishida Dai Katayose Mitsutoshi ShinkawaTakashi Oikawa Takanori Aonuma Soichiro Kaneko Junichi Tanaka Seiki Kanemura Koh IwasakiTadashi Ishii and Nobuo YaegashiVolume 2014 Article ID 231258 8 pages

EditorialComplementary and Alternative Therapies forFunctional Gastrointestinal Diseases

Jiande D Z Chen1 Jieyun Yin1 Toku Takahashi2 and Xiaohua Hou3

1Division of Gastroenterology and Hepatology Department of Medicine Johns Hopkins University School of MedicineBaltimore MD 21224 USA2Department of Surgery Medical College of Wisconsin Milwaukee WI 53226 USA3Department of Medicine Union Hospital Huazhong University of Science and Technology Wuhan 430030 China

Correspondence should be addressed to Jiande D Z Chen jiandedzchengmailcom

Received 23 March 2015 Accepted 23 March 2015

Copyright copy 2015 Jiande D Z Chen et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Functional gastrointestinal diseases (FGID) are common inthe world and account for more than 40 of clinical visitsto gastroenterology clinics Common FGID include gas-troesophageal reflux disease (GERD) functional dyspha-gia functional dyspepsia gastroparesis irritable bowel syn-drome (IBS) functional constipation diarrhea and fecalincontinence While pathogeneses of FGID are not com-pletely understood major pathophysiological factors includeimpaired gastrointestinal motility visceral hypersensitivityand psychological issues as well as disruption of the gutmicrobiota [1] Gastrointestinal dysmotility is most commonin FGID For example impaired lower esophageal sphincterfunctionmay lead to dysphagia in case of impaired relaxationduring swallowing or GERD in case of reduced pressure orincreased transient relaxation In the stomach reduced gas-tric relaxation during food intake may lead to impaired gas-tric accommodation causing symptoms of early satiety andbloating impaired antral peristalsis may lead to delayed gas-tric emptying causing symptoms of nausea and vomiting Inthe lower gut impaired colon motility slows down transitresulting in constipation whereas a weak anal sphincter maylead to fecal incontinence Visceral hypersensitivity is one ofthe major causes of pain and discomfort It is commonlyreported in patients with noncardiac chest pain functionaldyspepsia and IBS Depression and anxiety are commonlypresent in patients with FGID Recently disruption of the gutmicrobiota has also been reported in patients with FGID

Although FGID affect a large number of general popula-tions treatment options for FGID have been limited Only a

few medications have been developed for the treatment ofFGID and few or none are available in the market currentlydepending on where one lives Meanwhile alternative andcomplementary medicine (CAM) has received more andmore attention among patients with gastrointestinal diseasesand gastroenterologists In general population the use ofCAM was reported to range from 5 to 72 [2] In patientswith gastrointestinal diseases the use ofCAMwas reported tobe 40 in pediatric patients [3] 495 in patients withinflammatory dowel disease [4] and 509 in patients withIBS [5]

Major CAM methods that have been applied for thetreatment of FGID include acupunctureelectroacupunctureherbal medicine and behavioral therapies Electroacupunc-ture was initially designed to mimic manual acupunctureelectrical current was used to produce muscle contractions atthe acupointmimicking the effect ofmanualmanipulation ofthe needle inserted into the acupoint Gradually electroa-cupuncture has been evolved to function as neuromodulationor electrical nerve stimulation That is the parameters ofelectrical stimulation are chosen to alter certain functions ofthe body such as release of certain hormones andor neuro-transmitter and alterations of certain physiological functionsRecently a novel method of transcutaneous electroacupunc-ture (TEA) has been proposed surface electrodes are used toreplace acupuncture needles This makes the therapy com-pletely noninvasive and self-administrable By replacing theacupuncture needles with cutaneous electrodes the therapycan be administrated at home by patients and as frequently

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015 Article ID 138645 2 pageshttpdxdoiorg1011552015138645

2 Evidence-Based Complementary and Alternative Medicine

as needed Acupuncture electroacupuncture and TEA havebeen shown to improve gastrointestinal intestinal motilityand reduce visceral hypersensitivity in both humans andanimal models of FGID [6] A number of original researchpapers are included in this special issue The study by XZhang et al reported antiemetic effect of TEA in patientswith chemotherapy andmechanisms involving serotonin anddopamine The ameliorating effects of the noninvasive TEAon nausea and vomiting in the delayed phase are appealingas the commonmedical therapy has limited effects on nauseaand vomiting in the delayed phase The same TEA methodwas used in a study by F Xu et al The authors applied TEAin patients with functional dyspepsia and reported improve-ment in impaired gastric accommodation and gastric slowwaves (electrical rhythms controlling peristalsis of the stom-ach) It was also reported that these effects were mediatedvia the vagal mechanisms In another study by N Da et alelectroacupuncture was used to treat patients with functionalconstipation and a comparison was made between shallowpuncture and deep puncture Both methods resulted in asignificant increase in spontaneous bowel movement andelectroacupuncture with deep puncture was reported to bemore potent than shallow puncture

Herbal medicine has also been used for the treatment ofFGID such as STW 5 (Iberogast) Rikkunshito (also knownas Liu-Jun-Zi-Tang) Daikenchuto Simotang Taraxacumofficinale modified Xiaoyao San and Banxiaxiexin decoction[7] In this special issue Y Saegusa et al reviewed the treat-ment strategy of Rikkunshito for anorexia and gastrointesti-nal dysfunction Rikkunshito was reported to improve gastricmotility in both humans and animals and upper gastrointesti-nal symptoms such as dyspepsia epigastric pain and post-prandial fullness in a number of clinical studies Numata et alin this issue reported improvement in functional constipationin poststroke patients with the use of Daikenchuto A 4-weektreatment with Daikenchuto significantly improved majorsymptoms or symptom scores associated with constipationin patients after stroke In a placebo-controlled clinical studyby Kamiya et al in this special issue Biobran modifiedarabinoxylan rice bran was reported to improve symptoms ofdiarrhea in IBS patients with diarrhea or mixed diarrhea andconstipation whereas no improvement was noted in the con-trol group It was speculated that the symptom improvementmight be attributed to anti-inflammatory andor immunemodulatory effects of Biobran

Behavioral therapies include cognitive behavioral ther-apy hypnotherapy relaxation exercise mindfulness-basedtherapies and biofeedback training Most of these therapieshave been applied for the treatment of FGID One originalstudy and one review paper are included in this special issueIn a study by Tang et al an adaptive biofeedback trainingmethod was proposed and applied for the treatment of func-tional constipation due to paradoxical contractions of therectum and the anal sphincter In this method the patientswere trained to adequately control the contraction of thelower abdomen and relax the anal sphincter during strainingthe actual manometric tracings showing the contractileactivity of the rectum and anal sphincter were shown to thepatients as visual feedbacks A significant improvement in

constipation-related symptoms was noted with both conven-tional and intensive biofeedback trainings

In addition to original studies this special issue alsoincludes three reviews covering threemajor diseases of FGIDfunctional dyspepsia IBS and constipation The paper by XWang and J Yin provides a comprehensive and critical reviewon the applications of various CAM methods for the treat-ment of functional constipation The review by M Aucoinet al provides a meta-analysis on the treatment of IBS usingmindfulness-based therapies The review by Y Saegusa et alpresents a summary on the treatment of functional dyspepsiausing a special herbal medicine Rikkunshito

Jiande D Z ChenJieyun Yin

Toku TakahashiXiaohua Hou

References

[1] G de Palma S M Collins and P Bercik ldquoThe microbiota-gut-brain axis in functional gastrointestinal disordersrdquo GutMicrobes vol 5 no 3 pp 419ndash429 2014

[2] M Frass R P Strassl H Friehs M Mullner M Kundi and AD Kaye ldquoUse and acceptance of complementary and alternativemedicine among the general population andmedical personnela systematic reviewrdquo Ochsner Journal vol 12 no 1 pp 45ndash562012

[3] A M Vlieger M Blink E Tromp andM A Benninga ldquoUse ofcomplementary and alternative medicine by pediatric patientswith functional and organic gastrointestinal diseases resultsfrom a multicenter surveyrdquo Pediatrics vol 122 no 2 pp e446ndashe451 2008

[4] L Langmead M Chitnis and D S Rampton ldquoUse of comple-mentary therapies by patients with IBDmay indicate psychoso-cial distressrdquo Inflammatory Bowel Diseases vol 8 no 3 pp 174ndash179 2002

[5] S C Kong D P Hurlstone C Y Pocock et al ldquoThe incidenceof self-prescribed oral complementary and alternativemedicineuse by patients with gastrointestinal diseasesrdquo Journal of ClinicalGastroenterology vol 39 no 2 pp 138ndash141 2005

[6] J Yin and J D Z Chen ldquoGastrointestinal motility disorders andacupuncturerdquo Autonomic Neuroscience Basic and Clinical vol157 no 1-2 pp 31ndash37 2010

[7] L A Lee J Chen and J Yin ldquoComplementary and alternativemedicine for gastroparesisrdquo Gastroenterology Clinics of NorthAmerica vol 44 no 1 pp 137ndash150 2015

Review ArticleA New Strategy Using Rikkunshito to Treat Anorexia andGastrointestinal Dysfunction

Yayoi Saegusa1 Tomohisa Hattori1 Miwa Nahata1

Chihiro Yamada1 and Hiroshi Takeda23

1Tsumura Research Laboratories Tsumura amp Co 3586 Yoshiwara Ami-machi Inashiki-gun Ibaraki 300-1192 Japan2Pathophysiology andTherapeutics Faculty of Pharmaceutical Sciences Hokkaido University SapporoHokkaido 060-0812 Japan3Department of Gastroenterology and Hepatology Hokkaido University Graduate School of Medicine SapporoHokkaido 060-8638 Japan

Correspondence should be addressed to Tomohisa Hattori hattori tomohisamailtsumuracojp

Received 4 July 2014 Revised 26 September 2014 Accepted 7 October 2014

Academic Editor Jieyun Yin

Copyright copy 2015 Yayoi Saegusa et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Because the clinical condition of gastrointestinal dysfunction including functional dyspepsia involves tangled combinations ofpathologies there are some cases of insufficient curative efficacy Thus traditional herbal medicines (Kampo medicines) uniquelydeveloped in Japan are thought to contribute to medical treatment for upper gastrointestinal symptoms Rikkunshito is a Kampomedicine often used to treat dyspeptic symptoms Over the past few years several studies have investigated the efficacy ofrikkunshito for dysmotility for example upper abdominal complaints in animals and humans Rikkunshito ameliorated thedecrease in gastric motility and anorexia in cisplatin-treated rats stress-loaded mice and selective serotonin reuptake inhibitor-treated rats by enhancing plasma ghrelin levels via serotonin2B2C receptor antagonism In addition rikkunshito ameliorated thedecrease in food intake in aged mice and stress-loaded decreased gastric motility via enhanced ghrelin receptor signaling Severalclinical studies revealed that rikkunshito was effective in ameliorating upper gastrointestinal symptoms including dyspepsiaepigastric pain and postprandial fullness In this review we discuss these studies and propose additional evidence-based researchthat may promote the clinical use of Kampo medicines particularly rikkunshito for treating anorexia and gastrointestinaldysfunction

1 Introduction

A representative gastrointestinal dysfunction functional dys-pepsia (FD) is associated with symptoms such as gastricpain anorexia and postprandial sense of distension Theclinical condition of FD involves numerous factors such asdelayed gastric emptying [1] gastric accommodation [2] andpsychological factors [3] The quality of life (QOL) of FDpatients ismarkedly reduced physicallymentally and socially[4 5] In addition some reports have indicated beneficialtherapeutic effects on QOL following improvements in FDsymptoms after treatment [6] thus the clinical treatmentof FD is very important Although many medications andtherapies such as administration of proton-pump inhibitors

(PPI) prokinetics or antidepressants have been attemptedthere are some cases of limited curative efficacyThus Kampomedicines have been anticipated to be effective

Kampomedicines have been uniquely developed in Japanand have been approved by the Ministry of Health Labourand Welfare of Japan Clinically Kampo medicines are usedin combination with Western medications or alone One ofthese Kampo medicines is rikkunshito prepared from eightcrude drugs Atractylodis Lanceae Rhizoma Ginseng RadixPinelliae Tuber Poria Zizyphi Fructus Aurantii NobilisPericarpium Glycyrrhizae Radix and Zingiberis RhizomaFigure 1 shows the UV absorbance characteristics of itsherbal ingredients after separation using 3-dimensional high-performance liquid chromatography (3D-HPLC)



0

0

200

220

240

260

280

300

320

340

360

380

400

(nm

)

10 13 16 19 22 25 28 31 34 37 40 43 46 49

(min) 2001 TSUMURA amp CO all rights reserved

mAbs1400

1400

c

Figure 1 3D-HPLC profiles of rikkunshito components Data were provided by Tsumura amp Co

In Japan rikkunshito is commonly used for dyspepticsymptoms [7ndash9] It was shown to improve gastrointestinalsymptoms in chronic idiopathic dyspepsia patients in adouble-blinded randomized placebo-controlled trial [10]In 1998 a large-scale comparative clinical study of 235patients conducted by Harasawa et al showed improvementof dyspepsia in dysmotility-like dyspepsia patients after theadministration of rikkunshito (the original report was inJapanese and was summarized in English by Hattori [11 12])A recent randomized placebo-controlled trial of rikkunshitofor FD patients was conducted by Suzuki et al and itdemonstrated that the administration of rikkunshito reduceddyspepsia and partially improved symptoms of epigastricpain and postprandial fullness in FD patients [13]

Here we summarize the results of animal studies thatinvestigated the effects of rikkunshito for treating anorexiacaused by various factors by focusing on ghrelin an appetite-promoting hormone In addition we discuss the usefulness oftreating gastrointestinal disorders such as FD using Kampomedicines particularly rikkunshito on the basis of recentclinical studies

2 Gastrointestinal Function-Related FactorsGhrelin and Serotonin

Ghrelin a 28-amino-acid peptide is an orexigenic hormoneprimarily secreted from XA-like cells which are ghrelin-producing cells localized in the stomach mucosa [14] Ghre-lin is found in the blood in two main forms namelyldquoacylated ghrelinrdquo and ldquodes-acyl ghrelinrdquo at a ratio of 110Acylated ghrelin is rapidly metabolized to des-acyl ghrelin byremoval of the octanoyl group in blood which is catalyzed

by esterases such as carboxylesterase (CES) in rodents orbutyrylcholinesterase (BuChE) in humans [15]

Acylated ghrelin binds to specific receptor growth hor-mone secretagogue receptor type 1a (GHS-R1a) localized atthe end of the vagus nerve around the stomach [16 17] Ghre-lin signals are transmitted to the nuclei of the solitary tractand activate neuropeptide Y (NPY)agouti-related peptide(AgRP) neurons in the hypothalamic arcuate nucleus (ARC)via noradrenergic neurons resulting in appetite stimulation[16 17]

Administration of exogenous acylated ghrelin increasesfood intake in rodents [16] In addition acylated ghrelinplays an important role in stomach and duodenal motility[14 18] The peak of plasma acylated ghrelin levels is stronglylinkedwith phase III-like contractions in rodents [19] Exoge-nous ghrelin administration results in enhanced stomachand duodenal motility [18] leading to accelerated gastricemptying

Serotonin (5-hydroxytryptamine 5-HT) plays an impor-tant role in various physiological processes including gas-trointestinal function Central 5-HT plays a role in fear andanxiety manifestations and is involved in appetite regulationThe 5-HT2 receptor family is involved in appetite control [20]5-HT2C receptors are primarily localized in the brain [21]and 5-HT2C receptor activation induces feeding suppressionand anxiety-like behavior in young mice [22ndash26] 5-HT2Creceptors expressed on proopiomelanocortin (POMC) neu-rons promote 120572-melanocyte-stimulating hormone produc-tion [27] leading to suppression of feeding Several reportshave established that stimulating 5-HT2C1B receptors byadministering 119898-chlorophenylpiperazine (mCPP) inducesanorexia in rodents [20 24 28ndash30]

Evidence-Based Complementary and Alternative Medicine 3

In contrast 5-HT2B receptors are primarily found inperipheral tissues including the gastrointestinal tract andstomach fundus [31] and are localized in the brain as demon-strated recently [32] Intraperitoneal (IP) administration ofBW723C86 (16mgkg) a selective 5-HT2B receptor agonistdecreased food intake in rats [33]

IP administration of BW723C86 and mCPP a 5-HT2C1Breceptor agonist decreased plasma acylated ghrelin levels inrodents [28] This suggested that activation of central andorperipheral 5-HT2B2C receptors results in decreased ghrelinsecretion from XA-like cells

3 Cisplatin-Induced Anorexia

31 Cisplatin-Induced Gastrointestinal Disorders In clinicalpractice anticancer drugs such as cisplatin are known toinduce gastrointestinal disorders including acutedelayednausea vomiting anorexia diarrhea and weight loss [34]These markedly affect QOL and may make it difficult tocontinue chemotherapy This emetic effect is induced by theactivation of 5-HT3 receptors [35] in the medulla oblongataowing to the release of large amounts of 5-HT from intestinalenterochromaffin cells [36] However the detailed mecha-nism underlying the loss of appetite because of cisplatinremains unclear

With regard to anorexia caused by cisplatin we andothers found that in rats treated with cisplatin there was adecreased 24 h food intake after treatment [28 37 38] Yakabiet al showed that the decreased food intake caused by IPadministration of cisplatin at 4mgkg to rats persists up to48 h after treatment [38]

In both clinical and basic research recent reports havedemonstrated a relationship between anorexia and ghrelindynamics induced by cisplatin Some reports have shownthat in humans plasma ghrelin concentrations decreasedduring cisplatin-based chemotherapy [39 40] In animalstudies we and others showed that cisplatin treatmentdecreased plasma acylated ghrelin levels in rats [28 38]IP administration of 5-HT or cisplatin decreased plasmaacylated ghrelin levels in a dose-dependent manner inaddition to decreasing the 24 h food intake [28] Moreoverthe reduced plasma acylated ghrelin levels and 24 h foodintake following cisplatin treatment could be completelyrecovered by treatment with 5-HT2B2C receptor antagonistsIn addition decreased food intake in cisplatin-treated ratscould be recovered by exogenous ghrelin treatment Thisshowed that the reduced plasma acylated ghrelin levelsreduced via 5-HT2B2C receptor activities play a major rolein cisplatin-induced anorexia [28] Interestingly althoughplasma acylated ghrelin levels recovered to their baselinelevels at 24 h after cisplatin treatment in rats decreasedghrelin secretion in the hypothalamus persisted even 24 hafter treatment which resulted in a late phase of decreasedfood intake caused by cisplatin [38] This suggested thatcentral ghrelin dynamics play an important role in regulatingfeeding behaviors

32 The Effects of Rikkunshito and Its Components onCisplatin-Induced Anorexia Rikkunshito administration has

been shown to recover decreased food intake and plasmaghrelin levels caused by cisplatin treatment [28 41] Theseeffects were also shown to be abolished by administrationof [D-Lys3]-GHRP-6 a GHS-R antagonist [28 41] Thus theeffects of rikkunshito in terms of improving decreased foodintake and acylated ghrelin levels in cisplatin-treated ratsare likely caused by enhanced ghrelin secretion via 5-HTreceptor antagonism particularly that involving 5-HT2B2Creceptors

We screened 33 compounds among the many compo-nents of rikkunshito for their binding activities with 5-HT receptor subtypes [28] We found that 331015840410158405678-heptamethoxyflavone (HMF) nobiletin tangeretin (con-tained in Aurantii Nobilis Pericarpium) and 8-shogaol(contained in Zingiberis Rhizoma) exhibited the strongestinhibitory activity against 5-HT2B receptors these com-pounds had inhibition constant (119870119894) values of 021 031059 and 18 120583molL respectively Hesperetin contained inAurantii Nobilis Pericarpium the aglycon form of hes-peridin had119870119894 values of 53 120583molL against 5-HT2B receptorsand 209120583molL against 5-HT2C receptors Although thisinhibitory activity of hesperetin was comparatively weak theamounts of hesperidin were higher than those of the othercompounds tested in our binding assays [42]Thus overall itmay exhibit potent 5-HT2B2C receptor antagonistic activityFurthermore hesperetin flavonoids have been reported toenter the brain by passing through the blood-brain barrier[43]

In addition isoliquiritigenin contained in GlycyrrhizaeRadix exhibited the most potent inhibitory activity against5-HT2C receptor binding (119870119894 value 35 120583molL) among allthe components tested In addition it inhibited 5-HT2Breceptor binding inhibitory activity (119870119894 value 33 120583molL)Isoliquiritigenin inhibited 5-HT2C receptor activation in a cellfunctional assay [30] Furthermore oral administration ofHMF hesperidin or isoliquiritigenin in a cisplatin-inducedanorexia model resulted in amelioration of the reducedplasma acylated ghrelin levels in a dose-dependent manner[28]

We believe that changes in plasma acylated ghrelinto des-acyl ghrelin (AD) ratios are also important forregulating feeding behavior An increase in the AD ratioafter oral administration of rikkunshito in normal controlrats and cisplatin-treated rats suggested that rikkunshitoinhibits the degradation of acylated ghrelin [44] We tested48 rikkunshito components for their inhibitory activitiesagainst CES and BuChE and found that 10-gingerol con-tained in Zingiberis Rhizoma had the most potent CESinhibitory activity [44] We also showed that oral admin-istration of rikkunshito or 10-gingerol increased plasmaacylated ghrelin levels and the AD ratios in acylated ghrelin-treated rats In addition administering the CES inhibitorbis(4-nitrophenyl) phosphate resulted in the ameliorationof a cisplatin-induced decrease in food intake [44] Theseresults suggested that the amelioration of cisplatin-induceddecreases in food intake and plasma acylated ghrelin levelsby rikkunshito is partly attributable to its CES inhibitoryeffect


4 Stress-Induced Anorexia

41 Stress and Ghrelin Stress is a significant social problem[45 46] known to be associated with anorexia and gastroin-testinal function [47 48] It has been strongly suggestedthat stress causes several abnormalities of feeding behaviorsuch as bulimia and anorexia In animal studies food intakereportedly decreases after stress loading including restraintstress and immobilization stress [49ndash51] and emotional stressusing a communication box [52] In contrast increased foodintake has been observed after long-term isolation for 3weeks[53]

Ghrelin levels may also be affected by feeding behaviorsof animals under stress However there are conflicting dataregarding the effects of several stressors on plasma ghrelinlevels Increased plasma ghrelin concentrations were foundin a water avoidance stress [54] chronic social defeat stress[55] and repeated restraint stress [56] in rodents Trier SocialStress Test in humans [57] and cold stress in rodents [58]and humans [59] In comparison decreased plasma ghrelinlevels have been found to result from immune stress inducedby lipopolysaccharide in rodents [60ndash62] administration ofurocortin 1 to rodents [63 64] and humans [65] and physicalexercise at 50 of VO2max in humans [66] We recentlyreported that restraint stress causes a significant elevation ofplasma des-acyl ghrelin levels only whereas plasma acylatedghrelin levels remain unaffected [67]

42 Plasma Ghrelin Levels in Novelty Stressed Mice One ofthe stressors that wemay experience during daily life is expo-sure to a new environment Psychological factors lonelinesssocial networks and environmental changes contribute todecreased food intake particularly in the elderly [68 69] Ina novelty stress model animals are removed from their homecage and placed somewhere they have never been beforeThis model has been used to estimate anxiety and depressionlevels [70ndash72] We tested the effects of a novel environmentalstress on food intake and plasma acylated ghrelin dynamicsin young mice [29 73] and aged mice [30]

We found that novelty stress causes a decrease in foodintake which is associated with decreased plasma ghrelinlevels after stress [29] However increased plasma ghrelinlevels with fasting were not observed in a young mouse novelstress model [73] Exogenous acylated ghrelin amelioratedthe decreased food intake by temporarily increasing plasmaacylated ghrelin levels above the physiological concentration[29]Thus the transmission of ghrelin signals to the hypotha-lamic feeding center may be abnormal under novelty stress

A few studies have investigated a possible relationshipbetween corticotropin-releasing factor (CRF) receptors andplasma ghrelin dynamics Administration of urocortin 1 aCRF family peptide that binds to both CRF1 and CRF2receptors reduced plasma acylated ghrelin levels in rodents[63 64] Yakabi et al demonstrated that urocortin 1-inducedreductions in plasma acylated ghrelin levels and food intakewere mediated via CRF2 receptors but not CRF1 receptors[64]We reported that novelty stress and CRF administrationreduced plasma ghrelin levels and food intake and that aCRF1 receptor antagonist but not a CRF2 receptor antagonist

prevented these decreases [29] Interestingly we also foundthat a selective 5-HT2C or 5-HT1B receptor antagonist anda melanocortin-4 (MC4) receptor antagonist prevented thedecreased plasma acylated ghrelin levels in novelty stressedmice [29] We hypothesized that the acute appetite loss andthe decrease in plasma ghrelin levels occurred via CRF1receptors the effects of which were mediated through 5-HT2C1B and MC4 receptor systems

In a novelty stress model higher levels of central 5-HT and 5-HT receptor expression resulted in the activationof serotonergic signals [72] 5-HT2C1B receptor stimulationmay downregulate appetite control [25 74 75] We showedthat compared with normal mice intracerebroventricularadministration of mCPP induced a significant decrease infood intake in novelty stressed mice [29] Administration of5-HT2C1B receptor antagonists ameliorated the decrease infood intake and plasma acylated ghrelin levels [29] Thusan increase in 5-HT2C1B receptor activity may occur afternovelty stress resulting in anorexia or reduced plasma ghrelinlevels

In addition we showed that peripheral administrationof SB215505 and SB204741 selective 5-HT2B receptor antag-onists prevented the decrease in food intake in noveltystressed mice [73] 5-HT2B receptor activation also resultedin decreased food intake [33] It is therefore possible that 5-HT2B receptors participate in part of themechanism of actioninvolved in this novelty stress model

43 Differential Effects in Aged Mice It is well known that5-HT2C receptors are expressed on CRF neurons in theparaventricular nucleus (PVN) and that its activation by 5-HT2C receptor agonists results in adrenocorticotropic hor-mone (ACTH) secretion [74] Other studies have shown thatCRF mRNA expression and ACTH secretion were enhancedby 5-HT administration to PVN [74 76] and that mCPP-induced serum corticosterone increases were inhibited by 5-HT2C receptor antagonism [77] We showed that exposureto a novel environment caused long-term secretion of stresshormones and a continuously decreased food intake inaged mice but not in young mice [30] In addition mCPPadministration resulted in more severe anorexia in agedcontrol mice than that in young control mice [30] Thus thebasal level of signal transduction via 5-HT2C receptors mayhave been enhanced in aged mice

In our previous report we also found that administering aselective 5-HT2C receptor antagonist SB242084 to agedmiceat a dose that had no effect on food intake in young micesignificantly ameliorated both the decrease in food intake andthe increase in stress hormone levels after novelty stress [30]We and others found that novelty stress and social isolationstress enhanced mCPP-responsiveness [29 71] which mayhave been linked to upregulated 5-HT2C1B receptor activityIn addition we observed increased 5-HT2C receptor geneexpression in the hypothalamus at 24 h after novelty stressin aged mice but not in young mice [30] In summary wehypothesized that the stimulation or activation of 5-HT2Creceptors on CRF neurons in PVN results in activation ofthe hypothalamic-pituitary-adrenal (HPA) axis in aged miceafter novelty stress


44 The Effects of Rikkunshito and Its Components on NoveltyStressed Mice Rikkunshito ameliorated the novelty stress-induced decreases in food intake and plasma ghrelin levelsin youngmice [29 73] and in agedmice [30] and coadminis-tering [D-Lys3]-GHRP-6 abolished the effects of rikkunshito[29] Rikkunshito completely ameliorated the decreased foodintake in young and aged mice after mCPP injection [30]Rikkunshito administration attenuated the hyperactivationof the HPA axis and the decreased food intake induced bynovelty stress which was similar to the effects of SB242084[30]We and others reported that rikkunshito had an antago-nistic effect on 5-HT2C receptors in vivo [18 28] In additionthe results of in vitro radiobinding assays revealed that com-ponents in rikkunshito such as isoliquiritigenin exhibited5-HT2B2C receptor binding inhibitory activity [28] We alsofound that glycycoumarin and isoliquiritigenin which arecontained in Glycyrrhizae Radix ameliorated the reducedfood intake in novelty stressed mice [29 73] These findingssuggest that rikkunshito ameliorates novelty stress-inducedanorexia and reduced plasma ghrelin levels via antagonism-like effects on 5-HT2C and 5-HT2B receptors

45The Effects of Rikkunshito on Postprandial Gastric Motilityin a Restraint Stress Model We found that restraint stressdecreased the frequency of phase III-like contractions inthe fasted state and postprandial gastric contractions inmice [67] leading to delayed gastric emptying Furthermoreexogenously administered acylated ghrelin and rikkunshitoimproved the delayed gastric emptying and decreased gas-tric motility caused by restraint stress and the rikkunshitoeffects were completely abolished by a GHS-R antagonist[67] However there were no changes in plasma acylatedghrelin levels Thus we hypothesized that rikkunshito mayhave improved the delayed gastric emptying and decreasedmotility via mechanisms of action other than the enhancingeffects on ghrelin release

Fujitsuka et al demonstrated that rikkunshito potentiatedghrelin receptor signaling via increased binding betweenghrelin and ghrelin receptors [78] Thus exogenous ghrelinsupplementation or ghrelin signal enhancement by rikkun-shito may be effective for improving symptoms in FDpatients

5 Aging-Induced Anorexia

51 Anorexia-Associated Malnutrition in the Elderly In theelderly malnutrition can cause various problems such asproblems related to daily life activities reduced immunefunction and loss of muscle strength [79ndash81] Thereforedealing with malnutrition is quite important Anorexia isthe main cause of malnutrition in the elderly [82] Foodintake has been shown to decrease gradually with age [82]Various factors are responsible for anorexia in the elderlyincluding social isolation diseases such as depression andphysical disorders reduced gustatory and olfactory sensesand medicines [83]

Appetite is controlled by central and peripheral orexi-genicanorexigenic factors [84] As a central control

mechanism NPY and AgRP levels are altered with aging[85ndash88] and NPY signaling is dysfunctional in old rats [89]However few reports regarding the changes in neuro-transmitters of the central nervous system that accompanyaging in humans are available

The elderly have lower levels of plasma ghrelin thanthe young people and ghrelin secretion from the stomachdecreases with aging [90 91] However some reports haveshown that there were no differences in the ghrelin levelsbetween young and aged humans [92] and mice [93] whichreflects controversy with regard to age-associated changes inghrelin dynamics

52 Ghrelin Resistance and Hyperleptinemia in Aged Mice Inanimal models 24 h food intake and 2-week body weightgain decreased in aged mice compared with young mice[94] Our results showed that the plasma ghrelin levels inaged mice did not increase while fasting and that the levelswere higher while feeding than those in young mice [94]These results prompted us to conclude that the regulation ofghrelin secretion may be disturbed in aged mice Moreoverexogenous ghrelin administration markedly enhanced foodintake in young mice but not in aged mice [94]Thus ghrelinsignaling may be impaired in aged mice

Leptin an adipocyte-derived hormone suppresses foodintake and decreases body adiposity [95] We found thatplasma leptin levels in aged mice were very high and thisincreased plasma leptin level was maintained regardless ofingestion [94] In ARC leptin receptors are expressed onNPY neurons and POMC neurons [96 97] and GHS-R isexpressed onNPY neurons [98] Ghrelin and leptinmay haveopposing actions on NPY neurons thus abnormally highconcentrations of leptin are considered to reduce the effectsof ghrelin [99] Another report showed that hyperleptinemiaprevented an increase in ghrelin levels [100]

It was also suggested that leptin suppressed ghrelinsignaling by NPY neurons via the activation of the phos-phoinositide 3-kinase- (PI3K-) phosphodiesterase 3 (PDE3)pathway which may have abolished the adenylate cyclase-cAMP-protein kinase A system implicated in the effects ofghrelin [101] We found that the administration of a PI3Kinhibitor and a PDE3 inhibitor ameliorated the anorexia inaged mice [94] Thus we propose that the hyperleptinemiaaccompanying aging may induce resistance to ghrelin reac-tivity in aged mice by downregulating cAMP levels [94]

53 The Effects of Rikkunshito and Its Components onAnorexia inAgedMice Weshowed that the administration ofrikkunshito could ameliorate some effects of aging-associatedanorexia [94] Exogenous ghrelin ameliorated decreased foodintake in a cisplatin-induced anorexia model [28] and anovelty stress-induced anorexia model [29 73] but not in ouraging-anorexia model [94] After administering rikkunshitoincreased plasma ghrelin levels were not observed in agedmice thus increased ghrelin secretion was not the mainmechanism underlying the amelioration caused by rikkun-shito


We tested 33 components of rikkunshito and found thatHMF nobiletin isoliquiritigenin and glycycoumarin exhib-ited inhibitory effects on PDE3 activity It was previouslyreported that nobiletin flavonoids could enter the brain bypassing through the blood-brain barrier [102] Thus theseresults suggested that rikkunshito ameliorates aging-inducedanorexia via enhanced ghrelin receptor signaling by PDE3inhibition

6 Clinical Applications of Rikkunshito

FD is likely to occur through the combined effects of differentpathologies As described in this paper the results of animalstudies suggest that rikkunshito enhances appetite and gastricmotility [18 67] by increasing endogenous ghrelin levels[18 28 29 73 103] or ghrelin signals [78 94] and therebyameliorates upper gastrointestinal dysfunctions includingFD Studies of healthy human volunteers [103 104] and FDpatients [105] have shown that endogenous acylated ghrelinlevels increase after rikkunshito administration

In a clinical study conducted byArai et al using a parallelrandomized controlled trial of gastroprokinetic agents for27 patients it was shown that rikkunshito was effective inameliorating upper gastrointestinal symptoms as evaluatedby their scores on the Gastrointestinal Symptom Rating Scalequestionnaire [105] Tominaga et al conducted a randomizedplacebo-controlled double-blind clinical trial of rikkunshitofor 242 patients with nonerosive reflux disease refractory toPPI [106] Treatment for 4 weeks with rikkunshito signifi-cantly improved their mental component summary (MCS)scores in the Short-Form Health Survey-8 (SF-8) After 8weeks of treatment with rikkunshito MCS scores in SF-8improved in patients with low body mass index values (lt22)and acid-related dysmotility symptoms assessed by the Fre-quency Scale for the Symptoms of Gastroesophageal RefluxDisease also improved in females and the elderly Anotherclinical trial was conducted by Suzuki et al it was amulticen-ter randomized double-blind placebo-controlled parallel-group trial on the effect of rikkunshito on 247 patients [13]Administration of rikkunshito for 8weeks reduced dyspepsiaepigastric pain was significantly improved and postprandialfullness tended to improve

Anorexia is a cause of concern for cancer patients sincea persistent loss of appetite develops into cancer cachexiaA clinical trial of ghrelin receptor agonists has revealedthat there is a remarkable effect on weight gain in patientswith non-small-cell lung cancer [107] It has been confirmedthat rikkunshito also improves QOL in advanced esophagealcancer patients [108] and prolongs survival in stage IIIIVpancreatic cancer patients and tumor-bearing rats [78]Unlike other ghrelin receptor agonists rikkunshito displaysmultiple actions related to ghrelin signal activation that isstimulation of ghrelin secretion and sustained activity ofGHS-R and prevention of the degradation of endogenousacylated ghrelin Therefore it is expected that rikkunshitomay be effective to the ghrelin resistance seen in canceranorexia-cachexia [78] Further rikkunshito is potentiallyeffective in improving gastrointestinal symptoms in patientsafter gastrectomy [109 110] However since there are few

reports in patients with cancer cachexia or with uppergastrointestinal surgery further large-scale clinical trials arerequired

Evidence of the relevance of using rikkunshito to treatanorexia and gastrointestinal dysfunction continues to accu-mulate as summarized here In addition the use of Kampomedicines as therapeutic agents for FD has recently beenproposed in Japan (guidelines for functional gastrointestinaldiseases 2014)With continuing evidence-based high-qualityresearch the mechanisms of action of Kampo medicinesparticularly those of rikkunshito may be elucidated to agreater extent and the use of Kampo medicines may expandas a front line treatment for anorexia and gastrointestinaldysfunction

Conflict of Interests

Yayoi Saegusa Tomohisa Hattori Miwa Nahata and ChihiroYamada are employed by Tsumura amp Co

Acknowledgment

Hiroshi Takeda received grant support from Tsumura amp Co

References

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[2] J Tack H Piessevaux B Coulie P Caenepeel and J JanssensldquoRole of impaired gastric accommodation to a meal in func-tional dyspepsiardquo Gastroenterology vol 115 no 6 pp 1346ndash1352 1998

[3] P AroN J Talley J Ronkainen et al ldquoAnxiety is associatedwithuninvestigated and functional dyspepsia (Rome III criteria) in aSwedish population-based studyrdquo Gastroenterology vol 137 no1 pp 94ndash100 2009

[4] P Aro N J Talley L Agreus et al ldquoFunctional dyspepsiaimpairs quality of life in the adult populationrdquo AlimentaryPharmacology and Therapeutics vol 33 no 11 pp 1215ndash12242011

[5] N J Talley G R Locke III B D Lahr et al ldquoFunctionaldyspepsia delayed gastric emptying and impaired quality ofliferdquo Gut vol 55 no 7 pp 933ndash939 2006

[6] V Meineche-Schmidt N J Talley A Pap et al ldquoImpactof functional dyspepsia on quality of life and health careconsumption after cessation of antisecretory treatment Amulticentre 3-month follow-up studyrdquo Scandinavian Journal ofGastroenterology vol 34 no 6 pp 566ndash574 1999

[7] H Suzuki J M Inadomi and T Hibi ldquoJapanese herbalmedicine in functional gastrointestinal disordersrdquo Neurogas-troenterology amp Motility vol 21 no 7 pp 688ndash696 2009

[8] K Tominaga and T Arakawa ldquoKampo medicines for gastroin-testinal tract disorders a review of basic science and clinical evi-dence and their future applicationrdquo Journal of Gastroenterologyvol 48 no 4 pp 452ndash462 2013

[9] T Oka H Okumi S Nishida et al ldquoEffects of Kampo on func-tional gastrointestinal disordersrdquoBioPsychoSocialMedicine vol8 no 1 article 5 2014


[10] M Tatsuta and H Iishi ldquoEffect of treatment with Liu-Jun-Zi-Tang (TJ-43) on gastric emptying and gastrointestinal symp-toms in dyspeptic patientsrdquo Alimentary Pharmacology amp Ther-apeutics vol 7 no 4 pp 459ndash462 1993

[11] T Hattori ldquoRikkunshito and ghrelinrdquo International Journal ofPeptides vol 2010 Article ID 283549 3 pages 2010

[12] T Hattori N Fujitsuka A Asakawa and A Inui ldquoA newstrategy using Rikkunshito (Liu-Jun-Zi-Tang) a Japanese tra-ditional medicine to treat gastrointestinal diseaserdquo in Basics ofEvidences-Based Herbal Medicine H Satoh Ed pp 149ndash160Research Signpost Kerala India 2010

[13] H Suzuki JMatsuzaki Y Fukushima et al ldquoRandomized clini-cal trial rikkunshito in the treatment of functional dyspepsiamdasha multicenter double-blind randomized placebo-controlledstudyrdquoNeurogastroenterology ampMotility vol 26 no 7 pp 950ndash961 2014

[14] M Kojima H Hosoda Y Date M Nakazato H Matsuo andK Kangawa ldquoGhrelin is a growth-hormone-releasing acylatedpeptide from stomachrdquoNature vol 402 no 6762 pp 656ndash6601999

[15] C De Vriese F Gregoire R Lema-Kisoka M Waelbroeck PRobberecht and C Delporte ldquoGhrelin degradation by serumand tissue homogenates identification of the cleavage sitesrdquoEndocrinology vol 145 no 11 pp 4997ndash5005 2004

[16] M Nakazato N Murakami Y Date et al ldquoA role for ghrelin inthe central regulation of feedingrdquo Nature vol 409 no 6817 pp194ndash198 2001

[17] Y Date N Murakami K Toshinai et al ldquoThe role of the gastricafferent vagal nerve in Ghrelin-induced feeding and growthhormone secretion in ratsrdquo Gastroenterology vol 123 no 4 pp1120ndash1128 2002

[18] N Fujitsuka A AsakawaMHayashi et al ldquoSelective serotoninreuptake inhibitorsmodify physiological gastrointestinalmotoractivities via 5-HT2c receptor and acyl ghrelinrdquo BiologicalPsychiatry vol 65 no 9 pp 748ndash759 2009

[19] H Ariga K Tsukamoto C Chen C Mantyh T N Pappas andT Takahashi ldquoEndogenous acyl ghrelin is involved inmediatingspontaneous phase III-like contractions of the rat stomachrdquoNeurogastroenterology and Motility vol 19 no 8 pp 675ndash6802007

[20] J de Vry and R Schreiber ldquoEffects of selected serotonin 5-HT1 and 5-HT2 receptor agonists on feeding behavior pos-sible mechanisms of actionrdquo Neuroscience and BiobehavioralReviews vol 24 no 3 pp 341ndash353 2000

[21] D E Wright K B Seroogy K H Lundgren B M Davis andL Jennes ldquoComparative localization of serotonin11198601119862 and 2receptor subtype mRNAs in rat brainrdquo Journal of ComparativeNeurology vol 351 no 3 pp 357ndash373 1995

[22] S Dryden Q Wang H M Frankish and G Williams ldquoDiffer-ential effects of the 5-HT11198612119862 receptor agonist mCPP and the5-HT1119860 agonist flesinoxan on hypothalamic neuropeptide Y inthe rat evidence that NPY may mediate serotoninrsquos effects onfood intakerdquo Peptides vol 17 no 6 pp 943ndash949 1996

[23] M B Gatch ldquoDiscriminative stimulus effects of m-chlorophenylpiperazine as a model of the role of serotoninreceptors in anxietyrdquo Life Sciences vol 73 no 11 pp 1347ndash13672003

[24] A Hayashi M Suzuki M Sasamata and K Miyata ldquoAgonistdiversity in 5-HT2C receptor-mediated weight control in ratsrdquoPsychopharmacology vol 178 no 2-3 pp 241ndash249 2005

[25] J C Halford J A Harrold E J Boyland C L Lawton and JE Blundell ldquoSerotonergic drugs effects on appetite expression

and use for the treatment of obesityrdquo Drugs vol 67 no 1 pp27ndash55 2007

[26] K Nonogaki ldquoGhrelin and feedback systemsrdquo Vitamins andHormones vol 77 pp 149ndash170 2008

[27] L K Heisler M A Cowley L H Tecott et al ldquoActivation ofcentral melanocortin pathways by fenfluraminerdquo Science vol297 no 5581 pp 609ndash611 2002

[28] H Takeda C Sadakane T Hattori et al ldquoRikkunshito anherbal medicine suppresses cisplatin-induced anorexia in ratsvia 5-HT2 receptor antagonismrdquo Gastroenterology vol 134 no7 pp 2004ndash2013 2008

[29] Y Saegusa H Takeda SMuto et al ldquoDecreased plasma ghrelincontributes to anorexia following novelty stressrdquo AmericanJournal of PhysiologymdashEndocrinology and Metabolism vol 301no 4 pp E685ndashE696 2011

[30] M Nahata S Muto K Nakagawa et al ldquoSerotonin 2C receptorantagonism ameliorates novelty-induced hypophagia in agedmicerdquo Psychoneuroendocrinology vol 38 no 10 pp 2051ndash20642013

[31] J D Kursar D L Nelson D B Wainscott M L Cohenand M Baez ldquoMolecular cloning functional expression andpharmacological characterization of a novel serotonin receptor(5-hydroxytryptamine2F) from rat stomach fundusrdquoMolecularPharmacology vol 42 no 4 pp 549ndash557 1992

[32] D-S Choi and L Maroteaux ldquoImmunohistochemical localisa-tion of the serotonin 5-HT2B receptor in mouse gut cardiovas-cular system and brainrdquoFEBSLetters vol 391 no 1-2 pp 45ndash511996

[33] T Hattori K Yakabi and H Takeda ldquoCisplatin-inducedanorexia and ghrelinrdquoVitamins and Hormones vol 92 pp 301ndash317 2013

[34] T Ohno S Kato M Wakatsuki et al ldquoIncidence and temporalpattern of anorexia diarrhea weight loss and leukopenia inpatients with cervical cancer treated with concurrent radiationtherapy and weekly cisplatin comparison with radiation ther-apy alonerdquoGynecologicOncology vol 103 no 1 pp 94ndash99 2006

[35] A Ozaki and T Sukamoto ldquoImprovement of cisplatin-inducedemesis and delayed gastric emptying by KB-R6933 a novel 5-HT3 receptor antagonistrdquo General Pharmacology vol 33 no 3pp 283ndash288 1999

[36] L X Cubeddu and I S Hoffmann ldquoParticipation of serotoninon early and delayed emesis induced by initial and subsequentcycles of cisplatinum-based chemotherapy effects of antiemet-icsrdquo Journal of Clinical Pharmacology vol 33 no 8 pp 691ndash6971993

[37] B C de Jonghe and C C Horn ldquoChemotherapy-induced picaand anorexia are reduced by common hepatic branch vagotomyin the ratrdquo American Journal of PhysiologymdashRegulatory Integra-tive and Comparative Physiology vol 294 no 3 pp R756ndashR7652008

[38] K Yakabi C Sadakane M Noguchi et al ldquoReduced ghrelinsecretion in the hypothalamus of rats due to cisplatin-inducedanorexiardquo Endocrinology vol 151 no 8 pp 3773ndash3782 2010

[39] T Ohno M Yanai H Ando et al ldquoRikkunshito a traditionalJapanese medicine suppresses cisplatin-induced anorexia inhumansrdquoClinical and Experimental Gastroenterology vol 4 no1 pp 291ndash296 2011

[40] Y Hiura S Takiguchi K Yamamoto et al ldquoFall in plasmaghrelin concentrations after cisplatin-based chemotherapy inesophageal cancer patientsrdquo International Journal of ClinicalOncology vol 17 no 4 pp 316ndash323 2012


[41] K Yakabi S Kurosawa M Tamai et al ldquoRikkunshito and 5-HT2C receptor antagonist improve cisplatin-induced anorexiavia hypothalamic ghrelin interactionrdquo Regulatory Peptides vol161 no 1ndash3 pp 97ndash105 2010

[42] T Kido Y Nakai Y Kase et al ldquoEffects of Rikkunshi-to atraditional Japanese medicine on the delay of gastric emptyinginduced by N119866-nitro-L-argininerdquo Journal of PharmacologicalSciences vol 98 no 2 pp 161ndash167 2005

[43] K A Youdim M S Dobbie G Kuhnle A R Proteggente NJ Abbott and C Rice-Evans ldquoInteraction between flavonoidsand the blood-brain barrier in vitro studiesrdquo Journal of Neuro-chemistry vol 85 no 1 pp 180ndash192 2003

[44] C Sadakane S Muto K Nakagawa et al ldquo10-Gingerol a com-ponent of rikkunshito improves cisplatin-induced anorexiaby inhibiting acylated ghrelin degradationrdquo Biochemical andBiophysical Research Communications vol 412 no 3 pp 506ndash511 2011

[45] A Steptoe N Owen S R Kunz-Ebrecht and L BrydonldquoLoneliness and neuroendocrine cardiovascular and inflam-matory stress responses in middle-aged men and womenrdquoPsychoneuroendocrinology vol 29 no 5 pp 593ndash611 2004

[46] C O Luanaigh and B A Lawlor ldquoLoneliness and the health ofolder peoplerdquo International Journal of Geriatric Psychiatry vol23 no 12 pp 1213ndash1221 2008

[47] V Bhatia and R K Tandon ldquoStress and the gastrointestinaltractrdquo Journal of Gastroenterology and Hepatology vol 20 no3 pp 332ndash339 2005

[48] C lo Sauro C Ravaldi P L Cabras C Faravelli and VRicca ldquoStress hypothalamic-pituitary-adrenal axis and eatingdisordersrdquo Neuropsychobiology vol 57 no 3 pp 95ndash115 2008

[49] O Martı J Martı and A Armario ldquoEffects of chronic stress onfood intake in rats influence of stressor intensity and durationof daily exposurerdquo Physiology and Behavior vol 55 no 4 pp747ndash753 1994

[50] I I Rybkin Y Zhou J Volaufova G N Smagin D H Ryanand R B S Harris ldquoEffect of restraint stress on food intake andbody weight is determined by time of dayrdquo American Journal ofPhysiologymdashRegulatory Integrative and Comparative Physiologyvol 273 no 5 part 2 pp R1612ndashR1622 1997

[51] A Valles OMartı A Garcıa and A Armario ldquoSingle exposureto stressors causes long-lasting stress-dependent reduction offood intake in ratsrdquoAmerican Journal of PhysiologymdashRegulatoryIntegrative and Comparative Physiology vol 279 no 3 ppR1138ndashR1144 2000

[52] MHotta T Shibasaki K Aral andHDemura ldquoCorticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes inratsrdquo Brain Research vol 823 no 1-2 pp 221ndash225 1999

[53] H Sakakibara A Suzuki A Kobayashi et al ldquoSocial isolationstress induces hepatic hypertrophy in C57BL6J micerdquo Journalof Toxicological Sciences vol 37 no 5 pp 1071ndash1076 2012

[54] E KristensssonM SundqvistMAstin et al ldquoAcute psycholog-ical stress raises plasma ghrelin in the ratrdquo Regulatory Peptidesvol 134 no 2-3 pp 114ndash117 2006

[55] M Lutter I Sakata S Osborne-Lawrence et al ldquoThe orexi-genic hormone ghrelin defends against depressive symptoms ofchronic stressrdquo Nature Neuroscience vol 11 no 7 pp 752ndash7532008

[56] J Zheng A Dobner R Babygirija K Ludwig and T TakahashildquoEffects of repeated restraint stress on gastric motility in ratsrdquoTheAmerican Journal of PhysiologymdashRegulatory Integrative andComparative Physiology vol 296 no 5 pp R1358ndashR1365 2009

[57] V Rouach M Bloch N Rosenberg et al ldquoThe acute ghrelinresponse to a psychological stress challenge does not predict thepost-stress urge to eatrdquo Psychoneuroendocrinology vol 32 no 6pp 693ndash702 2007

[58] A Stengel M Goebel A Luckey P-Q Yuan L Wang and YTache ldquoCold ambient temperature reverses abdominal surgery-induced delayed gastric emptying and decreased plasma ghrelinlevels in ratsrdquo Peptides vol 31 no 12 pp 2229ndash2235 2010

[59] P J Tomasik K Sztefko andM Pizon ldquoThe effect of short-termcold and hot exposure on total plasma ghrelin concentrationsin humansrdquoHormone and Metabolic Research vol 37 no 3 pp189ndash190 2005

[60] N R Basa L Wang J R Arteaga D Heber E H Livingstonand Y Tache ldquoBacterial lipopolysaccharide shifts fasted plasmaghrelin to postprandial levels in ratsrdquo Neuroscience Letters vol343 no 1 pp 25ndash28 2003

[61] Y Hataya T Akamizu H Hosoda et al ldquoAlterations of plasmaghrelin levels in rats with lipopolysaccharide-induced wastingsyndrome and effects of ghrelin treatment on the syndromerdquoEndocrinology vol 144 no 12 pp 5365ndash5371 2003

[62] A Stengel M Goebel L Wang J R Reeve Jr Y Tache and NW G Lambrecht ldquoLipopolysaccharide differentially decreasesplasma acyl and desacyl ghrelin levels in rats potential role ofthe circulating ghrelin-acylating enzyme GOATrdquo Peptides vol31 no 9 pp 1689ndash1696 2010

[63] C Tanaka A Asakawa M Ushikai et al ldquoComparison of theanorexigenic activity of CRF family peptidesrdquo Biochemical andBiophysical Research Communications vol 390 no 3 pp 887ndash891 2009

[64] K Yakabi M Noguchi S Ohno et al ldquoUrocortin 1 reducesfood intake and ghrelin secretion via CRF2 receptorsrdquoAmericanJournal of Physiology Endocrinology and Metabolism vol 301no 1 pp E72ndashE82 2011

[65] M E Davis C J Pemberton T G Yandle et al ldquoUrocortin-1infusion in normal humansrdquo Journal of Clinical Endocrinologyand Metabolism vol 89 no 3 pp 1402ndash1409 2004

[66] T Shiiya H Ueno K Toshinai et al ldquoSignificant lowering ofplasma ghrelin but not des-acyl ghrelin in response to acuteexercise in menrdquo Endocrine Journal vol 58 no 5 pp 335ndash3422011

[67] M Nahata Y Saegusa C Sadakane et al ldquoAdministrationof exogenous acylated ghrelin or rikkunshito an endogenousghrelin enhancer improves the decrease in postprandial gastricmotility in an acute restraint stress mouse modelrdquo Neurogas-troenterology and Motility vol 26 no 6 pp 821ndash831 2014

[68] L M Donini C Savina and C Cannella ldquoEating habitsand appetite control in the elderly the anorexia of agingrdquoInternational Psychogeriatrics vol 15 no 1 pp 73ndash87 2003

[69] G Hughes K M Bennett and M M Hetherington ldquoOld andalone barriers to healthy eating in older men living on theirownrdquo Appetite vol 43 no 3 pp 269ndash276 2004

[70] R J Handa M K Cross M George et al ldquoNeuroendocrineand neurochemical responses to novelty stress in young andold male F344 rats effects of d-fenfluramine treatmentrdquo Phar-macology Biochemistry and Behavior vol 46 no 1 pp 101ndash1091993

[71] K C F Fone K Shalders Z D Fox R Arthur and C AMarsden ldquoIncreased 5-HT2C receptor responsiveness occurson rearing rats in social isolationrdquoPsychopharmacology vol 123no 4 pp 346ndash352 1996

[72] H Miura H Qiao and T Ohta ldquoInfluence of aging andsocial isolation on changes in brain monoamine turnover and


biosynthesis of rats elicited by novelty stressrdquo Synapse vol 46no 2 pp 116ndash124 2002

[73] C Yamada Y Saegusa K Nakagawa et al ldquoRikkunshitoa japanese kampo medicine ameliorates decreased feedingbehavior via ghrelin and serotonin 2b receptor signaling in aNovelty Stress Murine Modelrdquo BioMed Research Internationalvol 2013 Article ID 792940 9 pages 2013

[74] L K Heisler N Pronchuk K Nonogaki et al ldquoSerotoninactivates the hypothalamic-pituitary-adrenal axis via serotonin2C receptor stimulationrdquo The Journal of Neuroscience vol 27no 26 pp 6956ndash6964 2007

[75] K Nonogaki K Nozue Y Takahashi et al ldquoFluvoxamine aselective serotonin reuptake inhibitor and 5-HT 2C receptorinactivation induce appetite-suppressing effects in mice via 5-HT1B receptorsrdquo International Journal of Neuropsychopharma-cology vol 10 no 5 pp 675ndash681 2007

[76] K Kageyama F Tozawa N Horiba H Watanobe and TSuda ldquoSerotonin stimulates corticotropin-releasing factor geneexpression in the hypothalamic paraventricular nucleus ofconscious ratsrdquoNeuroscience Letters vol 243 no 1ndash3 pp 17ndash201998

[77] S K Hemrick-Luecke and D C Evans ldquoComparison of thepotency of MDL 100907 and SB 242084 in blocking theserotonin (5-HT)2 receptor agonist-induced increases in ratserum corticosterone concentrations evidence for 5-HT2Areceptor mediation of the HPA axisrdquo Neuropharmacology vol42 no 2 pp 162ndash169 2002

[78] N Fujitsuka A Asakawa Y Uezono et al ldquoPotentiationof ghrelin signaling attenuates cancer anorexia-cachexia andprolongs survivalrdquo Translational Psychiatry vol 1 article e232011

[79] J E Morley ldquoAnorexia in older persons epidemiology andoptimal treatmentrdquo Drugs and Aging vol 8 no 2 pp 134ndash1551996

[80] J E Morley ldquoAnorexia of aging physiologic and pathologicrdquoAmerican Journal of Clinical Nutrition vol 66 no 4 pp 760ndash763 1997

[81] I M Chapman ldquoThe anorexia of agingrdquo Clinics in GeriatricMedicine vol 23 no 4 pp 735ndash756 2007

[82] V Di Francesco F Fantin F Omizzolo et al ldquoThe anorexia ofagingrdquo Digestive Diseases vol 25 no 2 pp 129ndash137 2007

[83] N P Hays and S B Roberts ldquoThe anorexia of aging in humansrdquoPhysiology and Behavior vol 88 no 3 pp 257ndash266 2006

[84] E Valassi M Scacchi and F Cavagnini ldquoNeuroendocrine con-trol of food intakerdquo Nutrition Metabolism and CardiovascularDiseases vol 18 no 2 pp 158ndash168 2008

[85] C Kowalski J Micheau R Corder R Gaillard and BConte-Devolx ldquoAge-related changes in cortico-releasing factorsomatostatin neuropeptide Y methionine enkephalin and 120573-endorphin in specific rat brain areasrdquo Brain Research vol 582no 1 pp 38ndash46 1992

[86] D A Gruenewald B TMarck andAMMatsumoto ldquoFasting-induced increases in food intake and neuropeptide Y geneexpression are attenuated in aging male brown Norway ratsrdquoEndocrinology vol 137 no 10 pp 4460ndash4467 1996

[87] T M McShane M E Wilson and P M Wise ldquoEffects oflifelong moderate caloric restriction on levels of neuropeptideY proopiomelanocortin and Galanin mRNArdquo Journals ofGerontology Series A Biological Sciences and Medical Sciencesvol 54 no 1 pp B14ndashB21 1999

[88] E H Sohn T Wolden-Hanson and A M MatsumotoldquoTestosterone (T)-induced changes in arcuate nucleus cocaine-amphetamine-regulated transcript and NPYmRNA are attenu-ated in old compared to young male brown Norway rats con-tribution of T to age-related changes in cocaine-amphetamine-regulated transcript and NPY gene expressionrdquo Endocrinologyvol 143 no 3 pp 954ndash963 2002

[89] C A Blanton B A Horwitz J E Blevins J S Hamilton E JHernandez and R B McDonald ldquoReduced feeding responseto neuropeptide Y in senescent fischer 344 ratsrdquoThe AmericanJournal of PhysiologymdashRegulatory Integrative and ComparativePhysiology vol 280 no 4 pp R1052ndashR1060 2001

[90] A E Rigamonti A I Pincelli B Corra et al ldquoPlasma ghrelinconcentrations in elderly subjects comparison with anorexicand obese patientsrdquo Journal of Endocrinology vol 175 no 1 ppR1ndashR5 2002

[91] A E Schutte H W Huisman R Schutte J M van RooyenL Malan and N T Malan ldquoAging influences the level andfunctions of fasting plasma ghrelin levels the POWIRS-StudyrdquoRegulatory Peptides vol 139 no 1ndash3 pp 65ndash71 2007

[92] V Di Francesco M Zamboni E Zoico et al ldquoUnbalancedserum leptin and ghrelin dynamics prolong postprandial satietyand inhibit hunger in healthy elderly another reason for thelsquoanorexia of agingrsquordquo The American Journal of Clinical Nutritionvol 83 no 5 pp 1149ndash1152 2006

[93] Y Sun J M Garcia and R G Smith ldquoGhrelin and growthhormone secretagogue receptor expression in mice duringagingrdquo Endocrinology vol 148 no 3 pp 1323ndash1329 2007

[94] H Takeda S Muto T Hattori et al ldquoRikkunshito amelioratesthe aging-associated decrease in ghrelin receptor reactivity viaphosphodiesterase III inhibitionrdquo Endocrinology vol 151 no 1pp 244ndash252 2010

[95] J M Friedman and J L Halaas ldquoLeptin and the regulation ofbody weight in mammalsrdquo Nature vol 395 no 6704 pp 763ndash770 1998

[96] C F Elias C Aschkenasi C Lee et al ldquoLeptin differentiallyregulates NPY and POMC neurons projecting to the lateralhypothalamic areardquo Neuron vol 23 no 4 pp 775ndash786 1999

[97] J K Elmquist ldquoHypothalamic pathways underlying theendocrine autonomic and behavioral effects of leptinrdquo Physi-ology and Behavior vol 74 no 4-5 pp 703ndash708 2001

[98] X-M Guan H Yu O C Palyha et al ldquoDistribution of mRNAencoding the growth hormone secretagogue receptor in brainand peripheral tissuesrdquoMolecular Brain Research vol 48 no 1pp 23ndash29 1997

[99] M Traebert T Riediger S Whitebread E Scharrer and H ASchmid ldquoGhrelin acts on leptin-responsive neurones in the ratarcuate nucleusrdquo Journal of Neuroendocrinology vol 14 no 7pp 580ndash586 2002

[100] R Barazzoni M Zanetti M Stebel G Biolo L Cattin and GGuarnieri ldquoHyperleptinemia prevents increased plasma ghrelinconcentration during short-termmoderate caloric restriction inratsrdquo Gastroenterology vol 124 no 5 pp 1188ndash1192 2003

[101] D Kohno M Nakata F Maekawa et al ldquoLeptin suppressesghrelin-induced activation of neuropeptide Y neurons in thearcuate nucleus via phosphatidylinositol 3-kinase- and phos-phodiesterase 3-mediated pathwayrdquo Endocrinology vol 148 no5 pp 2251ndash2263 2007

[102] J Yao J P Zhou Q N Ping Y Lu and L Chen ldquoDistribution ofnobiletin chitosan-basedmicroemulsions in brain following ivinjection in micerdquo International Journal of Pharmaceutics vol352 no 1-2 pp 256ndash262 2008


[103] T Matsumura M Arai Y Yonemitsu et al ldquoThe traditionalJapanese medicine Rikkunshito increases the plasma level ofghrelin in humans and micerdquo Journal of Gastroenterology vol45 no 3 pp 300ndash307 2010

[104] M Shiratori T Shoji M Kanazawa M Hongo and S FukudoldquoEffect of rikkunshito on gastric sensorimotor function underdistentionrdquo Neurogastroenterology amp Motility vol 23 no 4 pp323ndashe156 2011

[105] M Arai T Matsumura N Tsuchiya et al ldquoRikkunshitoimproves the symptoms in patients with functional dyspepsiaaccompanied by an increase in the level of plasma ghrelinrdquoHepato-Gastroenterology vol 59 no 113 pp 62ndash66 2012

[106] K Tominaga M Kato H Takeda et al ldquoA randomizedplacebo-controlled double-blind clinical trial of rikkunshito forpatients with non-erosive reflux disease refractory to proton-pump inhibitor the G-PRIDE studyrdquo Journal of Gastroenterol-ogy vol 49 no 10 pp 1392ndash1405 2014

[107] D C Currow and A P Abernethy ldquoAnamorelin hydrochloridein the treatment of cancer anorexia-cachexia syndromerdquo FutureOncology vol 10 no 5 pp 789ndash802 2014

[108] J Seike T SawadaNKawakita et al ldquoAnew candidate support-ing drug rikkunshito for theQOL in advanced esophageal can-cer patients with chemotherapy using docetaxel5-FUCDDPrdquoInternational Journal of Surgical Oncology vol 2011 Article ID715623 7 pages 2011

[109] T Takahashi S Endo K Nakajima Y Souma and T NishidaldquoEffect of rikkunshito a Chinese herbal medicine on stasis inpatients after pylorus-preserving gastrectomyrdquoWorld Journal ofSurgery vol 33 no 2 pp 296ndash302 2009

[110] S Takiguchi Y Hiura T Takahashi et al ldquoEffect of rikkunshitoa Japanese herbal medicine on gastrointestinal symptoms andghrelin levels in gastric cancer patients after gastrectomyrdquoGastric Cancer vol 16 no 2 pp 167ndash174 2013

Research ArticleThe Effectiveness of Electroacupuncture for FunctionalConstipation A Randomized Controlled Clinical Trial

Nili Da12 Xinjun Wang1 Hairong Liu1 Xiuzhu Xu1 Xun Jin1 Chaoming Chen3 Dan Zhu1

Jiejing Bai1 Xiaoqing Zhang1 Yangyang Zou1 Guangyong Hu1 and Jianbin Zhang1

1Second Clinic Medical School Nanjing University of Chinese Medicine Nanjing 210000 China2Department of Acupuncture Peoplersquos Hospital of Jurong Road 60 West Street of Huayang Town Jurong Zhenjiang 212400 China3Anorectal Department Third Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing China

Correspondence should be addressed to Jianbin Zhang zhangjianbinnjutcmeducn

Received 21 May 2014 Revised 25 July 2014 Accepted 12 September 2014


Copyright copy 2015 Nili Da et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background Electroacupuncture (EA) has been reported to treat functional constipation (FC) The aim of this study was toinvestigate the efficacy and safety of EA with different needle insertion method for FC Methods Sixty-seven participants wererandomly assigned to control (EAwith shallow puncture) and EA (with deep puncture) groups Every patient received 5 treatmentsperweek in the first twoweeks then 3 treatments perweek during the following sixweeks Complete spontaneous bowelmovements(CSBM) spontaneous bowel movements (SBM) Bristol stool scores (BSS) and Patient Assessment of Constipation Quality of Life(PAC-QOL) were assessed Results Both shallow and deep EA significantly increased CSBM frequency compared to the baselineCSBM was increased from 050 plusmn 059wk to 200 plusmn 167wk with deep EA and from 048 plusmn 059wk to 133 plusmn 109wk with shallowEA (P lt 005 resp) Similar finding was noted in SBM Deep EA was more potent than shallow EA (P lt 005) during the treatmentperiod No difference was found on BSS and PAC-QOL between two groups Conclusion It is effective and safe with EA to treat FCStudies with large sample size and long-term observation are needed for further investigation

1 Introduction

According to Rome III diagnostic criteria [1] functionalconstipation (FC) is characterized by hard infrequent orincomplete defecationThe prevalence of FC in North Amer-ica is from 19 to 272 [2] 74 inMexico [3] and 24ndash112in Iran [4] In recent years functional constipation occursmore frequently in China with total prevalence of 918 [5]and in the elderly was 6787 [6]

Constipation may cause disorders in perianal such asperianal abscess and anal fistula anorectal lesions such ashemorrhoids and colorectal cancer digestive systemdiseasessuch as bloating indigestion and diverticulosis psychiatricsymptoms such as headache insomnia and irritabilityaggravating the symptoms even threatening the life such asincreasing blood pressure inducing acute cerebral vasculardisease and even sudden death [7 8] Constipation alsoseriously affects the quality of life [9] It was reported thatin 2010 the costs related to hospitalizations of constipation as

the primary diagnosis were over 850 million dollars in theUS [10] In addition patients with constipation were knownto have reduced quality of life

More and more constipation patients prefer alternativeand complementary treatment because of worry from drugside effect and deficiency of long-term effect [11] despitelaxatives having been widely used A few studies havereported the effectiveness of acupuncture for treating FC[12 13] however these studies lacked comprehensive studydesign Therefore it is necessary to complete a randomizedcontrolled patient blinded and clinical trial to investigatethe efficacy and safety of electroacupuncture treatment offunctional constipation

2 Methods

21 Study Design and Ethics Approval The recruitment ofsubjects took place from October 2012 to September 2013The study was approved by Medical Ethics Committee and



completed in the Outpatient Department of Guo Yi Tang inNanjing China

As shown in Figure 1 total 67 patients (13 male and 54female) with FC were finally enrolled to the experimentParticipants were included if they met all of the followingconditions (1) diagnosed with FC according to the RomanIII criteria [1] (2) aged between 18 and 65 years (3) CSBM letwice per week at least three months (4) without any treat-ments (except rescue methods being used when participantshad intolerable discomfort) at least two weeks before joiningthis study

Participants were excluded from the study if they had adiagnosis of irritable bowel syndrome (IBS) or constipationcaused by other diseases or medicine or other significantdiseases and medicine that may interfere with completionof the study Pregnant or breastfeeding women were alsoexcluded

Patients had the rights to decide to whether participatein or withdraw the study at any time Their decisions did notaffect their deserved treatments

Participants recruited through advertisements in hospi-tals and schools were randomized by stochastic systems incomputer and decided to receive control or EA treatmentAll participants were blinded to the type of treatmentmethodreceived until completion of the study

22 Treatments The total study period was shown inFigure 2 After two-week baseline assessment each patientwas treated with either deep EA or shallow EA for 8 weeksfollowed by 12 weeks follow-up period

Each patient received total 28 treatments including 5times per week for the first two weeks and 3 times per weekfor the following six weeks

Patients in EA group received EA at 6 acupoints ST25(Tianshu) and SP14 (Fujie) and ST37 (Shangjuxu) bilaterallyThe physician inserted into ST25 and SP14 with HuaTuo 030times 75mm needles deep to the parietal peritoneum withoutlifting and twisting The two needles at ST25 and SP14unilaterally were connected to an electric stimulator (HANS-200A Nanjing Jisheng Co China) for 30 minThe frequencywas 215Hz alternately The current was strong enough(01mAndash10mA) to produce a slight tremor in patientsrsquoabdominal muscles HuaTuo 030 times 40mm needles wereinserted into ST37 with depth of 1 cun lifted and twistedslightly three times to Deqi every 10 minutes for a total of30 minutes Patients in the control group received EA withsame techniques and parameters but with shallow puncturewith depth of 2mm and at points located one cun away fromthose 6 acupoints (on themedian between StomachMeridianof Foot Yang-ming and Spleen Meridian of Foot Tai-yin)respectively without lifting and twisting for 30 minutes

23 Assessment The primary outcome was CSBM (completespontaneous bowel movements) the secondary outcomesconsisted of spontaneous bowel movements (SBM) Bris-tol stool scores (BSS) hard defecation score and PatientAssessment of Constipation Quality of Life (PAC-QOL) The

Table 1 Patients demographics (mean plusmn SD)

Control (119899 = 33) EA (119899 = 34) 119875

Sex (female()) 8182 7941 0803

Age (years) 3700 plusmn 1789 3794 plusmn 1806 0768Course(months) 10621 plusmn 9198 13959 plusmn 11268 0289

Table 2 The cure rate

119899 Cured Not cured Cure rate 119875

Control 33 1 32 303 0014EA 34 8 26 2353

participants filled the defecation diary every day during theentire experimental period

24 Statistical Analysis All of statistical analysis was per-formed in both ITT analysis (intention-to-treat analysis) andPP analysis (per-protocol analysis) The data are expressed asthe mean plusmn standard error (SEM) in each group SPSS WinVer140 software was used and 119875 lt 005 was considered assignificance

3 Results

31 Outcomes One hundred and nine volunteers were fil-tered in this study and 37 volunteers were excluded dueto either failure to meet the Rome III criteria or beingafraid of needle insertion or lacking of time to complete theexperiment Then 72 participants were divided into controlgroup (119899 = 37) or EA group (119899 = 35) randomly67 participants completed all treatments and the follow-upvisits In control group two participants lost contact and theother two failed in blinding One participant in EA groupreceived another treatment of constipation (Figure 1)

At the 1st assessment (baseline before treatment) therewere no significant differences between the two groupsincluding gender age and disease course (Table 1)

At the 2nd assessment (after treatment of 8 weeks) CSBMand SBM were increased significantly in EA group (119899 = 34200 plusmn 167week and 410 plusmn 229week resp) compared tocontrol group (119875 lt 005 119899 = 33 133 plusmn 109week and 306 plusmn153week resp Figure 3) However at the 3rd assessment(follow-up visits of 12weeks) therewas no difference betweenthe two groups on CSBM (data not supplied)

Both treatment methods significantly increased BSS andPAC-QOL compared to the baseline (119875 lt 001 resp) how-ever no differences were found between the two treatmentmethods (119875 gt 005) (Figures 4 and 5)

According to Rome III criteria we consider CSAM ≧ 3 asa standard indicating the success of treatment The cure rateof EAgroupwas higher than that in control group (119875 = 0014)(Table 2)


109 volunteers assessed for eligibility

72 randomized

37 volunteers excluded did not meet the Rome III criteria were afraid of needles

lacked of time

37 in control group 35 in EA group

1 abroad 1 lost contact 2 failed to patient-blind 1 received another treatment

33 completed trial(treatment and follow-up)


Figure 1 Trail flow chart

1stassessment

2ndassessment

3rdassessment

8WBaseline Treatment Follow-up visits

middot middot middot middot middot middotminus1Wminus2W 19W 20W0W 7W

Figure 2 The total study period and the timepoint of evaluation

0

1

2

3

4

5

6

7

Baseline Aftertreatment


CSBM SBM

Tim

es p

er w

eek

ControlEA

lowast

lowast

lowastP lt 005

Figure 3 CSBM and SBM (mean plusmn SD)

0

05

1

15

2

25

3

35

4

45

5

Baseline After treatment

Tim

es p

er w

eek

ControlEA

lowast

lowast

lowastP lt 001

P gt 005

Figure 4 BSS (mean plusmn SD)

32 Safety There were no serious adverse events reportedLocal subcutaneous congestion appeared in two participantsone participant reported mild abdominal pain

4 Discussion

Electroacupuncture (EA) is based on acupuncture an ancientChinese traditional medicine therapy in which electric cur-rent is transmitted to needles inserted acupoints on skin


0

20

40

60

80

100

120


PAC-

QO

L sc

ores

ControlEA

lowast

lowast

lowastP lt 001

P gt 005

Figure 5 PAC-QOL score (mean plusmn SD)

During the past decade EA has been reported to treat consti-pation by acupuncturists However evidences to efficacy andsafety are deficiency because of less randomized controlledclinic trails reported

In this study EA showed effective on constipation Timesof spontaneous bowel movements per week were increasedproperties of stool were improved so that evacuation becamesmooth qualities of life of patients with constipation weretaking a turn for the better

Nonacupoints were active in control group despite thefact that they locate at one cun away from normal acu-points and the middle of two meridians In the literatureopinions on nonacupoints were controversial especially thedistance between nonacupoint and normal acupoint Someresearchers consider that acupoint is not located at a pointon skin but in a field [14] therefore the more proper name ofacupoint is ldquoacupuncture fieldrdquo [15] Moisberger recommendldquoa minimum distance of 6 cm between verum and shampoints on face hands and feet and up to 12 cm for allother parts of the bodyrdquo [15] However this is not feasiblebecause there are so many acupoints throughout the body itis understandable that all acupoints interfere with each otherwithin the distance of 6 cm or 12 cm In the current studyalthough using the shallow needle insertion the controlgroup also received EA treatment and therefore improveddefecation frequency and constipation symptom scores

The technique of deep puncture performed on acupointsST25 and SP14 caused that EA group acted better than controlgroup Taking needles perpendicularly and slowly into skinof abdomen until penetrating the peritoneum had beenproved effective for constipation [16] Operative techniqueof puncture is deemed to be one of important factorswhich can affect acupuncture action So the direction anddepth of puncture should be required Needles penetrated

the peritoneum stimulated intestine directly and improvedmotility and at the same time avoided impairing organs due towithout lifting and twisting The safety of ldquodeep acupuncturerdquoon ST25 had been confirmed through study of anatomy andoperation standard had been set up [17] No obvious adverseevents have been noted in the current study

The mechanism of EA for treating constipation couldbe attributed to the improvement of colonic motility It wasreported that EA promotes contractility of distal colon inrats [18] EA was also shown to accelerate colon motility andtransit in rats [19] Rectal distention a common model tomimic feces stasis has been shown to alter gastric slow wavesand delay gastrointestinal transit Using the rectal distentionmodel EA was shown to normalize the impaired gastricslow waves and improve antral contractions in dogs andimprove upper and lower abdominal symptoms in healthyvolunteers [20 21] These effects are believed to be mediatedvia cholinergic and opioid pathways [18ndash21]

In conclusion it is effective and safe with EA to treat FCThere are deficiencies in this study including small samplesizes and single blind More rigorous studies with largersample sizes are required


The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Nili Da and Xinjun Wang contributed equally to this work

References

[1] G F LongstrethW GThompsonW D Chey L A HoughtonF Mearin and R C Spiller ldquoFunctional bowel disordersrdquoGastroenterology vol 130 no 5 pp 1480ndash1491 2006

[2] P D R Higgins and J F Johanson ldquoEpidemiology of constipa-tion in North America a systematic reviewrdquo American Journalof Gastroenterology vol 99 no 4 pp 750ndash759 2004

[3] A Lopez-Colombo D Morgan D Bravo-Gonzalez AMontiel-Jarquın S Mendez-Martınez and M SchmulsonldquoThe epidemiology of functional gastrointestinal disorders inMexico a population-based studyrdquo Gastroenterology Researchand Practice vol 2012 Article ID 606174 8 pages 2012

[4] N Iraji A H Keshteli S Sadeghpour P DaneshpajouhnejadM Fazel and P Adibi ldquoConstipation in Iran Sepahan system-atic review no 5rdquo International Journal of Preventive Medicinevol 3 supplement 1 pp 34ndash41 2012

[5] G Li Y Wang and L Tang ldquoResearch progress of functionalconstipationrdquo Chinese Journal of Gerontology vol 31 no 12 pp2372ndash2375 2011

[6] M Ke and Y Wang ldquoProgress in epidemiological study of theelderly and chronic constipationrdquo Practical Geriatrics vol 24no 2 pp 92ndash94 2010

[7] Yanfeng ldquoHarm and treatment of constipation in childrenrdquoChinese Medicine Guide vol 11 no 18 pp 793ndash794 2013

[8] C Li ldquoThe harm of constipation in the elderly and commontreatment methodsrdquo Inner Mongolia Journal of TraditionalChinese Medicine vol 8 no 4 pp 31ndash32 2011


[9] J Belsey S Greenfield D Candy and M Geraint ldquoSystematicreview impact of constipation on quality of life in adults andchildrenrdquo Alimentary Pharmacology and Therapeutics vol 31no 9 pp 938ndash949 2010

[10] S Sethi S Mikami J Leclair et al ldquoInpatient burden ofconstipation in the United States an analysis of national trendsin the United States from 1997 to 2010rdquoTheAmerican Journal ofGastroenterology vol 109 no 2 pp 250ndash256 2014

[11] S Muller-Lissner J Tack Y Feng F Schenck and R SGryp ldquoLevels of satisfaction with current chronic constipationtreatment options in Europemdashan internet surveyrdquo AlimentaryPharmacology ampTherapeutics vol 37 no 1 pp 137ndash145 2013

[12] F Ma J Gan and Q Wang ldquoThe clinical development ofacupuncture andmoxibustion in treating constipationrdquoYunnanJournal of Traditional ChineseMedicine vol 30 no 2 pp 60ndash632009

[13] Y Wang B Pei and W Zhang ldquoThe ancient literature researchon acupuncture treatment of constipationrdquo Journal of ClinicalAcupuncture and Moxibustion vol 27 no 8 pp 67ndash69 2011

[14] L Huang and Y Huang Acupuncture Point of General PeoplersquosMedical Publishing House Beijing China 2011

[15] A F Molsberger J Manickavasagan H H Abholz W BMaixner andHG Endres ldquoAcupuncture points are large fieldsthe fuzziness of acupuncture point localization by doctors inpracticerdquo European Journal of Pain vol 16 no 9 pp 1264ndash12702012

[16] W-N Peng L Wang Z-S Liu et al ldquoAnalysis on follow-upefficacy and safety of slow transit constipation treated withindividualized deep puncture at Tianshu (ST 25) a multi-central randomized controlled trialrdquo Chinese Acupuncture andMoxibustion vol 33 no 10 pp 865ndash869 2013

[17] J X Duan and Z S Liu ldquoReview on the safety of deepacupuncture at Tianshu (ST 25)rdquoAcupuncture Research vol 35no 3 pp 232ndash235 2010

[18] D Luo S Liu X Xie and X Hou ldquoElectroacupuncture atacupoint ST-36 promotes contractility of distal colon via acholinergic pathway in conscious ratsrdquo Digestive Diseases andSciences vol 53 no 3 pp 689ndash693 2008

[19] M Iwa M Matsushima Y Nakade T N Pappas M Fujimiyaand T Takahashi ldquoElectroacupuncture at ST-36 acceleratescolonic motility and transit in freely moving conscious ratsrdquoAmerican Journal of Physiology Gastrointestinal and LiverPhysiology vol 290 no 2 pp G285ndashG292 2006

[20] J Liu H Huang X Xu and J D Z Chen ldquoEffects and possiblemechanisms of acupuncture at ST36 on upper and lowerabdominal symptoms induced by rectal distension in healthyvolunteersrdquo The American Journal of PhysiologymdashRegulatoryIntegrative and Comparative Physiology vol 303 no 2 ppR209ndashR217 2012

[21] J Chen G-Q Song J Yin T Koothan and J D Z ChenldquoElectroacupuncture improves impaired gastric motility andslow waves induced by rectal distension in dogsrdquo AmericanJournal of PhysiologymdashGastrointestinal and Liver Physiologyvol 295 no 3 pp G614ndashG620 2008

Research ArticleEfficacy of Adaptive Biofeedback Training inTreating Constipation-Related Symptoms

Jing Tang1 Zhihui Huang23 Yan Tan1 Nina Zhang24 Anping Tan1

Jun Chen1 and Jianfeng Chen5

1Division of Gastroenterology Affiliated Hospital of Hainan Medical College Haikou 571000 China2Ningbo Pace Translational Medical Research Center Beilun Ningbo 315000 China3Department of Gastroenterology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310000 China4Divison of Gastroenterology The First Affiliated Hospital of Nanjing Medical University Nanjing 210000 China5Ningbo Medkinetic Inc Ningbo 315000 China

Correspondence should be addressed to Jing Tang 13006003523163com and Zhihui Huang huangzhihui808gmailcom

Received 18 July 2014 Accepted 26 August 2014

Academic Editor Jiande Chen

Copyright copy 2015 Jing Tang et alThis is an open access article distributed under the Creative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Biofeedback therapy is a well-known and effective therapeutic treatment for constipation A previous study suggested that adaptivebiofeedback (ABF) training was more effective than traditional (fixed training parameters) biofeedback training The aim of thisstudy was to verify the effectiveness of ABF in relieving constipation-related symptoms We noticed that in traditional biofeedbacktraining a patient usually receives the training twice per weekThe long training sessions usually led to poor complianceThis studyproposes an intensive biofeedback therapy and compares intensive therapy with nonintensive therapy in patients with constipation-related symptomsMethods 63 patients with constipation-related symptoms were treated with ABF between 2012 and 2013 Thesepatients were further divided into the intensive therapy and nonintensive therapy groupsResultsA total of 63 patients were enrolledin the study including 24 in the nonintensive therapy group and 39 in the intensive therapy group 100 (119873 = 21) of constipationpatients achieved the primary efficacy endpoint (ge3 bowel movementsweek) There was significant improvement in constipation-related symptoms after adaptive biofeedback The intensive biofeedback therapy did not show better performance compared tononintensive biofeedback therapy ConclusionsThis investigation provides support for the efficacy of biofeedback for constipation-related symptoms The efficacy of intensive therapy is similar to nonintensive therapy

1 Introduction

Chronic constipation is a common disorder characterizedby defecation difficulty or decreased bowel movements (lessthan three times a week) The worldwide prevalence ofchronic constipation varies from 12 to 17 [1] It is moreprevalent in females thanmales (prevalence rate of 22 1) andthe prevalence increases with age [2] Patients who reportedpersistent constipation have decreased health-related qualityof life and higher level of depression [3] Chronic constipationhas a great economic and social impact including laboratorytests diagnostic procedures and healthcare expenditures [4]

Constipation is primarily a functional disorder and itcould also be caused by medications diseases of the colon

metabolic disturbances and neurologic disorders Consti-pation can be categorized into 3 subgroups (obstructeddefecation slow transit constipation and normal transitconstipation) [5 6] About 40 of constipation is due toobstructed defecation [7 8] Obstructed defecation (alsoknown as dyssynergic defecation pelvic floor dyssynergia oroutlet obstruction) is characterized by the lack of coordina-tion between the abdominal and pelvic floor muscles duringdefecation Obstructed defecation is caused by one of thefollowing problems impaired rectal contraction paradoxicalanal contraction or inadequate anal relaxation

Although currently available treatment options have beenreported to be effective at improving patientsrsquo symptoms thecurative effect is still unsatisfactory There is insufficient data



to support that lifestyle and diet change such as increasedfiber and fluid intake can improve chronic constipationLaxatives (including bulking agents osmotic and stimulantlaxatives and stool softeners) have been approved to relievethe symptoms [9ndash11] However laxatives do not target theunderlying pathophysiology such as paradoxical anal con-traction Biofeedback therapy an instrument-based learningprocess can correct the incoordination of the abdominalrectal and anal sphincter pressures [12] The efficacy ofbiofeedback therapy is reported to range from 44 to 100 invarious clinical studies [13] However training requires com-plex processing and the training targets are fixed meaningall patients receive the same training regardless of differentanorectal motility and ability to achieve the training goal Anovel method of adaptive biofeedback (ABF) training report-edly changes the training targets and protocols according topatientsrsquo anorectal motility This method of ABF has shownto be superior to the traditional biofeedback training [14]

The frequency and duration of traditional biofeedbacktraining are variable in different clinical trials [15ndash18] Onaverage patients are asked to receive treatment for 3 monthsat a frequency of twice per week The inconvenience andlengthy duration of biofeedback treatment often lead to poorcompliance We propose an intensive biofeedback therapyonce a day or once every other day The aim of the presentstudy was to confirm the efficacy of ABF and compare theefficacy of intensive therapy with nonintensive therapy inpatients with constipation-related symptoms

2 Materials and Methods

A retrospective cohort study was conducted on subjectswho had been treated with ABF for constipation-relatedsymptoms between April 2012 and September 2013 Theresults were compared between the intensive therapy andnonintensive therapy in terms of constipation-related symp-tomsThe subjects were selected in this study according to thefollowing inclusionexclusion criteria

21 Inclusion and Exclusion Criteria The study enrolledmen and women aged ge 18 years with a history ofconstipation-related symptoms Constipation-related symp-toms are defined as follows lt3 bowel movements (BMs)per week on average hard stools low stool volume sen-sation of incomplete evacuation straining at defecationor a need for manual maneuver to facilitate evacua-tion Exclusion criteria included drug-induced constipa-tion metabolic endocrine neurological disorders surgicalobstruction megacolonmegarectum surgical obstructionand pseudoobstruction Other exclusion criteria were severecardiovascular renal liver or lung diseases

22 Outcomes and Data Collection

221 Primary Outcomes Patients rate the severity of con-stipation in terms of bowel movements with the three-pointscale classification [0 = normal (ge3 BMs per week) 1 = mild(1-2 BMs per week) 2 = severe (lt1 BMs per week)] Criteria

for therapeutic effects are being cured (BMs changed fromsevere ormild to normal) being effective (BMs changed fromsevere to mild) and having no effect (BMs did not change)

222 Secondary Outcomes Secondary outcome measuresusage of medications defecation difficulty hard stoolsstraining incomplete bowel movement low stool volumemanual maneuver to facilitate abdominal bloating and anusdiscomfort Symptoms of defecation difficulty hard stoolsincomplete bowel movement low stool volume are describedon a 0ndash3 scale (0 = absent 1 = mild 2 = moderate3 = severe) manual maneuver to facilitate [0 = absent1 = mild (lt1 time per week) 2 = moderate (1ndash3 times perweek) 3 = severe (gt3 times per week)]

223 Impact on Social Activities and Work The impact onsocial activities and work is rated on a 0ndash2 scale where 0 =absent 1 = mild (a mild effect on normal social activitiesand normal work) and 2 = severe (a severe effect) Criteriafor therapeutic effects are being cured (change from severe ormild to absent) being effective (change from severe to mild)and having no effect (no change)

23 Adaptive Biofeedback Training Biofeedback training forthe treatment of constipation is to train the relaxation of analsphincter enhance the sensory perception and improve therectoanal coordination Training of rectoanal coordinationis to increase the pushing effort as reflected by an increasein intra-abdominalintrarectal pressures and synchronizedrelaxation reflected by a decrease in anal sphincter pressureHowever the traditional biofeedback training algorithm usesthe fixed training target it cannot increase (or decrease)the training strength or duration based on patientrsquos capacityOn the other hand the adaptive biofeedback training (ABT)(NingboMaidaMedical Device Inc Ningbo China) methoduses the training strength and duration based on patientrsquosown capacity and trains the patient at strength slightly abovehis or her own threshold with the purpose to graduallyincrease the strength threshold until the targeted thresholdis met It was reported to have a better efficacy for thetreatment of constipation than the traditional biofeedbacktraining method Each patient received a total of 16 trainingsessions with each training session lasting half an hour

Intensive Therapy Patients were asked to receive intensivebiofeedback therapy once a day or once every other day

NonintensiveTherapy Patients received nonintensive trainingtwice a week in the motility lab

24 Statistical Analysis The data are expressed as mean plusmnstandard errorThe paired-sample t-test was used to comparedefecation difficulty hard stools straining incomplete bowelmovement low stool volume manual maneuver to facilitateabdominal bloating and anus discomfort before and aftertreatment with ABF An independent t-test was used tocompare the nonintensive therapy with the intensive therapy


0

20

40

60

80

Pre-treatmentPost-treatment

Normal Mild Severe

Num

ber o

f sub

ject

s

Figure 1 Effects of ABF on bowel movement (BM)

group Data were considered statistically significant if 119875 lt005

3 Result

A total of 63 subjectsmet the inclusive criteria 21 subjects hada long history of constipation defined as an average oflt3 BMsper week The mean age of the participants was 4560 plusmn 1660and 42 (6666) were women and 21 were men There wasno significant difference in age and gender between the twotreatment groups

After adaptive biofeedback training treatment all con-stipation patients (119873 = 21) reported a significantly greaternumber of weekly bowel movements (ge3 times) comparedwith the baseline (lt3 times) The cure rate of nonintensivetherapy (119873 = 8) and intensive therapy (119873 = 13) both reached100 None of the patients reported less than 3 BMs perweek after the treatment (Figure 1) The usage of medicationsdecreased considerably during the training period in bothtreatment groups compared to baseline The medicationusage at the start of treatment was 100 for nonintensivetherapy group and 923 for intensive therapy group Duringthe treatment period medication usage decreased to 125for the nonintensive therapy group and 51 for the intensivetherapy group (Figure 2)

As shown in Table 1 defecation difficulty hard stoolsand straining significantly improved with nonintensive ther-apyintensive therapy compared with baseline (119875 lt 005)Intensive therapy patients also reported significant improve-ments in incomplete BM Intensive therapy also improvedlow stool volume (119875 = 0006) and decreased manual maneu-ver frequency (119875 = 0048) Both treatments significantlydecreased abdominal bloating (119875 lt 005) Nonintensivetherapy but not intensive therapy significantly reduced thescores for anus discomfort (0 versus 048 + 087 119875 =0011 0 versus 010 + 050 119875 = 021) However there wasno statistically difference between the two methods in allsymptoms (119875 gt 005)

Overall 825 (119873 = 52) of subjects reported that con-stipation symptoms interfered with normal social activities

0

20

40

60

80

100

Pre-treatment

Post-treatment

Traditional training Intensive training

()

Figure 2 Usage of medications during the biofeedback training

0

10

20

30

Non-intensive therapyIntensive therapy

Num

ber o

f sub

ject

s

Ineffective Effective Cured

Figure 3 Improve the impact on social activities and work

and normal work The number of patients receiving eithernonintensive therapy or intensive therapy who were curedwas high (22 and 27 resp) Only 1 patient with nonintensivetherapy showed no improvement (Figure 3)

4 Discussion

The results of this study indicate that adaptive biofeedbacktraining was effective in the treatment of patients withconstipation-related symptoms The adaptive biofeedbacktraining was able to significantly increase weekly bowelmovements Patients also showed major improvement indefecation difficulty hard stools and straining incompleteBM low stool volume manual maneuver to facilitate andabdominal bloating In the current study adaptive biofeed-back training also reduced the impact on social activities andwork created by constipation-related symptoms


Table 1 Constipation-related symptoms before and after intensive therapynonintensive therapy

Intensive therapy Nonintensive therapyBefore training After training Before training After training

Defecation difficulty 118 + 112 013 + 041lowast

079 + 106 017 + 048lowast

Staining 044 + 097 005 + 022lowast

058 + 093 0lowast

Incomplete BM 041 + 082 003 + 016lowast

025 + 068 0Low stool volume 067 + 101 026 + 050

lowast017 + 057 004 + 020

Hard stools 067 + 106 010 + 031lowast

104 + 108 013 + 045lowast

Manual maneuver to facilitate 023 + 071 0lowast 008 + 041 0Abdominal bloating 046 + 088 003 + 016

lowast096 + 120 004 + 020

lowast

Anus discomfort 010 + 050 0 050 + 089 0lowastlowast119875 lt 005 versus before training

Our results are consistent with the study conducted byXu et al [14] who recently reported that adaptive biofeedbacktraining was more effective in improving bowel movementsthan those of conventional fixed biofeedback training (34 plusmn13 versus 26 plusmn 05 119875 lt 0005) In this study twenty-oneconstipation patients (100) had bowel movements of morethan 3 times per week after ABF therapy Chiarioni et al[15] reported 82 of patients had ge3 bowel movements perweek at 12-month follow-up after fixed biofeedback trainingOnly 29 patients reported ge3 bowel movements per weekat 4 weeks of prucalopride therapy [19] The ABF had ahigher bowel movement response rate than fixed biofeedbacktraining and laxative

ABF significantly improved symptoms of constipationsuch as defecation difficulty incomplete BM hard stools andstraining based on ROME III criteria [20] Xu et al [14]reported that ABF significantly improved these symptomscompared with fixed biofeedback training

In addition the impact of constipation symptoms onsocial activities and work was significantly decreased at theend of ABF A growing evidence shows that constipationpatients have a significantly impaired health-related quality oflife compared with population norms [21ndash23] Although thisstudy did not use standard assessment tools to characterizequality of life the results indicated that symptoms had animpact on social function Other studies reported that fixedbiofeedback training improved the quality of life scorescompared with control group [18 24]

In this study we investigated the efficacy of intensivetherapy compared to nonintensive therapy In previous stud-ies patients were asked to receive nonintensive biofeedbacktraining twice a week with a total of 4 to 6 sessions [25]We proposed an intensive biofeedback therapy of whichfrequency was once a day or once every other day Therewas no significant difference in constipation-related symp-toms between the two treatment groups Several random-ized controlled trials had variable duration and number ofbiofeedback sessions but the efficacy of therapy was similar[15ndash18 26] But the intensive biofeedback therapy had shortduration and may have better compliance

In conclusion treatment with adaptive biofeedback train-ing produced significant improvement in bowel movementsABF also significantly improved symptoms associated with

constipationThe intensive biofeedback therapy did not seemto be superior to nonintensive therapy




Jing Tang and Zhihui Huang contributed equally to thispaper

References

[1] N C Suares and A C Ford ldquoPrevalence of and risk factors forchronic idiopathic constipation in the community systematicreview and meta-analysisrdquo The American Journal of Gastroen-terology vol 106 no 9 pp 1582ndash1591 2011

[2] E Rey A Balboa and F Mearin ldquoChronic constipation irri-table bowel syndrome with constipation and constipation withpaindiscomfort similarities and differencesrdquo The AmericanJournal of Gastroenterology vol 109 no 6 pp 876ndash884 2014


[4] C Dennison M Prasad A Lloyd S K Bhattacharyya RDhawan and K Coyne ldquoThe health-related quality of life andeconomic burden of constipationrdquo PharmacoEconomics vol 23no 5 pp 461ndash476 2005

[5] WAshraf F Park J Lof and EMMQuigley ldquoAn examinationof the reliability of reported stool frequency in the diagnosis ofidiopathic constipationrdquoTheAmerican Journal of Gastroenterol-ogy vol 91 no 1 pp 26ndash32 1996

[6] A Lembo and M Camilleri ldquoChronic constipationrdquo The NewEngland Journal of Medicine vol 349 no 14 pp 1360ndash13682003

[7] S Gonlachanvit and T Patcharatrakul ldquoCauses of idiopathicconstipation in Thai patients associations between the causesand constipation symptoms as defined in the Rome II criteriardquoJournal of the Medical Association of Thailand vol 87 supple-ment 2 pp S22ndashS28 2004

[8] S Shahid Z Ramzan A H Maurer H P Parkman and R SFisher ldquoChronic idiopathic constipation More than a simple


colonic transit disorderrdquo Journal of Clinical Gastroenterologyvol 46 no 2 pp 150ndash154 2012

[9] L W Liu ldquoChronic constipation current treatment optionsrdquoCanadian Journal of Gastroenterology vol 25 pp 22Bndash28B2011

[10] E Klaschik F Nauck and C Ostgathe ldquoConstipation modernlaxative therapyrdquo Supportive Care in Cancer vol 11 no 11 pp679ndash685 2003

[11] M El-Salhy R Svensen J G Hatlebakk O H Gilja andT Hausken ldquoChronic constipation and treatment options(Review)rdquo Molecular Medicine Reports vol 9 no 1 pp 3ndash82014

[12] S S Rao ldquoBiofeedback therapy for constipation in adultsrdquo BestPractice and Research Clinical Gastroenterology vol 25 no 1pp 159ndash166 2011

[13] S Heymen K R Jones Y Scarlett and W E WhiteheadldquoBiofeedback treatment of constipation a critical reviewrdquo Dis-eases of the Colon amp Rectum vol 46 no 9 pp 1208ndash1217 2003

[14] Y Xu X Li F Xu D W Lu J Chen and J D Z Chen ldquoA novelmethod of adaptive biofeedback training for dyssynergic defe-cationrdquoNeurogastroenterology ampMotility vol 25 supplement 1pp 13ndash45 2013

[15] G Chiarioni L Salandini and W E Whitehead ldquoBiofeedbackbenefits only patients with outlet dysfunction not patients withisolated slow transit constipationrdquoGastroenterology vol 129 no1 pp 86ndash97 2005

[16] S S C Rao K Seaton MMiller et al ldquoRandomized controlledtrial of biofeedback sham feedback and standard therapy fordyssynergic defecationrdquo Clinical Gastroenterology and Hepatol-ogy vol 5 no 3 pp 331ndash338 2007

[17] S S C Rao J Valestin C K Brown B Zimmerman and KSchulze ldquoLong-term efficacy of biofeedback therapy for dyssyn-ergic defecation randomized controlled trialrdquo The AmericanJournal of Gastroenterology vol 105 no 4 pp 890ndash896 2010

[18] S Heymen Y Scarlett K Jones Y Ringel D Drossmanand W E Whitehead ldquoRandomized controlled trial showsbiofeedback to be superior to alternative treatments for patientswith pelvic floor dyssynergia-type constipationrdquo Diseases of theColon and Rectum vol 50 no 4 pp 428ndash441 2007

[19] E M M Quigley L Vandeplassche R Kerstens and JAusma ldquoClinical trial the efficacy impact on quality of lifeand safety and tolerability of prucalopride in severe chronicconstipationmdasha 12-week randomized double-blind placebo-controlled studyrdquo Alimentary Pharmacology and Therapeuticsvol 29 no 3 pp 315ndash328 2009

[20] D A Drossman and D L Dumitrascu ldquoRome III newstandard for functional gastrointestinal disordersrdquo Journal ofGastrointestinal and Liver Diseases vol 15 no 3 pp 237ndash2412006

[21] A Wald C Scarpignato M A Kamm et al ldquoThe burden ofconstipation on quality of life results of a multinational surveyrdquoAlimentary Pharmacology and Therapeutics vol 26 no 2 pp227ndash236 2007

[22] A K Tuteja N J Talley S K Joos J V Woehl and D HHickam ldquoIs constipation associated with decreased physicalactivity in normally active subjectsrdquo The American Journal ofGastroenterology vol 100 no 1 pp 124ndash129 2005

[23] S S Rao K Seaton M J Miller et al ldquoPsychological profilesand quality of life differ between patients with dyssynergia andthose with slow transit constipationrdquo Journal of PsychosomaticResearch vol 63 no 4 pp 441ndash449 2007

[24] S L Hart J W Lee J Berian T R Patterson A del Rosarioand M G Varma ldquoA randomized controlled trial of anorectalbiofeedback for constipationrdquo International Journal of Colorec-tal Disease vol 27 no 4 pp 459ndash466 2012

[25] E Battaglia A M Serra G Buonafede et al ldquoLong-term studyon the effects of visual biofeedback and muscle training asa therapeutic modality in pelvic floor dyssynergia and slow-transit constipationrdquo Diseases of the Colon and Rectum vol 47no 1 pp 90ndash95 2004

[26] G Chiarioni W E Whitehead V Pezza A Morelli and GBassotti ldquoBiofeedback is superior to laxatives for normal transitconstipation due to pelvic floor dyssynergiardquo Gastroenterologyvol 130 no 3 pp 657ndash664 2006

Research ArticleAmeliorating Effect of TranscutaneousElectroacupuncture on Impaired Gastric Accommodation inPatients with Postprandial Distress Syndrome-PredominantFunctional Dyspepsia A Pilot Study

Feng Xu1 Yan Tan23 Zhihui Huang34 Nina Zhang3 Yuemei Xu1 and Jieyun Yin3

1Division of Gastroenterology Yinzhou Hospital Affiliated to Medical School of Ningbo University Ningbo 315000 China2Division of Gastroenterology Affiliated Hospital of Hainan Medical College Haikou 571000 China3Ningbo Pace Translational Medical Research Center Beilun Ningbo 315000 China4Department of Gastroenterology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310000 China

Correspondence should be addressed to Feng Xu xufengxh19163com and Jieyun Yin jieyunyin07gmailcom

Received 18 July 2014 Accepted 2 September 2014


Copyright copy 2015 Feng Xu et alThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Patients with functional dyspepsia (FD) have both reduced gastric accommodation and impaired gastric motility that are difficultto treat The aim of this study was to investigate the therapeutic potential of transcutaneous electroacupuncture (TEA) for both ofthese disorders in FD patients Acute experiments were performed in FD patients to study the effect of TEA and sham-TEA ongastric accommodation assessed by a nutrient drink test and gastric motility assessed by the measurement of the electrogastrogram(EGG) TEA or sham-TEA was performed via cutaneous electrodes at acupoints ST36 and PC6 or sham-points nonacupoints Itwas found that (1) gastric accommodation (maximum tolerable volume) was reduced in FD patients compared with the controls(119875 lt 003) TEA improved gastric accommodation in FD patients (119875 lt 002) (2) Acute TEA significantly increased the percentageand power of normal gastric slow waves in the fed state assessed in the FD patients by the EGG in comparison with sham-TEA(3) TEA increased vagal activity assessed by the spectral analysis of the heart rate variability in the fed state in FD patients Itwas concluded that needleless method of transcutaneous electroacupuncture may have a therapeutic potential for treating bothimpaired gastric accommodation and impaired gastric motility in patients with FD

1 Introduction

The prevalence of functional dyspepsia (FD) is high butthe treatment options have been limited [1] Patients withFD complain about symptoms of epigastric pain abdominalfullness early satiety and abdominal discomfort Patho-physiologies of FD include visceral hypersensitivity reducedgastric accommodation and impaired gastric motility suchas gastric dysrhythmia antral hypomotility and delayedgastric emptying [2]

Gastric accommodation is mediated by the vagal nerveUpon food ingestion the vagal nerve is activated and nitricoxide is released resulting in a relaxation of the stomachThis relaxation reflex accommodates ingested food without

causing an increase in gastric pressure [3] Impaired gastricaccommodation leads to early satiety and postprandial full-ness possibly attributed to weakening of the vagal nerve

After the patients with GI disorder eat food a series ofindigestion symptoms of early satiety and abdominal disten-sionwill appear due to insufficient relaxation of proximal gas-tric and intragastric pressure increasing About 40 to 70of FD patients have proximal GI disorder [4] Accordinglytreatment for impaired gastric accommodation is of greatclinical significance [5 6]

Common treatment options for FD include dietary mea-sures pharmacologic treatments such as acid-suppressiondrugs prokinetic agents fundus relaxing drugs and antinoci-ceptive agents and psychological interventions [7ndash16] In



general targeted therapies directed at the underlying patho-physiology are desirable However efficacy of the therapy isusually very limited due to multiple symptoms and patho-physiologies in individual patients For example a patientmay have impaired accommodation and delayed gastricempting at the same time in this case prokinetic agents canbe used to treat delayed gastric emptying but would worsenthe symptoms related to gastric accommodation becauseavailable prokinetics often impair gastric accommodationFor the same reason fundus relaxing drugs may be usedfor treating impaired accommodation however these drugsmay delay gastric emptying because they relax muscles Thetreatment approach to the patients with hypersensitivity togastric distension has not been established Antidepressantsare commonly used in functional gastrointestinal disordersand were thought to exert a visceral analgesic rather thanan antidepressant effect However studies of the effectsof antidepressants on visceral sensitivity are rare and theexisting data on visceral sensitivity are controversial [14 15]

Acupuncture has been used to treat gastrointestinalsymptoms in China for thousands of years The most com-monly used acupuncture points (acupoints) for the treat-ment of gastrointestinal symptoms are Neiguan (PC6) andZusanli (ST36) In clinical research manual acupuncture iscommonly replaced with electroacupuncture that is morereproducible In a comparative study electroacupuncturewasfound to be as effective as manual acupuncture in treatingpain [17] Electroacupuncture at ST36 and PC6 has beendocumented to increase the regularity of gastric slow wavesand accelerate gastric emptying of liquids in animals [18] Inrecent studies electroacupuncture was reported to accelerategastric emptying of solids and improve dyspeptic symptomsand gastric dysrhythmia in patients with FD and patientswith diabetes [19 20] and similar beneficial effects can beobserved in patients with FD when electroacupuncture isapplied without needles or a method called transcutaneouselectroacupuncture (TEA) [21] TEA is a completely noninva-sivemethodwhich is readily accepted by patients However itis unknownwhether TEA is able to treat both reduced gastricaccommodation and impaired gastric motility in patientswith FD

The aims of this study were to investigate the therapeuticpotential of TEA for patients with FD by assessing its acuteeffects on gastric accommodation assessed by a noninvasivenutrient drink test and gastric motility assessed by noninva-sive electrogastrography as well as dyspeptic symptoms andto explore vagal mechanisms involved with TEA

2 Materials and Methods21 Subjects Eight FD patients with postprandial distresssyndrome and 8 healthy volunteers aged 21 to 65 years oldwere recruited in this study Patients included fulfilled RomeIII criteria for FDpostprandial distress syndrome [1] Patientswho were unable to give informed consent were takingprokinetic anticholinergic or dopaminergic agents duringthe experimental period had a history of gastrointestinalsurgery were pregnant or preparing to conceive a child haddiabetes and were allergic to skin preparation and familiar

with acupoints and their functions were excluded from thestudy Inclusion criteria of healthy volunteers include nohistory of supreme gastrointestinal diseases including pepticulcer disease gastroesophageal reflux disease and hepatobil-iary and pancreatic diseases a history of abdominal surgeryno history of alcohol abuse no serious systemic illness andpossible malignancy and usually no dyspeptic symptomsincluding upper abdominal pain upper abdominal discom-fort postprandial fullness upper abdominal swelling earlysatiety nausea vomiting excessive belching and heartburnAll general information including height weight addressand relating medical history is recorded and all the subjectshad signed the informed consent prior to the study Theexperimental protocol was approved by the ethical committeeof Yinzhou Peoplersquos Hospital and all the subjects signed theconsent form before participation

22 Experimental Protocol All subjects were studied in themorning after a 12-hour fast Each subject was studied fortwo sessions in a randomized order TEA and sham-TEAsessions The experiment protocol was as follows 30-minutebaseline recording 30-minute TEAsham-TEA treatment inthe fasting state and then a satiety drinking test conductedwith a liquidmeal of Ensure (095 kcalmL) with TEASham-TEA After the completion of satiety drinking test there was a30-minute recovery periodwithTEAsham-TEA Electrogas-trogram (EGG) and electrocardiogram (ECG) were recordedduring the entire experimental period except during thesatiety drinking test

23 Transcutaneous Electroacupuncture Acupoints ST36(Zusanli) and PC6 (Neiguan) were used in the TEA sessionST36 is located at the place of 4-finger-breadth measuringdown from the outer eye of the knee between the fibulaand the tibia 1-finger-breadth measurement beside the tibiaPC6 is located at the place of one-sixth of remote endand five-sixths of proximal end of the connection stripebetween the transverse wrist crease and cubical crease Thestimulation was delivered by two portable neuromodulationdevices at ST36 and PC6 respectively (SNM-FDC01 NingboMaidaMedicalDevice Inc)The stimulation parameterswerechosen as 2s-on 3s-off 25Hz 06ms and amplitude of2mA to 10mA depending on tolerance of the subject whichwas shown to improve gastrointestinal symptoms in patientswith diabetic gastroparesis [22] In the sham-TEA group thesham-acupoint for PC6 was located at about 15ndash20 cm awayfrom PC6 (up to the elbow and outside coastal margin of theforearm not on any meridian) and the sham-point for ST36was located at 10ndash15 cm down from and to the lateral side ofST36 not on any meridian The stimulation parameters usedfor sham-TEA were the same as in the TEA

24 Satiety Drinking Test The gold-standard method of as-sessing gastric accommodation is the barostat method How-ever this method is not well tolerated by patients dueto intubation of a plastic bag into the stomach Recentlythe satiety drinking test has been used as a surrogate forthe measurement of gastric accommodation [23] A highervolume taken by the subject is indicative of a higher gastric


accommodation In this method after an overnight fast thesubject was instructed to take Ensure (095 kcalmL) at a rateof 120mL every 4 minutes (average 30mLmin) until thesubject reported to reach satiety (complete fullness) Duringthe test each subject was asked to score satiety at a 5-minute interval using following scores 0 no symptoms 1initial satiety (threshold) 2 mild 3 moderate 4 severe 5maximum or intolerable satiety When reaching score 5 thesubjectwas asked to stop drinking and the total volumedrunkwas recorded which reflected themaximum tolerable volume(MTV)

25 Assessment of Autonomic Function The electrocardio-gram (ECG)was recorded using a one-channel amplifier witha cut-off frequency of 100Hz (NingboMaida Medical DeviceInc Ningbo China) from two active ECG electrodes and oneground electrode The two leads were attached to the rightedge of the sternum and apex of the subjects and the groundto the right side of the abdomen The heart rate variability(HRV) signal was derived from the ECG recording usinga special program developed [24] by identifying R peakscalculating and interpolating the R-R intervals so that thetime interval between consecutive samples was equal andfinally downsampling the interpolated data to a frequency of1Hz

Overall power spectral analysis was applied to the HRVsignal and the power in each frequency subband wascalculated The power in the low frequency band (004ndash015Hz) LF represents mainly sympathetic activity and partof parasympathetic activity The power in the high frequencyband (015ndash050Hz) HF stands purely for parasympatheticor vagal activity For LF and HF standard calculations weredone respectively by LF(HF + LF) and HF(HF + LF)[25]

26 Recording and Analysis of Electrogastrogram (EGG)The gastric myoelectrical activity was recorded using a4-channel electrogastrogram (EGG) device (MEGG-04ANingbo Maida Medical Device Inc Ningbo ZhejiangChina) via 6 cutaneous electrodes described as follows Firstthe abdomen where electrodes were to be placed was cleanedwith a special gel (Nuprep Weaver and Company AuroraUSA) then conductive gel (Ten20 Weaver and CompanyAurora USA) was applied to the cleaned skin area toreduce skin-electrode impedance After this six cutaneouselectrodes were placed on the abdominal skin surface basedon a previously established method [2] The subject was in asupine position for the EGG recordings and talking readingor sleeping was not allowed

Established EGG parameters were derived from the EGGsignals using a spectral analysis software package (NingboMaida Medical Device Inc Ningbo China) after a carefuldeletion of motion artifacts [26 27] (1) dominant frequentand power representing the frequency and amplitude ofgastric slow waves (2) percentage of normal 2ndash4 cyclesminslow waves representing the regularity of gastric slow waves(3) postpreprandial ratio of EGG dominant power standingfor postprandial increase in gastric motility

Table 1 Effects of acute TEA treatment on EGG in patients withfunctional dyspepsia in the study

SessionTEA Sham-TEA

Dominant frequency (cpm)Fasting 302 plusmn 003 304 plusmn 006Postprandial 284 plusmn 007 325 plusmn 010

Dominant power (dB)Fasting 3398 plusmn 158 3446 plusmn 175Postprandial 4235 plusmn 135 4024 plusmn 147lowast

Percentage of normal slow waves ()Fasting 826 plusmn 31 837 plusmn 27Postprandial 8542 plusmn 427 7497 plusmn 660lowast

Postpreprandial power ratio 103 plusmn 003 092 plusmn 004lowast119875 lt 005

27 Assessment of Dyspeptic Symptoms Gastric cardinalsymptom index was used to assess dyspeptic symptoms atbaseline and after the acute TEA or sham-TEA [28] Theseincluded upper abdominal pain upper abdominal discom-fort postprandial fullness upper abdominal swelling earlysatiety nausea vomiting excessive belching and heartburnEach symptom was graded based on severity grade 0 nosymptoms grade 1 mild grade 2 moderate grade 3 severe

28 Statistical Analysis Results are expressed as mean plusmnstandard deviation Paired Studentrsquos t-test was used to studythe difference between TEA and sham-TEA and betweenbaseline and after the acute treatment using SPSS 160statistical software 119875 lt 005 was considered statisticallysignificant

3 Results

31 Effects of TEA on Gastric Accommodation FD patientsshowed a reduced gastric accommodation that was improvedwith acute TEA The MTV was 725 plusmn 46mL in the normalcontrol group and 548plusmn38mL in the FD patients (119875 = 0022see Figure 1(a)) Acute TEA increased the MTV in the FDpatients to 663 plusmn 29mL (119875 = 0007 versus baseline) whereasthe sham-TEA did not increase the MTV in patients with FD(549 plusmn 36mL after sham-TEA (119875 = 0121 versus 700mL))There was a difference (119875 = 0017) inMTV in the FD patientsafter TEA and sham-TEA (Figure 1(b))

32 Effects of TEAonGastric SlowWaves TheEGGrecordingwas found to be normal in 2 patients but abnormal in 6patients with FD (percentage of normal slow waves below65 in either fasting or fed state or this was a postprandialdecrease in dominant power) The major EGG parametersin the TEA and sham-TEA sessions are shown in Table 1TEA improved the percentage of normal 2ndash4 cyclesminslow waves in the fed state (Figure 2) and also increasedthe dominant EGG power in the fed state (Figure 3)


500

550

600

650

700

750

800

FDControl

Gastric accommodationlowast

lowastP = 0022

The m

axim

um to

lera

ble v

olum

e (m

L)

(a)

500

550

600

650

700

750

Gastric accommodation

Sham-TEA

lowast

lowastP = 0017

TEA

The m

axim

um to

lera

ble v

olum

e (m

L)

(b)

Figure 1 (a)Themaximum tolerable volume (gastric accommodation) in normal controls and patients with FD (b)Themaximum tolerablevolume after TEA and sham-TEA

70

75

80

85

90

95

Gastric normal slow waves

TEASham-TEA

2ndash4

cpm

slow

wav

es (

) lowast

lowastP = 0048

Figure 2 TEA improved the percentage of normal 2ndash4 cyclesminslow waves in the fed state

38

39

40

41

42

43

44

Sham-TEA

Dom

inan

t pow

er

TEA

lowast

lowastP = 0043

Figure 3 The comparison of EGG dominant power in the fed stateafter sham-TEA and TEA

The postpreprandial EGG power ratio was significantlyhigher in the TEA sessions than in the sham-TEA session(Figure 4)

33 TEA Enhanced Vagal Activity The acute TEA signifi-cantly increased the vagal activity in the 30 min postprandialperiod in patients with FD assessed by the spectral analysis ofHRV The HF(LF + HF) was 017 plusmn 001 in the TEA session

08

085

09

095

1

105

11

Sham-TEAPostp

repr

andi

al E

GG

pow

er ra

tio

TEA

lowast

lowastP = 0045

Figure 4 The comparison of postpreprandial EGG power ratiobetween sham-TEA and TEA

0

005

01

015

02

Sham-TEA TEAlowastP lt 0001

HF(LF

+H

F)

lowast

Figure 5 The vagal activity HF(LF + HF) assessed by the spectralanalysis of HRV in patients with FD treated with sham-TEA andTEA

and 006 plusmn 003 in the sham-TEA session (119875 lt 0001) (seeFigure 5)

34 Effects of Acute TEA on Dyspeptic Symptoms Acute TEAimproved the dyspeptic symptoms in the FD patients Themean total symptom score was 235 plusmn 29 at baseline anddecreased significantly to 119 plusmn 14 (119875 = 0007 versusbaseline) after TEA but was 219 plusmn 29 after sham-TEA


10

12

14

16

18

20

22

24

26

28

30

Sham-TEA TEAlowastP = 0012

lowast

Clin

ical

sym

ptom

scor

es

Figure 6The clinical symptom scores in FD patients after TEA andsham-TEA treatment

(119875 = 0102 versus baseline)There was a significant differencein the clinical symptom scores between the FD patients aftertrue treatment and those after sham treatment (Figure 6)

4 Discussion

In this study we found that acute TEA at the acupointsof ST36 and PC6 improved gastric accommodation andenhanced postprandial gastric slow waves in patients withFD (increased the amplitude and regularity of slow waves)A concurrent increase in vagal activity was also noted withthe acute TEA suggesting a vagal mechanism Acupunctureor electroacupuncture has been used to treat the symp-toms of upper abdomen such as nausea and vomitingHu et al [29] reported that electroacustimulation at pointPC6 reduced significantly the severity of the symptoms ofmotion sickness The number of emetic episodes induced bymorphine [30] or cyclophosphamide [31] was significantlyreduced by electroacupuncture at the PC6 point in ferretsElectroacupuncture at both the PC6 and the ST36 pointsreduced the incidence of vomiting induced by vasopressin indogs [32] A few papers reported the effect of acupunctureor electroacupuncture on dyspeptic symptoms in patientswith FD In one study with FD patients acupuncture wasdemonstrated to be effective in reducing dyspeptic symptoms[19]

While electroacupuncture has been proven effective intreating certain functional gastrointestinal diseases the inser-tion of acupuncture needles is required and the treatment hasto be done at a doctorrsquos office The method proposed in thisstudy TEA did not require the insertion of any needles andthe procedure could be done by the patient at hisher homeThis was more attractive than electroacupuncture and waswell accepted by the patients as the compliance of the therapywas 100 none of the patients quitted the study It is similarto transcutaneous electrical nerve stimulation except thatthe stimulation electrodes in this study were placed on theacupuncture points related to the targeting disorder Liu et al[33] found that a two-week treatment of TEAat ST36 andPC6significantly improved dyspeptic symptoms and increasedvagal activity in patients with FD These findings were inagreement with the present study However the effect of TEAon gastric accommodation was not previously investigated

Impaired gastric accommodation in FD is difficult totreat because it requires the use of muscle relaxant The

use of muscle relaxant however worsens impaired gastricmotility that is common in FD In this study acute TEAsignificantly and substantially improved gastric accommoda-tion while concurrently improving gastric motility assessedby electrogastrography This is an attractive strength ofthe proposed method of TEA As stated earlier impairedgastric accommodation is associated with symptoms of earlysatiety and postprandial fullness and bloating The TEA-induced increase in gastric accommodation could lead toimprovement in these symptoms Although exact mecha-nisms involved in the increase of gastric accommodationwere unknown the concurrent increase in vagal activitynoted in this study was believed to play a major role

Electrogastrography has previously been shown to be anaccurate and reliable method for studying gastric myoelec-trical activity Several studies have reported EGG abnormal-ities in FD patients [34 35] Meanwhile it is known thatelectroacupuncture may affect gastric myoelectrical activityA number of studies have investigated the effect of elec-troacupuncture on the gastric slow waves Ouyang et al [18]showed that electroacupuncture at ST36 and PC6 increasedthe regularity of gastric slow waves in both the proximaland distal stomach Chang et al [20] found that electricalstimulation at ST36 increased the percentage of normalEGG frequency and decreased the percentage of tachygastrialfrequency in diabetic patients Electroacupuncture at ST36and PC6 increased the percentage of regular slow wavesresulting in the normalization of dysrhythmia in healthyhuman [36] However Liu et al [33] study showed thatTEA at ST36 and PC6 points did not change the EGGparameters in the patients with FD suggesting that TEAmay not treat disorders induced by gastric myoelectricaldisturbances In this study however we found that acuteTEA at the acupoints of ST36 and PC6 improved gastric slowwaves in the postprandial state It should be noted that in thisstudy the EGG in the postprandial state was recorded afterthe maximum ingestion of a nutrient liquid meal This wasapparently different from the postprandial recording after aregular meal

Altered HF and LFHF in the spectral analysis of HRV inpatients with FDhave been previously reported [37 38] It hasbeen proposed that the autonomic dysfunctions could playa role in the development of disturbed gastric motility andperception Spectral analysis of the HRV is a noninvasive andsimple method for the quantitative evaluation of autonomicactivity [39 40] We used this method to evaluate the effectof acute TEA on HRV in patients with FD and found asignificant increase inHF after the TEA treatmentThis resultis in good agreement with others reported previously [18 3341] Although we did not have proof that this was responsiblefor the improvement in dyspeptic symptoms it was consistentwith the hypothesis that the visceral effects of TEAare at leastpartially mediated by the autonomic nerve pathway

In summary acute TEA at ST36 and PC6 significantlyimproves gastric accommodation and postprandial slowwaves as well as dyspeptic symptoms possibly mediated viathe vagal mechanisms Chronic clinical studies are warrantedto establish clinical role of this noninvasive method of TEAfor treating FD


Ethical Approval

This work was performed to the principles expressed inthe Declaration of Helsinki This study was approved bythe ethical committee in the Yinzhou Affiliated HospitalAn informed consent was obtained from all patients andcontrols


The authors declared no potential conflict of interests withrespect to the research authorship andor publication of thispaper


The work presented here was carried out through collabo-ration between all authors Jieyun Yin defined the researchtheme Jieyun Yin and Yan Tan designed the methods andexperiments Feng Xu Yan Tan Zhihui Huang Nina Zhangand Yuemei Xu carried out the clinical experiments and YanTan analyzed the data Yan Tan and Jieyun Yin interpreted theresults and wrote the paper All authors have contributed toand approved the paper Feng Xu and Yan Tan contributedequally

Acknowledgments

This study was partially supported by grants from BeilunDistrict Government and Ningbo Municipal Government

References

[1] J Tack N J Talley M Camilleri et al ldquoFunctional gastroduo-denal disordersrdquoGastroenterology vol 130 no 5 pp 1466ndash14792006

[2] X Lin D Levanon and J D Z Chen ldquoImpaired postprandialgastric slow waves in patients with functional dyspepsiardquoDigestive Diseases and Sciences vol 43 no 8 pp 1678ndash16841998

[3] S Kindt and J Tack ldquoImpaired gastric accommodation and itsrole in dyspepsiardquo Gut vol 55 no 12 pp 1685ndash1691 2006

[4] M W Mundt and M Samsom ldquoFundal dysaccommodationin functional dyspepsia head-to-head comparison between thebarostat and three-dimensional ultrasonographic techniquerdquoGut vol 55 no 12 pp 1725ndash1730 2006

[5] O H Gilja T Hausken I Wilhelmsen and A BerstadldquoImpaired accommodation of proximal stomach to a meal infunctional dyspepsiardquo Digestive Diseases and Sciences vol 41no 4 pp 689ndash696 1996


[7] C AMaggi ldquoTherapeutic potential of capsaicin-likemoleculesstudies in animals and humansrdquo Life Sciences vol 51 no 23 pp1777ndash1781 1992

[8] M Bortolotti G Coccia G Grossi and M Miglioli ldquoThetreatment of functional dyspepsia with red pepperrdquo Alimentary

Pharmacology and Therapeutics vol 16 no 6 pp 1075ndash10822002

[9] N J Talley V Meineche-Schmidt P Pare et al ldquoEfficacy ofomeprazole in functional dyspepsia double-blind randomizedplacebo-controlled trials (the Bond and Opera studies)rdquo Ali-mentary Pharmacology and Therapeutics vol 12 no 11 pp1055ndash1065 1998

[10] S Soo P Moayyedi J Deeks B Delaney M Innes and DForman ldquoPharmacological interventions for non-ulcer dyspep-siardquo Cochrane Database of Systematic Reviews no 2 Article IDCD001960 2000

[11] M D Gershon and G M Jonakait ldquoUptake and release of 5-hydroxytryptamine by enteric 5-hydroxytryptaminergic neu-rones effects of fluoxetine (Lilly 110140) and chlorimipraminerdquoBritish Journal of Pharmacology vol 66 no 1 pp 7ndash9 1979

[12] J Tack D Broekaert B Coulie B Fischler and J JanssensldquoInfluence of the selective serotonin re-uptake inhibitor parox-etine on gastric sensorimotor function in humansrdquo AlimentaryPharmacology andTherapeutics vol 17 no 4 pp 603ndash608 2003

[13] A B Gorelick S S Koshy F G Hooper T C Bennett WD Chey and W L Hasler ldquoDifferential effects of amitriptylineon perception of somatic and visceral stimulation in healthyhumansrdquoThe American Journal of PhysiologymdashGastrointestinaland Liver Physiology vol 275 no 3 pp G460ndashG466 1998

[14] P L Peghini P O Katz and D O Castell ldquoImipraminedecreases oesophageal pain perception in human male volun-teersrdquo Gut vol 42 no 6 pp 807ndash813 1998

[15] E J Bennett C Piesse K Palmer C-A Badcock C C Tennantand J E Kellow ldquoFunctional gastrointestinal disorders psycho-logical social and somatic featuresrdquoGut vol 42 no 3 pp 414ndash420 1998

[16] S Soo P Moayyedi J Deeks B Delaney M Lewis and DForman ldquoPsychological interventions for non-ulcer dyspepsiardquoCochrane Database of Systematic Reviews no 4 Article IDCD002301 2011

[17] R G Ghaly K T J Fitzpatrick and J W Dundee ldquoAntiemeticstudies with traditional Chinese acupuncture A comparisonof manual needling with electrical stimulation and commonlyused antiemeticsrdquo Anaesthesia vol 42 no 10 pp 1108ndash11101987

[18] H Ouyang J Yin Z Wang P J Pasricha and J D Z ChenldquoElectroacupuncture accelerates gastric emptying in associa-tion with changes in vagal activityrdquo The American Journal ofPhysiologymdashGastrointestinal and Liver Physiology vol 282 no2 pp G390ndashG396 2002

[19] S Xu X Hou H Zha Z Gao Y Zhang and J D ZChen ldquoElectroacupuncture accelerates solid gastric emptyingand improves dyspeptic symptoms in patients with functionaldyspepsiardquo Digestive Diseases and Sciences vol 51 no 12 pp2154ndash2159 2006

[20] C S Chang C W Ko C Y Wu and G H Chen ldquoEffect ofelectrical stimulation on acupuncture points in diabetic patientswith gastric dysrhythmia a pilot studyrdquoDigestion vol 64 no 3pp 184ndash190 2001

[21] A C-P Kwan T N Bao S Chakkaphak et al ldquoValidationof Rome II criteria for functional gastrointestinal disorders byfactor analysis of symptoms in Asian patient samplerdquo Journal ofGastroenterology and Hepatology (Australia) vol 18 no 7 pp796ndash802 2003

[22] I Sarosiek R W McCallum Y Sun et al ldquoSelf-administeredneedleless acupuncture therapy to control dyspepsia andGERD


symptoms in patients diagnosed with diabetic gastroparesisrdquoGastroenterology vol 144 no 5 supplement 1 p S-135 2013

[23] J Tack P Caenepeel H Piessevaux R Cuomo and J JanssensldquoAssessment of meal induced gastric accommodation by a sati-ety drinking test in health and in severe functional dyspepsiardquoGut vol 52 no 9 pp 1271ndash1277 2003

[24] Z S Wang and J D Z Chen ldquoRobust ECG R-R wave detectionusing evolutionary-programming-based fuzzy inference system(EPFIS) and application to assessing brain-gut interactionrdquo IEEProceedings Science Measurement and Technology vol 147 no6 pp 351ndash356 2000

[25] C-L Lu X Zou W C Orr and J D Z Chen ldquoPostprandialchanges of sympathovagal balance measured by heart ratevariabilityrdquo Digestive Diseases and Sciences vol 44 no 4 pp857ndash861 1999

[26] J D Z Chen R D Richards and R W McCallum ldquoIdentifica-tion of gastric contractions from the cutaneous electrogastro-gramrdquo The American Journal of Gastroenterology vol 89 no 1pp 79ndash85 1994

[27] J D Z Chen W R Stewart Jr and R W McCallum ldquoSpectralanalysis of episodic rhythmic variations in the cutaneous elec-trogastrogramrdquo IEEE Transactions on Biomedical Engineeringvol 40 no 2 pp 128ndash135 1993

[28] J Tack A Masclee and R Heading ldquoA dose-ranging placebo-controlled pilot trial of Acotiamide in patients with functionaldyspepsiardquoNeurogastroenterology andMotility vol 21 no 3 pp272ndash280 2009

[29] S Hu R M Stern and K L Koch ldquoElectrical acustimulationrelieves vection-induced motion sicknessrdquo Gastroenterologyvol 102 no 6 pp 1854ndash1858 1992

[30] L Lao R H Wong B Berman and R L Wynn ldquoElec-troacupuncture reduces morphine-induced emesis in ferretsa pilot studyrdquo Journal of Alternative and ComplementaryMedicine vol 1 no 3 pp 257ndash261 1995

[31] L Lao G Zhang R H Wong A K Carter R L Wynn and BM Berman ldquoThe effect of electroacupuncture as an adjunct oncyclophosphamide-induced emesis in ferretsrdquo PharmacologyBiochemistry and Behavior vol 74 no 3 pp 691ndash699 2003

[32] J D Z Chen L Qian H Ouyang and J Yin ldquoGastricelectrical stimulation with short pulses reduces vomiting butnot dysrhythmias in dogsrdquo Gastroenterology vol 124 no 2 pp401ndash409 2003

[33] S Liu S Peng X Hou M Ke and J D Z Chen ldquoTranscu-taneous electroacupuncture improves dyspeptic symptoms andincreases high frequency heart rate variability in patients withfunctional dyspepsiardquo Neurogastroenterology and Motility vol20 no 11 pp 1204ndash1211 2008

[34] A Leahy K Besherdas C Dayman I Mason and O EpsteinldquoAbnormalities of the electrogastrogram in functional gastroin-testinal disordersrdquo The American Journal of Gastroenterologyvol 94 no 4 pp 1023ndash1028 1999

[35] B Pfaffenbach R J Adamek C Bartholomaus and MWegener ldquoGastric dysrhythmias and delayed gastric emptyingin patients with functional dyspepsiardquo Digestive Diseases andSciences vol 42 no 10 pp 2094ndash2099 1997

[36] X Lin J Liang J Ren F Mu M Zhang and J D Z ChenldquoElectrical stimulation of acupuncture points enhances gastricmyoelectrical activity in humansrdquo The American Journal ofGastroenterology vol 92 no 9 pp 1527ndash1530 1997

[37] S L Silva Lorena M J De Oliveira Figueiredo J R SouzaAlmeida and M A Mesquita ldquoAutonomic function in patients

with functional dyspepsia assessed by 24-hour heart rate vari-abilityrdquo Digestive Diseases and Sciences vol 47 no 1 pp 27ndash312002

[38] T Hausken S Svebak I Wilhelmsen et al ldquoLow vagal toneand antral dysmotility in patients with functional dyspepsiardquoPsychosomatic Medicine vol 55 no 1 pp 12ndash22 1993

[39] G G Berntson JThomas Bigger Jr D L Eckberg et al ldquoHeartrate variability origins methods and interpretive caveatsrdquoPsychophysiology vol 34 no 6 pp 623ndash648 1997

[40] J Vila F Palacios J Presedo M Fernandez-Delgado P Felixand S Barro ldquoTime-frequency analysis of heart-rate variabilityrdquoIEEE Engineering in Medicine and Biology Magazine vol 16 no5 pp 119ndash126 1997

[41] M Tatewaki M Harris K Uemura et al ldquoDual effects ofacupuncture on gastric motility in conscious ratsrdquo The Amer-ican Journal of Physiology vol 285 no 4 pp R862ndashR872 2003

Review ArticleComplementary and Alternative Therapies forChronic Constipation

Xinjun Wang12 and Jieyun Yin3

1Division of Gastroenterology and Hepatology John Hopkins University Baltimore MD 21224 USA22nd Clinic Medical School Nanjing University of Chinese Medicine Nanjing Jiangsu 210023 China3Veterans Research and Education Foundation VA Medical Center Oklahoma City OK 73104 USA

Correspondence should be addressed to Jieyun Yin jieyunyin07gmailcom

Received 26 October 2014 Accepted 8 January 2015

Academic Editor Muhammad N Ghayur

Copyright copy 2015 X Wang and J Yin This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Chronic constipation an ancient disease is prevalent and costly in the general population Complementary and alternativetherapies are frequently used for constipationThis review introduces variousmethods of complementary and alternative therapiesincluding acupuncture moxibustion massage and herbal medicine Efficacy safety influence factors sham control design andmechanisms of these therapies are discussed and evaluated Acupuncture or electroacupuncture was found to be most commonlyused for constipation among these complementary and alternative therapies followed by herbal medicine Although only a smallnumber of clinical studies are flawless our review of the literature seems to suggest that acupuncture or electroacupuncture andherbal medicine are effective in treating constipation whereas findings on massage and moxibustion are inconclusive More well-designed clinical trials are needed to improve and prove the efficacy of the complementary and alternative therapies for constipationmechanistic studies that would lead to wide spread use and improvement of the methods are also discussed in this review

1 Introduction

Chronic constipation (CC) is a complaining problem formany patients with or without other diseasesThe prevalenceof constipation in the general adult population ranges from2 to 269 with a mean of 154 revealed by an integrativeliterature review of 11 population-based studies Femalegender was identified as the first associated factor in all ofthese studies and the secondmost common associated factorwas advanced age [1]

Physical and mental components of quality of life (QoL)scores have been consistently reported to be low in bothadult and pediatric patients with CC meanwhile the greatestinfluence is seen in secondary care studies [2] The meanexpenditures per hospital costs for constipation increasedfrom $8869 in 1997 to $17518 in 2010 whereas the totalcharges increased from $188109249 in 1997 to $851713263in 2010 (adjusted for long-term inflation) [3]

The vast majority of CC belongs to functional con-stipation (FC) According to the Rome III criteria [4] astandardized definition of FC is presented as follows

Rome III Functional Constipation Criteria

(1) It must include at least 2 of the following

(a) straining during at least 25 of defecations(b) lumpy or hard stools in at least 25 of defeca-

tions(c) sensation of incomplete evacuation for at least

25 of defecations(d) sensation of anorectal obstructionblockage for

at least 25 of defecations(e) manual manoeuvres to facilitate at least 25 of

defecations (eg digital evacuation support ofthe pelvic floor)

(f) fewer than three defecations per week



(2) Loose stools are rarely present without the use oflaxatives

(3) There are insufficient criteria for diagnosis of irritablebowel syndrome

Criteria fulfilled for the previous threemonths with symptomonset at least 6 months prior to diagnosis

This definition of FC is for adult patients For childpatients there are other criteria [4] (as follows)


(1) It must include two or more of the following in achild with a developmental age of at least 4 years withinsufficient criteria for diagnosis of IBS

(a) two or fewer defecations in the toilet per week(b) at least one episode of fecal incontinence per

week(c) history of retentive posturing or excessive voli-

tional stool retention(d) history of painful or hard bowel movements(e) presence of a large fecal mass in the rectum(f) history of large diameter stools which may

obstruct the toilet

(2) Criteria are fulfilled at least once per week for at leastmonths prior to diagnosis

CC is very general including all kinds of constipationwhereas functional constipation is only one major part of itCC is classified into outlet obstruction constipation (OOC)slow transit constipation (STC) and both The OOC ischaracterized with impaired relaxation and coordination ofabdominal and pelvic floor muscles during evacuation [5]STC is defined as prolonged stool transit (gt3 days) throughthe colon [6] In fact most of patients with STC are associatedwith outlet obstruction [7 8] It was reported that more thanhalf of patients with STC simultaneously had some degree ofoutlet obstruction [9 10]

Pharmacologic agents for CC are available However 28of participants were dissatisfied with their laxatives In alarge sample survey as high as 83 of respondents indicatedthat they were absolutely or probably interested in othertreatment options and complementaryalternative therapies[11] In another survey Johanson and Kralstein reportedthat the causes of laxatives dissatisfaction included ldquodoesnot work wellrdquo or ldquoinconsistent resultsrdquo and safety-related oradverse-effect concerns [12] In children the adherence rateto medical therapies of constipation was reported to be lowattributed to financial difficulties (232 of cases) and sideeffects (402) [13]

This article reviews complementary and alternative ther-apies for CC including acupuncture moxibustion massageand herbal medicine

2 Acupuncture

Acupuncture is an ancient Chinese Traditional Medicinetherapy in which acupoints on skin are manually stimulated

by needles It is usually termed hand-acupuncture Elec-troacupuncture (EA) is a method in which electrical currentis delivered to needles inserted into acupoints Transcuta-neous electroacupuncture (TEA) is similar to EA but theneedles are replaced with electrodes Auricular acupuncture(AA) is the one in which acupuncture is performed atacupoints on the skin of ear All of the above methods hadbeen used in the treatment of CC

Clinic studies on acupuncture or EA for CC weresearched in PubMed database from inception to October2014 Keywords used in the search included ldquoacupuncturerdquoor ldquoelectroacupuncturerdquo and ldquoconstipationrdquo The language ofpublications was instructed as English or abstract in EnglishSeventeen reports yielded from this search were summarizedin Table 1

21 Quality Assessment of Acupuncture Trials for CC Amongthe 17 articles 11 of them were RCTrsquos and 90 of the RCTstudies were published after 2010 There were 6 high qualitytrials [14 16 17 23 24 27] which could be assessed as 5according to Jadad scoring system [31] but sample sizes ofthem were all small A trial containing 553 samples wasevaluated to have a Jadad score of less than 3 due to the flawin design [15]

Multiple methods of the design for control were usedin clinical studies on CC The control groups in the liter-ature included medications other methods of stimulationand acupuncture plus medications Medications used in thecontrol group included conventional medicine [15 16 23 24](Mosapride Macrogol 4000 Lactulose) and Chinese herbalmedicine [15 22] (Fuzhengliqi mixture and Plantain andSenna Granule) Sham acupuncture [17 27 29] shallowacupuncture [16 23 24] regular electrical stimulation [19]and other methods of stimulation were performed as controlmethods Combinational use of medications included EAplus Fuzhengliqi mixture [15] and EA plus Plantain andSenna Granule [22] There was only one trial in which twokinds of stimulationmethods acupuncture andmoxibustionwere used together [21]

The treatment duration [14ndash17 22ndash24 27] ranged from 4weeks to 7 weeks and the follow-up time [14ndash16 22 24 2627] ranged from 4 weeks to 64 weeks The primary outcomewas the number of weekly spontaneous bowel movementsThe secondary outcomes included opaque X-ray markerpatientrsquos satisfaction and clinical symptom score (such asweekly defecation frequency defecation time stool charac-teristics straining and abdominal pain) The questionnairesused in trials included Bristol score Cleveland Clinic Scoreand Quality of Life Some indicators about mechanisms ofacupuncture for constipation also were measured includingplasma motilin [15] plasma panopioid [29] and heart ratevariability [17]

22 Efficacy and Safety of Acupuncture for CC Severalsystematic reviews including meta-analysis indicated thatacupuncture for CC was effective and did not cause obviousadverse events [32ndash36]

The overall efficacy rate of hand-acupuncture for chronicfunctional constipation was 520 [21] It improved weekly


Table1Articleso

facupu

ncture

orEA

forC

C

Reference

Stud

ydesig

n(partic

ipants)

Acup

oints

Implem

entatio

nof

acup

uncture

Keyeffi

cacy

results

Adverser

eactions

Wuetal2014

[14]

RCT

(119899=104)

adult

ST25B

L25LI11ST3

7

EA1ST

25B

L25

EA2LI11ST3

7EA

3ST

25B

L25LI11ST3

7C

Mosaprid

ecitrate

Weeklyfre

quency

ofdefecatio

ndefecatio

ndifficulty

lifeandqu

ality

scorew

erea

llim

proved

significantly

inthefou

rgroup

sin

follow-upweeklyfre

quency

ofdefecatio

nof

LI11andST

37(EA2)

was

superio

rtothe

otherthree

grou

ps

NA

Zhangetal2013

[15]

RCT

(119899=553)

adult

ST25ST3

7ST

36B

L25TE

6

EA2

Hz200H

zDFuzheng

liqim

ixture

EA+Dbothof

above

CMosaprid

eand

Macrogol400

0

Allgrou

psdecreasedthed

efecationintervalstool

prop

ertycon

stipatio

nsymptom

gradeaccompanying

symptom

gradeandGITT

EA+Dwas

bette

rthan

othersE

Acouldkeep

long

-term

effect

No

Peng

etal2013

[16]

RCT

(119899=128)

adult

ST25

EA-deep20

to65

mm

indepth

EA-shallow5ndash8

mm

depth

Dlactulose

oralliq

uid

Allgrou

psincreasedthew

eeklydefecatio

nfre

quency

EA-deepcouldkeep

long

-term

effect

No

Chen

etal2013

[17]

RCT

(119899=NA)

adultfem

ale

ST36ST3

7ST

25ST2

8CV

4CV

6EA

Sham

-EA

EAim

proved

constip

ationsymptom

sand

increased

autono

micnervou

ssystem

activ

itiessham-EAno

tNA

Zhou

etal2012

[18]

RCT

(119899=200)

elder

AT34iA

T3A

T4C

O7CO

17

AH8CO

18C

onstipatio

nPo

int

ATaccording

tothe

patte

rnsyn

drom

edifferentia

tion

Csolid

points

Thee

ffectiver

ateAT

920C

760

NA

Xuetal2012

[19]

RCT

(119899=64)

adult

TE6ST

25ST3

6ST

37EA

Hwatoneuroandmuscle

stimulator

Cregu

lare

lectronics

timulator

Thee

ffectiver

ateo

fsho

rtterm

EA546C

290

NA

And

erse

tal2012

[20]

Retro

spectiv

ecases

eries

study

(119899=10)children

Quchi

(LI11)

Fixedindw

ellin

gacup

uncture

needles(09m

min

leng

th)

Afte

ramedianof

3days

ofHICallchild

rendefecated

with

in2h

Localconstip

ationtherapywas

notrequired

No

L-J

WangandL-L

Wang2011[21]

RCT

(119899=100)

adult

Group

1ST

25SP15CV

6CV

4ST

36ST3

7SP

6Group

2BL

33

BL34B

L5B

L23BL

20Alternatively

HApun

ctured

byhand

sHA+moxibustio

ngrain-shaped

moxibustio

nwas

givenatCV

6ST

36

BL25B

L20andotherswith

puncture

Thetotaleffectiv

erateHA+moxibustio

nas

740

(3750)v

ersus5

20

(2650)

NA

Guo

etal2011[22]

RCT

(119899=378)

adult

ST25ST3

7ST

36B

L25TE

6EA

2Hz100H

zDP

lantainandSenn

aGranu

leEA

+Dbothof

thea

bove

Allgrou

psdecreasedthes

coreso

fdefecationcycle

stool

prop

ertycon

stipatio

nsymptom

gradeaccompanying

symptom

gradeandGITT

EA+Dwas

bette

rthan

othersE

AandEA

+Dcouldkeep

long

-term

effect

No

Wangetal2010

[23]

RCT

(119899=95)

adult

ST25

EA-deep45

mm

indepth

EA-shallow5

mm

indepth

Dlactulose

oralliq

uid

EA-deepandEA

-shado

wweres

ignificantly

superio

rto

Dgrou

pin

increasin

gnu

mberu

pto

4andim

proved

CCSEA

-deepworkedfaste

rthanEA

-shado

wNA

Wangetal2010

[24]

RCT

(119899=95)

adult

ST25

EA-deep

EA-shallo

wDD

uphalac

EA-deepwas

similartoEA

-shallo

win

numberu

pto

4andCC

Sandits

efficacy

remainedmuchlonger

NA

Jinetal2010

[25]

Before-afte

rstudy

(119899=90)

adult

Group

1ST

25C

V6ST

37G

roup

2BL

33B

L34BL

25Alternatively

EAB

L33BL

34ST2

5T3

7

Thes

coreso

fdefecationfre

quencydiffi

culty

degree

ofdefecatio

ndefecatio

ntim

eendlesssensatio

nof

defecatio

nsto

olqu

alityawarenesso

fdefecation

and

QoL

wereo

bviouslyim

proved

after

treatmentTh

etotal

effectiv

eratew

as677(619

0)

NA

Dingetal2009

[26]

Before-afte

rstudy

(119899=30)

adult

Group

1ST

25SP15SP

14C

V6

CV4ST

36ST3

7Group

2BL

25

BL23B

L31BL

32B

L33BL

34

Ex-H

N1A

lternatively

Deepneedlin

gwas

appliedon

acup

ointso

fabd

ominalandback

region

andmoxibustio

nwas

puto

nEx

-HN1

Redu

cedlaxativ

escores

fora

warenessandQoL

Increasedfre

quency

ofdefecatio

nNo


Table1Con

tinued

Reference

Stud

ydesig

n(partic

ipants)

Acup

oints

Implem

entatio

nof

acup

uncture

Keyeffi

cacy

results

Adverser

eactions

Zhangetal2007

[27]

RCT

EA SATE

6EA

EAatZh

igou

SAE

Aatno

nacupo

int

EAcouldobviou

slyim

proveC

CSandCT

Tdecrease

cathartic

seffectiv

erateo

f944

No

Zhuetal2003

[28]

Before-afte

rstudy

(119899=188)

adult

ST25ST3

6ST

37B

L25BL

57HA

Totaleffectiver

ateo

f100

NA

Broide

etal2001

[29]

CCT-self

(119899=17)

child

NA

Treatedby

fivew

eeklyplacebo

acup

unctures

essio

nsfollowed

by10

weeklytrue

acup

unctures

essio

ns

Thefrequ

ency

ofbo

welmovem

entsincreasedon

lyaft

er10

true

acup

unctures

essio

nsNA

Klauser

etal1993

[30]

CCT-self

(119899=8)

adult

LI4ST

25LE3

BL2

5EA

10H

zStoo

lfrequ

encies

andCC

Tweren

otaltered

Twopatie

ntsd

ropp

edou

tbecause

symptom

sworsened

RCT

rand

omized

controlledtrialCC

Tcontrolledclinicaltria

lHAhand-acup

unctureEA

EAA

Tauric

ulotherapySAsham

acup

unctureDdrugHA+Dhand-acup

uncture+

drugE

A+DE

A+drugC

controlPE

patientrsquosendu

ranceMAm

eanagePO

bymou

thC

CSC

leveland

Con

stipatio

nScorenu

mberu

pto

4then

umbero

fcon

stipatio

npatientsw

hose

defecatio

nwas

upto

4tim

esperw

eekBM

sbo

wel

movem

ents

GITTgastr

ointestin

altransit

timeTG

ITTtotalgastro

intestinaltransittim

eM-ITT

mou

th-in

testine

transit

timeCT

Tcolonictransittim

eRC

TTright

colonictransittim

eLC

TTle

ftcolonictransit

timeRS

TTrectosig

moidcolonictransittim

eMTL

motilin

QoL

qualityof

lifeCI

con

fidence

intervalQ

Devery

dayBIDtwicep

erdayTIDtrip

leperd

ayN

Anot

acqu

irable


Table 2 Acupoints appeared ge3 times for CC in these 17 articles

Acupoints Times appearedTianshu (ST25) 13Shangjuxu (ST37) 9Dachangshu (BL25) 8Zusanli (ST36) 7Zhigou (TE6) 5Qihai (CV6) 4Guanyuan (CV4) 3Zhongliao (BL33) 3Xialiao (BL34) 3

spontaneous defecation times abdominal pain evacuationdifficulty endless sensation of defecation obstruction senseof anus laxative prescription dependence and quality of life[21 32] as well as psychological symptoms score [21]

The overall efficacy rate of EA for chronic functionalconstipation raged from 546 to 944 [15 19 27] EAincreased the frequency of weekly defecation and the numberof persons who had defecation 4 times or more a week(responder) [16 23] decreased stool property constipationsymptom grade accompanying symptom grade and gas-trointestinal transit time (GITT) [15 22 24 27]

Several articles reported that acupuncture or EA out-performed conventional medicine such as lactulose [1623 24] and Plantain and Senna Granule [22] This wasdifferent with the conclusion drawn from a systematic reviewwhich indicated that acupuncture was probably as effectiveas conventional medical therapy in the change of bowelmovements and colonic transit activity [32] This differencemight be attributed to the small sample sizes in these trialsA trial including 553 patients reported that the effectiverate of EA was not different from Fuzhengliqi mixture orMosapride combined with Macrogol 4000 in short term butwas superior to them in long term because constipationsymptoms recurred in the two control groups [15]

Zhou et al performed an RCT study and reported thatthe effective rate of AA for functional constipation was92 [18] However the reliability of this conclusion waslow due to small sample size and lack of control It wasindicated in a systematic review that no conclusion should bemade on the effectiveness of acupuncture due to significantmethodological flaws [34]

Acupuncture for the treatment of pediatric patients withhospital-induced constipation was evaluated in a pilot studyfor the feasibility and acceptability with encouraging results[20]

23 Most Popular Acupoints for CC Acupoints used morethan 3 times for CC in the 17 articles included ST25 ST37BL25 ST36 TE6 CV6 CV4 BL33 and BL34 (Table 2)Theseacupoints usually are considered as representative choicesadopted by doctors and researchers The top five acupointsbeing used most frequently for treating CC are discussedhere

ST25 is on the upper abdomen laterally to the umbilicusabove the small intestine according to World Health Organi-zation (WHO) standard acupoint locations [37] EA at ST25was reported to enhance small intestinal motility in rodentmodel of slow transit constipation [38] However in normalor fasted rats EA at ST25 was found to produce inhibitoryeffects on jejunum electrical and mechanical activities [3940] These findings seem to suggest that EA at ST25 exertsdifferent effects under different conditions

ST36 and ST37 are located on the anterior aspect ofthe leg and above of tibialis anterior muscle ST36 is aboveST37 [37] Acupuncture stimulation of ST36 was reportedto increase intragastric pressure and gastric peristaltic fre-quency in rats with gastric hypomotility [41] In patientsafter abdominal surgery ST36 was able to shorten the timeof first flatus passage and improve gastrointestinal functions[42] Significant acceleration of colonic transit with EA atST36 was mediated via the sacral parasympathetic efferentpathway [43] Acupuncture at ST37 was reported to alterrectalmotility and the effect appeared one hour after needling[44]

BL25 is located on the lumbar region at the samelevel as the inferior border of the spinous process of thefourth lumbar vertebra (L4) laterally to the posterior medianline [37] Acupuncture at BL25 reduced early postoperativeinflammatory small bowel obstruction [45] improved symp-toms of ulcerative colitis [46] and irritable bowel syndrome[47]

TE6 is located on the posterior aspect of the forearmmidpoint of the interosseous space between the radius andthe ulna proximal to the dorsal wrist crease [37] EA atTE6 and ST36 was effective for adhesive ileus remarkablyimproved abdominal pain and distention and acceleratedintestinal peristalsis [48]

The above discussion indicates that acupuncture or EA atall of the top five acupoints improves gastrointestinalmotilityAccording to the anatomy of the nervous system tibialnerve L4 spinal nerve and posterior interosseous nerve areunder ST36 and ST37 BL25 and TE6 respectivelyThereforeacupuncture effects of these four acupoints are probablymediated via these nervous pathways Special acupuncturetechnique is required on ST25 to get a better therapeuticeffect In this technique the needle is inserted perpendicu-larly and slowly till penetrating the peritoneum about 20ndash65mm in depth [16] direct intestinal stimulation might beimplicated with this technique

24 Influence Factors of Acupuncture for Constipation Thereare several factors influencing the effective rate of acupunc-ture for CC [21 27] These include acupoint group operativetechnique of puncture stimulation parameters and treat-ment interval

Various acupoint groups had been used in clinical trialsAll of acupoints for CC can be classified into four categoriesaccording to their locations abdomen acupoints (ST25ST28 CV4 CV6 SP15) lumbosacral acupoints (BL25 BL20BL23 BL33 BL34) crus acupoints (ST36 ST37 BL57 SP6)and forearm acupoints (TE6 LI11 LI4) Acupoint groupsresult in the combination coming from at least one kind


of acupoints Abdomen acupoints plus crus acupoints orforearm acupoints are counted as acupoint group regularly[14 17 19 21 22 25 26 28 30] Lumbosacral acupointsare taken as a group usually [21 25] One trial used threekinds of acupoints simultaneously abdomen lumbosacraland crus [15] In five trials only one acupoint was used[16 20 23 24 27] No studies are available in the literaturecomparing different acupoint groups Studies of searchingoptimal acupoint group are needed

ST25 the most frequently used acupoint was dealt withthrough a special operative technique of puncture whichwas named as deep-puncture technique [16 23 24] Hereis the deep-puncture technique of ST25 needle is insertedperpendicularly and slowly till penetrating the peritoneumabout 20ndash65mm in depth [16] Using the deep-acupuncturetechnique the number of functional constipation patientswhose defecation was up to 4 times per week was increasedcompared with the shallow-acupuncture technique duringthe second treatment week [23] However at the forthtreatmentweek there was no difference between the two tech-niques in the number of responders the defecation intervalstool property constipation symptom grade accompanyingsymptom grade or GITT [16 23] At the 6-month follow-updeep-acupuncture was reported to be still effective whereasthe shallow-acupuncture became ineffective [24] The stan-dard definition and operation about ldquodeep-acupuncturerdquo ofST25 was studied in the fields of anatomy and safety [49] Inacupuncture theory the operative technique of puncture isconsidered as one of key factors that affects the outcomes ofacupuncture Therefore the direction and depth of needlingare required This technique was applied in puncturing ST25for constipation but not for other acupoints and otherdiseases

There are 11 trials which adopted EA for constipationamong the 17 articles The parameters used in EA treatmentseem to be important Different stimulation frequencies wereused in these studies including 2Hz200Hz [15] 1 Hz20Hz[19] 2Hz100Hz [22] and 10Hz [30] In rough EA frequencycan be divided into low-frequency (1Hz 2Hz 10Hz etc)and high-frequency (100Hz 200Hz etc) In acupunctureanalgesia high- and low-frequency of EA could facilitate therelease of endogenous opioid peptides The effect of low-frequency EA was found to be mediated by the 120581 opioidreceptor whereas high-frequency EA was reported to bemediated by the 120575 and 120583 opioid receptors [50] Howeverit is unclear whether the EA frequencies for analgesia areapplicable to EA for constipation and more studies areneeded to determine the best EA stimulation frequency forconstipation

In addition to the stimulation frequency the frequencyof treatment (treatments per week) is also an importantfactor Five treatments per week seemed to be most popularin the previous studies [15 16 22ndash24] Most of acupunc-turists believe that efficacy induced by acupuncture can bemaintained for one or two days and thus require patientsto receive treatment every day or every other day Howeverone of major problems with clinical acupuncture is that thetreatment is administrated infrequently such as 1 or 2 timesper week yielding insignificant or inconsistent results [30]

25 Sham Acupuncture Design Sham acupuncture was usedas control in two of the articles [17 27] Sham acupuncturedesign is based on two key points one is the use of nonacu-points and the other is nonneedle For blindfolding patientssham needles were glued on skin It looks like being insertedhowever this is exposed easily for experienced patients dueto different feelings between the needle being inserted at theacupoint and the one placed on the surface of acupoint Shamacupuncture at nonacupoints refers to needle manipulationat points that are not on any meridian or acupoints Differentfrom the specific technique of acupuncture which can inducea higher intensity of de qi that substantially improves thetherapeutic effect acupuncture that does not induce de qi canalso be regarded as sham acupuncture This method of shamdesign was used in acupuncture for Bellrsquos palsy a recent RCTcompleted by Xu et al [51] and appreciated by John Fletcherwho is Editor-in-Chief of Canadian Medical AssociationJournal Fletcher considered that results of that trial werereasonable because every patients received acupuncture butwith valid or invalid technique [52] What calls for specialattention is that valid or invalid technique should be definedaccording to different diseases and types of acupuncture Forexample EA-shallow being regarded as control in some trials[16 23 24] should not be designed as sham control unlesselectric current was shut off

26 Mechanisms of Acupuncture for Constipation Despitethe fact that acupuncture for constipation has been provedeffective in clinical studies [32] enhancing contractility inthe distal colon [53] and accelerating colonic transit [43]in animal studies mechanisms involved in these effects arestill unclear A lower level of motilin was noted in patientsof functional constipation and found to be elevated withacupuncture at ST36 and ST37 [54] EA at bilateral ST25was reported to increase colonic smooth muscle thicknessand number of Cajal cells considerably [38] Vagal andparasympathetic mechanisms have also been implicated inthe accelerative effect of acupuncture or EA on colonmotility[55] Overall little is known on the mechanisms involved inthe effect of acupuncture on constipation More studies areneeded to reveal possible pathways such as neural pathwayendocrine pathway opioid pathway andor serotonic path-way

3 Moxibustion

Moxibustion is a traditional therapy in Chinese Medicineto stimulate acupoints with burning moxa made from driedmugwort Little has been reported in the literatures on themanagement of CC with moxibustion A systematic review[56] published in 2010 only included 3 RCTs with a totalof 256 patients and no randomization or blinding (two inChinese and one in Korean) Given that the methodologicalquality of these trials was poor the review reported that therewas insufficient evidence to suggest that moxibustion was aneffective treatment for constipation [56]

In PubMed database RCTs of moxibustion for CC weresearched from its inception to October 2014 with keywordsincluding ldquoconstipationrdquo plus ldquomoxibustionrdquo resulting in only


one high quality RCT published in 2011 in English Thistrial was randomized sham-controlled patient blinded andpilot clinical [57]The trial noted that moxibustion treatmentappeared safe but showed no positive effect on constipation[57]

However this conclusion does not stand up to be scruti-nized due to the design of sham control Sham moxibustionused in this trial [57] was given with adding insulation belowthe moxa pillar in order to prevent the transfer of heat frompatients The sham moxa pillar looked similar to real moxapillar on its appearance and burning procedure and that thesmoke from moxa could be smelled and the burning couldbe observed This method of sham moxibustion seems wellestablished as blinded to the participants [58 59] Howevershammoxibustionwould be recognized easily by experiencedpatients and thus patients with previous experience of moxi-bustion should be excluded from a controlled study [59]

Studies of moxibustion for constipation have been solimited that no mechanistic research has been publishedLong-term larger sample size rigorously designed andmechanism studies are desired

4 Massage

Massage is the manipulation of activating deeper and super-ficial layers of connective tissues and muscles using varioustechniques It has been practiced for thousands of years inmany ancient civilizations [60]

Seventeen clinic articles were derived from the PubMedsearch with keywords ldquomassagerdquo and ldquoconstipationrdquo [61ndash77]Among them there are only 3 articles with a Jadad score ge3[31] In spite of this the 3 articles were in lack of sham controland blind method and of very small sample size In briefthese 17 studies showed that massage increased defecationfrequency [63 65 66 76] relieved abdominal pain syndrome[66] and decreased Gastrointestinal Symptoms Rating Scale[66] and Constipation Assessment Scale [71] but could notdecrease laxative use [66]

Various mediums have been used in manipulation ofmassage but it is unclear which methods are better Aromaoil which is often used in massage did not seem to bemore effective than the meridian massage [65] Massagemay work on constipation in children and seniors A studyindicated thatmassage was beneficial to hospitalized childrenwith constipation due to brain injury [61] But it is notrecommended because of the lack of sufficient evidenceaccording to an integrative review of the literature [78]Abdominal massage using essential oils seems helpful forconstipation in the elderly [71]

It is difficult for massage to design a method of shamor blind technique Various techniques of massage havebeen developed through thousands of years originated fromdifferent ancient civilizations Up till now there is no well-recognized standard technique for massage Therefore tech-nique of sham or blind massage could not be defined

Abdominal massage was performed in patients withconstipation and healthy volunteers with negative results

Neither in patients nor in healthy controls did the abdom-inal massage alter stool frequency or colon transit measuredby radiopaque markers [75]

There are a number of advantages with massage Firstlydespite the fact that the trials about massage for constipationwere various in terms of designs patient samples andtypes of massage used there were no adverse side effectsSecondlymassage can be self-administrated or administratedby patients since it is easily learnt [77] Thirdly expenditureand cost-effectiveness could be reduced greatly since it can beself-administrated [79]

Overall the experience of abdominal massage is appre-ciated by consumers not only feeling embraced and in safehands but also improving their bowel habits [62]

5 Herbal Medicine

Constipation as an ancient disease has been treated withmany kinds of herbal medicines in the human historyAccording to quantity of herbal medicines it can be dividedinto two types single herb and multiple herbs According toactive ingredient of single herb it also can be divided into twotypes bulk laxative and stimulant laxative

51 Single Herb Medicine

511 Bulk Herbal Laxative Psyllium and Ficus carica arefrequently used bulk laxatives Psyllium increased stool fre-quency and improved stool consistency but was not effectiveon colon transit or anorectal motility [80] Similar resultswere reported in CC patients with Parkinsonrsquos disease [81]Psyllium increased more stool water content and weightmore total stool output and higher OrsquoBrien rank-type scoresthan docusate sodium according to a multicenter random-ized double-blind and parallel-design study in which 170subjects with chronic idiopathic constipation were treatedfor 2 weeks [82] About the efficacy of Psyllium for con-stipation a general understanding is that its high fiber andmucilaginous content contribute to a laxative action Gut-stimulatory effect of Psyllium mediated partially by 5-HT4(5-hydroxytryptamine 4) receptor and muscarinic receptoractivation was beneficial as complement actor [83] Howeverhigh dose Psyllium was effective on diarrhea resulting fromits inhibitory effect on the gut possiblymediated by activationof nitric oxide-cyclic guanosine monophosphate pathwaysand blockade of Ca2+ channels [83]

Ficus carica was not used in clinic trials despite the factthat it is considered as laxative in some countries Ficus caricapaste for loperamide-induced constipation in rats increasedpellet number weight water content tension and peristalsisof intestinal ileum as well as thickness and mucin area in thedistal colon [84] No abnormal symptoms were observed onserum and whole blood parameters [84] Similar results wereobtained in constipated beagles induced by a high-proteindiet and movement restriction [85] The ameliorating effecton constipation was believed to be attributed to cellulose oneof the main components of Ficus carica [84 85] Celluloseimproved fecal excretion by increasing water content and


bulk elevating viscosity and shortening fecal transit time[86]

512 StimulantHerbal Laxative Anthranoid-containing lax-atives themost frequent in stimulant herbal laxatives includesenna aloe rheum officinale and cascara

Anthraquinones are effective components in this kindof stimulant herbal laxatives Glycosides naturally occur-ring from senna aloe rheum officinale and cascara passunchangedly through the small intestine and are split intoactive ingredient rhein-anthrone by the colonic microbiota[87]Theywere reported to improve stool frequency and con-sistency in a number of clinical studies [88ndash90] Pseudome-lanosis coli or melanosis coli which are a dark-brown discol-oration of colonmucosa would be induced by anthraquinonein 9ndash12 months [91] and would disappear over weeks tomonths after termination of the use of anthraquinone [92]It is controversial whether there is a link between pseudome-lanosis coli and colorectal cancer

52MultipleHerbsMedicine Multiple herbsmedicinemeanstwo or more of single herb medicines are used in combi-nation For example Psyllium and senna as a group occursin a lot of over-the-counter brands Agiolax a representativesample comprising Plantago ovata 52 g ispaghula husk 22 gand Tinnevelly senna Pods 124 g per 100 g granules wasproved superior to lactulose in measurement of mean dailybowel frequency stool consistency and ease of evacuationin a double-blind crossover study [93] The expansion ofPsyllium and stimulation of sennosides under safe andrecommended doses are perfect in cooperation

53 Chinese Herbal Medicine Chinese herbal medicine forconstipation is complex on its formation Usually it com-prises not only multiple herbal laxatives but also some otherherbs which contribute to relieve side effect of stimulantherbal laxatives for example Ma Zi Ren Pill [94ndash96] andCCH1 [97]

Ma Zi Ren Pill whorsquos other name is Hemp Seed Pill com-prises six herbs Semen Cannabis Sativae Radix PaeoniaeSemen Pruni Armeniacae Fructus Immaturus Citri AurantiiRadix et Rhizoma Rhei and Cortex Magnoliae Accordingto the Chinese traditional medicine theory it moistens theintestines relaxes the bowel and promotes the movement ofQi [95] An 18-week prospective randomized double-blindplacebo-controlled clinical study on 120 subjects documentedthat Ma Zi Ren Pill increased complete spontaneous bowelmovement and decreased straining at evacuation and noserious adverse effects were noted [95]

CCH1 comprises six herbs Panax ginseng C A MeyerZingiber officinale Rosc Glycyrrhiza uralensis FischAtractylodes macrocephala Koide Aconitum carmichaeliiDebx and Rheum tanguticum Maxim [97] A randomizeddouble-dummy double-blind and placebo-controlled trialon 120 participants showed that CCH1 was superior tolactulose in spontaneous bowel movements [97] Anotherhigh quality trial showed that efficacy of CCH1 could beproved but maintenance effect needs further trial [98]

The two Chinese herbal medicines were tested in highquality trials However the evidence and reliability of manyothers are compromised by methodological flaws [99]Further randomized placebo-controlled double-blind trialsneed to be promoted and reported in detail [99]

6 Conclusion

Among the four kinds of complementary and alternativetherapies for constipation discussed in this review the effi-cacy of acupuncture and herbal medicine has been indicatedWell-designed high quality studies are needed to investigatethe efficacy of moxibustion and massage for constipationSince constipation is a chronic and highly prevalent diseaseconvenient and cost-effective therapies are neededThereforecomplementary and alternative medicine is expected to playa more important role in the future Novel and innovativetherapies of complementary and alternative medicine areneeded in treating constipation To increase the efficacy ofexisting methods combinational methods may be exploredEqually if not more importantly mechanistic studies areneeded in order to improve and disseminate the applicationof the available complementary and alternative therapies forconstipation



References

[1] F M Q Schmidt and V L C D G Santos ldquoPrevalence ofconstipation in the general adult population an integrativereviewrdquo Journal of Wound Ostomy amp Continence Nursing vol41 no 1 pp 70ndash76 2014


[3] S Sethi S Mikami J Leclair et al ldquoInpatient burden ofconstipation in the United States an analysis of national trendsin the United States from 1997 to 2010rdquo American Journal ofGastroenterology vol 109 no 2 pp 250ndash256 2014

[4] Rome Foundation ldquoGuidelinesmdashRome III diagnostic criteriafor functional gastrointestinal disordersrdquo Journal of Gastroin-testinal and Liver Diseases vol 15 no 3 pp 307ndash312 2006

[5] A E Foxx-OrensteinM AMcNally and S T Odunsi ldquoUpdateon constipation one treatment does not fit allrdquo Cleveland ClinicJournal of Medicine vol 75 no 11 pp 813ndash824 2008

[6] J F Gallegos-Orozco A E Foxx-Orenstein S M Sterler andJ M Stoa ldquoChronic constipation in the elderlyrdquo The AmericanJournal of Gastroenterology vol 107 no 1 pp 18ndash25 2012

[7] J Ragg R McDonald R Hompes O M Jones C Cunning-ham and I Lindsey ldquoIsolated colonic inertia is not usually thecause of chronic constipationrdquo Colorectal Disease vol 13 no 11pp 1299ndash1302 2011

[8] R Tomita and E R Howard ldquoClinical studies on anorectalmyectomy for chronically constipated patients with outlet


obstruction in childhoodrdquoHepato-Gastroenterology vol 55 no86-87 pp 1600ndash1605 2008

[9] C P Sanmiguel and E E Soffer ldquoConstipation caused by func-tional outlet obstructionrdquo Current Gastroenterology Reportsvol 5 no 5 pp 414ndash418 2003

[10] A DrsquoHoore and F Penninckx ldquoObstructed defecationrdquoColorec-tal Disease vol 5 no 4 pp 280ndash287 2003


[12] J F Johanson and J Kralstein ldquoChronic constipation a surveyof the patient perspectiverdquo Alimentary Pharmacology andTher-apeutics vol 25 no 5 pp 599ndash608 2007

[13] S A Steiner M R F Torres F J Penna et al ldquoChronicfunctional constipation in children adherence and factorsassociated with drug treatmentrdquo Journal of Pediatric Gastroen-terology and Nutrition vol 58 no 5 pp 598ndash602 2014

[14] J N Wu B Y Zhang W Z Zhu R S Du and Z S LiuldquoComparison of efficacy on functional constipation treatedwith electroacupuncture of different acupoint prescriptions arandomized controlled pilot trialrdquo Zhongguo Zhen Jiu vol 34no 6 pp 521ndash528 2014

[15] C Zhang L Guo X Guo and G Li ldquoShort and long-termefficacy of combining Fuzhengliqi mixture with acupuncturein treatment of functional constipationrdquo Journal of TraditionalChinese Medicine vol 33 no 1 pp 51ndash59 2013

[16] W-N Peng L Wang Z-S Liu et al ldquoAnalysis on follow-upefficacy and safety of slow transit constipation treated withindividualized deep puncture at Tianshu (ST 25) a multi-central randomized controlled trialrdquoZhongguo Zhen Jiu vol 33no 10 pp 865ndash869 2013

[17] C-Y Chen M-D Ke C-D Kuo C-H Huang Y-H Hsuehand J-R Chen ldquoThe Influence of electro-acupuncture stimula-tion to female constipation patientsrdquo The American Journal ofChinese Medicine vol 41 no 2 pp 301ndash313 2013

[18] X X Zhou Y Zhong and J Teng ldquoSenile habitual constipationtreated with auricular therapy based on the patternsyndromedifferentiation a randomized controlled trialrdquo Zhongguo ZhenJiu vol 32 no 12 pp 1090ndash1092 2012

[19] J Xu C-S Jia L Qin and X-K Xu ldquoComparative study ontherapeutic effect between SXDZ-100 and SDZ-II on chronicfunctional constipationrdquo Zhongguo Zhen Jiu vol 32 no 1 pp79ndash82 2012

[20] E F Anders A Findeisen A Nowak M Rudiger and TI Usichenko ldquoAcupuncture for treatment of hospital-inducedconstipation in children a retrospective case series studyrdquoAcupuncture in Medicine vol 30 no 4 pp 258ndash260 2012

[21] L-J Wang and L-L Wang ldquoRandomized controlled studyon chronic functional constipation treated with grain-shapedmoxibustion and acupuncturerdquo Zhongguo Zhen Jiu vol 31 no4 pp 320ndash324 2011

[22] L-KGuo C-X Zhang andX-FGuo ldquoAcupuncture combinedwith Chinese herbal medicine plantain and Senna Granule intreatment of functional constipation a randomized controlledtrialrdquo Journal of Chinese Integrative Medicine vol 9 no 11 pp1206ndash1214 2011

[23] C-W Wang N Li H-B He J-Q Lu and Z-S Liu ldquoEffectof electroacupuncture of Tianshu (ST 25) on the rationalsymptoms of functional constipation patients and evaluationon its efficacy satisfaction a single-center prospective practical

and randomized control trialrdquo Zhen Ci Yan Jiu vol 35 no 5 pp375ndash379 2010

[24] C-W Wang H-B He N Li Q Wen and Z-S Liu ldquoObser-vation on therapeutic effect of electroacupuncture at Tianshu(ST 25) with deep needling technique on functional constipa-tionrdquo Zhongguo Zhen Jiu vol 30 no 9 pp 705ndash708 2010

[25] X Jin Y-J Ding L-L Wang et al ldquoClinical study onacupuncture for treatment of chronic functional constipationrdquoZhongguo Zhen Jiu vol 30 no 2 pp 97ndash101 2010

[26] S-Q Ding Y-J Ding and X-FWang ldquoStudy on thirty patientswith slow-transmission constipation treated by acupunctureand moxibustionrdquo Chinese Journal of Integrated Traditional andWestern Medicine vol 29 no 11 pp 1031ndash1034 2009

[27] Z-L Zhang X-Q Ji S-H Zhao et al ldquoMulti-central random-ized controlled trials of electroacupunture at Zhigou (TE 6) fortreatment of constipation induced by stagnation or deficiencyof qirdquo Zhongguo Zhen Jiu vol 27 no 7 pp 475ndash478 2007

[28] Z Zhu H Li L Chen G Wang and C Kan ldquoAcupuncturetreatment of habitual constipationrdquo Journal of Traditional Chi-nese Medicine vol 23 no 2 p 133 2003

[29] E Broide S Pintov S Portnoy J Barg E Klinowski and EScapa ldquoEffectiveness of acupuncture for treatment of childhoodconstipationrdquo Digestive Diseases and Sciences vol 46 no 6 pp1270ndash1275 2001

[30] A G Klauser A Rubach O Bertsche and S A Muller-LissnerldquoBody acupuncture effect on colonic function in chronicconstipationrdquoZeitschrift fur Gastroenterologie vol 31 no 10 pp605ndash608 1993

[31] A R Jadad R A Moore D Carroll et al ldquoAssessing the qualityof reports of randomized clinical trials is blinding necessaryrdquoControlled Clinical Trials vol 17 no 1 pp 1ndash12 1996

[32] T Zhang T Y Chon B Liu et al ldquoEfficacy of acupuncturefor chronic constipation a systematic reviewrdquo The AmericanJournal of Chinese Medicine vol 41 no 4 pp 717ndash742 2013

[33] W-F Du L Yu X-K Yan and F-C Wang ldquoMet-analysison randomized controlled clinical trials of acupuncture andmoxibustion on constipationrdquo Zhongguo Zhen Jiu vol 32 no1 pp 92ndash96 2012

[34] M-K Li T-F D Lee and K-P L Suen ldquoA review on thecomplementary effects of auriculotherapy in managing consti-pationrdquo Journal of Alternative and Complementary Medicinevol 16 no 4 pp 435ndash447 2010

[35] L-W Lin Y-T Fu T Dunning et al ldquoEfficacy of traditionalChinese medicine for the management of constipation a sys-tematic reviewrdquo The Journal of Alternative and ComplementaryMedicine vol 15 no 12 pp 1335ndash1346 2009

[36] T Takahashi ldquoAcupuncture for functional gastrointestinal dis-ordersrdquo Journal of Gastroenterology vol 41 no 5 pp 408ndash4172006

[37] W R O f t W PacificWho Standard Acupuncture Point Loca-tions in the Western Pacific Region World Health OrganizationManila Philippines 2008

[38] J-H Sun H Guo L Chen et al ldquoEffect of electroacupunctureat lsquoTianshursquo(ST 25) on colonic smooth muscle structure andinterstitial cells of cajal in slow transit constipation ratsrdquo ZhenCi Yan Jiu vol 36 no 3 pp 171ndash175 2011

[39] H P Wang Q G Qin K Liu X Y Gao and B Zhu ldquoEffectsof acupuncture at lsquotianshursquo (st 25) on electrical and mechanicalmotor of jejunum smooth muscles at different phases of theinterdigestive migrating motor complex in normal ratsrdquo ZhenCi Yan Jiu vol 39 no 2 pp 117ndash123 2014


[40] Z Yu Y B XiaM X Lu J LinW J Yu and B Xu ldquoInfluence ofelectroacupuncture stimulation of lsquotianshursquo (ST 25) lsquoquchirsquo (LI11) and lsquoshangjuxursquo (ST 37) and their pairs on gastric motility inthe ratrdquo Zhen Ci Yan Jiu vol 38 no 1 pp 40ndash47 2013

[41] C-C Yan Y Peng Y-P Lin et al ldquoEffect ofmanual acupuncturestimulation of lsquoZusanlirsquo (ST 36) on gastric motility and SP andmotilin activities in gastric antrum and nucleus raphe magnusin gastric hyperactivity and hypoactivity ratsrdquo Zhen Ci Yan Jiuvol 38 no 5 pp 345ndash351 2013

[42] H-L Chao S-J Miao P-F Liu et al ldquoThe beneficial effect ofST-36 (Zusanli) acupressure on postoperative gastrointestinalfunction in patients with colorectal cancerrdquo Oncology NursingForum vol 40 no 2 pp E61ndashE68 2013


[44] Y Liu and Y-L Chen ldquoAnalysis of information detection ofbiological energy on Shangjuxu (ST 37) with acupuncturerdquoChinese Acupuncture ampMoxibustion vol 30 no 6 pp 481ndash4842010

[45] L-P Shen J Guan and K-Y Ding ldquoClinical observation onelectroacupuncture combined with acupoint injection for treat-ment of early postoperative inflammatory intestinal obstruc-tionrdquo Zhongguo Zhen Jiu vol 30 no 1 pp 27ndash30 2010

[46] H-J Li G-P Li andH-Y Li ldquoClinical observation on acupointcatgut embedding therapy for treatment of ulcerative colitisrdquoChinese Acupuncture ampMoxibustion vol 26 no 4 pp 261ndash2632006

[47] Z-M Shi Y-S Zhu Q-X Wang andM-N Lei ldquoComparativestudy on irritable bowel syndrome treated with acupunctureand Western medicinerdquo Zhongguo Zhen Jiu vol 31 no 7 pp607ndash609 2011

[48] Q Wen W-W Chen J Li Y Zhao N Li and C-W WangldquoAdhesive ileus treated by electroacupuncture at Zhigou (TE 6)and Zusanli (ST 36) a randomized controlled studyrdquo ZhongguoZhen Jiu vol 32 no 11 pp 961ndash965 2012

[49] J-X Duan and Z-S Liu ldquoReview on the safety of deepacupuncture at Tianshu (ST 25)rdquoAcupuncture Research vol 35no 3 pp 232ndash235 2010

[50] J-S Han ldquoAcupuncture neuropeptide release produced byelectrical stimulation of different frequenciesrdquo Trends in Neu-rosciences vol 26 no 1 pp 17ndash22 2003

[51] S-B Xu B Huang C-Y Zhang et al ldquoEffectiveness ofstrengthened stimulation during acupuncture for the treatmentof bell palsy a randomized controlled trialrdquo Canadian MedicalAssociation Journal vol 185 no 6 pp 473ndash479 2013

[52] J Fletcher ldquoAcupuncturemdashno shamrdquo CanadianMedical Associ-ation Journal vol 185 no 6 article 459 2013


[54] S Aydin E Donder O K Akin F Sahpaz Y Kendir andM M Alnema ldquoFat-free milk as a therapeutic approach forconstipation and the effect on serummotilin and ghrelin levelsrdquoNutrition vol 26 no 10 pp 981ndash985 2010


[56] M S Lee T-Y Choi J-E Park and E Ernst ldquoEffects ofmoxibustion for constipation treatment a systematic review ofrandomized controlled trialsrdquo Chinese Medicine vol 5 article28 2010

[57] J-E Park J-U Sul K Kang B-C Shin K-E Hong and S-M Choi ldquoThe effectiveness of moxibustion for the treatmentof functional constipation a randomized sham-controlledpatient blinded pilot clinical trialrdquo BMC Complementary ampAlternative Medicine vol 11 article 124 2011

[58] J E Park C H Han KW KangM S Shin D S Oh and SMChoi ldquoA shammoxibustion device andmasking testrdquo Journal ofKorean Oriental Medicine vol 13 pp 93ndash100 2007

[59] B Zhao X Wang Z Lin R Liu and L Lao ldquoA novel shammoxibustion device a randomized placebo-controlled trialrdquoComplementary Therapies in Medicine vol 14 no 1 pp 53ndash602006

[60] P Weerapong P A Hume and G S Kolt ldquoThe mechanismsof massage and effects on performance muscle recovery andinjury preventionrdquo Sports Medicine vol 35 no 3 pp 235ndash2562005

[61] M J Nam Y I Bang and T I Kim ldquoEffects of abdominalmeridian massage with aroma oils on relief of constipationamong hospitalized children with brain related disabilitiesrdquoJournal of Korean Academy of Nursing vol 43 no 2 pp 247ndash255 2013

[62] K Lamas U H Graneheim and C Jacobsson ldquoExperiencesof abdominal massage for constipationrdquo Journal of ClinicalNursing vol 21 no 5-6 pp 757ndash765 2012

[63] D McClurg S Hagen S Hawkins and A Lowe-StrongldquoAbdominal massage for the alleviation of constipation symp-toms in people withmultiple sclerosis a randomized controlledfeasibility studyrdquo Multiple Sclerosis vol 17 no 2 pp 223ndash2332011

[64] TK T LaiMCCheungCK Lo et al ldquoEffectiveness of aromamassage on advanced cancer patients with constipation a pilotstudyrdquo ComplementaryTherapies in Clinical Practice vol 17 no1 pp 37ndash43 2011

[65] M Chung and E Choi ldquoA comparison between effects of aromamassage and meridian massage on constipation and stress inwomen college studentsrdquo Journal of KoreanAcademy of Nursingvol 41 no 1 pp 26ndash35 2011

[66] K Lamas L Lindholm H Stenlund B Engstrom and CJacobsson ldquoEffects of abdominal massage in managementof constipationmdasha randomized controlled trialrdquo InternationalJournal of Nursing Studies vol 46 no 6 pp 759ndash767 2009

[67] L M T Silva A Cignolini R Warren S Budden and ASkowron-Gooch ldquoImprovement in sensory impairment andsocial interaction in young children with autism followingtreatment with an original Qigong massage methodologyrdquoTheAmerican Journal of Chinese Medicine vol 35 no 3 pp 393ndash406 2007

[68] M A Khan I P Bobrovnitskiı A S Potapov M I BakanovE V Komarova and A V Petrova ldquoEffects of interference cur-rents crypmassage and their combination on lipid peroxidationin children with chronic constipationrdquo Voprosy KurortologiiFizioterapii i Lechebnoı Fizicheskoı Kultury no 5 pp 31ndash322006

[69] S Ayas B Leblebici S Sozay M Bayramoglu and E A NironldquoThe effect of abdominal massage on bowel function in patientswith spinal cord injuryrdquo American Journal of Physical Medicineamp Rehabilitation vol 85 no 12 pp 951ndash955 2006


[70] B Albers H Cramer A Fischer A Meissner A Schurenbergand S Bartholomeyczik ldquoAbdominal massage as interventionfor patients with paraplegia caused by spinal cord injurymdashapilot studyrdquo Pflege Zeitschrift vol 59 no 3 pp 2ndash8 2006

[71] M-A Kim J-K Sakong E-J Kim and E-H Kim ldquoEffectof aromatherapy massage for the relief of constipation in theelderlyrdquo Taehan Kanho Hakhoe Chi vol 35 no 1 pp 56ndash642005

[72] S Y Jeon and H M Jung ldquoThe effects of abdominal meridianmassage on constipation among cva patientsrdquo Taehan KanhoHakhoe Chi vol 35 no 1 pp 135ndash142 2005

[73] A Konig S Radke H Molzen et al ldquoRandomised trial ofacupuncture compared with conventional massage and lsquoshamrsquolaser acupuncture for treatment of chronic neck painmdashrange ofmotion analysisrdquo Zeitschrift fur Orthopadie und Ihre Grenzgebi-ete vol 141 no 4 pp 395ndash400 2003

[74] Y Zhang Y L Zhang and Y Q Cheng ldquoClinical observation ofconstipation due to deficiency of vital energy treated bymassageand finger pressuremethodsrdquoChinese Journal of Nursing vol 31no 2 pp 97ndash98 1996

[75] A G Klauser J Flaschentrager A Gehrke and S A Muller-Lissner ldquoAbdominal wall massage effect on colonic function inhealthy volunteers and in patients with chronic constipationrdquoZeitschrift fur Gastroenterologie vol 30 no 4 pp 247ndash251 1992

[76] S Woodward C Norton and K L Barriball ldquoA pilot study ofthe effectiveness of reflexology in treating idiopathic constipa-tion in womenrdquo Complementary Therapies in Clinical Practicevol 16 no 1 pp 41ndash46 2010

[77] D McClurg and A Lowe-Strong ldquoDoes abdominal massagerelieve constipationrdquo Nursing Times vol 107 no 12 pp 20ndash222011

[78] J Alcantara J D Alcantara and J Alcantara ldquoAn integrativereview of the literature on the chiropractic care of infants withconstipationrdquoComplementaryTherapies in Clinical Practice vol20 no 1 pp 32ndash36 2014

[79] K Lamas L Lindholm B Engstrom and C JacobssonldquoAbdominal massage for people with constipation a cost utilityanalysisrdquo Journal of Advanced Nursing vol 66 no 8 pp 1719ndash1729 2010

[80] W Ashraf F Park J Lof and E M M Quigley ldquoEffects ofpsyllium therapy on stool characteristics colon transit andanorectal function in chronic idiopathic constipationrdquo Alimen-tary Pharmacology and Therapeutics vol 9 no 6 pp 639ndash6471995

[81] W Ashraf R F Pfeiffer F Park J Lof and E M M QuigleyldquoConstipation in Parkinsonrsquos disease objective assessment andresponse to psylliumrdquo Movement Disorders vol 12 no 6 pp946ndash951 1997

[82] JWMcrorie B P Daggy J GMorel P S Diersing P BMinerand M Robinson ldquoPsyllium is superior to docusate sodium fortreatment of chronic constipationrdquoAlimentary PharmacologyampTherapeutics vol 12 no 5 pp 491ndash497 1998

[83] M H Mehmood N Aziz M N Ghayur and A-H GilanildquoPharmacological basis for the medicinal use of psyllium husk(Ispaghula) in constipation and diarrheardquo Digestive Diseasesand Sciences vol 56 no 5 pp 1460ndash1471 2011

[84] H Y Lee J H Kim H W Jeung et al ldquoEffects of Ficus caricapaste on loperamide-induced constipation in ratsrdquo Food andChemical Toxicology vol 50 no 3-4 pp 895ndash902 2012

[85] H-GOhH-Y LeeM-Y Seo et al ldquoEffects of ficus carica pasteon constipation induced by a high-protein feed and movement

restriction in beaglesrdquo Laboratory Animal Research vol 27 no4 pp 275ndash281 2011

[86] E H Hwang and H J Lee ldquoEffects of alginic acid cellulose andpectin level on bowel function in ratsrdquo The Korean Journal ofNutrition vol 30 no 5 pp 465ndash477 1997

[87] J Lemli ldquoMetabolism of sennosidesmdashan overviewrdquo Pharmacol-ogy vol 36 supplement 1 pp 126ndash128 1988

[88] J A Marlett B U K Li C J Patrow and P Bass ldquoComparativelaxation of psyllium with and without senna in an ambulatoryconstipated populationrdquoTheAmerican Journal of Gastroenterol-ogy vol 82 no 4 pp 333ndash337 1987

[89] A P Passmore K Wilson-Davies C Stoker and M E ScottldquoChronic constipation in long stay elderly patients a compari-son of lactulose and a senna-fibre combinationrdquo British MedicalJournal vol 307 no 6907 pp 769ndash771 1993

[90] O Kinnunen and J Salokannel ldquoThe carry-over effect on thebowel habit in elderly long-term patients of long-term bulk-forming products containing stimulant laxativerdquo Acta MedicaScandinavica vol 222 no 5 pp 477ndash479 1987

[91] M Willems H R van Buuren and R de Krijger ldquoAnthranoidself-medication causing rapid development of melanosis colirdquoNetherlands Journal of Medicine vol 61 no 1 pp 22ndash24 2003

[92] G S Speare ldquoMelanosis coli Experimental observations onits production and elimination in twenty-three casesrdquo TheAmerican Journal of Surgery vol 82 no 5 pp 631ndash637 1951

[93] A P Passmore K W Davies P G Flanagan C Stoker andM G Scott ldquoA comparison of agiolax and lactulose in elderlypatients with chronic constipationrdquo Pharmacology vol 47 no1 pp 249ndash252 1993

[94] L L D Zhong C W Cheng Y Chan et al ldquoChinese herbalmedicine (Ma Zi Ren Wan) for functional constipation studyprotocol for a prospective double-blinded double-dummyrandomized controlled trialrdquo Trials vol 14 no 1 article 3662013

[95] Z X Bian C W Cheng and L Z Zhu ldquoChinese herbalmedicine for functional constipation a randomised controlledtrialrdquoHong KongMedical Journal vol 19 supplement 9 pp 44ndash46 2013

[96] C-W Cheng Z-X Bian L-X Zhu J C Y Wu and J JY Sung ldquoEfficacy of a Chinese herbal proprietary medicine(Hemp Seed Pill) for functional constipationrdquo The AmericanJournal of Gastroenterology vol 106 no 1 pp 120ndash129 2011

[97] C-H Huang J-S Lin T-C Li et al ldquoComparison of a chineseherbal medicine (cch1) and lactulose as first-line treatment ofconstipation in long-term care a randomized double-blinddouble-dummy and placebo-controlled trialrdquo Evidence-BasedComplementary and Alternative Medicine vol 2012 Article ID923190 12 pages 2012

[98] C-HHuang Y-C Su T-C Li et al ldquoTreatment of constipationin long-term care with chinese herbal formula a randomizeddouble-blind placebo-controlled trialrdquo Journal of Alternativeand Complementary Medicine vol 17 no 7 pp 639ndash646 2011

[99] C-W Cheng Z-X Bian and T-X Wu ldquoSystematic review ofChinese herbal medicine for functional constipationrdquo WorldJournal of Gastroenterology vol 15 no 39 pp 4886ndash4895 2009

Review ArticleMindfulness-Based Therapies in the Treatment of FunctionalGastrointestinal Disorders A Meta-Analysis

Monique Aucoin Marie-Jasmine Lalonde-Parsi and Kieran Cooley

Canadian College of Naturopathic Medicine 1255 Sheppard Ave East Toronto ON Canada M2K 1E2

Correspondence should be addressed to Monique Aucoin maucoinccnmedu

Received 4 July 2014 Accepted 19 August 2014 Published 11 September 2014

Academic Editor Toku Takahashi

Copyright copy 2014 Monique Aucoin et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Background Functional gastrointestinal disorders are highly prevalent and standard treatments are often unsatisfactoryMindfulness-based therapy has shown benefit in conditions including chronic pain mood and somatization disordersObjectivesTo assess the quality and effectiveness reported in existing literature we conducted a meta-analysis of mindfulness-based therapyin functional gastrointestinal disordersMethods Pubmed EBSCO and Cochrane databases were searched from inception to May2014 Study inclusion criteria included randomized controlled studies of adults using mindfulness-based therapy in the treatmentof functional gastrointestinal disorders Study quality was evaluated using the Cochrane risk of bias Effect sizes were calculatedand pooled to achieve a summary effect for the intervention on symptom severity and quality of life Results Of 119 records eightarticles describing seven studies met inclusion criteria In six studies significant improvements were achieved or maintained atthe end of intervention or follow-up time points The studies had an unclear or high risk of bias Pooled effects were statisticallysignificant for IBS severity (059 95 CI 033 to 086) and quality of life (056 95 CI 047 to 079) Conclusion Studies suggest thatmindfulness based interventions may provide benefit in functional gastrointestinal disorders however substantial improvementsin methodological quality and reporting are needed

1 Introduction

Functional gastrointestinal disorders (FGIDs) have a highprevalence a significant impact on patientsrsquo wellbeing andare costly to the health care system [1] Patients with thesedisorders report a marked impact on quality of life and anaverage of 30 sick days per year per person constituting asubstantial health care burden [2]

The pathophysiology underlying FGIDs is unclear asthey lack any discernable organic or structural pathologyCurrent knowledge suggests the involvement of factors suchas abnormal gut motor function increased visceral percep-tion abnormalities in central pain processing and disruptionof the gut microbiota as well as genetic and psychologicalfactors [1] Psychiatric disorders are frequent comorbiditiesin patients with FGIDs and recent prospective study evidencesuggests that the relationship is bidirectional [1]

Of the FGIDs the most common is irritable bowel syn-drome (IBS) affecting 7ndash10 of the population worldwide It

is characterized by recurring abdominal pain or discomfortand diarrhea or constipation [1]

Standard treatment for IBS is targeted at symptom controlthrough the use of laxatives antidiarrheal agents antispas-modics and antidepressant medications Studies report thatless than 50 of patients with IBS are satisfied with thestandard medical treatment and many turn to alternativesStudies of complementary and alternative medicine use inIBS populations have reported rates of 21ndash51 [2]

Treatment and burden of other FGIDs such as func-tional abdominal pain vomiting and dyspepsia are lesswell understood although there is considerable categoricaloverlap with IBS Similarly to IBS other FGIDs are associatedwith high rates of complementary and alternative medicineusage Pharmacological treatments for other FGIDs aimedat targeting receptors with enteric and central nervous systemeffects are similarly in the early stages of development [3ndash5]

Because of the significant involvement of emotionalcognitive and neurological factors in IBS a number of



studies have investigated psychological interventions includ-ing cognitive behavioural therapy (CBT) hypnotherapy andrelaxation exercises An early review suggested that all ofthese interventions have shown benefit [2]

A more recent addition to this list of interventions ismindfulness-based therapy (MBT) a form of psychothera-peutic treatment which uses meditation practices to assistpatients in the cultivation of nonjudgemental awareness ofthe present moment This involves monitoring of cognitionemotion perception and sensations and the developmentof nonreactivity to difficult or negative aspects of theseexperiences [6] The use of mindfulness as a therapeutictool began in the late 1970s with the development of themindfulness-based stress reduction (MBSR) program as atreatment for chronic pain [7] The MBSR program has beencombined with CBT in the development of mindfulness-based cognitive therapy (MBCT) It was developed for theprevention of major depressive disorder relapse [7] howeverevidence to support its use in anxiety and active depressioncontinues to emerge [8] The programs typically consist of8 weekly 25 hour group sessions involving various forms ofmeditation group discussion and other exercises one day ofmeditation retreat and approximately one hour of daily homepractice [9]

In addition to the treatment of mental health concernsthere is an expanding body of research supporting theuse of mindfulness-based interventions for stress pain andsomatization disorders such as fibromyalgia and chronicfatigue syndrome [7]

A review article exploring the neural mechanisms ofmindfulness and meditation found significant structuraland functional changes within the brain both during andresulting from mindful states and practices [10] Basedon patterns of cortical thickening meditation is associatedwith structural changes in brain regions related to sensorycognitive and emotional processing [11]

Because of the significant involvement of emotionalfactors in IBS it was initially suspected that the benefit ofpsychological interventions was achieved through improve-ment of comorbid psychological distress [6] A recent studyutilized a number of assessment tools to explore somehypothesized mechanisms for the benefit exerted by MBTon IBS The results of their analysis revealed that severalcognitive processes are involved MBT led to a decreasein reactivity to thoughts emotions and physical sensationswhich led to a decrease in visceral sensitivity The decreasedvisceral sensitivity was related to a decrease in IBS symptomseverity and an improvement in quality of life Addition-ally nonreactivity was associated with a decrease in paincatastrophizing which predicts improvement in quality of lifeand increased reinterpretation of pain sensations predictedreductions in IBS severity [6]

Previous reviews studying the use of MBT in FGIDshave combined it with other psychotherapeutic interventionsor with other disorders [7 12] A recent systematic reviewand meta-analysis investigated the use of mindfulness-basedtherapy in the treatment of somatization disorders includingfibromyalgia chronic fatigue and IBS [7] In the time sincethis reviewwas completed additional clinical trials have been

publishedThe review examined efficacy outcomes at the endof treatment only and did not discuss risk of bias or otherelements describing the quality of reporting of the studiesA synthesis which includes these components is essential toprovide context to the findings as well as provide guidance forfuture research

This review will discuss the effectiveness of mindfulnesstherapy at improving symptom severity and quality of lifemeasures in patients diagnosed with FGIDs compared towaitlist or active control groups The review will explore theeffectiveness at the end of the intervention as well as aftera follow-up period Additionally the quality of the studieswill be assessed to describe the current state of reporting andstudy bias in the existing literature

2 Methods

The PRISMA statement was used to guide the conduct andreporting of this meta-analysis [13]

21 Systematic Literature Searches Systematic literature sear-ches were performed using the Pubmed EBSCO and Coch-rane databases The following search terms were used mind-fulness MBCT MBSR mindfulness-based cognitive ther-apy mindfulness-based stress reduction mindful functionalgastrointestinal functional bowel colonic disease functio-nal colonic disease functional abdominal pain recurrentabdominal pain abdominal pain IBS irritable bowel spasticcolon irritable colon constipation diarrhea bloating dis-tention gastroesophageal refluxGERD dysphagia and func-tional dyspepsia Studies in any stage of publication fromdatabase inception onward in English were considered Thepurpose of this strategy was to be inclusive of the existingliterature and noting that previous reviews did not identify alarge base of non-English publicationsThe last date searchedwas May 29 2014

The search results were combined and duplicates wereremoved A screen of article titles and abstracts was per-formed to identify clinical trials that utilized mindfulness-based interventions for the treatment of FGIDs After review-ing the full-text articles those with control groups random-ization and an adult population with FGID symptoms wereincluded

22 Data Collection Data was extracted by one reviewerData for the following study variables was extracted studysize and percent female participants participant diagno-sis intervention and duration control follow-up symptomseverity at the end of the intervention and at follow-up andquality of life assessment at the end of the intervention andat follow-up The principle summary outcome measures forsynthesis were the changes in symptoms severity betweenbaseline end-of-intervention and follow-up Correspondingauthors of included studies were contacted regardingmissingor unclear data thoughnotably this did not result in any addi-tional information beyond what was originally publishedTwo attempts to contact authors via email were made beforeceasing attempts at correspondence


23 Data Analysis Effect sizes (Cohenrsquos 119889) were calculatedfor relevant validated outcome measures (effect on IBSseverity at end of intervention effect at postinterventionfollow-up and quality of life) from individual studies usingreportedmean standard deviation and group size A randomeffects model (DerSimonian-Laird (DL)) was assumed toaccount for the small number of studies with pool-able data(119899 = 5-6) small sample sizes and high degree of variancewithin the studies Studies were weighted based on samplesize in order to generate a pooled point estimate and 95confidence interval for effect size Heterogeneity was assessedusing the 1198682 statistic Cochran 119876 is reported as an inferenceof combinability of studies Kendallrsquos tau and Eggerrsquos test willbe reported to assess for power and risk of bias affecting thecumulative result Statistical analysis and figure generation(funnel and forest plots) were accomplished using StatsDirect(version 30119) software

24 Quality Analysis Assessment of study quality was con-ducted using the Cochrane Risk of Bias [22] and the CON-SORT checklist for reporting trials of nonpharmacologictreatments [23] Assessment was completed by two reviewersindependently and any discrepancies were discussed until aconsensus was reached

3 Results

31 Literature Search The literature search yielded 119 uniquerecords (Figure 1) After these records were screened basedon title and abstract 106 studies were excluded The reasonsincluded the following did not assess the use of mindful-ness in FGIDs (85) review articles (14) protocol only (2)uncontrolled design (1) pediatric population (1) other typesof pain included (1) outcomes limited to cost effectiveness(1) and outcomes limited to psychological symptoms (1) Ofthe 13 full-text articles assessed for eligibility eight articlesreporting the results of seven randomized controlled trialsmet the criteria for inclusion in this analysis The reasons forexclusion were a lack of adequate control (1) combinationwith other somatic disorders (1) not written in English(1) only mechanism of action outcomes reported (1) andreporting the same results as another included study (1)

32 EfficacymdashEnd of Intervention Of the seven studiesincluded in this review five (714) reported significantimprovements in IBS symptom severity at the end of theintervention compared towaitlist or comparison intervention(Table 1) One study did not report end-of-interventionresults [24] One study which included patients with inflam-matory bowel disease (IBD) who were in remission andexperiencing IBS-like symptoms showed a nonsignificanttrend towards improvement compared to waitlist controlThese patients represented a subgroup analysis within thestudy and thus had a small sample size [14]

33 EfficacymdashFollow-Up Data from a follow-up time pointwas reported in all eight publications These follow-up peri-ods ranged from two to 18 months after the end of theintervention The study of IBD patients continued to show a

Number of records identified through database screening

Number of records after duplicates removed

Number of studies

in qualitative synthesis

Number of full-text

assessed for

Number of records

Number of full-text articles excluded

Reason for exclusion (1) Lack of control(2) Included other somatic disorders(3) Not written in english(4) Only mechanism of action reported

(5) Reported the same results as another included study

Number of full-text articles excludedReason for exclusion (1) Not MBT for FGIDs(2) Review article(3) Protocol only(4) Pediatric population(5) FGID symptoms not measured (6) Combined with other types of pain

(7) Lack of control

(n = 163)

(n = 119)

screened (n = 119)

eligibility (n = 13)

(n = 8)

(n = 1)

(n = 1)

(n = 1)

(n = 1)

(n = 1)

(n = 5)

(n = 1)

(n = 1)

(n = 2)

(n = 2)

(n = 1)

(n = 14)

(n = 85)

(n = 106)

included

articles

Figure 1 PRISMA flow chart showing number of screenedincluded and excluded studies

trend towards improvement that did not reach significance[14] The study that only reported data from the follow-upassessment showed significant improvement [21] The othersix studies reported that participants maintained improve-ment in the severity of their IBS symptoms Among these oneshowed a nonsignificant trend towards further improvement[19] One study that showed maintenance of improvementshowed improvement in the control group resulting in aloss of statistical significance [20] During the follow-upperiod the participants did not receive further treatment withmindfulness-based therapy however the programs taughtparticipants skills and exercises which they were encouragedto continue using Two studies assessed for the use ofadditional treatments during the follow-up period and foundno significant difference in the outcomes reported by thosewho had sought additional treatment and those who had not[17 18]

34 EfficacymdashQuality of Life Five studies utilized the irrita-ble bowel syndrome quality of life instrument (IBS-QOL) asa secondary outcome and of these 800 (119899 = 4) reporteda significant improvement at end-of-intervention Betweenthe end-of-intervention and the follow-up assessment signif-icant further improvement was seen in two of these studieswhile the other two studies showed maintenance of improve-ment One study demonstrated a significant improvementin IBS-QOL in both the intervention group and the waitlist control group that was maintained at follow-up [20]The study reporting long-term follow-up data only showedmaintenance of QOL improvement

The study that enrolled IBD patients used an objectivebiomarker for the assessment of intestinal inflammation [14]


Table1Ch

aracteris

ticsa

ndou

tcom

esof

studies

inclu

dedin

syste

maticreview

Stud

y119873

female

Popu

latio

nInterventio

namp

duratio

nCon

trol

Follo

w-up

IBSseverityat

end-of-in

terventio

nIBSseverityat

follo

w-up

Qualityof

life

Berrill

etal2014

[14]

3877

IBDwith

IBS-type

symptom

sMCT

16weeks

Waitin

glist

(TAU

)8and12

mon

ths

DecreaseinIBS-SS

but

didno

treach

statistical

significance

(325

vs

68

redu

ction

119875=0219)

DecreaseinIBS-SS

but

didno

treach

statistical

significance

(300

vs

0redu

ction

119875=0213)

Not

assessed

Gaylord

etal2011[15]75

100

IBS

Mindfulness-based

stressa

ndpain

managem

ent

program8

weeks

Supp

ortg

roup

3mon

ths

Sign

ificantlygreater

improvem

entinIBS-SS

(264vs62redu

ction

119875=0006)

Improvem

ent

maintained(382vs

118redu

ction

119875=0001)

Sign

ificant

improvem

ent

inIBS-QOLatfollo

w-up

only(119875=0027)

Lj otsson

etal2010

[16]

8585

IBS

ICBT

10weeks

Onlinec

losed

discussio

nforum

3mon

ths

Sign

ificant

improvem

ent

indiarysymptom

ratin

gs(pain

diarrhea

constip

ation

and

bloatin

g)andGSR

S-IBS

(42

redu

ctionvs12

increase119875lt0001)

Improvem

entin

GSR

S-IBSmaintained

Sign

ificant

improvem

ent

inIBS-QOLpo

sttre

atment(119875=0001)

furthersignificant

improvem

entatfollow-up

(119875=004)

Lj otsson

etal2011[17]

Long

term

follo

w-upof

Lj otsson

etal(2010)[16]

15ndash18(m

ean=164)

mon

ths

Improvem

entin

GSR

S-IBSmaintained

(119875lt005)

Sign

ificant

improvem

ent

inIBS-QOL(119875lt005)

maintainedatfollo

w-up

nodifferenceb

etween

thosew

hodiddidno

tseek

additio

nalcarefor

IBS

Lj otsson

etal2011[18]6

174

IBS

ICBT

10weeks

Onlinec

losed

discussio

nforum

before

crossin

gover

12mon

ths

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(305

redu

ctionvs28

increase)(Coh

enrsquos119889077

(019

ndash13495CI

))

Improvem

entin

GSR

S-IBSmaintained

Sign

ificantlygreater

improvem

entinIBS-QOL

(Coh

enrsquos119889079

(020ndash

135

95CI

))further

improvem

entatfollow-up

(119875=004)

Lj otsson

etal2011[19]19

579

IBS

ICBT

10weeks

Internet-based

stress

managem

ent

6mon

ths

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(236

vs

131

redu

ction)

(difference

inscoreo

f48(12ndash8495CI

))

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(difference

inscoreo

f59(19ndash99

95CI

))

nonsignificanttrend

towards

continued

improvem

ent

Sign

ificantlylarger

improvem

entinIBS-QOL

(difference

inscoreo

f10

(45ndash15695CI

))

maintainedatfollo

w-up

(difference

inscoreo

f62

(02ndash12295CI

))


Table1Con

tinued

Stud

y119873

female

Popu

latio

nInterventio

namp

duratio

nCon

trol

Follo

w-up

IBSseverityat

end-of-in

terventio

nIBSseverityat

follo

w-up

Qualityof

life

Zernicke

etal2013

[20]

9090

IBS

MBS

R8weeks

TAUwaitlist

6mon

ths

Sign

ificantlygreater

improvem

entinIBS-SS

(307vs52redu

ction

119875lt00001am

ong

completers169vs

35

usingITT)

Improvem

ent

maintainedsome

improvem

entseenin

TAUgrou

pleadingto

nosta

tistic

ally

significantd

ifference

(119875=017)

IBS-QOLim

proved

inbo

thgrou

pspo

sttreatmentand

follo

w-up(119875lt0001)

Zomorod

ietal2014

[21]

4844

IBSandhealthy

controls

MBS

Ror

CBT8

weeks

Nopsycho

logical

interventio

n2mon

ths

Not

provided

Sign

ificantlygreater

improvem

entinIBS

questio

nnaire

vsC

BTor

control(350vs

58

119875lt005)

Not

assessed

GSR

S-IBSgastr

ointestin

alsymptom

ratin

gscalemdash

IBSversion

ICBT

internet-b

ased

cogn

itive

behavior

therapywhich

inclu

dese

xposuremindfulnessand

acceptance

IBS-SSirritableb

owelsynd

romes

everity

score

IBDQinfl

ammatorybo

weldiseaseq

uestion

naire

IBS-QOLirr

itableb

owelsynd

romeq

ualityof

lifeinstrum

ent

MCT

multic

onvergenttherapy-com

binatio

nof

mindfulnessmeditatio

nandCB

TMBS

Rmindfulness-based

stressredu

ction

TAUtreatmentasu

sual


however none of the other studies used objective tests forthe assessment of FGID symptoms as primary or secondaryoutcome measures All of the assessment tools relied onvalidated patientself-report outcome measures

Two studies [18 19] used a linear mixed-effects modelto observe the difference in rates of change between theMBT and control intervention over time amid significantinteraction effects between group and time were seen (119875 lt001)

35 Quality Assessment Quality assessment of the studiesincluded in the review revealed strengths as well as weak-nesses and opportunities for the introduction of bias TheCochrane risk of bias assessment showed overall unclear orhigh risk of bias for the included studies (Table 2)

The most significant contributor to risk of bias was alack of blinding of participants facilitators and outcomeassessment In three studies the mindfulness interventionwas compared with a support group or another psychologicalintervention and the participants were not aware of theirallocation in the study however the remaining studies useda waitlist control or treatment-as-usual comparison and inthese cases the participants were aware that they werereceiving the intervention being tested In all studies person-nel who were administering the therapy were not blindedalthough this is acknowledged as an inherent challenge inpsychological interventions

Another area that presented a risk of bias is incompleteoutcome data In many studies the rate of withdrawal was thesame in the intervention and control groups and intentionto treat analyses were utilized however in many cases thedropout rates were large ranging from 10 to 44 One studyfailed to report outcome measures at the end of the interven-tion and only reported data from the follow-up assessmentTwo studies failed to describe their funding source Somestudies lacked clarity in their description of random sequencegeneration (119899 = 1) and allocation concealment (119899 = 3)

Assessment of the studies using the CONSORT checklistof items for reporting trials of nonpharmacologic treatmentalso highlighted strengths and weaknesses (Figure 2) Themajority of studies included adequately reported backgroundinformation study objectives sample size determinationrandomization method statistical analysis methods partic-ipant flow recruitment dates baseline data numbers ana-lyzed outcomes additional analyses interpretations gen-eralizability and overall evidence Partially complete infor-mation was reported in most titles and abstracts Therewas limited reporting of the inclusion criteria for studysites and intervention providers as well as the location ofdata collection Additionally only two studies completelydescribed standardization of the intervention and assessmentof adherence to the protocol None of the studies reportedadverse event data or results of how the interventions wereimplemented As previously stated the details of allocationconcealment were often incomplete or absent as well asinformation about blinding of participants and personnel Ofthe eight studies four reported registration in an open accessclinical trial registry

0 1 2 3 4 5 6 7 8(22) Overall evidence(21) Generalizability

(20) Interpretation(19) Adverse events

(18) Ancillary analyses(17) Outcomes and estimation

(16) Numbers analyzed(15) Baseline data(14) Recruitment

Implementation intervention(13) Participant flow

(12) Statistical methods(11) Blinding

(10) Implementation(9) Allocation concealment

(8) Randomization(7) Sample size

(6) Outcomes(5) Objectives

(4) Intervention(3) Participants(2) Background

(1) Title and abstract

YesPartial

NoReported elsewhere

Figure 2 CONSORT checklist of items for reporting trials ofnonpharmacologic treatments

Overall the studies included had deficiencies in reportingand significant risk of influence of bias

36Meta-Analysis Six studies reported IBS severity at end ofintervention data that was amenable to calculation of effectsize five studies contained data available for pooling for eachof IBS severity at postintervention follow-up and quality oflife

Mild-moderate heterogeneity existed between studieswith respect to effects of MBT on IBS severity at end ofintervention (1198682 = 499 95CI = 0 to 782 Cochran119876=9982 119875 = 0076) on IBS severity at postintervention follow-up (1198682 = 233 95 CI = 0 to 718 Cochran 119876 = 5216119875 = 0266) and on QOL (1198682 = 304 95 CI = 0 to 74Cochran 119876 = 5747 119875 = 0219)

Funnel plots (Figure 3) Kendallrsquos tau and Eggerrsquos test forbias are suggestive of low power low likelihood for unpub-lished or unreported studies and not statistically significantfor bias across IBS severity at end-of-intervention (Kendallrsquostau = 0333 119875 = 0469 Egger = 1901 95 CI = minus4376 to 8182119875 = 0448) on IBS severity at postintervention follow-up(Kendallrsquos tau = 04119875 = 0483 Egger = 1256 95CI =minus3988to 6501119875 = 0501) and onQOL (Kendallrsquos tau = 0119875 = 0817Egger = 1345 95 CI = minus6742 to 9432 119875 = 0633)

Forest plots (Figure 4) outline a statistically significantpooled effect size for IBS severity at end of intervention(Pooled 119889 = 0596 95CI = 0334 to 0858) on IBS severity atpostintervention follow-up (Pooled 119889 = 0352 95 CI = 0112to 0593) and on QOL (Pooled 119889 = 0564 95 CI = 0340to 0789) using random effects model No major difference infindings was observed using a fixed effects model for poolingdata (data not reported)


Table2Cochraner

iskof

bias

assessmento

fstudies

inclu

dedin

syste

maticreview

Reference

Rand

omsequ

ence

generatio

n(sele

ction

bias)

Allo

catio

nconcealm

ent

(selectio

nbias)

Blinding

ofparticipants

andperson

nel

(perform

ance

bias)

Blinding

ofou

tcom

eassessment(detection

bias)

Incomplete

outcom

edata

(attrition

bias)

Selective

repo

rting

(reportin

gbias)

Other

bias

Overall

Berrill

etal2014

[14]

Low

Low

High

Unclear

High

Low

Low

High

Gaylord

etal2011

[15]

Low

Unclear

Lowlowast

Low

Unclear

Low

Low

Unclear

Lj otsson

etal2010

[16]

Low

Low

High

Unclear

Low

Low

Unclear

High

Lj otsson

etal2011

(long

term

)[17]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

Low

Low

Low

High

Lj otsson

etal2011

(Acceptability)

[18]

Low

Low

High

Unclear

Unclear

Low

Low

High

Lj otsson

etal2011

(Internet)[19]

Low

Low

Lowlowast

Unclear

Low

Low

Low

Unclear

Zernicke

etal2013

[20]

Low

Unclear

High

Unclear

Unclear

Low

Low

High

Zomorod

ietal

2014

[21]

Unclear

Unclear

Lowlowast

Unclear

Unclear

High

Unclear

High

Lowlowaststudy

participantswereb

lindho

wever

duetothen

atureo

fapsycho

logicalintervention

thosep

roviding

theinterventionweren

otblind


minus03 01 05 09 13034

029

024

019

014

Effect size

Stan

dard

erro

r

(a)

minus10 minus05 00 05 10 150475

0400

0325

0250

0175

0100

Effect size

Stan

dard

erro

r

(b)

minus02 03 08 13030

026

022

018

014

Effect size

Stan

dard

erro

r

(c)

Figure 3 Funnel plots for IBS severity at end of intervention (a) IBS severity at postintervention follow-up (b) and quality of life (c)

4 Discussion

The results of the studies reviewed suggest that MBT may bean effective treatment for FGIDs achieving both a reductionof symptom severity and an improvement in quality oflife The mean decrease in symptom severity ranged from23 to 42 Though the sample size is small this suggestssome consistency in effectiveness observed amongst studiesA previous meta-analysis suggests that the variability ofeffectiveness of mindfulness therapies is no greater than thatobserved in other pharmacological or cognitive behaviouraltherapies across disorders [24] In Zernicke et al [20] themean decrease of 307 amongst completers equated to 50of participants achieving a clinically meaningful reduction intheir IBS symptoms (ie a reduction of 50 points on the IBSSeverity Scale)

41 Duration of Effect Additionally the results suggest thatthe improvement achieved during treatment is lasting andmay even lead to continued improvement All of the studiesthat yielded statistically significant improvement in symptomseverity at end-of-intervention demonstrated maintenance

of that improvement at follow-up In addition three stud-ies observed statistically significant improvement in qualityof life between end-of-intervention and follow-up Lastingeffects have been observed in previous studies using MBTOne study which sought to investigate the long-term effectsofMBCT in the treatment of depression found that improve-ments achieved during treatment were maintained for up to598 months of follow-up [25] The lasting effects of MBTare likely related to changes in the way participants attendto moment-by-moment cognition emotion perception andsensationsmdashthe development of trait or dispositional mind-fulness [6]

42 Quality Quality assessment of the studies revealed somestrengths but largely weaknesses and deficiencies Overallthe current literature has not responded to challenges relatingto increased quality in design conduct and reporting thatmay impact credibility in the field of mindfulness or otherpsychological interventions [26]

Some of the studies used active control groups includ-ing support groups discussion forums cognitive behavioraltherapy and stress-management training This allowed for


minus05 05 10 15 20

Zernicke et al 2013

Ljoacutetsson et al 2011 (internet)

Ljoacutetsson et al 2011Ljoacutetsson et al 2010

Gaylord et al 2011

Berrill et al 2014

0DL pooled effect size = 0596049 (95 CI = 0334391 to 0857708)

(acceptability)

(a)

minus04 01 06 11 16 21

Zomorodi et al 2014

Zernicke et al 2013

Ljoacutetsson et al 2010

Gaylord et al 2011

Berrill et al 2014

0DL pooled effect size = 0352428(95 CI = 0112126 to 059273)

(internet)

(b)

minus05 05 10 15

Zernicke et al 2013




Gaylord et al 2011


(acceptability)

(c)

Figure 4 Forest plots for effect size on IBS Severity at end of intervention (a) IBS severity at postintervention follow-up (b) and quality oflife (c)

participant blinding as well as insight into the mechanism ofthe effect In all cases the mindfulness based therapy showedsuperior efficacy to the other interventions suggesting thatthe therapeutic benefit is specific to the material coveredrather than nonspecific factors such as peer-support atten-tion or the expectation effect However a major challengein the study of psychological interventions is the inabilityto blind all study personnel to participant allocation Somestudies took steps to help conceal allocation and preserveblinding amongst outcome assessors however no studiestook into account blinding of the individuals facilitatingthe interventions or other steps that might help manageexpectation and performance bias

Another area that posed a risk of bias is incompleteoutcome data due to dropouts MBT requires a large amountof participant involvement and time often including weeklygroup sessions and daily home practice This may havecontributed to the high dropout rates observed Many studiesutilized intention to treat analysis to account for theseoccurrences however some articles did not address this orreport the specificmanner in which intention to treat analysiswas done

A major limitation to this review is a relatively smallnumber of studies with (qualitatively) significant heterogene-ity in their methodology The follow-up time period variedfrom two to 18 months Additionally the type of interventionvaried Of the seven studies reviewed three were conductedby the same research group using a unique methodologycalled internet-based cognitive behaviour therapy (ICBT)which includes mindfulness and acceptance-based exercisesin combination with exposure While it is accessible overthe internet it is not available to the public at this time IncontrastMBSR andMBCTprograms are offered in hospitalsuniversities and health clinics worldwide

Most of the studies reviewed enrolled patients with adiagnosis of IBS The one study that included participantswith IBD in remission and IBS-like symptoms was theonly study that failed to yield a statistically significantimprovement in IBS symptoms The patients with IBS-typesymptoms in this study were a subset of a larger patientpopulation and as a result there was a small sample sizewhich may have contributed to the failure to reach statisticalsignificance Alternatively it may be that patients withoutorganic gastrointestinal disease are more responsive to MBT


Many of the studies had a high percentage of femaleparticipants While there is a risk that this may limit thegeneralizability of the results it is known that IBS is moreprevalent among women [7]

The studies reviewed demonstrated benefits in theplacebo groups however this is a common finding amongtrials involving patients with IBS and other subjective com-plaints A meta-analysis of the placebo effect in IBS founda range of 16ndash71 improvement (27) and a randomizedcontrolled trial using open-label placebo for the treatment ofIBS demonstrated a statistically significant benefit (28)

Although a statistically significant finding was demon-strated on pooled effect sizes the low power small numberof studies and overall high risk of bias in study designor completeness of reporting suggest that this should beinterpreted with some discretion

5 Conclusions

Analysis of these studies suggests that mindfulness-basedinterventions may be useful in improving FGID symptomseverity and quality of life with lasting effects howeversubstantial improvements in methodological quality must beimplemented in future studies in order to fully assess itsimpact Due to absence of reporting of adverse events nodefinitive conclusions can be drawn with respect to safetyFuture studies would benefit from use of established criteriafor reporting clinical trials using nonpharmacological inter-ventions registration of studies in an open-access clinicaltrial registry and improvements in blinding to decrease therisk of bias



Acknowledgment

Deborah Kennedy assisted in the development of the searchstrategy and paper editing

References

[1] G De Palma S M Collins and P Bercik ldquoThe microbiota-gut-brain axis in functional gastrointestinal disordersrdquo GutMicrobes vol 5 no 3 2014

[2] D J Kearney and J Brown-Chang ldquoComplementary and alter-native medicine for IBS in adults mindndashbody interventionsrdquoNature Clinical Practice Gastroenterology amp Hepatology vol 5pp 624ndash636 2008

[3] M Camilleri ldquoNovel therapeutic agents in neurogastroenterol-ogy advances in the past yearrdquo Neurogastroenterology andMotility vol 26 no 8 pp 1070ndash1078 2014

[4] F Cremonini ldquoStandardized herbal treatments on functionalbowel disorders moving from putative mechanisms of actionto controlled clinical trialsrdquo Neurogastroenterology amp Motilityvol 26 no 7 pp 893ndash900 2014

[5] F Jing and J Zhang ldquoMetabolic kinetics of 5-hydroxytry-ptamine and the research targets of functional gastrointestinaldisordersrdquo Digestive Diseases and Sciences 2014

[6] E L Garland S A Gaylord O Palsson K Faurot J DouglasMann and W E Whitehead ldquoTherapeutic mechanisms ofa mindfulness-based treatment for IBS effects on visceralsensitivity catastrophizing and affective processing of painsensationsrdquo Journal of Behavioral Medicine vol 35 no 6 pp591ndash602 2012

[7] S E Lakhan and K L Schofield ldquoMindfulness-based therapiesin the treatment of somatization disorders a systematic reviewand meta-analysisrdquo PLoS ONE vol 8 no 8 Article ID e718342013

[8] A Chiesa and A Serretti ldquoMindfulness based cognitive ther-apy for psychiatric disorders a systematic review and meta-analysisrdquo Psychiatry Research vol 187 no 3 pp 441ndash453 2011

[9] M Sharma and S E Rush ldquoMindfulness-based stress reductionas a stress management intervention for healthy individuals asystematic reviewrdquo Journal of Evidence-BasedComplementaryampAlternative Medicine In press

[10] WRMarchand ldquoNeuralmechanisms ofmindfulness andmed-itation evidence from neuroimaging studiesrdquoWorld Journal ofRadiology vol 6 no 7 pp 471ndash479 2014

[11] S W Lazar C E Kerr R H Wasserman et al ldquoMeditationexperience is associated with increased cortical thicknessrdquoNeuroReport vol 16 no 17 pp 1893ndash1897 2005

[12] F Asare S Storsrud and M Simren ldquoMeditation over medica-tion for irritable bowel syndrome On exercise and alternativetreatments for irritable bowel syndromerdquo Current Gastroen-terology Reports vol 14 no 4 pp 283ndash289 2012

[13] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo PLoS Medicine vol 6 no 6 Article IDe1000097 2009

[14] W Berrill M Sadlier K Hood and J T Green ldquoMindfulness-based therapy for inflammatory bowel disease patients withfunctional abdominal symptoms or high perceived stress levelsrdquoJournal of Crohnrsquos and Colitis vol 8 no 9 pp 945ndash955 2014

[15] S A Gaylord O S Palsson E L Garland et al ldquoMindfulnesstraining reduces the severity of irritable bowel syndrome inwomen results of a randomized controlled trialrdquoThe AmericanJournal of Gastroenterology vol 106 no 9 pp 1678ndash1688 2011

[16] B Ljotsson L Falk A W Vesterlund et al ldquoInternet-deliveredexposure and mindfulness based therapy for irritable bowelsyndromemdasha randomized controlled trialrdquo Behaviour ResearchandTherapy vol 48 no 6 pp 531ndash539 2010

[17] B Ljotsson E Hedman P Lindfors et al ldquoLong-term follow-up of internet-delivered exposure and mindfulness based treat-ment for irritable bowel syndromerdquo Behaviour Research andTherapy vol 49 no 1 pp 58ndash61 2011

[18] B Ljotsson G Andersson E Andersson et al ldquoAcceptabilityeffectiveness and cost-effectiveness of internet-based exposuretreatment for irritable bowel syndrome in a clinical samplea randomized controlled trialrdquo BMC Gastroenterology vol 11article 110 2011

[19] B Ljotsson E Hedman E Andersson et al ldquoInternet-deliveredexposure-based treatment vs Stress management for irritablebowel syndrome a randomized trialrdquo The American Journal ofGastroenterology vol 106 no 8 pp 1481ndash1491 2011

[20] K A Zernicke T S Campbell P K Blustein et al ldquoMind-fulness-based stress reduction for the treatment of irritable


bowel syndrome symptoms a randomized wait-list controlledtrialrdquo International Journal of Behavioral Medicine vol 20 no3 pp 385ndash396 2013

[21] S Zomorodi S Abdi and S K Tabatabaee ldquoComparisonof long-term effects of cognitive-behavioral therapy versusmindfulness-based therapy on reduction of symptoms amongpatients suffering from irritable bowel syndromerdquo Gastroen-terology and Hepatology from Bed to Bench vol 7 no 2 pp 118ndash124 2014

[22] J P T Higgins D G Altman P C Goslashtzsche et al ldquoTheCochrane Collaborationrsquos tool for assessing risk of bias inrandomised trialsrdquo The British Medical Journal vol 343 no7829 Article ID d5928 2011

[23] I Boutron DMoher D G Altman K F Schulz and P RavaudldquoExtending the CONSORT statement to randomized trialsof nonpharmacologic treatment explanation and elaborationrdquoAnnals of Internal Medicine vol 148 no 4 pp 295ndash309 2008

[24] B Khoury T Lecomte G Fortin et al ldquoMindfulness-basedtherapy a comprehensive meta-analysisrdquo Clinical PsychologyReview vol 33 no 6 pp 763ndash771 2013

[25] K Munshi S Eisendrath and K Delucchi ldquoPreliminarylong-term follow-up of mindfulness-based cognitive therapy-induced remission of depressionrdquoMindfulness vol 4 no 4 pp354ndash361 2013

[26] J C Coyne ldquoAre most positive findings in health psychologyfalse or at least somewhat exaggeratedrdquoTheEuropean HealthPsychologist vol 11 pp 49ndash51 2009

Research ArticleEffects and Mechanisms of Transcutaneous Electroacupunctureon Chemotherapy-Induced Nausea and Vomiting

Xing Zhang12 Hai-feng Jin1 Yi-hong Fan1 Bin LU1 Li-na Meng1 and Jiande D Z Chen34

1 Division of Gastroenterology The First Affiliated Hospital of Zhejiang Chinese Medical University Hangzhou 310006 China2Division of Gastroenterology Sixth Peoplersquos Hospital of Shaoxing Shaoxing 312000 China3Ningbo Pace Translational Medical Research Center Beilun Ningbo 315043 China4Division of Gastroenterology and Hepatology Johns Hopkins University Baltimore MD 21224 USA

Correspondence should be addressed to Yi-hong Fan yhfansjryahoocomcn and Jiande D Z Chen jiandedzchengmailcom

Received 17 July 2014 Accepted 13 August 2014 Published 31 August 2014


Copyright copy 2014 Xing Zhang et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Nausea and vomiting are one of the major complications of chemotherapy for cancers The aim of this study is to investigatethe emetic effects and mechanisms involving serotonin and dopamine of needleless transcutaneous electroacupuncture (TEA)at Neiguan (PC6) and Jianshi (PC5) on chemotherapy-induced nausea and vomiting in patients with cancers Seventy-two patientswith chemotherapy were randomly divided into sham-TEA group (sham-TEA 119899 = 34) and TEA group (119899 = 38) TEA wasperformed at PC 6 and PC 5 (1 h bid) in combination with granisetron Sham-TEA was delivered at nonacupoints using the sameparameters We found the following (1) In the acute phase the conventional antiemetic therapy using Ondansetron effectivelyreduced nausea and vomiting the addition of TEA did not show any additive effects In the delayed phase however TEAsignificantly increased the rate of complete control (119875 lt 001) and reduced the nausea score (119875 lt 005) compared with sham-TEA (2) TEA significantly reduced serum levels of 5-HT and dopamine in comparison with sham-TEAThose results demonstratethat needleless transcutaneous electroacupuncture at PC6 using a watch-size digital stimulator improves emesis and reduces nauseain the delayed phase of chemotherapy in patients with cancersThis antiemetic effect is possiblymediated viamechanisms involvingserotonin and dopamine

1 Introduction

Chemotherapy is an important component of comprehensivetreatments for cancers Nausea and vomiting are one ofthe major complications of chemotherapy Chemotherapy-induced nausea and vomiting (CINV) lead to a varietyof adverse clinical consequences including noncompliancewith therapy undermining of the efficacy of therapy andunwillingness or even refusal of therapy [1ndash3]

Antiemetics include 5-HT3 receptor antagonists gluco-corticoids dopamine receptor antagonists benzodiazepineclass of drugs antipsychotic drugs and marijuana Amongthem 5-HT3 receptor antagonists are most widely used [4]Introduction of 5-HT3 receptor antagonists in the early 1990srepresents major advance in the management of acute CINVCommon adverse events of 5-HT3 receptor antagonists

includemild headache transient increase in hepatic transam-inase level and constipation [5]Themajor problemswith the5-HT3 receptor antagonist are (1) lack of efficacy in treatingdelayed emesis and (2) lack of efficacy in treating nausea inboth acute and delayed phases [6] According to the func-tional living index nausea was reported to have a strongernegative impact on patientsrsquo daily life than vomiting [7]Neither clinical evidence nor the ratio of costeffectivenessjustifies the use of the 5-HT3 antagonist beyond 24 hours afterchemotherapy for prevention of delayed emesis Thereforethe outcome of the treatment for CINV is unsatisfactory andthere is still an urgent need for the development of noveltherapies for CINV especially delayed CINV

Acupuncture has been used to treat nausea and vomitingin China for thousands of years The most commonly usedacupoints for the treatment of gastrointestinal symptoms are



Neiguan (PC6) Zusanli (ST36) and Jianshi (PC5) A largenumber of studies have demonstrated that acupuncture orelectroacupuncture (EA) can effectively reduce nausea andvomiting under various conditions such as postsurgery [8ndash10] pregnancy [11 12] andmotion sickness [13] Dundee et alreported that acupuncture treatment might also significantlyreduce CINV [14 15] Acupuncture and EA are performedby acupuncturists or doctors due to the insertion of needlesinto the acupoints and therefore the patient can receivethe treatment only in clinics or hospitals To make thetherapy readily available at patientrsquos home a needleless self-administrated method of transcutaneous electroacupuncture(TEA) was proposed in this study

The aim of this study was to investigate the emetic effectsand mechanisms involving serotonin and dopamine of theproposed needleless TEA at PC6 and PC5 on CINV inpatients with cancers

2 Material and Methods

21 Study Population The study was conducted accordingto the Declaration of Helsinki and approved by the ethicalcommittee of the Zhejiang Provincial Hospital of TraditionalChinese Medicine (TCM) Patients meeting the inclusionand exclusion criteria scheduled for CINV from July 2011 toSeptember 2012 in Zhejiang Provincial Hospital of TCMweredivided into two groups sham-TEA (17 female 17 male) andTEA group (12 females 26 males) Written informed consentwas obtained from all subjects before the study

22 Inclusion and Exclusion Criteria The inclusion crite-ria were as follows (1) ages 18ndash80 years with confirmeddiagnosis of cancer (2) either being naive to chemotherapyor having received only moderately or highly emetogenicchemotherapy (3) being scheduled to receive one cycle ofmoderately or highly emetogenic chemotherapy (ge50mgm2cisplatin gt1500mgm2 cyclophosphamide and gt250mgm2Carmustine) (3) Karnofskyrsquos score ge60 (4) white bloodcell ge3 times 109L and adequate hepatorenal function aspar-tate aminotransferase lt100 IUl alanine aminotransferaselt100 IUl and creatinine clearance ge60mLmin and (5)being scheduled to stay at hospital for chemotherapy

Exclusion criteria included the following (1) receivingconcurrent radiotherapy of the upper abdomen or cra-nium (2) vomiting or gegrade 2 nausea (the National Can-cer InstitutemdashCommon Terminology Criteria for AdverseEvents v30 (CTCAE)) not clear to me (3) severe uncon-trolled complications (4) unstablemetastases in the brain (5)uncontrolled pleural effusion or ascites (6) gastrointestinalobstruction (7) unwillingness or inability to accept acupunc-ture treatment such as wrist disability or hematonosis (8)contraindications to 5-HT3 receptor antagonists (9) historyof convulsions or seizure disorder and (10) inability tounderstand or cooperate with study procedures

23 Treatment Regimens At the beginning of the studypatients who met all entry criteria were assigned to either

TEA or sham-TGEA group according to a computer gener-ated randomization schedule The patients in the TEA groupwere treated with TEA at acupoints PC 6 and PC 5 whereasthe patients in the sham-TEA group were treated with thesame electrical stimulation at sham-points (neither on acu-points nor on any meridians) Sham-point 1 was at the lateralend of the transverse cubital crease 2 cun (50mm) from thebicipital muscle of arm sham-point 2 was at medial end ofthe transverse cubital crease condylus medialis humeri Thetreatment was given twice daily each lasting one hr using aspecial watch-size stimulator (SNM-FDC01 Ningbo MaiDaMedical Device Inc Ningbo China) with the followingparameters monophasic rectangular-wave pulses with pulsewidth of 03ms frequency of 20Hz and amplitude of up to10mA (individually adjusted according to the tolerance of thesubject) The stimulation was delivered intermittently withon-time of 01 s and off-time of 04msThis set of parameterswas previously used in animals to exert antiemetic [16] andanalgesic effects [17] Both groups received granisetron (3mgiv bid) during the three-day treatment

24 Clinical Efficacy Nausea and vomiting were noted start-ing from administration of moderately or highly emetogenicchemotherapy up to 3 days Patients recorded the date andtime of episodes of emesis and the degree of nausea indiaries The definition of an emetic episode was as followsone episode of vomiting or a sequence of episodes in veryclose succession not relieved by a period of at least onemin relaxation any number of retching episodes in anygiven 5 min period or an episode of retching lasting lt5mincombinedwith vomiting not relieved by a period of relaxationof at least 1min [18] Nausea was classified into four grades (0none 1 mild 2 moderate and 3 severe) Any use of rescuemedications was recorded including drug name dose andtime of administration Rescue medication was administeredfor an emetic event or nausea upon request of the patientThe patientsrsquo diaries were checked daily by research staff foraccuracy and completion

Clinical efficacy was assessed as follows (1) the propor-tion of patients with complete response (CR) no emesis andno rescue medications during the acute phase (0ndash24 h) afterchemotherapy (2) the proportion of patients with CR duringthe delayed phase (24ndash72 h) after chemotherapy (3) theproportion of patients with complete control (CC) no emeticepisode no rescuemedication andnomore thanmild nauseaduring the delayed phase (24ndash72 h) after chemotherapy

25 Mechanistic Measurements Blood samples were col-lected at 6AMon day 1 and day 3 after overnight fasting usingtubes with EDTA and Aprotinin centrifuged at 4200 g and4∘C for 10min and stored at 4∘C until extraction Plasmalevels of 5-HT and dopamine were determined with thecorresponding commercial ELISA kits (Beifang Institute ofBiology and Technology Beijing Rigorbio Science Develop-ment Co Ltd Beijing China)

26 Safety Measurements Vital signs (body temperatureheart rate and respiratory rate) 12-lead electrocardiogram


blood tests (white blood cell aspartate aminotransferasealanine aminotransferase and creatinine clearance) andurinalysis were assessed on days 1 and 3 Safety was alsoassessed by recording adverse events (AEs) up to 14 days afterthe therapy AEs were assessed using common terminologycriteria for adverse events (CTCAE) v40 by the investigatorsfor intensity [19 20]

27 Statistical Methods All data are presented as mean plusmnSEM Studentrsquos 119905-test was used to determine the differencebetween before and after the treatment in any measurement(nausea score 5-HT or dopamine level) and the differencein any measurement between the two treatments (SPSS 170forWindows-standard version SPSS Inc Chicago IL USA)Fisherrsquos exact test was used to compare the clinical efficacyof the two treatment methods (TEA versus sham-TEA)Statistical significance was assigned for 119875 lt 005

3 Results

31 Effects on Nausea and Vomiting TEA improved vomitingin the delayed phase although it did not in the acute phaseThe average number of vomiting episodes was 085 plusmn 026with sham-TEA and 082 plusmn 020 with TEA (119875 = 09) in thefirst 24 hours (acute phase) (119875 = 09) In the delayed phasehowever this number was significantly lower with TEA thansham-TEA (119875 = 0046 for the second day and 119875 = 068 forthe third day) (see Figure 1)

The nausea scores during the delayed phase (48 h 72 h)were 188 plusmn 010 and 168 plusmn 010 in the sham-TEA group and121 plusmn 015 and 126 plusmn 015 in the TEA group respectively(Figure 2) The differences between two groups were signif-icant (119875 = 0001 and 0025 resp) No significant differencewas noted in the rate of complete response between the twogroups neither in the acute phase nor in the delayed phase

The rate of complete control was significantly increasedwith TEA during the second day as shown in Table 1 (119875 =0008 for the second day and 119875 = 03 during the third day)

32 Mechanisms Involving Serotonin and Dopamine TEAsignificantly reduced circulating 5-HT and dopamine Atbaseline no difference was noted in serum 5-HT anddopamine levels between the TEA and sham-TEA groupsAfter the treatment however the serum levels of 5-HT anddopamine were significantly reduced (119875 = 003 and 119875 = 002resp) (Figures 3 and 4)

33 Adverse Events Safety was assessed in all patients Labo-ratory examinations (white blood cell aspartate aminotrans-ferase alanine aminotransferase and creatinine clearance)and electrocardiogramwere foundnormal after the treatmentin all patients (both groups) except one who had allergicreaction of medical adhesive tape judged to be unrelated orunlikely related to TEA

000020040060080100120140160

The acute phase The second day The third day

Vom

iting

tim

es

Sham-TEATEA

Figure 1 Effect of TEA on vomiting times TEA significantlyreduced the vomiting times on the second day after chemotherapycompared to sham-TEA group and reduced it on the third day afterchemotherapy but the difference was not significant (119875 lt 005)

000

050

100

150

200

250

The second day The third day

Nau

sea s

core

Sham-TEATEA

Figure 2 TEA reduced the nausea scores at both 48 h and 72 hafter chemotherapy TEA reduced substantially the nausea scores by555 at 48 h and significantly by 327 at 72 h compared to sham-TEA group (119875 lt 005)

000

5000

10000

15000

20000

25000

Before After

Sham-TEATEA

5-H

T (n

gm

L)

Figure 3 Effect of TEA on serum levels of 5-HT before and afterthe treatment TEA significantly reduced the serum level of 5-HTcompared to sham-TEA (119875 lt 005)


000

10000

20000

30000

40000

50000

60000

70000

Before After

DA

(ng

mL)

Sham-TEATEA

Figure 4 Effect of TEA on serum levels of DA before and afterthe treatment There are significant differences of serum level of DAbetween TEA and sham-TEA (119875 lt 005)

Table 1 Patients with the CC rates in delayed emesis (48 h 72 hcase)

The second day The third daySham-TEA TEA Sham-TEA TEA8 (236) 21 (553) 12 (353) 18 (474)The rate of complete control was significantly increased with TEA during thesecond day compared to sham-TEA (119875 lt 001)

4 Discussion

In this study we found that TEA at PC6 and PC5 reducednausea and vomiting in the delayed phase of chemother-apy in patients with cancers This antiemetic effect waspossibly mediated via mechanisms involving serotonin anddopamine

Various methods of acupuncture have been applied fortreating CINV such as manual acupuncture acupressureelectroacupuncture auricular acupuncture and pharmacop-uncture Dundee et al were the first ones who reported theantiemetic effect of acupuncture on CINV [14 15] Recentlyit was reported that acupressure also exerted an antiemeticeffect on CINV in patients with breast cancers [21] Auricularacupuncture was applied to treat CINV in children withcancers who underwent chemotherapy and shown to beeffective but not different from sham stimulation [22] Arecent review on pharmacopuncture (medications deliveredvia the acupoints) analyzed 22 studies involving about 2500patients but failed to provide a confirmative conclusion dueto high risk of bias and clinical heterogeneity [23] Althoughacupuncture and its variations are promising in treatingCINV no definitive conclusions could be made from studiesreported in the literature due to poor study design and highrisk of bias In a recent systematic review of acupuncture incancer care a total of 2151 publications were screened it wasconcluded that acupuncture was an adequate complementarytherapy for CINV but additional studies were needed [24]

In this study a needleless method of TEA was introducedand a placebo controlled clinical trial was designed toinvestigate the antiemetic effect of TEA on CINV in patients

with cancers A special set of parameters was used based on aprevious study in our lab with gastric electrical stimulationshowing an antiemetic effect in dogs treated with cisplatinand an analgesic effect in rats with gastric hypersensitivity[16 17] Using these special settings we found that TEAwas able to significantly improve delayed emesis and nauseaduring the second day of the treatment No significant effectwas noted in the acute phase attributed to the fact thatOndansetron effectively controlled emesis during the firstday of the chemotherapy Previously acupuncture and elec-troacupuncture were shown to improve gastric motility andsymptoms of upper abdomen such as nausea and vomitingIn canine study we found that electroacupuncture at PC6reduced vasopressin-induced nausea and vomiting mediatedvia the vagal mechanism [25] Ouyang et al reported thatelectroacupuncture at points PC6 and ST36 significantlyaccelerated gastric emptying in dogs also mediated via thevagal mechanism [26] Clinically there is evidence thatacupuncture at PC6 and ST36 improved dyspeptic symptomsincluding nausea and vomiting and accelerates solid gastricemptying in patients [27]These findings seem to suggest thatelectroacupuncture or TEA is capable of improving nauseaand vomiting of different causes

To the best of our knowledge this was the first studyinvestigating and demonstrating the antiemetic mechanismsof TEA involving 5-HT and dopamine Serotonin anddopamine are two main neurotransmitters known to induceCINV Many drugs of chemotherapy can cause emesisand nausea via upregulation of 5-HT and dopamine andantagonists of serotonin and dopamine are commonly usedin CINV [28 29] and antagonists of serotonin are morecommon than antagonists of dopamine in treatment of CINVOndansetron a 5-HT3 antagonist was used in this study asthe primary antiemetic It effectively reduced the number ofvomiting times to an average level of 1 Interestingly TEAwasfound to reduce circulating 5-HT in comparison with sham-TEA Exact mechanisms involved in the reduction of 5-HTwith TEA deserve further investigation In gastrointestinalmotility study electroacupuncture was found to accelerategastric emptying mediated via the 5-HT mechanism [18]It was reported that electroacupuncture on the lumbar andhindlimb segments decreased the dopamine and serotoninlevels which were increased by restraining stress in the dorsalraphe nucleus indicating that electroacupuncture applied tothe lumbar and hindlimb segments has an antistress effect viamediation of the levels of serotonin and dopamine [30] How-ever different subtypes of 5-HT receptors are believed to beinvolved in the antiemetic effect and the prokinetic effect ofacupunctureThe prokinetic effect of acupuncture is believedto involve 5-HT4 mechanism whereas the antiemetic effectof acupuncture is believed to involve 5-HT3 mechanisms[29 31] In addition a reduction in circulating dopaminewas also noted after the treatment of TEA This reductionmight also play a role in the antiemetic effect of TEA Themechanism involving dopamine was reported in the effectof acupuncture on drug addiction [32] it was however first


reported in this study regarding the effect of acupuncture onCINV

Traditional acupuncture or electroacupuncture treatmentneeds to be done in clinics and needle should be piercedinto points In this study TEA did not require the insertionof any needles and the patientrsquos activity was not restrictedSo TEA seems to be more attractive than acupuncture orelectroacupuncture and will be well received by patients Inthis study the compliance of the therapy was 100 noneof the patients quitted the study Typically acupuncture orelectroacupuncture is performed a few times weekly due torequired visits to doctorrsquos office This substantially reducesthe efficacy and consistency of the therapy With the TEAmethod the treatment can be self-administrated at home andthus could be performed daily or a few times daily whichwould greatly increase the efficacy of the therapy

5 Conclusions

In conclusion a needleless method of transcutaneous elec-troacupuncture is proposed in this study The needlelessTEA is effective in reducing delayed nausea and vomiting inpatients undergoing chemotherapy possiblymediated via thedownregulation of serotonin and dopamine




Xing Zhang and Hai-feng Jin are cofirst authors they con-tributed equally to the work

Acknowledgments

This paper was supported by Zhejiang Province Admin-istration of Traditional Chinese Medicine (2012ZB048)and Science Technology Department of Zhejiang Province(2012C33038)

References

[1] L Lohr ldquoChemotherapy-induced nausea and vomitingrdquoCancerJournal vol 14 no 2 pp 85ndash93 2008

[2] K Jordan H J Schmoll andM S Aapro ldquoComparative activityof antiemetic drugsrdquo Critical Reviews in OncologyHematologyvol 61 no 2 pp 162ndash175 2007

[3] NCCN Clinical Practice Guidelines in Oncology NationalComprehensiveCancerNetwork Antiemesis 2010 httpwwwnccnorg

[4] P J Hesketh ldquoChemotherapy-induced nausea and vomitingrdquoTheNew England Journal of Medicine vol 358 no 23 pp 2432ndash2494 2008

[5] O Geling and H-G Eichler ldquoShould 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours

after chemotherapy to prevent delayed emesis Systematic re-evaluation of clinical evidence and drug cost implicationsrdquoJournal of Clinical Oncology vol 23 no 6 pp 1289ndash1294 2005

[6] J A Roscoe G R Morrow J T Hickok and R M SternldquoNausea and vomiting remain a significant clinical problemtrends over time in controlling chemotherapy-induced nauseaand vomiting in 1413 patients treated in community clinicalpracticesrdquo Journal of Pain and Symptom Management vol 20no 2 pp 113ndash121 2000

[7] B Bloechl-Daum R R Deuson P Mavros M Hansen and JHerrstedt ldquoDelayed nausea and vomiting continue to reducepatientsrsquo quality of life after highly and moderately emetogenicchemotherapy despite antiemetic treatmentrdquo Journal of ClinicalOncology vol 24 no 27 pp 4472ndash4478 2006

[8] A Alkaissi K Evertsson V A Johnsson L Ofenbartl and SKalman ldquoP6 acupressure may relieve nausea and vomiting aftergynecological surgery an effectiveness study in 410 womenrdquoCanadian Journal of Anesthesia vol 49 no 10 pp 1034ndash10392002

[9] P F White T Issioui J Hu et al ldquoComparative efficacyof acustimulation (ReliefBand) versus ondansetron (Zofran)in combination with droperidol for preventing nausea andvomitingrdquo Anesthesiology vol 97 no 5 pp 1075ndash1081 2002

[10] D Harmon J Gardiner R Harrison and A Kelly ldquoAcupressureand the prevention of nausea and vomiting after laparoscopyrdquoBritish Journal of Anaesthesia vol 82 no 3 pp 387ndash390 1999

[11] N M Steele J French J Gatherer-Boyles S Newman and SLeclaire ldquoEffect of acupressure by Sea-Bands on nausea andvomiting of pregnancyrdquo Journal of Obstetric Gynecologic ampNeonatal Nursing vol 30 no 1 pp 61ndash70 2001

[12] E Werntoft and A K Dykes ldquoEffect of acupressure on nau-sea and vomiting during pregnancy a randomized placebo-controlled pilot studyrdquo The Journal of Reproductive Medicinevol 46 no 9 pp 835ndash839 2001

[13] P Bertalanffy K Hoerauf R Fleischhackl et al ldquoKorean handacupressure for motion sickness in prehospital trauma care aprospective randomized double-blinded trial in a populationrdquoAnesthesia and Analgesia vol 98 no 1 pp 220ndash223 2004

[14] J W Dundee R G Ghaly K T J Fitzpatrick G A Lynchand W P Abram ldquoAcupuncture to prevent cisplatin-associatedvomitingrdquoThe Lancet vol 329 no 8541 p 1083 1987

[15] J W Dundee R G Ghaly K T J Fitzpatrick W PAbram and G A Lynch ldquoAcupuncture prophylaxis of cancerchemotherapy-induced sicknessrdquo Journal of the Royal Society ofMedicine vol 82 no 5 pp 268ndash271 1989

[16] X Yu J Yang X Hou K Zhang W Qian and J D Z ChenldquoCisplatin-induced gastric dysrhythmia and emesis in dogs andpossible role of gastric electrical stimulationrdquoDigestive Diseasesand Sciences vol 54 no 5 pp 922ndash927 2009

[17] Y Sun Y Tan G Song et al ldquoEffects andmechanisms of gastricelectrical stimulation on visceral pain in a rodent model ofgastric hyperalgesia secondary to chemically induced mucosalulcerationrdquo Neurogastroenterology amp Motility vol 26 no 2 pp176ndash186 2014

[18] G C M Sugai A De O Freire A Tabosa Y YamamuraS Tufik and L E A M Mello ldquoSerotonin involvementin the electroacupuncture- and moxibustion-induced gastricemptying in ratsrdquo Physiology and Behavior vol 82 no 5 pp855ndash861 2004

[19] M Maemondo N Masuda I Sekine et al ldquoA phase II study ofpalonosetron combined with dexamethasone to prevent nausea


and vomiting induced by highly emetogenic chemotherapyrdquoAnnals of Oncology vol 20 no 11 pp 1860ndash1866 2009

[20] A P Chen A Setser M J Anadkat et al ldquoGrading der-matologic adverse events of cancer treatments the commonterminology criteria for adverse events version 40rdquo Journal ofthe American Academy of Dermatology vol 67 no 5 pp 1025ndash1039 2012

[21] F Genc and M Tan ldquoThe effect of acupressure applicationon chemotherapy-induced nausea vomiting and anxiety inpatients with breast cancerrdquo Palliative amp Supportive Care vol30 pp 1ndash10 2014

[22] C H Yeh L-C Chien Y C Chiang S W Lin C K Huangand D Ren ldquoReduction in nausea and vomiting in childrenundergoing cancer chemotherapy by either appropriate or shamauricular acupuncture points with standard carerdquo The Journalof Alternative and Complementary Medicine vol 18 no 4 pp334ndash340 2012

[23] S Cheon X Zhang I S Lee S H Cho Y Chae and HLee ldquoPharmacopuncture for cancer care a systematic reviewrdquoEvidence-Based Complementary and Alternative Medicine vol2014 Article ID 804746 14 pages 2014

[24] M Kay Garcia J Mcquade R Haddad et al ldquoSystematic reviewof acupuncture in cancer care a synthesis of the evidencerdquoJournal of Clinical Oncology vol 31 no 7 pp 952ndash960 2013


[26] H Ouyang J Yin Z Wang P J Pasricha and J D Z ChenldquoElectroacupuncture accelerates gastric emptying in associationwith changes in vagal activityrdquo American Journal of PhysiologyGastrointestinal and Liver Physiology vol 282 no 2 pp G390ndashG396 2002


[28] M Minami T Ogawa T Endo et al ldquoCyclophosphamideincreases 5-hydroxytryptamine release from the isolated ileumof the ratrdquo Research Communications in Molecular Pathologyand Pharmacology vol 97 no 1 pp 13ndash24 1997

[29] P Glare J Miller T Nikolova and R Tickoo ldquoTreating nauseaand vomiting in palliative care a reviewrdquo Clinical Interventionsin Aging vol 6 no 1 pp 243ndash259 2011

[30] T Yano B Kato F Fukuda et al ldquoAlterations in the functionof cerebral dopaminergic and serotonergic systems follow-ing electroacupuncture and moxibustion applications possiblecorrelates with their antistress and psychosomatic actionsrdquoNeurochemical Research vol 29 no 1 pp 283ndash293 2004

[31] E S Hsu ldquoA review of granisetron 5-hydroxytryptamine3receptor antagonists and other antiemeticsrdquo The AmericanJournal of Therapeutics vol 17 no 5 pp 476ndash486 2010

[32] C H Yang B H Lee and S H Sohn ldquoA possible mechanismunderlying the effectiveness of acupuncture in the treatment ofdrug addictionrdquo Evidence-Based Complementary and Alterna-tive Medicine vol 5 no 3 pp 257ndash266 2008

Research ArticleTherapeutic Effects of Biobran Modified Arabinoxylan RiceBran in Improving Symptoms of Diarrhea Predominant orMixed Type Irritable Bowel Syndrome A Pilot RandomizedControlled Study

Takeshi Kamiya1 Michiko Shikano1 Mamoru Tanaka1 Keiji Ozeki1 Masahide Ebi1

Takahito Katano1 Shingo Hamano1 Hirotaka Nishiwaki1 Hironobu Tsukamoto1

Tsutomu Mizoshita1 Yoshinori Mori1 Eiji Kubota1 Satoshi Tanida1 Hiromi Kataoka1

Noriaki Okuda2 and Takashi Joh1

1 Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences 1 KawasumiMizuho-cho Mizuho-ku Nagoya 457-0036 Japan

2Okuda Naika Clinic 2-9-3 Hinata-cho Mizuho-ku Nagoya 467-0047 Japan

Correspondence should be addressed to Takeshi Kamiya kamitakemednagoya-cuacjp

Received 15 January 2014 Revised 5 July 2014 Accepted 16 July 2014 Published 5 August 2014


Copyright copy 2014 Takeshi Kamiya et alThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background Recently it was revealed that low grade mucosal inflammation andor immune imbalance of the lower digestive tractis one of the mechanisms involved in symptom generation in patients with irritable bowel syndrome (IBS) Biobran arabinoxylancompound derived from rice bran has been reported to have several biological actions such as anti-inflammatory and immunemodulatory effects So we investigated the therapeutic effects of Biobran in patients with IBSMethod Forty patients with diarrheapredominant or mixed type IBS were randomly assigned to either a Biobran group for treatment with Biobran or a placebo groupTherapeutic efficacy and IBS symptoms were assessed subjectively by the patients after 4 weeks of administration Results Theglobal assessment was effective in 632 of the Biobran group and in 30 of the placebo group (119875 lt 005 Biobran group versusplacebo group) Biobran group showed a significant decrease in the score of diarrhea and constipation and in CRP value Howeverno significant changes were observed in the placebo group Conclusion The administration of Biobran improved IBS symptoms Itis likely that anti-inflammatory andor immune modulatory effects of Biobran might be useful in IBS patients

1 Introduction

Irritable bowel syndrome (IBS) is a common functionalbowel disorder [1] in which abnormal discomfort or pain isassociated with defecation or a change in bowel habit andwith features of disordered defecation Many studies [2ndash8] inWestern countries and Japan have estimated the prevalenceof IBS to be between 10 and 30 in the adult populationFurthermore IBS is a chronic problem that affects all aspectsof daily life and has a significant negative impact on qualityof life (QOL) It is widely accepted that various factorscontribute to the development of IBS symptoms Although

disturbed gastrointestinal motility sensory hypersensitivityandpsychosomatic factors have beenproposed as the possiblereasons behind IBS [9] no final mechanisms have beenagreed upon to date Many IBS treatments are currently avail-able ranging from specifically designed drugs such as 5-HT3antagonist and antidepressants to nonpharmacological thera-pies including hypnotherapyMost of themare unsatisfactoryand new approaches to find the underlying pathogenesis aredesirable

Recently there has been a general agreement that lowgrade mucosal inflammation andor immune imbalance ofthe lower digestive tract are one of the mechanisms involved



in symptom generation in IBS patients Several studies [10ndash14] have reported inflammation in mucosal biopsies of thecolon rectum and terminal ileum in IBS patients Thesestudies have shown that IBS patients have an increased num-ber of inflammatory cells including lymphocytes dendriticcells and mast cells in their mucosa and 12 of IBS patientshavemicroscopic inflammation compatible withmicroscopiccolitis Furthermore IBS may occur in about 7sim30 ofpatients recovering from acute enterocolitis a conditioncalled postinfective IBS (PI-IBS) [15ndash17]

Modified arabinoxylan rice bran (Biobran) is highlywater-soluble modified rice bran composed of polysaccha-rides mainly arabinoxylan hemicelluloses It has been soldas a functional food for more than 10 years in over 40countries including some in North America Europe andJapan Biobran has shown a range of immune modulatoryactivities Some studies have reported that oral Biobranintake enhances natural killer (NK) cell activity in healthyhumans and aged mice [18 19] and the proliferation oflymphocytes (T and B cells) [20] and induces a significantincrease in some of cytokines that is IFN-120572 IL-6 IL-8and IL-10 [21] In addition Biobran enhances phagocytosisof E coli and causes a significant induction of cytokines byneutrophils and monocytes and a reduction of the toxicity ofchemotherapeutic agents [22 23]

Not many studies have examined the effect of immunemodulation on IBS symptoms The aim of this study is toinvestigate the therapeutic effects of Biobran in IBS patients

2 Methods

21 StudyDesign andPatients Thispilot studywas a random-ized double-blind placebo-control trial Patients aged gt20yearswhohad IBS as defined by theRome III criteria for diar-rhea predominant IBS (IBS-D) or mixed IBS (IBS-M) wererecruited for this studyThe patients had recurrent abdominalpain or discomfort associated with loose or watery stoolsfor at least 2 days per week within the preceding 3 weeksStudy patients had to undergo colonoscopy or colonographywithin 1 year of enrollment to show that there was no organicabnormality to explain the symptoms Patients who reportedthe following conditions were excluded (1) gastrointesti-nal organic lesions such as peptic ulcer Crohnrsquos diseaseulcerative colitis and pancreatitis (2) history of majorabdominal surgery (3) evidence of cardiovascular gastroin-testinal metabolic psychological or malignant disease and(4) pregnancy lactating or attempting to conceive Patientswho were using medications that could alter gastrointestinalfunction 2 weeks prior to enrollment were not eligible forthis study Patients taking nonsteroidal anti-inflammatorydrugs steroids or antibiotics were also excluded as wellas those regarded as unsuitable by the investigators of thisstudy If concomitant medications had been prescribed forcoexisting diseases before obtaining informed consent theywere continued during the study period without changingthe dosage and dosage timing Other concomitant therapiesbelieved to affect the evaluation of this study were prohibiteduntil the end of the study

Patients were randomly assigned using computerizedrandomnumbers between 1 and 40 to receive either 1 g of Bio-bran powder (352 kcal carbohydrate 752mg protein 115mglipid 0mg dietary fiber 25mg moisture 44mg DaiwaPharmaceutical Co Ltd Tokyo Japan) or placebo twice aday for a 4-week period This dose of Biobran is a commonuse for functional foodThe placebo powder included dietaryfiber and was identical to Biobran in volume color andtaste Each IBS symptom was assessed at baseline and weeklyintervals following treatment Gastrointestinal-specific QOLand anxiety were evaluated by a self-reported questionnairebefore and at the end of treatment All aspects of the protocolwere approved by the Medical Ethical Committee of theNagoya City University Graduate School of Medical Sciences(number 211-2) Written informed consent was obtainedfrom all patients prior to the study in accordance with theDeclaration of Helsinki

22 Symptom Assessment At the end of treatment thesubjective global therapeutic efficacy was assessed by thepatients The patientrsquos subjective global assessment of thetherapeutic efficacy in terms of its condition after treat-ment was evaluated according to 5 categories (1) markedlyimproved (2) slightly improved (3) unchanged (4) notso good and (5) deteriorated Categories 1 and 2 weredefined as effective and categories 3 4 and 5 were definedas not effective To evaluate the patientsrsquo QOL and anxi-ety state a gastrointestinal-specific QOL questionnaire theGastrointestinal Symptom Rating Scale (GSRS) [24] anda psychological test questionnaire the State-Trait AnxietyInventory (STAI) [25] were completed by the patients atbaseline and following the 4-week treatment The GSRSincludes 15 items and uses a 7-point Likert scale ranging fromldquono discomfortrdquo to ldquovery much discomfortrdquo The 15 itemswere combined into 5 symptom clusters reflux abdominalpain indigestion diarrhea and constipation A higher scorein a GSRS cluster indicates greater discomfort The STAIquestionnaire consisting of 40 questions 20 questions forstate and 20 for trait anxiety trait was converted to a scoringsystem standardized for a Japanese population

23 Laboratory Test A blood sample was collected fromall patients before and following 4 weeks of treatment Thecomplete blood count blood picture C-reactive protein(CRP) proportion of B cell to T cell in peripheral bloodlymphocytes and NK cell activity were used to evaluatethe changes of inflammation and immunological activity Tcell B cell percentage in lymphocytes and NK cell activitywere measured by flow cytometry [26] and 57Cr-releasedassay [26] respectively Plasma catecholamines adrenalinand noradrenalin were also examined as stress markers byhigh performance liquid chromatography (HPLC) [27]

24 Study End Point and Statistics The primary end point ofthis study was the subjective global assessment of the efficacyof Biobran following the 4 weeks of treatment


The secondary outcomes were change in total and eachGRSR abdominal symptom score change in STAI score andchange in value of each laboratory test

Values were presented as mean plusmn SD The differences inmean values between the Biobran and placebo group werecompared by the Studentrsquos 119905-test or 119880-test The IBS symptomscores were assessed with the analysis of covariance Scoresof GSRS and STAI and values of the laboratory test betweenbaseline and following the 4-week treatment were comparedusing theWilcoxon ranks test or paired 119905-test as appropriateThe global assessment categorical variables were evaluatedby the chi-squared test A 119875 value lt 005 was consideredstatistically significant

3 Results

This study was performed from 2006 to 2007 Forty patientsaged 492 plusmn 151 years were enrolled in this study withrandomization of 20 patients each to Biobran and placeboIBS subtypes according to the Rome III criteria were 28 IBSpatients with IBS-D and 12 IBS-M patients Table 1 showsthe baseline characteristics of the patients (Table 1) Therewere no significant differences in age gender duration ofdisease or the number of IBS subtypes between the Biobranand placebo groups One patient in the Biobran group wasexcluded from the endpoint analysis because he did not visitthe hospital following the 4-week treatment (Figure 1)

31 Symptom Assessment and Efficacy of Treatment Theglobal assessment was effective in 632 of the Biobran and30 of the placebo group (119875 = 00465) (Table 2)

Baseline values and changes in GSRS and STAI scoresbefore and after 4 weeks of treatment are shown in Table 3There were no significant differences in all GSRS scores ofboth baseline and after 4 weeks of treatment between theBiobran and placebo groups Significant improvement inthe total and category for reflux diarrhea and constipationof GSRS scores was observed after Biobran administrationHowever no significant changes were observed in total orany of the items in the GSRS scores in the placebo groupIn addition no significant change in the STAI score wasobserved after Biobran or placebo administration (Table 3)

32 Laboratory Test The changes in the values of hemato-logical and serological examinations are shown in Table 4No significant differences were observed in all baselinevalues of these data except the platelet count between theBiobran and placebo groups After the intake of Biobranthe percentage of neutrophil was significantly lower than inplacebo group whereas B-cell percentage in Biobran groupwas higher than in placebo group The lymphocyte ratioin peripheral white blood cells (WBCs) B-cell percentagein lymphocytes and NK cell activity after Biobran intakewere significantly increasedwhen comparedwith the baselinevalues In addition the neutrophil ratio in the WBC andserumCRPvalues showed a significant decrease in contrast tothe baseline value in the Biobran group These changes werenot observed after placebo intakeThe placebo group showed

Given BiobranN = 20

Given placeboN = 20

Follow-up Follow-upWithdrawalN = 1

N = 40

Enrolled

week 4 N = 19 week 4 N = 20

Figure 1 Flow diagram of study subjects

Table 1 Clinical characteristics of subjects

Biobran (119899 = 19) Placebo (119899 = 20)Age (years) 488 plusmn 147 496 plusmn 160Gender (MF) 910 119IBS subtype

IBS-D 14 13IBS-M 5 7

Duration of disease (years) 178 plusmn 118 158 plusmn 101Values are mean plusmn SDIBS irritable bowel syndromeIBS-D irritable bowel syndrome with diarrheaIBS-M mixed type irritable bowel syndrome

a significant decrease in the peripheral blood platelet countNo significant changes were observed in the values of theserum catecholamine concentration in either of the 2 groups

33 Adverse Events There were no adverse effects in eitherthe Biobran or placebo groups

4 Discussion

We have demonstrated the therapeutic effects of anti-inflammatory and immune modulatory treatments by Bio-bran administration in patients with IBS This has beenmanifested by Biobran ability to improve IBS symptomswhere subjective assessment of Biobran was effective in morethan 60 of patients In addition Biobran treated patientsshowed increase in lymphocyte ratio andNK cell activityTheGSRS scores in both diarrhea and constipation concerningIBS after Biobran intake were significantly improved whencompared with the baseline values

It is widely accepted that low grade inflammation andimmunological alterations play important roles in the devel-opment of IBS symptoms [13 14] IBS is believed to beassociated with an activated adaptive immune response Inan inflammatory environment in the gut mucosa increasedepithelial permeability [28 29] can allow antigens to entereasily and may lead to an increase in various immune cellsand abnormal gut floraThese gut dysfunctions and activationof the digestive immune system may affect gastrointestinal


Table 2 The global assessment to treatment of either Biobran orplacebo

Biobran (119899 = 19) Placebo (119899 = 20)Markedly improved 4 (211)lowast 2 (100)Slightly improved 8 (421)lowast 4 (200)Unchanged 6 (316) 11 (550)Not so good 1 (53) 2 (100)Deteriorated 1 (50)lowast119875 = 00465 versus placebo

Table 3 Changes in values of Gastrointestinal Symptom RatingScale (GSRS) and State Trait Anxiety (STAI) between baseline andafter 4 weeks of treatment

Baseline Treatment 119875

GSRSTotal dimension

Biobran 321 plusmn 093 260 plusmn 096 lt0001Placebo 293 plusmn 068 277 plusmn 075 NS

RefluxBiobran 233 plusmn 135 171 plusmn 117 0013Placebo 166 plusmn 090 155 plusmn 090 NS

Abdominal painBiobran 233 plusmn 135 171 plusmn 117 NSPlacebo 166 plusmn 090 155 plusmn 090 NS

IndigestionBiobran 321 plusmn 093 260 plusmn 096 NSPlacebo 293 plusmn 068 277 plusmn 075 NS

DiarrheaBiobran 488 plusmn 198 351 plusmn 202 lt0001Placebo 439 plusmn 159 395 plusmn 140 NS

ConstipationBiobran 387 plusmn 173 320 plusmn 167 0024Placebo 368 plusmn 182 328 plusmn 167 NS

STAIState

Biobran 321 plusmn 093 260 plusmn 096 NSPlacebo 293 plusmn 068 277 plusmn 075 NS

TraitBiobran 321 plusmn 093 260 plusmn 096 NSPlacebo 293 plusmn 068 277 plusmn 075 NS

Values are mean plusmn SD No significant changes between Biobran and Placebo

motility and visceral sensitivity which have been proposedas the pathophysiological factors of IBS

In this study the results of the laboratory tests revealedthe anti-inflammatory and immune modulatory effects ofBiobran After Biobran intake NK cell activity increased andthe CRP value showed a significant decrease when comparedwith the levels before intake In addition significant increasein the ratio of lymphocytes in WBCs and the B-cell percent-age in lymphocytes was also observed as well as a significantdecrease in the neutrophil ratio Ghonum et al have shownthat Biobran is a potent biological response modifier that

Table 4 Changes in values of hematological and serologicalexaminations between baseline and after 4 weeks of treatment


White blood cell (times102)Biobran 599 plusmn 170 587 plusmn 158 NSPlacebo 638 plusmn 183 607 plusmn 147 NS

Neutrophil ()Biobran 581 plusmn 81 543 plusmn 68lowast 0039Placebo 605 plusmn 83 603 plusmn 79 NS

Lymphocyte ()Biobran 320 plusmn 74 355 plusmn 62lowastlowast 0022Placebo 298 plusmn 70 303 plusmn 75 NS

Hemoglobin (gdl)Biobran 136 plusmn 12 138 plusmn 13 NSPlacebo 140 plusmn 19 138 plusmn 21 NS

Platelet countBiobran 195 plusmn 57 219 plusmn 47 NSPlacebo 232 plusmn 55 214 plusmn 52 0011

CRP (gdl)Biobran 012 plusmn 010 010 plusmn 013 0042Placebo 032 plusmn 047 025 plusmn 036 NS

NORBiobran 4458 plusmn 1661 5086 plusmn 1795 NSPlacebo 4126 plusmn 1830 3893 plusmn 1401 NS

T cell ()Biobran 879 plusmn 36 869 plusmn 47 NSPlacebo 871 plusmn 46 869 plusmn 37 NS

B cell ()Biobran 528 plusmn 249 644 plusmn 275 0042Placebo 584 plusmn 252 528 plusmn 287 NS

NK cell activity ()Biobran 317 plusmn 125 403 plusmn 157 0002Placebo 362 plusmn 154 356 plusmn 157 NS

Th1Th2Biobran 992 plusmn 560 1005 plusmn 599 NSPlacebo 871 plusmn 531 1024 plusmn 721 NS

Values are mean plusmn SD lowast119875 = 00184 versus Placebo lowastlowast119875 = 00384 versusPlaceboCRP C reactive protein NOR Noradrenalin

works through stimulation of different arms of the immunesystem such as NK T and B cells [18ndash21] These previousdata on Biobran support our result A significant decreasein platelet count however was observed only in the placebogroup The reason for this effect may be partly due to higherbaseline values in the placebo group than in the Biobrangroup However no data are available to explain this result

A few clinical trials [30ndash33] have suggested that treatmentwith various probiotic bacteria can improve IBS symptomsThe intestinalmicroflora plays an important role in the healthof the host [34ndash36] and possesses an immune modulatorycapacity Probiotic bacteria offer a means of modifying theenteric microflora and their therapeutic effects may influ-ence the immune response [34 37] by modulating mucosal


balance in the intestinal tract In our study oral Biobranintake increased the percentage of lymphocyte and enhancedNK cell activity indicating that Biobran has immune mod-ulatory effects in IBS patients In addition Biobran whichis a polysaccharide derived from rice bran may influencethe microflora in the digestive tract However the precisebiological Biobran functions are not well understood Furtherstudies are needed to clarify the mechanisms of the beneficialeffects of Biobran in IBS patients

Thepotential of Biobran to directlymediate psychologicalstress and the autonomic nervous systemwas considered lowPsychological factors are important in the pathogenesis ofIBS The concentration of serum catecholamines includingnoradrenalin rises under psychological stress and the pre-vailing state [38 39] of sympathetic nervous activity In thisstudy no changes in either the STAI scores or values of serumcatecholamine resulting from Biobran intake were observedsuggesting that there is no direct relationship between theeffect of Biobran and psychological stress

The first limitation of this study was that the sample sizewas small because of pilot study and that there was no datafor some of cytokines such as IL in subjects before and afterthe intake We could not investigate the correlation betweenthe profile of immune cells and IBS symptom severity

In conclusion this is the first study to examine theanti-inflammatory andor immunemodulatory effects in IBSpatientsWe detected a significant improvement in symptomsin the cases of Biobran treatment when compared with thatof the placebo These data provide a novel application forBiobran in treatment of IBS patients To confirm our resultsfurther trials should be encouraged in a more generalizedpopulation

5 Conclusion

Immune modulatory effects of Biobran modified arabinoxy-lan rice bran are probably useful in improving IBS symptoms

Abbreviations

IBS Irritable bowel syndromeQOL Quality of lifePI-IBS Postinfectious IBSNK cell Natural killer cellIFN InterferonIL InterleukinGSRS Gastrointestinal Symptom Rating ScaleSTAI State-Trait Anxiety InventoryCRP C-reactive proteinHPLC High performance liquid chromatographyIBS-D IBS with diarrheaIBS-M Mixed IBS


The authors declare that there is no conflict of interestsregarding the publication of this study

Acknowledgments

The authors wish to thank Dr Mamdooh Ghoneum and DrYuzo Endo for their advice in this paper They also thankDaiwa Pharmaceutical Co Ltd for supplying the powder ofboth Biobran and placebo and for the assistance of this papersubmission This study was supported in part by a grantof Japanese Society of Psychosomatic Medicine on DigestiveDisease

References


[2] R Jones and S Lydeard ldquoIrritable bowel syndrome in thegeneral populationrdquo British Medical Journal vol 304 no 6819pp 87ndash90 1992

[3] Y A Saito G R Locke N J Talley A R Zinsmeister S L Fettand L J Melton III ldquoA comparison of the Rome and Manningcriteria for case identification in epidemiological investigationof irritable bowel syndromerdquoTheAmerican Journal of Gastroen-terology vol 95 no 10 pp 2816ndash2824 2000

[4] W G Thompson K W Heaton G T Smyth and C SmythldquoIrritable bowel syndrome in general practice prevalencecharacteristics and referralrdquoGut vol 46 no 1 pp 78ndash82 2000

[5] W G Thompson E J Irvine P Pare S Ferrazzi and LRance ldquoFunctional gastrointestinal disorders in Canada Firstpopulation-based survey using Rome II criteria with sugges-tions for improving the questionnairerdquo Digestive Diseases andSciences vol 47 no 1 pp 225ndash235 2002

[6] A P S Hungin P J Whorwell J Tack and F Mearin ldquoTheprevalence patterns and impact of irritable bowel syndrome aninternational survey of 40 000 subjectsrdquoAlimentary Pharmacol-ogy andTherapeutics vol 11 no 5 pp 643ndash650 2003

[7] M Kanazawa Y Endo W E Whitehead M Kano M Hongoand S Fukudo ldquoPatients and nonconsulters with irritable bowelsyndrome reporting a parental history of bowel problems havemore impaired psychological distressrdquo Digestive Diseases andSciences vol 49 no 6 pp 1046ndash1053 2004

[8] J Y Kang ldquoSystematic review the influence of geography andethnicity in irritable bowel syndromerdquo Alimentary Pharmacol-ogy andTherapeutics vol 21 no 6 pp 663ndash676 2005

[9] B E Lacy and R D Lee ldquoIrritable bowel syndrome a syndromein evolutionrdquo Journal of Clinical Gastroenterology vol 39 no 5pp S230ndashS242 2005

[10] A P Weston W L Biddle P S Bhatia and P B Miner JrldquoTerminal ileal mucosal mast cells in irritable bowel syndromerdquoDigestive Diseases and Sciences vol 38 no 9 pp 1590ndash15951993

[11] M OrsquoSullivan N Clayton N P Breslin et al ldquoIncreased mastcells in irritable bowel syndromerdquo Neurogastroenterology andMotility vol 12 no 5 pp 449ndash457 2000

[12] R C Spiller D Jenkins J P Thornley et al ldquoIncreased rectalmucosal enteroendocrine cells T lymphocytes and increasedgut permeability following acute Campylobacter enteritis andin post-dysenteric irritable bowel syndromerdquoGut vol 47 no 6pp 804ndash811 2000

[13] V S Chadwick W Chen D Shu et al ldquoActivation of themucosal immune system in irritable bowel syndromerdquo Gas-troenterology vol 122 no 7 pp 1778ndash1783 2002


[14] G Barbara V Stanghellini R De Giorgio et al ldquoActivated mastcells in proximity to colonic nerves correlate with abdominalpain in irritable bowel syndromerdquoGastroenterology vol 126 no3 pp 693ndash702 2004

[15] D Limsui D S PardiM Camilleri et al ldquoSymptomatic overlapbetween irritable bowel syndrome and microscopic colitisrdquoInflammatory Bowel Diseases vol 13 no 2 pp 175ndash181 2007

[16] R C Spiller ldquoPostinfectious irritable bowel syndromerdquo Gas-troenterology vol 124 no 6 pp 1662ndash1671 2003

[17] S Ji H Park D Lee Y K Song J P Choi and S Lee ldquoPost-infectious irritable bowel syndrome in patients with Shigellainfectionrdquo Journal of Gastroenterology and Hepatology vol 20no 3 pp 381ndash386 2005

[18] M Ghoneum ldquoEnhancement of human natural killer cell activ-ity by modified arabinoxylane from rice bran (BIOBRAN)rdquoInternational Journal of Immunotherapy vol 14 no 2 pp 89ndash99 1998

[19] M Ghoneum and S Abedi ldquoEnhancement of natural killercell activity of aged mice by modified arabinoxylan rice bran(MGN-3Biobran)rdquo Journal of Pharmacy and Pharmacologyvol 56 no 12 pp 1581ndash1588 2004

[20] M Ghoneum ldquoAnti-HIV activity in vitro of BIOBRAN an acti-vated arabinoxylan from rice branrdquoBiochemical and BiophysicalResearch Communications vol 243 no 1 pp 25ndash29 1998

[21] M Ghoneum M Matsuura and S Gollapudi ldquoModifiedarabinoxylan rice bran (MGN-3biobran) enhances intracel-lular killing of microbes by human phagocytic cells in vitrordquoInternational Journal of Immunopathology and Pharmacologyvol 21 no 1 pp 87ndash95 2008

[22] H I JacobyGWnorowski K Sakata andHMaeda ldquoThe effectof BIOBRAN on cisplatin and doxorubicin induced toxicity inthe ratrdquo Journal of Nutraceuticals Functional amp Medical Foodsvol 3 pp 3ndash6 2001

[23] Y Endo and H Kanbayashi ldquoModified rice bran beneficialfor weight loss of mice as a major and acute adverse effect ofcisplatinrdquo Pharmacology and Toxicology vol 92 no 6 pp 300ndash303 2003

[24] E Dimenas H Glise B Hallerback H Hernqvist J Svedlundand I Wiklund ldquoQuality of life in patients with upper gas-trointestinal symptoms An improved evaluation of treatmentregimensrdquo Scandinavian Journal of Gastroenterology vol 28no 8 pp 681ndash687 1993

[25] K Nakazato and TMizuguchi ldquoDevelopment and validation ofJapanese version of State-Trait anxiety inventorymdasha study withfemale subjectsrdquo Japanese Journal of Psychosomatic Medicinevol 22 pp 107ndash112 1982 (Japanese)

[26] A J Cronin N M Aucutt-Walter T Budinetz et al ldquoLow-dose remifentanil infusion does not impair natural killer cellfunction in healthy volunteersrdquo British Journal of Anaesthesiavol 91 no 6 pp 805ndash809 2003

[27] P Hjemdahl ldquoCatecholamine measurements by high-performance liquid chromatographyrdquo The American Journal ofPhysiology vol 247 no 1 pp E13ndashE20 1984

[28] J Berkes V K Viswanathan S D Savkovic and G HechtldquoIntestinal epithelial responses to enteric pathogens effects onthe tight junction barrier ion transport and inflammationrdquoGut vol 52 no 3 pp 439ndash451 2003

[29] L Shen and J R Turner ldquoRole of epithelial cells in initiationand propagation of intestinal inflammation eliminating thestatic tight junction dynamics exposedrdquoThe American Journalof Physiology Gastrointestinal and Liver Physiology vol 290 no4 pp G577ndashG582 2006

[30] S Nobaek M Johansson G Molin S Ahrne and B JeppssonldquoAlteration of intestinal microflora is associated with reductionin abdominal bloating and pain in patients with irritable bowelsyndromerdquo The American Journal of Gastroenterology vol 95no 5 pp 1231ndash1238 2000

[31] K Niedzielin H Kordecki and B Birkenfeld ldquoA controlleddouble-blind randomized study on the efficacy of Lactobacillusplantarum 299V in patients with irritable bowel syndromerdquoEuropean Journal of Gastroenterology and Hepatology vol 13no 10 pp 1143ndash1147 2001

[32] H J Kim M Camilleri S McKinzie et al ldquoA randomizedcontrolled trial of a probiotic VSL3 on gut transit and symp-toms in diarrhoea-predominant irritable bowel syndromerdquoAlimentary Pharmacology and Therapeutics vol 17 no 7 pp895ndash904 2003

[33] L OrsquoMahony J Mccarthy P Kelly et al ldquoLactobacillus and Bifi-dobacterium in irritable bowel syndrome symptom responsesand relationship to cytokine profilesrdquoGastroenterology vol 128no 3 pp 541ndash551 2005

[34] R B Sartor ldquoTherapeutic manipulation of the entericmicroflora in inflammatory bowel diseases antibioticsprobiotics and prebioticsrdquo Gastroenterology vol 126 no 6 pp1620ndash1633 2004

[35] F Shanahan ldquoImmunology therapeutic manipulation of gutflorardquo Science vol 289 no 5483 pp 1311ndash1312 2000

[36] D Ma D Wolvers A M Stanisz and J BienenstockldquoInterleukin-10 and nerve growth factor have reciprocal upreg-ulatory effects on intestinal epithelial cellsrdquo The AmericanJournal of Physiology Regulatory Integrative and ComparativePhysiology vol 284 no 5 pp R1323ndashR1329 2003

[37] D Ma P Forsythe and J Bienenstock ldquoLive Lactobacillusreuteri is essential for the inhibitory effect on tumor necrosisfactor alpha-induced interleukin-8 expressionrdquo Infection andImmunity vol 72 no 9 pp 5308ndash5314 2004

[38] S R Snider andOKuchel ldquoDopamine an important neurohor-mone of the sympathoadrenal system Significance of increasedperipheral dopamine release for the human stress response andhypertensionrdquo Endocrine Reviews vol 4 no 3 pp 291ndash3091983

[39] B E Leonard ldquoStress norepinephrine and depressionrdquo Journalof Psychiatry and Neuroscience vol 26 pp S11ndashS16 2001

Research ArticleTraditional Japanese Medicine Daikenchuto ImprovesFunctional Constipation in Poststroke Patients

Takehiro Numata12 Shin Takayama23 Muneshige Tobita4 Shuichi Ishida5

Dai Katayose6 Mitsutoshi Shinkawa7 Takashi Oikawa8 Takanori Aonuma9

Soichiro Kaneko12 Junichi Tanaka10 Seiki Kanemura10 Koh Iwasaki11

Tadashi Ishii210 and Nobuo Yaegashi1

1 Department of Obstetrics and Gynecology Tohoku University Graduate School of Medicine 2-1 Seiryo-MachiAoba Ward Sendai City Miyagi 980-8575 Japan

2Department of Kampo Medicine Tohoku University Hospital 1-1 Seiryo-Machi Aoba Ward Sendai City Miyagi 980-8574 Japan3 Comprehensive Education Center for Community Medicine Tohoku University Graduate School of Medicine 2-1 Seiryo-MachiAoba Ward Sendai City Miyagi 980-8575 Japan

4National Yonezawa Hospital 26100-1 Oh-Aza Misawa Yonezawa City Yamagata 992-1202 Japan5 Ishinomaki Rehabilitation Hospital 1-2-21 Kadonowaki-cho Ishinomaki City Miyagi 986-0834 Japan6Miyagi Rifu Ekisaikai Hospital 51 Morigo Aza Shintaishido Rifu Town Miyagi 981-0103 Japan7Hikarigaoka Spellman Hospital 6-7-1 Higashi-Sendai Miyagino Ward Sendai City Miyagi 983-0833 Japan8National Hachinohe Hospital 3-13-1 Fukiage Hachinohe City Aomori 031-0003 Japan9Wakuya Medical and Welfare Center 278 Wakuya Aza Nakakonan Wakuya Town Miyagi 987-0121 Japan10Department of Education and Support for Community Medicine Tohoku University Hospital 1-1 Seiryo-Machi Aoba WardSendai City Miyagi 980-8574 Japan

11Center for Traditional Asian Medicine and Home Healthcare Southern Tohoku General Hospital 1-2-5 SatonomoriIwanuma City Miyagi 989-2483 Japan

Correspondence should be addressed to Shin Takayama tatahara1492gmailcom

Received 25 March 2014 Revised 5 May 2014 Accepted 13 May 2014 Published 25 June 2014


Copyright copy 2014 Takehiro Numata et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Poststroke patients with functional constipation assessed by the Rome III criteria from 6 hospitals were recruited in a study onthe effects of the traditional Japanese medicine Daikenchuto (DKT) on constipation Thirty-four patients (17 men and 17 womenmean age 781 plusmn 116 years) were randomly assigned to 2 groups all patients received conventional therapy for constipation andpatients in the DKT group received 15 gday of DKT for 4 weeks Constipation scoring system (CSS) points and the gas volumescore (GVS) (the measure of the intestinal gas volume calculated from plain abdominal radiographs) were recorded before andafter a 4-week observation period The total score on the CSS improved significantly in the DKT group compared to the control(119875 lt 001) In addition scores for some CSS subcategories (frequency of bowel movements feeling of incomplete evacuation andneed for enemadisimpaction) significantly improved in the DKT group (119875 lt 001 119875 = 0049 and 119875 = 003 resp) The GVSwas also significantly reduced in the DKT group compared to the control (119875 = 003) DKT in addition to conventional therapy iseffective in treating functional constipation in poststroke patients This study was a randomized controlled trial and was registeredin the UMIN Clinical Trial Registry (no UMIN000007393)

1 Introduction

There were over 134 million cerebrovascular patients in2008 reported by the Japanese Ministry of Health Labour

and Welfare [1] Constipation is one of the complicationsseen in poststroke patients Stratified by stroke severity onthe National Institutes of Health Stroke Scale the reportedincidence of constipation in poststroke patients is 389 to



882 [2] Functional constipation is thought to originatefrom decreased gastrointestinal motility as well as fromdecreased autonomic nervous system efficiency impairedphysical activity abdominal muscle weakness secondary tohemiplegia and diet [3] Conventional therapy to controlconstipation involves the use of laxatives or stimulant purga-tives and these drugs are often used in the long termin chronic constipation patients [4] However patients candevelop a tolerance to laxatives or stimulant purgatives andparalytic ileus occasionally occurs in the clinical setting evenwith conventional therapy [5]

DKT has historically been used to treat gastrointestinaldysfunction with abdominal coldness and pain in many EastAsian countries including Japan and China [6] Recentlyit has also been used to prevent ileus after gastrointestinalsurgery and to treat irritable bowel syndrome [7] Horiuchiet al reported that DKT significantly improved abdominalbloating and pain and reduced intestinal gas volume inpatients with intractable functional constipation [8] Physi-ological reactions to the administration of DKT have beenreported as promoting gastrointestinal motility [9ndash13] andincreasing intestinal blood perfusion [14ndash19] DKTrsquos effec-tiveness in treating defecation disorders in patients withcerebrovascular disease is commonly observed in the clinicalsetting Potential mechanisms underlying the physiologicalresponses to DKT have been investigated in animal modelsand include elevated levels of plasma vasoactive intestinalpolypeptide [14 17 20] substance P [14 17 21 22] motilin[23ndash25] and acetylcholine [10 11 13 26ndash28] which promotegastrointestinal motility as well as calcitonin gene-relatedpeptide (CGRP) [14 15 17 21] and adrenomedullin [15 16 2930] which increase intestinal blood flow Poststroke patientsare at risk for arteriosclerosis and often experience abdominalpain accompanied by a cold sensation in the abdomen associ-atedwith lowbloodperfusion in themesenteric arteriesDKThas been used to treat defecation disorders with abdominalcoldness and pain caused by decreased intestinal motility andblood flow We previously reported that administration ofDKT increased blood flow in the superior mesenteric arteryand promoted intestinal peristalsis in healthy subjects [18 19]Sato et al reported that DKT significantly increased plasmaCGRP levels in healthy subjects [21]Therefore plasmaCGRPmay be a useful biomarker to evaluate the effects of DKT onintestinal blood flow

This study aimed to investigate the efficacy of DKT intreating functional constipation in poststroke patients Inaddition this study investigated the impact of DKT therapyon CGRP concentration

2 Methods

21 Subject Eligibility Criteria Eligible patients were aged20 to 99 years of both genders had been diagnosed withfunctional constipation according to the Rome III criteria[31] and remained stable over a 6-month period fromthe onset of cerebral hemorrhage cerebral infarction andsubarachnoid hemorrhage Patients received nutrition orallyor through a nasogastric or gastrostomy tube Patients with

concurrent diabetes were required to have an HbA1c (NGSP)less than 9

22 Subject Exclusion Criteria Patients meeting or diag-nosed with any of the following criteria were excludedrisk of intestinal adhesion following abdominal surgeryinflammatory bowel disease or malignant gastrointestinaldisease hypoxic encephalopathy or myelopathy historyof interstitial pneumonia liver andor kidney dysfunctioncancer and neurodegenerative disease such as Parkinsonrsquosdisease or spinocerebellar degeneration However patientswho underwent laparoscopic cholecystectomy or underwentpercutaneous endoscopic gastrostomy were not excludedbecause the invasiveness of the operation was minimal

23 Patient Recruitment From September 2012 to Decem-ber 2013 eligible subjects were recruited from 6 hospitalsNational YonezawaHospital Ishinomaki RehabilitationHos-pital National Hachinohe Hospital Hikarigaoka SpellmanHospital Miyagi Rifu Ekisaikai Hospital and Wakuya Medi-cal and Welfare Center

24 Logistics Subjects were randomly assigned to the DKTgroup or the control groupThe study protocol was conductedin accordance with the Declaration of Helsinki and wasapproved by the Institutional Review Boards of TohokuUniversityHospital and the 6 collaborating hospitalsWritteninformed consent was obtained from all patients or theirfamilies

25 Trial Methods The study protocol included an intentionto treat analysis The control group underwent conventionaltherapy for constipation such as laxative administration ene-mas and disimpaction In addition to conventional therapythe DKT group continuously received 50 g of Daikenchutoextract granules (TJ-100 Tsumura amp Co Tokyo Japan)3 times a day before meals for 4 weeks Each clinicalparameter was measured before and after the 4-week trialFifteen grams of TJ-100 (DKT) extract granules contains adried herbal extract mixture in the following proportionsGinseng radix (Araliaceae Panax ginseng CAMeyer Radix)(30 g) processed ginger root (Zingiberaceae Zingiber offici-nale Roscoe rhizoma) (50 g) Zanthoxylum fruit (RutaceaeZanthoxylum piperitum De Candolle pericarpium) (20 g)and saccharum granorum (the candy produced from mal-tose) (100 g) This formulation is registered in the JapanesePharmacopoeia Sixteenth Edition [32] The production andsupply processes for TJ-100 comply with good manufac-turing practice standards for Kampo products and havebeen approved by the Japanese Ministry of Health Labourand Welfare

26 Evaluation of Clinical Symptoms

261 Activities of Daily Living The Barthel Index wasrecorded for each patient at study enrollment to assessactivities of daily living [33]


(a) (b)

Figure 1 Estimation of gas volume score (GVS) Plain abdominal radiographs obtained from fasting subjects were converted to digital dataThe data were read using ImageJ an image analysis program and intestinal gas was traced using the program (a) Tracing image and pixelcount of the gaswas 3533 in this patient (b)Thewindowof abdominal areaThe rectangular areawasmeasured as the area between the inferiorright sidemargin of the diaphragm the inner costalmargin and the superior border of the pubic symphysisThe pixel count of the rectangulararea was calculated as 92968 in (b) GVS was calculated as (a)(b) therefore the GVS of this image is ldquo3 53392 968 = 0038(38)rdquo

262 Clinical Constipation Scores Clinical scores for consti-pation were recorded before and after the 4-week trial periodusing the constipation scoring system (CSS see the appendix)[34] Questionnaires concerning constipation were adminis-tered to patients however if the patients could not completelyanswer the question their families or nurses evaluated thequestions depending on the objective findings (ie painfulevacuation effort or abdominal pain before defecation wasevaluated by family members or nurses using the patientsrsquofacial expressions feeling of incomplete evacuation wasevaluated with abdominal fullness after defecation) Becauseit was difficult to evaluate Q5 (ldquoTime minutes in lavatory perattemptrdquo) in the CSS for bedridden subjects using diapers weremoved Q5 from the statistical analysis Evaluations beforeand after the administration of DKT were performed bythe same family member or nurse with blinding of DKTadministration

263 Plain Abdominal Radiography Plain abdominal radio-graphs of fasting patients in a supine position were obtainedbefore and after the trial periodThe gas volume score (GVS)was calculated by Koidersquos method [35] using ImageJ [36](Figure 1)

264 Blood Sampling General blood counts and biochem-istry tests were performed in fasting patients before and afterthe trial period to assess potential adverse effects Bloodsample portions were stored in EDTA-2Na tubes Sampleswere centrifuged (3000 rev10min) and 05mL of plasmawas collected and stored at minus20∘C The concentration of

plasma CGRP was quantified using the Human CGRP ElisaKit (MyBioSource Inc San Diego USA) tested by SRL IncTokyo Japan

265 Statistical Analysis Statistical analysis was performedusing SPSS software (ver 16 SPSS Japan Inc Tokyo Japan)Baseline comparisons of group differences were conductedusing the independent samples t-test for continuous variablesand the chi-square test for categorical variablesMeasurementof the mean and standard deviation (SD) was performed atbaseline and at the endpoint for all parameters Comparisonsbetween theDKTand control groupswere performed by two-way analysis of variance (ANOVA) Changes within groupsbefore and after the trial period were compared using thepaired t-test when the intergroup difference was significantCorrelation between age and the CSS points was analyzed bycoefficient of product-moment correlation (Pearson correla-tion coefficient) P values lt005 were considered significant

3 Results

From September 2012 to December 2013 34 subjects (17 menand 17 women mean age 781 plusmn 116 years) at 6 hospitalsparticipated in the study Patients were randomly assigned to2 groups (control group or DKT group) The demographiccharacteristics CSS and GVS of each group at baseline areshown in Table 1There was no significant difference betweengroups in characteristics the way of nutrition intake CSS orGVS at baseline


Table 1 Baseline population demographics of DKT and controlgroups

Group119875lowast

DKTa Control119873 17 17Sex 073

Female 9 8Male 8 9

Age (y) 775 plusmn 119 787 plusmn 121 078Height (cm) 1563 plusmn 121 1541 plusmn 93 056Body weight (kg) 484 plusmn 102 483 plusmn 94 099Diagnoses119873 031

Brain infarction 10 14Cerebral hemorrhage 4 2Subarachnoid hemorrhage 3 1

Illness duration (y) 78 plusmn 61 48 plusmn 42 015Barthel Index 21 plusmn 31 12 plusmn 28 039The way of nutritional intake 014

Orally 5 1Through nasogastric tube 2 5Through gastrostomy tube 10 11

CSS totalb (points) 80 plusmn 31 81 plusmn 37 096CGRP (pgmL) 408 plusmn 482 262 plusmn 170 025GVS () 163 plusmn 67 144 plusmn 78 044aDKT Daikenchuto CSS constipation scoring system CGRP calcitoningene-related peptide GVS gas volume scorebCSS total not including point of Q5lowastSignificance designated at 119875 lt 005

31 Changes in Clinical Constipation Scores All 34 subjectscompleted the CCS questionnaire before and after the obser-vation period and results are summarized in Table 2 Therewas no significant correlation between age and theCSS pointson the baseline (119899 = 34) (119903 = 012 119875 = 049) Significantdifferences in the CSS scores were observed between the 2groups (two-way ANOVA 119875 lt 001) In the DKT groupthe CSS scores significantly improved from 80 plusmn 31 to 60plusmn 31 points (paired t-test 119875 lt 001) There was no significantcorrelation between age and the changes of the CSS scoresfor subjects in DKT group (119899 = 17) (119903 = minus016 119875 = 053)The control group did not show any significant improvement(Table 2) CSS subcategory findings are summarized forboth groups in Table 3 Among the CSS subcategories therewere significant differences between the DKT and controlgroups using two-way ANOVA for the following questionsQ1 (frequency of bowel movements 119875 lt 001) Q3 (feelingof incomplete evacuation 119875 = 003) and Q6 (need fordrugsenemadisimpaction 119875 = 002) In the DKT groupthe constipation scores significantly decreased over the trialperiod for Q1 (119875 lt 001) Q3 (119875 = 0049) and Q6 (119875 = 003)The control group however did not show any significantchanges (Table 3) Overall the average change of 1 point in thescore for Q1 means an improvement in defecation frequencyfrom ldquoonce per weekrdquo to ldquo2 times per weekrdquo or ldquoless thanonce per weekrdquo to ldquoonce per weekrdquo in the clinical setting

Baseline Endpoint Baseline Endpoint

P lt 001

P = 061

0

5

10

15

20

25

DKT Control

GVS

()

Figure 2 Changes in the gas volume score (GVS) Two-wayANOVA showed a significant difference between the groups (119875 =003) In the DKT group the GVS significantly improved from 163plusmn 67 to 99 plusmn 60 (paired t-test 119875 lt 001) and in the controlgroup it changed from 144 plusmn 71 to 135 plusmn 80with no significance(paired t-test 119875 = 061)

The average change of 04 points in the scores for Q3 andQ6 means that digital assistance or enemas were no longernecessary for approximately 30 of the patients in the DKTgroup

32 Changes in Gas Volume Score Figure 2 summarizeschanges in the GVS before and after the observation periodfor both groups There was a significant difference betweenthe 2 groups (two-way ANOVA 119875 = 003) and theintragroup comparison revealed a significant decrease in theDKT group from 163 plusmn 67 to 99 plusmn 60 (119875 lt 001)while the control group did not show any significant changes(119875 = 061) Representative abdominal radiographs of apatient before and after DKT administration show reducedintestinal gas volume (Figures 3(a) and 3(b)) In this caseDKT administration reduced the GVS from 260 to 123

33 Changes in Plasma Calcitonin Gene-Related Peptide Con-centrations In the DKT group the initial and final CGRPconcentrations were 409 plusmn 482 pgmL and 452 plusmn 574 pgmLrespectively In the control group the initial and final valueswere 270plusmn 172 pgmL and 251plusmn 118 pgmL respectivelyTherewas no significant difference between the 2 groups in plasmaCGRP (two-way ANOVA 119875 = 008)

34 Adverse Effects Notable adverse effects such as itchinggastrointestinal symptoms other subjective symptoms andabnormalities in blood counts and blood biochemistry werenot observed during and after DKT administration

4 Discussion

This study shows that DKT in addition to conventionaltherapy for functional constipation significantly improved


Table 2 Clinical constipation scores in both groups at baseline and endpoint

DKTa group (119873 = 17) Intragroupdifference Control group (119873 = 17) Intragroup

differenceIntergroupdifference

Baseline Endpointb 119875lowast Baseline Endpoint 119875 119875

CSS totalc (points) 80 plusmn 31 60 plusmn 31 lt001 81 plusmn 37 82 plusmn 37 033 lt001aDKT Daikenchuto CSS constipation scoring systembEndpoint after the 4-week trial periodcCSS total not including point of Q5lowastSignificance designated at 119875 lt 005

Table 3 Constipation scoring system (CSS) subcategory scores in both groups at baseline and endpoint




Q1 (points) 22 plusmn 15 12 plusmn 14 lt001 21 plusmn 14 21 plusmn 15 033 lt001Q2 (points) 05 plusmn 09 03 plusmn 07 mdash 06 plusmn 09 06 plusmn 09 mdash 007Q3 (points) 12 plusmn 12 08 plusmn 10 0049 15 plusmn 13 16 plusmn 14 033 003Q4 (points) 04 plusmn 08 04 plusmn 07 mdash 07 plusmn 09 07 plusmn 09 mdash 033Q5 (points) mdash mdash mdash mdash mdash mdash mdashQ6 (points) 18 plusmn 05 14 plusmn 08 003 17 plusmn 07 17 plusmn 07 100 002Q7 (points) 01 plusmn 02 01 plusmn 02 mdash 01 plusmn 02 01 plusmn 02 mdash 100Q8 (points) 19 plusmn 11 19 plusmn 11 mdash 15 plusmn 09 15 plusmn 09 mdash 100Intragroup difference was calculated using the paired 119905-test only when the intergroup difference was significantaDKT DaikenchutobEndpoint after the 4-week trial periodlowastSignificance designated at 119875 lt 005

the CSS scores and significantly reduced the GVS in post-stroke patients The incidence of adverse effects associatedwith DKT extract such as gastrointestinal discomfort andliver dysfunction has been reported as 19 in prior studies[37] but no adverse effects were observed during the 4-week treatment period in the present study Functionalconstipation has a complex pathophysiology and intestinalfunction is controlled by the autonomic nervous systemconsequently therapeutic protocols are limited in poststrokepatients [38 39] Several clinical studies of DKT therapyfor constipation have been reported but almost all of thesewere limited to healthy subjects or were case series Thepresent study was a prospective randomized controlled trialfor functional constipation in patients with stroke-relatedmorbidity and therefore could show stronger evidence thanprevious reports of the clinical effects of DKT

In a prior clinical study it was reported that DKT extractimproved colorectal function in patients diagnosed withParkinsonrsquos disease [40] Another study reported that admin-istration of DKT to patients with chronic intractable consti-pation improved abdominal bloating and pain symptoms [8]The present study similarly found improvement in clinicalconstipation scores and GVS Numerous studies have inves-tigated the active ingredients and mechanisms underlyingthe improved intestinal motility Intestinal contraction maybe induced by DKT through the cholinergic nervous systemvia serotonin receptors [13 27 28] motilin activity [23 24]and the transient receptor potential vanilloid type 1 channel

[11 41] Satoh et al reported that Zanthoxylum fruit andmaltose ingredients in DKT improved delayed propulsion inthe small intestine Zanthoxylum fruit also improved delayedpropulsion in the distal colon Endogenous cholecystokininsecretion resulting from maltose administration may play arole in the effect of DKT [42]These reports describe the pos-sible mechanisms through which DKT promotes intestinalmovement and explain some aspects of the improvement inthe CSS scores and the reduction of GVS noted in our study

Some studies reported that DKT extract increased CGRPin healthy subjects [21 25] In another report DKT did notchange CGRP levels in patients with constipation secondaryto palliative morphine therapy for cancer [24] In the presentstudy changes in CGRP did not reach statistical significanceSeveral mechanismsmay explain this lack of change in CGRPlevels in the DKT group Plasma CGRP is notably unsta-ble [43] An elevation following DKT administration mayhave been obscured by factors such as testing proceduresindividual differences daily fluctuations and day-to-dayvariations Furthermore although some studies confirmedelevated CGRP immediately after DKT administration [2125] the CGRP level may be too unstable to be used as atarget factor for evaluating the effects of DKTDKT is thoughtto affect the promotion of intestinal motility and intestinalblood flow Increase in intestinal blood flow is believed to bemediated through adrenomedullin and CGRP or through thetransient receptor potential ankyrin 1 channel [16 29 30]Themechanisms promoting intestinal motility and blood flow


(a) (b)

Figure 3 (a) Plain abdominal radiograph of an 86-year-old man prior to Daikenchuto administration The gas volume score (GVS) wascalculated as 260 (b) Plain abdominal radiograph of an 86-year-old man after 4 weeks of Daikenchuto administration The gas volumescore (GVS) was calculated as 123

have complex interactions which may be altered further bydisease pathology environment and individual differencesThe present results of improved constipation following DKTadministration are overall consistent with the findings ofprior studies despite the lack of significant change in CGRPlevels

41 Limitations The small sample size is the first limitationof the present study The CGRP level tended to differbetween the groups (ANOVA 119875 = 008) a larger samplesize could determine the significance of this difference Inaddition participants were limited to hospitalized patientstherefore patients who were hemiplegic yet stable enoughto receive outpatient care were not included As a result thepopulation was skewed toward patients with low activitiesof daily living Third there are no objective parameters forabdominal coldness at present Ultrasound assessment ofblood flow in the superior mesenteric artery was nearlyimpossible in poststroke patients with constipation owing tothe presence of intestinal gas Finally the placebo effect of oraladministration cannot be overlooked A randomized double-blind comparative study using a placebo would be ideal andwould eliminate the placebo effect DKT includes 4 crudeherbs and has a sweet and hot flavor It will be difficult toproduce a placebo without bioactivity that has a smell andflavor similar to DKT Accordingly the present study did notuse a placebo control but rather compared the effects of DKTadministration plus conventional treatment to conventionaltreatment alone

5 Conclusions

Administration of DKT extract in conjunction with conven-tional therapy to treat functional constipation in poststroke

patients improved clinical constipation scores and reducedintestinal gas volume Results of this study show that DKTis effective for defecation control in poststroke patients

Appendix

Constipation Scoring System (CSS) [34]

Minimum score 0 Maximum score 30 the numberingstarting from zero represents the scores

(1) Frequency of bowel movements

(0) 1-2 times per 1-2 days(1) 2 times per week(2) Once per week(3) Less than once per week(4) Less than once per month

(2) Difficulty painful evacuation effort(3) Completeness feeling incomplete evacuation(4) Pain abdominal pain

(0) Never(1) Rarely(2) Sometimes(3) Usually(4) Always

(5) Time minutes in lavatory per attempt

(0) Less than 5


(1) 5minus10(2) 10minus20(3) 20minus30(4) More than 30

(6) Assistance type of assistance

(0) Without assistance(1) Stimulative laxatives(2) Digital assistance or enema

(7) Failure unsuccessful attempts for evacuation per24 hours

(0) Never(1) 1ndash3(2) 3ndash6(3) 6ndash9(4) More than 9

(8) History duration of constipation (yr)

(0) 0(1) 1ndash5(2) 5ndash10(3) 10ndash20(4) More than 20


All authors declare no personal competing financial or non-financial interests in this study however Tohoku UniversityGraduate School of Medicine received a grant from TsumuraCo Ltd the manufacturer of TJ-100


Takehiro Numata took part in planning the study performedthe data analysis and wrote the paper Shin Takayama andKoh Iwasakiwere the original proposers of the study andwereinvolved in developing the protocol and paper preparationMuneshige Tobita Shuichi Ishida Dai Katayose MitsutoshiShinkawa Takashi Oikawa and Takanori Aonuma tookpart in recruiting subjects and laboratory management intheir hospitals Soichiro Kaneko Junichi Tanaka and SeikiKanemura helped to plan the study and provided advicerelated towriting the paper Tadashi Ishii andNobuoYaegashiwere responsible for the study design and execution andassisted in writing the paper All authors read and approvedthe final paper

Acknowledgments

The present study was conducted using a Grant-in-Aidfor Scientific Research (Academic Research Grant no23590867) The authors sincerely appreciate the individualswho participated in the trial throughout the entire study

as well as their families They are grateful to the staff atNational YonezawaHospital Ishinomaki RehabilitationHos-pital Miyagi Rifu Ekisaikai Hospital Hikarigaoka SpellmanHospital National HachinoheHospital andWakuyaMedicaland Welfare Center for their help with data collection

References

[1] Ministry of Health Labour and Welfare ldquoSummary of PatientSurvey 2008 5 Estimated Number of Patients ReceivingMedical Treatment for Selected Diseasesrdquo httpwwwmhlwgojpenglishdatabasedb-hssdlsps 2008 05pdf

[2] Y Su X Zhang J Zeng et al ldquoNew-onset constipation at acutestage after first stroke incidence risk factors and impact on thestroke outcomerdquo Stroke vol 40 no 4 pp 1304ndash1309 2009

[3] G Basilisco and M Coletta ldquoChronic constipation a criticalreviewrdquo Digestive and Liver Disease vol 45 no 11 pp 886ndash8932013

[4] M Coggrave C Norton and J D Cody ldquoManagement of faecalincontinence and constipation in adults with central neuro-logical diseasesrdquo Cochrane Database of Systematic Reviews vol2014 no 1 Article ID CD002115 2014

[5] K Krogh C Mosdal H Gregersen and S Laurberg ldquoRectalwall properties in patients with acute and chronic spinal cordlesionsrdquo Diseases of the Colon and Rectum vol 45 no 5 pp641ndash649 2002

[6] Z Zhang Synopsis of Prescriptions of the Golden Chamber NewWorld Press Beijing China 1987

[7] H Kawahara andK Yanaga ldquoThe herbalmedicineDai-Kenchu-To directly stimulates colonic motilityrdquo Surgery Today vol 39no 2 pp 175ndash177 2009

[8] A Horiuchi Y Nakayama and N Tanaka ldquoEffect of traditionalJapanese medicine Daikenchuto (TJ-100) in patients withchronic constipationrdquo Gastroenterology Research vol 3 no 4pp 151ndash155 2010

[9] Y Furukawa Y Shiga N Hanyu et al ldquoEffect of Chinese herbalmedicine on gastrointestinal motility and bowel obstructionrdquoThe Japanese Journal of Gastroenterological Surgery vol 28 no4 pp 956ndash960 1995 (Japanese)

[10] X L Jin C Shibata H Naito et al ldquoIntraduodenal and intra-jejunal administration of the herbal medicine Dai-kenchu-toustimulates small intestinal motility via cholinergic receptors inconscious dogsrdquo Digestive Diseases and Sciences vol 46 no 6pp 1171ndash1176 2001

[11] D Kikuchi C Shibata H Imoto T Naitoh K Miura andM Unno ldquoIntragastric Dai-Kenchu-To a Japanese herbalmedicine stimulates colonic motility via transient receptorpotential cation channel subfamily V member 1 in dogsrdquo TheTohoku Journal of Experimental Medicine vol 230 no 4 pp197ndash204 2013

[12] N Manabe M Camilleri A Rao et al ldquoEffect of Daikenchuto(TU-100) on gastrointestinal and colonic transit in humansrdquoAmerican Journal of Physiology Gastrointestinal and LiverPhysiology vol 298 no 6 pp G970ndashG975 2010

[13] C Shibata I Sasaki H Naito T Ueno and S Matsuno ldquoTheherbal medicine Dai-Kenchu-Tou stimulates upper gut motilitythrough cholinergic and 5-hydroxytryptamine 3 receptors inconscious dogsrdquo Surgery vol 126 no 5 pp 918ndash924 1999

[14] T Kono T Koseki S Chiba et al ldquoColonic vascular con-ductance increased by Daikenchuto via calcitonin gene-related


peptide and receptor-activity modifying protein 1rdquo Journal ofSurgical Research vol 150 no 1 pp 78ndash84 2008

[15] T Kono Y Omiya Y Hira et al ldquoDaikenchuto (TU-100)ameliorates colon microvascular dysfunction via endogenousadrenomedullin in Crohns disease rat modelrdquo Journal ofGastroenterology vol 46 no 10 pp 1187ndash1196 2011

[16] T Kono A Kaneko Y Omiya K Ohbuchi N Ohno and MYamamoto ldquoEpithelial transient receptor potential ankyrin 1(TRPA1)-dependent adrenomedullin upregulates blood flow inrat small intestinerdquo American Journal of Physiology Gastroin-testinal and Liver Physiology vol 304 no 4 pp G428ndashG4362013

[17] P Murata Y Kase A Ishige H Sasaki S Kurosawa and TNakamura ldquoThe herbal medicine Dai-kenchu-to and one of itsactive components [6]-shogaol increase intestinal blood flow inratsrdquo Life Sciences vol 70 no 17 pp 2061ndash2070 2002

[18] S Takayama T Seki M Watanabe et al ldquoThe herbal medicineDaikenchuto increases blood flow in the superior mesentericarteryrdquo The Tohoku Journal of Experimental Medicine vol 219no 4 pp 319ndash330 2009

[19] S Takayama T Seki M Watanabe et al ldquoThe effect ofwarming of the abdomen and of herbal medicine on superiormesenteric artery blood flowmdasha pilot studyrdquo Forschende Kom-plementarmedizin vol 17 no 4 pp 195ndash201 2010

[20] T Nagano H Itoh and M Takeyama ldquoEffects of Dai-kenchu-to on levels of 5-hydroxytryptamine (serotonin) and vasoactiveintestinal peptides in human plasmardquo Biological and Pharma-ceutical Bulletin vol 23 no 3 pp 352ndash353 2000

[21] Y Sato F Katagiri S Inoue H Itoh and M Takeyama ldquoDai-kenchu-to raises levels of calcitonin gene-related peptide andsubstance P in human plasmardquo Biological and PharmaceuticalBulletin vol 27 no 11 pp 1875ndash1877 2004

[22] Y Suzuki H Itoh R Yamamura R Tatsuta Y Sato and MTakeyama ldquoSignificant increase in salivary substance P levelafter a single oral dose of Japanese herbalmedicineDai-kenchu-to in humansrdquo Biomedicine amp Aging Pathology vol 2 no 3 pp81ndash84 2012

[23] T Nagano H Itoh and M Takeyama ldquoEffect of Dai-kenchu-to on levels of 3 brain-gut peptides (motilin gastrin andsomatostatin) in human plasmardquo Biological and PharmaceuticalBulletin vol 22 no 10 pp 1131ndash1133 1999

[24] Y SatohH Itoh andMTakeyama ldquoDaikenchuto raises plasmalevels of motilin in cancer patients with morphine-Inducedconstipationrdquo Journal of Traditional Medicines vol 27 no 3 pp115ndash121 2010

[25] Y Sato S Inoue F Katagiri H Itoh and M TakeyamaldquoEffects of pirenzepine on Dai-kenchu-to-induced elevationof the plasma neuropeptide levels in humansrdquo Biological andPharmaceutical Bulletin vol 29 no 1 pp 166ndash171 2006

[26] H Fukuda C Chen C Mantyh K Ludwig T N Pappas andT Takahashi ldquoTheherbalmedicineDai-Kenchu-To acceleratesdelayed gastrointestinal transit after the operation in ratsrdquoJournal of Surgical Research vol 131 no 2 pp 290ndash295 2006

[27] K Satoh K Hashimoto T Hayakawa et al ldquoMechanism ofatropine-resistant contraction induced by Dai-kenchu-to inguinea pig ileumrdquo The Japanese Journal of Pharmacology vol86 no 1 pp 32ndash37 2001

[28] K Satoh T Hayakawa Y Kase et al ldquoMechanisms for con-tractile effect of Dai-kenchu-to in isolated guinea pig ileumrdquoDigestive Diseases and Sciences vol 46 no 2 pp 250ndash256 2001

[29] A Kaneko T Kono N Miura N Tsuchiya and M YamamotoldquoPreventive effect of TU-100 on a type-2model of colitis inmice

possible involvement of enhancing adrenomedullin in intestinalepithelial cellsrdquo Gastroenterology Research and Practice vol2013 Article ID 384057 8 pages 2013

[30] T Kono A Kaneko Y Hira et al ldquoAnti-colitis and -adhesioneffects of Daikenchuto via endogenous adrenomedullinenhancement in Crohns disease mouse modelrdquo Journal ofCrohns and Colitis vol 4 no 2 pp 161ndash170 2010

[31] D A Drossman and E Corazziari Rome III The FunctionalGastrointestinal Disorders Degnon Associates Virginia VaUSA 3rd edition 2006

[32] The Japanese Pharmacopoeia the Electronic Version 16th edi-tion 2011 httpjpdbnihsgojpjp16e

[33] F I Mahoney and D W Barthel ldquoFunctional evaluation thebarthel indexrdquo Maryland State Medical Journal vol 14 pp 61ndash65 1965

[34] F Agachan T Chen J Pfeifer P Reissman and S D WexnerldquoA constipation scoring system to simplify evaluation andmanagement of constipated patientsrdquo Diseases of the Colon andRectum vol 39 no 6 pp 681ndash685 1996

[35] A Koide T Yamaguchi T Odaka et al ldquoQuantitative analysisof bowel gas using plain abdominal radiograph in patients withirritable bowel syndromerdquo The American Journal of Gastroen-terology vol 95 no 7 pp 1735ndash1741 2000

[36] ldquoImageJ Image Processing and Analysis in Javardquo httpimagejnihgovij

[37] Y Katori M Tsukamoto and H Agenosono ldquoInvestigation ofthe frequency of adverse drug reaction toTsumuraDaikenchutoextract granules for ethical use in Japanrdquo Progress in Medicinevol 32 no 9 pp 1973ndash1982 2012 (Japanese)

[38] K Winge D Rasmussen and L M Werdelin ldquoConstipation inneurological diseasesrdquo Journal of Neurology Neurosurgery andPsychiatry vol 74 no 1 pp 13ndash19 2003

[39] S F Lim and C Childs ldquoA systematic review of the effectivenessof bowel management strategies for constipation in adults withstrokerdquo International Journal of Nursing Studies vol 50 no 7pp 1004ndash1010 2013

[40] R Sakakibara T Odaka Z Lui et al ldquoDietary herb extract Dai-kenchu-to ameliorates constipation in parkinsonian patients(Parkinsons disease and multiple system atrophy)rdquo MovementDisorders vol 20 no 2 pp 261ndash262 2005

[41] Y Tokita M Yamamoto K Satoh et al ldquoPossible involvementof the transient receptor potential vanilloid type 1 channelin postoperative adhesive obstruction and its prevention by akampo (traditional Japanese) medicine Daikenchutordquo Journalof Pharmacological Sciences vol 115 no 1 pp 75ndash83 2011

[42] K Satoh Y Kase M Yuzurihara K Mizoguchi K Kurauchiand A Ishige ldquoEffect of Dai-kenchu-to (Da-Jian-Zhong-Tang)on the delayed intestinal propulsion induced by chlorpro-mazine in micerdquo Journal of Ethnopharmacology vol 86 no 1pp 37ndash44 2003

[43] H Takami J-I Shikata H Horie J Horiuchi H Sakurai andK Ito ldquoRadioimmunoassay of plasma calcitonin gene-relatedpeptide (CGRP) levels in patients with endocrine tumorrdquoJapanese Journal of Cancer and Chemotherapy vol 16 no 6 pp2219ndash2225 1989 (Japanese)







Editorial Board










Contents






























References

















1 Introduction






0

0

200

220

240

260

280

300

320

340

360

380

400

(nm

)

10 13 16 19 22 25 28 31 34 37 40 43 46 49


mAbs1400

1400

c

























































Acknowledgment


References






























































































































1 Introduction





2 Methods














Control (119899 = 33) EA (119899 = 34) 119875

Sex (female()) 8182 7941 0803




Control 33 1 32 303 0014EA 34 8 26 2353



3 Results








72 randomized


lacked of time






1stassessment

2ndassessment

3rdassessment




0

1

2

3

4

5

6

7



CSBM SBM

Tim

es p

er w

eek

ControlEA

lowast

lowast

lowastP lt 005


0

05

1

15

2

25

3

35

4

45

5


Tim

es p

er w

eek

ControlEA

lowast

lowast

lowastP lt 001

P gt 005



4 Discussion



0

20

40

60

80

100

120


PAC-

QO

L sc

ores

ControlEA

lowast

lowast

lowastP lt 001

P gt 005













References
































1 Introduction






















0

20

40

60

80


Normal Mild Severe

Num

ber o

f sub

ject

s



3 Result





0

20

40

60

80

100

Pre-treatment

Post-treatment


()


0

10

20

30


Num

ber o

f sub

ject

s




4 Discussion






079 + 106 017 + 048lowast


058 + 093 0lowast


025 + 068 0Low stool volume 067 + 101 026 + 050

lowast017 + 057 004 + 020


104 + 108 013 + 045lowast


lowast096 + 120 004 + 020

lowast












References





































1 Introduction























SessionTEA Sham-TEA







3 Results




500

550

600

650

700

750

800

FDControl


lowastP = 0022

The m

axim

um to

lera

ble v

olum

e (m

L)

(a)

500

550

600

650

700

750


Sham-TEA

lowast

lowastP = 0017

TEA

The m

axim

um to

lera

ble v

olum

e (m

L)

(b)


70

75

80

85

90

95


TEASham-TEA

2ndash4

cpm

slow

wav

es (

) lowast

lowastP = 0048


38

39

40

41

42

43

44

Sham-TEA

Dom

inan

t pow

er

TEA

lowast

lowastP = 0043




08

085

09

095

1

105

11

Sham-TEAPostp

repr

andi

al E

GG

pow

er ra

tio

TEA

lowast

lowastP = 0045


0

005

01

015

02


HF(LF

+H

F)

lowast





10

12

14

16

18

20

22

24

26

28

30


lowast

Clin

ical

sym

ptom

scor

es



4 Discussion









Ethical Approval






Acknowledgments


References






















































1 Introduction























obstruct the toilet





2 Acupuncture










Table1Articleso

facupu

ncture

orEA

forC

C

Reference

Stud

ydesig

n(partic

ipants)

Acup

oints

Implem

entatio

nof

acup

uncture

Keyeffi

cacy

results

Adverser

eactions

Wuetal2014

[14]

RCT

(119899=104)

adult

ST25B

L25LI11ST3

7

EA1ST

25B

L25

EA2LI11ST3

7EA

3ST

25B

L25LI11ST3

7C

Mosaprid

ecitrate

Weeklyfre

quency

ofdefecatio

ndefecatio

ndifficulty

lifeandqu

ality

scorew

erea

llim

proved

significantly

inthefou

rgroup

sin

follow-upweeklyfre

quency

ofdefecatio

nof

LI11andST

37(EA2)

was

superio

rtothe

otherthree

grou

ps

NA

Zhangetal2013

[15]

RCT

(119899=553)

adult

ST25ST3

7ST

36B

L25TE

6

EA2

Hz200H

zDFuzheng

liqim

ixture

EA+Dbothof

above

CMosaprid

eand

Macrogol400

0

Allgrou

psdecreasedthed


prop

ertycon

stipatio

nsymptom

gradeaccompanying

symptom

gradeandGITT

EA+Dwas

bette

rthan

othersE

Acouldkeep

long

-term

effect

No

Peng

etal2013

[16]

RCT

(119899=128)

adult

ST25

EA-deep20

to65

mm

indepth

EA-shallow5ndash8

mm

depth

Dlactulose

oralliq

uid

Allgrou

psincreasedthew

eeklydefecatio

nfre

quency

EA-deepcouldkeep

long

-term

effect

No

Chen

etal2013

[17]

RCT

(119899=NA)

adultfem

ale

ST36ST3

7ST

25ST2

8CV

4CV

6EA

Sham

-EA

EAim

proved

constip

ationsymptom

sand

increased

autono

micnervou

ssystem

activ

itiessham-EAno

tNA

Zhou

etal2012

[18]

RCT

(119899=200)

elder

AT34iA

T3A

T4C

O7CO

17

AH8CO

18C

onstipatio

nPo

int

ATaccording

tothe

patte

rnsyn

drom

edifferentia

tion

Csolid

points

Thee

ffectiver

ateAT

920C

760

NA

Xuetal2012

[19]

RCT

(119899=64)

adult

TE6ST

25ST3

6ST

37EA

Hwatoneuroandmuscle

stimulator

Cregu

lare

lectronics

timulator

Thee

ffectiver

ateo

fsho

rtterm

EA546C

290

NA

And

erse

tal2012

[20]

Retro

spectiv

ecases

eries

study

(119899=10)children

Quchi

(LI11)

Fixedindw

ellin

gacup

uncture

needles(09m

min

leng

th)

Afte

ramedianof

3days

ofHICallchild

rendefecated

with

in2h

Localconstip

ationtherapywas

notrequired

No

L-J

WangandL-L

Wang2011[21]

RCT

(119899=100)

adult

Group

1ST

25SP15CV

6CV

4ST

36ST3

7SP

6Group

2BL

33

BL34B

L5B

L23BL

20Alternatively

HApun

ctured

byhand

sHA+moxibustio

ngrain-shaped

moxibustio

nwas

givenatCV

6ST

36

BL25B

L20andotherswith

puncture

Thetotaleffectiv

erateHA+moxibustio

nas

740

(3750)v

ersus5

20

(2650)

NA

Guo

etal2011[22]

RCT

(119899=378)

adult

ST25ST3

7ST

36B

L25TE

6EA

2Hz100H

zDP

lantainandSenn

aGranu

leEA

+Dbothof

thea

bove

Allgrou

psdecreasedthes

coreso

fdefecationcycle

stool

prop

ertycon

stipatio

nsymptom

gradeaccompanying

symptom

gradeandGITT

EA+Dwas

bette

rthan

othersE

AandEA

+Dcouldkeep

long

-term

effect

No

Wangetal2010

[23]

RCT

(119899=95)

adult

ST25

EA-deep45

mm

indepth

EA-shallow5

mm

indepth

Dlactulose

oralliq

uid

EA-deepandEA

-shado

wweres

ignificantly

superio

rto

Dgrou

pin

increasin

gnu

mberu

pto

4andim

proved

CCSEA

-deepworkedfaste

rthanEA

-shado

wNA

Wangetal2010

[24]

RCT

(119899=95)

adult

ST25

EA-deep

EA-shallo

wDD

uphalac

EA-deepwas

similartoEA

-shallo

win

numberu

pto

4andCC

Sandits

efficacy

remainedmuchlonger

NA

Jinetal2010

[25]

Before-afte

rstudy

(119899=90)

adult

Group

1ST

25C

V6ST

37G

roup

2BL

33B

L34BL

25Alternatively

EAB

L33BL

34ST2

5T3

7

Thes

coreso

fdefecationfre

quencydiffi

culty

degree

ofdefecatio

ndefecatio

ntim

eendlesssensatio

nof

defecatio

nsto

olqu

alityawarenesso

fdefecation

and

QoL

wereo

bviouslyim

proved

after

treatmentTh

etotal

effectiv

eratew

as677(619

0)

NA

Dingetal2009

[26]

Before-afte

rstudy

(119899=30)

adult

Group

1ST

25SP15SP

14C

V6

CV4ST

36ST3

7Group

2BL

25

BL23B

L31BL

32B

L33BL

34

Ex-H

N1A

lternatively

Deepneedlin

gwas

appliedon

acup

ointso

fabd

ominalandback

region

andmoxibustio

nwas

puto

nEx

-HN1

Redu

cedlaxativ

escores

fora

warenessandQoL

Increasedfre

quency

ofdefecatio

nNo


Table1Con

tinued

Reference

Stud

ydesig

n(partic

ipants)

Acup

oints

Implem

entatio

nof

acup

uncture

Keyeffi

cacy

results

Adverser

eactions

Zhangetal2007

[27]

RCT

EA SATE

6EA

EAatZh

igou

SAE

Aatno

nacupo

int

EAcouldobviou

slyim

proveC

CSandCT

Tdecrease

cathartic

seffectiv

erateo

f944

No

Zhuetal2003

[28]

Before-afte

rstudy

(119899=188)

adult

ST25ST3

6ST

37B

L25BL

57HA

Totaleffectiver

ateo

f100

NA

Broide

etal2001

[29]

CCT-self

(119899=17)

child

NA

Treatedby

fivew

eeklyplacebo

acup

unctures

essio

nsfollowed

by10

weeklytrue

acup

unctures

essio

ns

Thefrequ

ency

ofbo

welmovem

entsincreasedon

lyaft

er10

true

acup

unctures

essio

nsNA

Klauser

etal1993

[30]

CCT-self

(119899=8)

adult

LI4ST

25LE3

BL2

5EA

10H

zStoo

lfrequ

encies

andCC

Tweren

otaltered

Twopatie

ntsd

ropp

edou

tbecause

symptom

sworsened

RCT

rand

omized

controlledtrialCC


lHAhand-acup

unctureEA

EAA

Tauric

ulotherapySAsham

acup


uncture+

drugE

A+DE

A+drugC

controlPE

patientrsquosendu

ranceMAm

eanagePO

bymou

thC

CSC

leveland

Con

stipatio

nScorenu

mberu

pto

4then

umbero

fcon

stipatio

npatientsw

hose

defecatio

nwas

upto

4tim

esperw

eekBM

sbo

wel

movem

ents

GITTgastr

ointestin

altransit

timeTG

ITTtotalgastro


eM-ITT

mou

th-in

testine

transit

timeCT

Tcolonictransittim

eRC

TTright

colonictransittim

eLC

TTle

ftcolonictransit

timeRS

TTrectosig


eMTL

motilin

QoL

qualityof

lifeCI

con

fidence

intervalQ

Devery

dayBIDtwicep

erdayTIDtrip

leperd

ayN

Anot

acqu

irable
























3 Moxibustion







4 Massage









5 Herbal Medicine














6 Conclusion




References


















































































































1 Introduction


















2 Methods








3 Results






Number of studies


Number of full-text

assessed for

Number of records





(7) Lack of control

(n = 163)

(n = 119)

screened (n = 119)


(n = 8)

(n = 1)

(n = 1)

(n = 1)

(n = 1)

(n = 1)

(n = 5)

(n = 1)

(n = 1)

(n = 2)

(n = 2)

(n = 1)

(n = 14)

(n = 85)

(n = 106)

included

articles






Table1Ch

aracteris

ticsa

ndou

tcom

esof

studies

inclu

dedin

syste

maticreview

Stud

y119873

female

Popu

latio

nInterventio

namp

duratio

nCon

trol

Follo

w-up

IBSseverityat

end-of-in

terventio

nIBSseverityat

follo

w-up

Qualityof

life

Berrill

etal2014

[14]

3877

IBDwith

IBS-type

symptom

sMCT

16weeks

Waitin

glist

(TAU

)8and12

mon

ths

DecreaseinIBS-SS

but

didno

treach

statistical

significance

(325

vs

68

redu

ction

119875=0219)

DecreaseinIBS-SS

but

didno

treach

statistical

significance

(300

vs

0redu

ction

119875=0213)

Not

assessed

Gaylord

etal2011[15]75

100

IBS

Mindfulness-based

stressa

ndpain

managem

ent

program8

weeks

Supp

ortg

roup

3mon

ths

Sign

ificantlygreater

improvem

entinIBS-SS

(264vs62redu

ction

119875=0006)

Improvem

ent

maintained(382vs

118redu

ction

119875=0001)

Sign

ificant

improvem

ent

inIBS-QOLatfollo

w-up

only(119875=0027)

Lj otsson

etal2010

[16]

8585

IBS

ICBT

10weeks

Onlinec

losed

discussio

nforum

3mon

ths

Sign

ificant

improvem

ent

indiarysymptom

ratin

gs(pain

diarrhea

constip

ation

and

bloatin

g)andGSR

S-IBS

(42

redu

ctionvs12


Improvem

entin

GSR

S-IBSmaintained

Sign

ificant

improvem

ent

inIBS-QOLpo

sttre

atment(119875=0001)

furthersignificant

improvem

entatfollow-up

(119875=004)

Lj otsson

etal2011[17]

Long

term

follo

w-upof

Lj otsson

etal(2010)[16]

15ndash18(m

ean=164)

mon

ths

Improvem

entin

GSR

S-IBSmaintained

(119875lt005)

Sign

ificant

improvem

ent


maintainedatfollo

w-up

nodifferenceb

etween

thosew

hodiddidno

tseek

additio

nalcarefor

IBS

Lj otsson

etal2011[18]6

174

IBS

ICBT

10weeks

Onlinec

losed

discussio

nforum

before

crossin

gover

12mon

ths

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(305

redu

ctionvs28

increase)(Coh

enrsquos119889077

(019

ndash13495CI

))

Improvem

entin

GSR

S-IBSmaintained

Sign

ificantlygreater

improvem

entinIBS-QOL

(Coh

enrsquos119889079

(020ndash

135

95CI

))further

improvem

entatfollow-up

(119875=004)

Lj otsson

etal2011[19]19

579

IBS

ICBT

10weeks

Internet-based

stress

managem

ent

6mon

ths

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(236

vs

131

redu

ction)

(difference

inscoreo

f48(12ndash8495CI

))

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(difference

inscoreo

f59(19ndash99

95CI

))

nonsignificanttrend

towards

continued

improvem

ent

Sign

ificantlylarger

improvem

entinIBS-QOL

(difference

inscoreo

f10

(45ndash15695CI

))

maintainedatfollo

w-up

(difference

inscoreo

f62

(02ndash12295CI

))


Table1Con

tinued

Stud

y119873

female

Popu

latio

nInterventio

namp

duratio

nCon

trol

Follo

w-up

IBSseverityat

end-of-in

terventio

nIBSseverityat

follo

w-up

Qualityof

life

Zernicke

etal2013

[20]

9090

IBS

MBS

R8weeks

TAUwaitlist

6mon

ths

Sign

ificantlygreater

improvem

entinIBS-SS

(307vs52redu

ction

119875lt00001am

ong

completers169vs

35

usingITT)

Improvem

ent

maintainedsome

improvem

entseenin

TAUgrou

pleadingto

nosta

tistic

ally

significantd

ifference

(119875=017)

IBS-QOLim

proved

inbo

thgrou

pspo

sttreatmentand

follo

w-up(119875lt0001)

Zomorod

ietal2014

[21]

4844

IBSandhealthy

controls

MBS

Ror

CBT8

weeks

Nopsycho

logical

interventio

n2mon

ths

Not

provided

Sign

ificantlygreater

improvem

entinIBS

questio

nnaire

vsC

BTor

control(350vs

58

119875lt005)

Not

assessed

GSR

S-IBSgastr

ointestin

alsymptom

ratin

gscalemdash

IBSversion

ICBT

internet-b

ased

cogn

itive

behavior

therapywhich

inclu

dese


acceptance

IBS-SSirritableb

owelsynd

romes

everity

score

IBDQinfl

ammatorybo

weldiseaseq

uestion

naire

IBS-QOLirr

itableb

owelsynd

romeq

ualityof

lifeinstrum

ent

MCT

multic


binatio

nof


nandCB

TMBS

Rmindfulness-based

stressredu

ction

TAUtreatmentasu

sual



















YesPartial









Table2Cochraner

iskof

bias

assessmento

fstudies

inclu

dedin

syste

maticreview

Reference

Rand

omsequ

ence

generatio

n(sele

ction

bias)

Allo

catio

nconcealm

ent

(selectio

nbias)

Blinding

ofparticipants

andperson

nel

(perform

ance

bias)

Blinding

ofou

tcom


bias)

Incomplete

outcom

edata

(attrition

bias)

Selective

repo

rting

(reportin

gbias)

Other

bias

Overall

Berrill

etal2014

[14]

Low

Low

High

Unclear

High

Low

Low

High

Gaylord

etal2011

[15]

Low

Unclear

Lowlowast

Low

Unclear

Low

Low

Unclear

Lj otsson

etal2010

[16]

Low

Low

High

Unclear

Low

Low

Unclear

High

Lj otsson

etal2011

(long

term

)[17]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

Low

Low

Low

High

Lj otsson

etal2011

(Acceptability)

[18]

Low

Low

High

Unclear

Unclear

Low

Low

High

Lj otsson

etal2011

(Internet)[19]

Low

Low

Lowlowast

Unclear

Low

Low

Low

Unclear

Zernicke

etal2013

[20]

Low

Unclear

High

Unclear

Unclear

Low

Low

High

Zomorod

ietal

2014

[21]

Unclear

Unclear

Lowlowast

Unclear

Unclear

High

Unclear

High

Lowlowaststudy

participantswereb

lindho

wever

duetothen

atureo

fapsycho

logicalintervention

thosep

roviding


otblind


minus03 01 05 09 13034

029

024

019

014

Effect size

Stan

dard

erro

r

(a)

minus10 minus05 00 05 10 150475

0400

0325

0250

0175

0100

Effect size

Stan

dard

erro

r

(b)

minus02 03 08 13030

026

022

018

014

Effect size

Stan

dard

erro

r

(c)


4 Discussion







minus05 05 10 15 20

Zernicke et al 2013



Gaylord et al 2011

Berrill et al 2014


(acceptability)

(a)

minus04 01 06 11 16 21

Zomorodi et al 2014

Zernicke et al 2013


Gaylord et al 2011

Berrill et al 2014


(internet)

(b)

minus05 05 10 15

Zernicke et al 2013




Gaylord et al 2011


(acceptability)

(c)










5 Conclusions




Acknowledgment


References





































1 Introduction






















3 Results






000020040060080100120140160


Vom

iting

tim

es

Sham-TEATEA


000

050

100

150

200

250


Nau

sea s

core

Sham-TEATEA


000

5000

10000

15000

20000

25000

Before After

Sham-TEATEA

5-H

T (n

gm

L)



000

10000

20000

30000

40000

50000

60000

70000

Before After

DA

(ng

mL)

Sham-TEATEA




4 Discussion









5 Conclusions






Acknowledgments


References
















































1 Introduction









2 Methods









3 Results





Given BiobranN = 20

Given placeboN = 20


N = 40

Enrolled

week 4 N = 19 week 4 N = 20








4 Discussion








GSRSTotal dimension







STAIState



























5 Conclusion


Abbreviations




Acknowledgments


References























































1 Introduction








2 Methods










(a) (b)







3 Results




Group119875lowast


Female 9 8Male 8 9








P lt 001

P = 061

0

5

10

15

20

25

DKT Control

GVS

()






4 Discussion


















(a) (b)




5 Conclusions



Appendix








(0) Less than 5













Acknowledgments



References





















































Contents






























References

















1 Introduction






0

0

200

220

240

260

280

300

320

340

360

380

400

(nm

)

10 13 16 19 22 25 28 31 34 37 40 43 46 49


mAbs1400

1400

c

























































Acknowledgment


References






























































































































1 Introduction





2 Methods














Control (119899 = 33) EA (119899 = 34) 119875

Sex (female()) 8182 7941 0803




Control 33 1 32 303 0014EA 34 8 26 2353



3 Results








72 randomized


lacked of time






1stassessment

2ndassessment

3rdassessment




0

1

2

3

4

5

6

7



CSBM SBM

Tim

es p

er w

eek

ControlEA

lowast

lowast

lowastP lt 005


0

05

1

15

2

25

3

35

4

45

5


Tim

es p

er w

eek

ControlEA

lowast

lowast

lowastP lt 001

P gt 005



4 Discussion



0

20

40

60

80

100

120


PAC-

QO

L sc

ores

ControlEA

lowast

lowast

lowastP lt 001

P gt 005













References
































1 Introduction






















0

20

40

60

80


Normal Mild Severe

Num

ber o

f sub

ject

s



3 Result





0

20

40

60

80

100

Pre-treatment

Post-treatment


()


0

10

20

30


Num

ber o

f sub

ject

s




4 Discussion






079 + 106 017 + 048lowast


058 + 093 0lowast


025 + 068 0Low stool volume 067 + 101 026 + 050

lowast017 + 057 004 + 020


104 + 108 013 + 045lowast


lowast096 + 120 004 + 020

lowast












References





































1 Introduction























SessionTEA Sham-TEA







3 Results




500

550

600

650

700

750

800

FDControl


lowastP = 0022

The m

axim

um to

lera

ble v

olum

e (m

L)

(a)

500

550

600

650

700

750


Sham-TEA

lowast

lowastP = 0017

TEA

The m

axim

um to

lera

ble v

olum

e (m

L)

(b)


70

75

80

85

90

95


TEASham-TEA

2ndash4

cpm

slow

wav

es (

) lowast

lowastP = 0048


38

39

40

41

42

43

44

Sham-TEA

Dom

inan

t pow

er

TEA

lowast

lowastP = 0043




08

085

09

095

1

105

11

Sham-TEAPostp

repr

andi

al E

GG

pow

er ra

tio

TEA

lowast

lowastP = 0045


0

005

01

015

02


HF(LF

+H

F)

lowast





10

12

14

16

18

20

22

24

26

28

30


lowast

Clin

ical

sym

ptom

scor

es



4 Discussion









Ethical Approval






Acknowledgments


References






















































1 Introduction























obstruct the toilet





2 Acupuncture










Table1Articleso

facupu

ncture

orEA

forC

C

Reference

Stud

ydesig

n(partic

ipants)

Acup

oints

Implem

entatio

nof

acup

uncture

Keyeffi

cacy

results

Adverser

eactions

Wuetal2014

[14]

RCT

(119899=104)

adult

ST25B

L25LI11ST3

7

EA1ST

25B

L25

EA2LI11ST3

7EA

3ST

25B

L25LI11ST3

7C

Mosaprid

ecitrate

Weeklyfre

quency

ofdefecatio

ndefecatio

ndifficulty

lifeandqu

ality

scorew

erea

llim

proved

significantly

inthefou

rgroup

sin

follow-upweeklyfre

quency

ofdefecatio

nof

LI11andST

37(EA2)

was

superio

rtothe

otherthree

grou

ps

NA

Zhangetal2013

[15]

RCT

(119899=553)

adult

ST25ST3

7ST

36B

L25TE

6

EA2

Hz200H

zDFuzheng

liqim

ixture

EA+Dbothof

above

CMosaprid

eand

Macrogol400

0

Allgrou

psdecreasedthed


prop

ertycon

stipatio

nsymptom

gradeaccompanying

symptom

gradeandGITT

EA+Dwas

bette

rthan

othersE

Acouldkeep

long

-term

effect

No

Peng

etal2013

[16]

RCT

(119899=128)

adult

ST25

EA-deep20

to65

mm

indepth

EA-shallow5ndash8

mm

depth

Dlactulose

oralliq

uid

Allgrou

psincreasedthew

eeklydefecatio

nfre

quency

EA-deepcouldkeep

long

-term

effect

No

Chen

etal2013

[17]

RCT

(119899=NA)

adultfem

ale

ST36ST3

7ST

25ST2

8CV

4CV

6EA

Sham

-EA

EAim

proved

constip

ationsymptom

sand

increased

autono

micnervou

ssystem

activ

itiessham-EAno

tNA

Zhou

etal2012

[18]

RCT

(119899=200)

elder

AT34iA

T3A

T4C

O7CO

17

AH8CO

18C

onstipatio

nPo

int

ATaccording

tothe

patte

rnsyn

drom

edifferentia

tion

Csolid

points

Thee

ffectiver

ateAT

920C

760

NA

Xuetal2012

[19]

RCT

(119899=64)

adult

TE6ST

25ST3

6ST

37EA

Hwatoneuroandmuscle

stimulator

Cregu

lare

lectronics

timulator

Thee

ffectiver

ateo

fsho

rtterm

EA546C

290

NA

And

erse

tal2012

[20]

Retro

spectiv

ecases

eries

study

(119899=10)children

Quchi

(LI11)

Fixedindw

ellin

gacup

uncture

needles(09m

min

leng

th)

Afte

ramedianof

3days

ofHICallchild

rendefecated

with

in2h

Localconstip

ationtherapywas

notrequired

No

L-J

WangandL-L

Wang2011[21]

RCT

(119899=100)

adult

Group

1ST

25SP15CV

6CV

4ST

36ST3

7SP

6Group

2BL

33

BL34B

L5B

L23BL

20Alternatively

HApun

ctured

byhand

sHA+moxibustio

ngrain-shaped

moxibustio

nwas

givenatCV

6ST

36

BL25B

L20andotherswith

puncture

Thetotaleffectiv

erateHA+moxibustio

nas

740

(3750)v

ersus5

20

(2650)

NA

Guo

etal2011[22]

RCT

(119899=378)

adult

ST25ST3

7ST

36B

L25TE

6EA

2Hz100H

zDP

lantainandSenn

aGranu

leEA

+Dbothof

thea

bove

Allgrou

psdecreasedthes

coreso

fdefecationcycle

stool

prop

ertycon

stipatio

nsymptom

gradeaccompanying

symptom

gradeandGITT

EA+Dwas

bette

rthan

othersE

AandEA

+Dcouldkeep

long

-term

effect

No

Wangetal2010

[23]

RCT

(119899=95)

adult

ST25

EA-deep45

mm

indepth

EA-shallow5

mm

indepth

Dlactulose

oralliq

uid

EA-deepandEA

-shado

wweres

ignificantly

superio

rto

Dgrou

pin

increasin

gnu

mberu

pto

4andim

proved

CCSEA

-deepworkedfaste

rthanEA

-shado

wNA

Wangetal2010

[24]

RCT

(119899=95)

adult

ST25

EA-deep

EA-shallo

wDD

uphalac

EA-deepwas

similartoEA

-shallo

win

numberu

pto

4andCC

Sandits

efficacy

remainedmuchlonger

NA

Jinetal2010

[25]

Before-afte

rstudy

(119899=90)

adult

Group

1ST

25C

V6ST

37G

roup

2BL

33B

L34BL

25Alternatively

EAB

L33BL

34ST2

5T3

7

Thes

coreso

fdefecationfre

quencydiffi

culty

degree

ofdefecatio

ndefecatio

ntim

eendlesssensatio

nof

defecatio

nsto

olqu

alityawarenesso

fdefecation

and

QoL

wereo

bviouslyim

proved

after

treatmentTh

etotal

effectiv

eratew

as677(619

0)

NA

Dingetal2009

[26]

Before-afte

rstudy

(119899=30)

adult

Group

1ST

25SP15SP

14C

V6

CV4ST

36ST3

7Group

2BL

25

BL23B

L31BL

32B

L33BL

34

Ex-H

N1A

lternatively

Deepneedlin

gwas

appliedon

acup

ointso

fabd

ominalandback

region

andmoxibustio

nwas

puto

nEx

-HN1

Redu

cedlaxativ

escores

fora

warenessandQoL

Increasedfre

quency

ofdefecatio

nNo


Table1Con

tinued

Reference

Stud

ydesig

n(partic

ipants)

Acup

oints

Implem

entatio

nof

acup

uncture

Keyeffi

cacy

results

Adverser

eactions

Zhangetal2007

[27]

RCT

EA SATE

6EA

EAatZh

igou

SAE

Aatno

nacupo

int

EAcouldobviou

slyim

proveC

CSandCT

Tdecrease

cathartic

seffectiv

erateo

f944

No

Zhuetal2003

[28]

Before-afte

rstudy

(119899=188)

adult

ST25ST3

6ST

37B

L25BL

57HA

Totaleffectiver

ateo

f100

NA

Broide

etal2001

[29]

CCT-self

(119899=17)

child

NA

Treatedby

fivew

eeklyplacebo

acup

unctures

essio

nsfollowed

by10

weeklytrue

acup

unctures

essio

ns

Thefrequ

ency

ofbo

welmovem

entsincreasedon

lyaft

er10

true

acup

unctures

essio

nsNA

Klauser

etal1993

[30]

CCT-self

(119899=8)

adult

LI4ST

25LE3

BL2

5EA

10H

zStoo

lfrequ

encies

andCC

Tweren

otaltered

Twopatie

ntsd

ropp

edou

tbecause

symptom

sworsened

RCT

rand

omized

controlledtrialCC


lHAhand-acup

unctureEA

EAA

Tauric

ulotherapySAsham

acup


uncture+

drugE

A+DE

A+drugC

controlPE

patientrsquosendu

ranceMAm

eanagePO

bymou

thC

CSC

leveland

Con

stipatio

nScorenu

mberu

pto

4then

umbero

fcon

stipatio

npatientsw

hose

defecatio

nwas

upto

4tim

esperw

eekBM

sbo

wel

movem

ents

GITTgastr

ointestin

altransit

timeTG

ITTtotalgastro


eM-ITT

mou

th-in

testine

transit

timeCT

Tcolonictransittim

eRC

TTright

colonictransittim

eLC

TTle

ftcolonictransit

timeRS

TTrectosig


eMTL

motilin

QoL

qualityof

lifeCI

con

fidence

intervalQ

Devery

dayBIDtwicep

erdayTIDtrip

leperd

ayN

Anot

acqu

irable
























3 Moxibustion







4 Massage









5 Herbal Medicine














6 Conclusion




References


















































































































1 Introduction


















2 Methods








3 Results






Number of studies


Number of full-text

assessed for

Number of records





(7) Lack of control

(n = 163)

(n = 119)

screened (n = 119)


(n = 8)

(n = 1)

(n = 1)

(n = 1)

(n = 1)

(n = 1)

(n = 5)

(n = 1)

(n = 1)

(n = 2)

(n = 2)

(n = 1)

(n = 14)

(n = 85)

(n = 106)

included

articles






Table1Ch

aracteris

ticsa

ndou

tcom

esof

studies

inclu

dedin

syste

maticreview

Stud

y119873

female

Popu

latio

nInterventio

namp

duratio

nCon

trol

Follo

w-up

IBSseverityat

end-of-in

terventio

nIBSseverityat

follo

w-up

Qualityof

life

Berrill

etal2014

[14]

3877

IBDwith

IBS-type

symptom

sMCT

16weeks

Waitin

glist

(TAU

)8and12

mon

ths

DecreaseinIBS-SS

but

didno

treach

statistical

significance

(325

vs

68

redu

ction

119875=0219)

DecreaseinIBS-SS

but

didno

treach

statistical

significance

(300

vs

0redu

ction

119875=0213)

Not

assessed

Gaylord

etal2011[15]75

100

IBS

Mindfulness-based

stressa

ndpain

managem

ent

program8

weeks

Supp

ortg

roup

3mon

ths

Sign

ificantlygreater

improvem

entinIBS-SS

(264vs62redu

ction

119875=0006)

Improvem

ent

maintained(382vs

118redu

ction

119875=0001)

Sign

ificant

improvem

ent

inIBS-QOLatfollo

w-up

only(119875=0027)

Lj otsson

etal2010

[16]

8585

IBS

ICBT

10weeks

Onlinec

losed

discussio

nforum

3mon

ths

Sign

ificant

improvem

ent

indiarysymptom

ratin

gs(pain

diarrhea

constip

ation

and

bloatin

g)andGSR

S-IBS

(42

redu

ctionvs12


Improvem

entin

GSR

S-IBSmaintained

Sign

ificant

improvem

ent

inIBS-QOLpo

sttre

atment(119875=0001)

furthersignificant

improvem

entatfollow-up

(119875=004)

Lj otsson

etal2011[17]

Long

term

follo

w-upof

Lj otsson

etal(2010)[16]

15ndash18(m

ean=164)

mon

ths

Improvem

entin

GSR

S-IBSmaintained

(119875lt005)

Sign

ificant

improvem

ent


maintainedatfollo

w-up

nodifferenceb

etween

thosew

hodiddidno

tseek

additio

nalcarefor

IBS

Lj otsson

etal2011[18]6

174

IBS

ICBT

10weeks

Onlinec

losed

discussio

nforum

before

crossin

gover

12mon

ths

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(305

redu

ctionvs28

increase)(Coh

enrsquos119889077

(019

ndash13495CI

))

Improvem

entin

GSR

S-IBSmaintained

Sign

ificantlygreater

improvem

entinIBS-QOL

(Coh

enrsquos119889079

(020ndash

135

95CI

))further

improvem

entatfollow-up

(119875=004)

Lj otsson

etal2011[19]19

579

IBS

ICBT

10weeks

Internet-based

stress

managem

ent

6mon

ths

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(236

vs

131

redu

ction)

(difference

inscoreo

f48(12ndash8495CI

))

Sign

ificantlylarger

improvem

entin

GSR

S-IBS(difference

inscoreo

f59(19ndash99

95CI

))

nonsignificanttrend

towards

continued

improvem

ent

Sign

ificantlylarger

improvem

entinIBS-QOL

(difference

inscoreo

f10

(45ndash15695CI

))

maintainedatfollo

w-up

(difference

inscoreo

f62

(02ndash12295CI

))


Table1Con

tinued

Stud

y119873

female

Popu

latio

nInterventio

namp

duratio

nCon

trol

Follo

w-up

IBSseverityat

end-of-in

terventio

nIBSseverityat

follo

w-up

Qualityof

life

Zernicke

etal2013

[20]

9090

IBS

MBS

R8weeks

TAUwaitlist

6mon

ths

Sign

ificantlygreater

improvem

entinIBS-SS

(307vs52redu

ction

119875lt00001am

ong

completers169vs

35

usingITT)

Improvem

ent

maintainedsome

improvem

entseenin

TAUgrou

pleadingto

nosta

tistic

ally

significantd

ifference

(119875=017)

IBS-QOLim

proved

inbo

thgrou

pspo

sttreatmentand

follo

w-up(119875lt0001)

Zomorod

ietal2014

[21]

4844

IBSandhealthy

controls

MBS

Ror

CBT8

weeks

Nopsycho

logical

interventio

n2mon

ths

Not

provided

Sign

ificantlygreater

improvem

entinIBS

questio

nnaire

vsC

BTor

control(350vs

58

119875lt005)

Not

assessed

GSR

S-IBSgastr

ointestin

alsymptom

ratin

gscalemdash

IBSversion

ICBT

internet-b

ased

cogn

itive

behavior

therapywhich

inclu

dese


acceptance

IBS-SSirritableb

owelsynd

romes

everity

score

IBDQinfl

ammatorybo

weldiseaseq

uestion

naire

IBS-QOLirr

itableb

owelsynd

romeq

ualityof

lifeinstrum

ent

MCT

multic


binatio

nof


nandCB

TMBS

Rmindfulness-based

stressredu

ction

TAUtreatmentasu

sual



















YesPartial









Table2Cochraner

iskof

bias

assessmento

fstudies

inclu

dedin

syste

maticreview

Reference

Rand

omsequ

ence

generatio

n(sele

ction

bias)

Allo

catio

nconcealm

ent

(selectio

nbias)

Blinding

ofparticipants

andperson

nel

(perform

ance

bias)

Blinding

ofou

tcom


bias)

Incomplete

outcom

edata

(attrition

bias)

Selective

repo

rting

(reportin

gbias)

Other

bias

Overall

Berrill

etal2014

[14]

Low

Low

High

Unclear

High

Low

Low

High

Gaylord

etal2011

[15]

Low

Unclear

Lowlowast

Low

Unclear

Low

Low

Unclear

Lj otsson

etal2010

[16]

Low

Low

High

Unclear

Low

Low

Unclear

High

Lj otsson

etal2011

(long

term

)[17]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

AsLj otsson

etal2010

[16]

Low

Low

Low

High

Lj otsson

etal2011

(Acceptability)

[18]

Low

Low

High

Unclear

Unclear

Low

Low

High

Lj otsson

etal2011

(Internet)[19]

Low

Low

Lowlowast

Unclear

Low

Low

Low

Unclear

Zernicke

etal2013

[20]

Low

Unclear

High

Unclear

Unclear

Low

Low

High

Zomorod

ietal

2014

[21]

Unclear

Unclear

Lowlowast

Unclear

Unclear

High

Unclear

High

Lowlowaststudy

participantswereb

lindho

wever

duetothen

atureo

fapsycho

logicalintervention

thosep

roviding


otblind


minus03 01 05 09 13034

029

024

019

014

Effect size

Stan

dard

erro

r

(a)

minus10 minus05 00 05 10 150475

0400

0325

0250

0175

0100

Effect size

Stan

dard

erro

r

(b)

minus02 03 08 13030

026

022

018

014

Effect size

Stan

dard

erro

r

(c)


4 Discussion







minus05 05 10 15 20

Zernicke et al 2013



Gaylord et al 2011

Berrill et al 2014


(acceptability)

(a)

minus04 01 06 11 16 21

Zomorodi et al 2014

Zernicke et al 2013


Gaylord et al 2011

Berrill et al 2014


(internet)

(b)

minus05 05 10 15

Zernicke et al 2013




Gaylord et al 2011


(acceptability)

(c)










5 Conclusions




Acknowledgment


References





































1 Introduction






















3 Results






000020040060080100120140160


Vom

iting

tim

es

Sham-TEATEA


000

050

100

150

200

250


Nau

sea s

core

Sham-TEATEA


000

5000

10000

15000

20000

25000

Before After

Sham-TEATEA

5-H

T (n

gm

L)



000

10000

20000

30000

40000

50000

60000

70000

Before After

DA

(ng

mL)

Sham-TEATEA




4 Discussion









5 Conclusions






Acknowledgments


References
















































1 Introduction









2 Methods









3 Results





Given BiobranN = 20

Given placeboN = 20


N = 40

Enrolled

week 4 N = 19 week 4 N = 20








4 Discussion








GSRSTotal dimension







STAIState



























5 Conclusion


Abbreviations




Acknowledgments


References























































1 Introduction








2 Methods










(a) (b)







3 Results




Group119875lowast


Female 9 8Male 8 9








P lt 001

P = 061

0

5

10

15

20

25

DKT Control

GVS

()






4 Discussion


















(a) (b)




5 Conclusions



Appendix








(0) Less than 5













Acknowledgments



References















































complementary and alternative therapies for functional ......complementary and alternative therapies...

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