Q1

Q5Q2

Gastroenterology 2014;-:1–3

All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line.Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

American Gastroenterological Association Institute Guidelineon the Pharmacological Management of IrritableBowel Syndrome

69

70

71

72

73

74

David S. Weinberg,1 Walter Smalley,2 Joel J. Heidelbaugh,3 and Shahnaz Sultan4

1Fox Chase Cancer Center, Philadelphia, Pennsylvania; 2VA Tennessee Valley Healthcare System, Vanderbilt University,Nashville, Tennessee; 3University of Michigan Ann Arbor, Michigan; and 4Department of Veterans Affairs Medical Center,Gastroenterology Section, North Florida/South Georgia Veterans Health System, Division of Gastroenterology, Hepatology,and Nutrition, University of Florida, Gainesville, Florida

75

76

77

78

his document presents the official recommendations

Abbreviations used in this paper: AGA, American Gastroenterological As-sociation; FDA, Food and Drug Administration; GRADE, Grading of Rec-ommendations Assessment, Development and Evaluation; IBS, irritablebowel syndrome; IBS-C, irritable bowel syndromewith constipation; IBS-D,irritable bowel syndrome with diarrhea; RCT, randomized controlled trial.

© 2014 by the AGA Institute0016-5085/$36.00

http://dx.doi.org/10.1053/j.gastro.2014.09.001

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

AGASE

CTION

Tof the American Gastroenterological Association(AGA) on the use of pharmacological agents for the treatmentof irritable bowel syndrome (IBS) in adults. The guidelinewas developed by the Clinical Practice and Quality MeasuresCommittee (currently the Clinical Practice Guideline Com-mittee) and approved by the AGA Governing Board.

The guideline was developed using a process outlinedelsewhere.1 Briefly, the AGA process for developing clinicalpractice guidelines incorporates Grading of Recommenda-tions Assessment, Development and Evaluation (GRADE)methodology2 and best practices as outlined by the Instituteof Medicine.3 GRADE methodology was used to prepare thebackground information for the guideline and the technicalreview that accompanies it (Table 1).4 Optimal under-standing of this guideline will be enhanced by readingapplicable portions of the technical review.

Members of the guideline panel, along with AGA supportstaff and a patient/consumer representative, met in personwith the authors of the technical review on April 11, 2014.The information in the technical review was discussed in asystematic manner, facilitating subsequent creation of theguideline recommendations for or against each intervention.The strength of each recommendation was also rated aseither strong or conditional.1

IBS is complex and encompasses several subgroups,including patients with constipation-predominant symptoms(IBS-C) and those with diarrhea-predominant symptoms(IBS-D). Many of the pharmacotherapy recommendationsoutlined in the following text apply to only one of thesesubgroups. The recommendations in this report apply topatients who meet the diagnostic criteria for IBS (IBS-C, IBS-D) and do not apply to the use of these agents for othersymptoms or conditions. Use of nonpharmaceutical agents(fiber) and other interventions (dietary modification,biofeedback, acupuncture) used in the treatment of patientswith IBS are not covered here.

1. Should Linaclotide Be Used inPatients With IBS-C?

The pooled effect estimates of 2 randomized controlledtrials (RCTs) of linaclotide in patients with IBS-C showed amodest beneficial effect with a combined improvement in

PGL 5.2.0 DTD � YGAST59331_proof �

abdominal pain and an increase in the number of completespontaneous bowel movements (Food and Drug Administra-tion [FDA] response). Additionally, these 2RCTs (plus anotherphase2b trial) showedan improvement in global symptomsofIBS. Diarrhea leading to treatmentdiscontinuationoccurred ina small percentage of treated patients. This recommendationwas made without taking resource use into account.

The AGA recommends using linaclotide (over nodrug treatment) in patients with IBS-C. (Strongrecommendation; High-quality evidence)

Comments: Patients who place a high value onavoiding diarrhea and avoiding higher out-of-pocketexpenses associated with linaclotide may preferalternate treatments.

2. Should Lubiprostone Be Used inPatients With IBS-C?

There are 2 randomized controlled trials of 12-weekduration examining the effectiveness of lubiprostone forglobal symptom relief in patients with IBS-C, with a pooledeffect estimate showing a small improvement in globalsymptoms of IBS. There were few adverse effects from usinglubiprostone. More data on patient-important outcomes,such as improvement in the number of spontaneous bowlmovements and abdominal pain, are still needed.

The AGA suggests using lubiprostone (over no drugtreatment) in patients with IBS-C. (Conditionalrecommendation; Moderate-quality evidence)

Comments: Patients who place a high value onavoiding higher out-of-pocket expenses associatedwith lubiprostone may prefer alternate treatments.

24 September 2014 � 2:53 pm � ce

Table 1.GRADE Quality of Evidence, Strength ofRecommendations, and Implications

Implications of strong and conditional (weak) guidelinerecommendations� Strong recommendations

B Patients: Most people in this situation would want the rec-ommended course of action, and only a small proportionwould not. Formal decision aids are not likely to be needed tohelp patients make decisions consistent with their values andpreferences.

B Clinicians: Most patients should receive the recommendedcourse of action. Adherence to this recommendation ac-cording to guidelines could be used as a quality criterion or aperformance indicator.

B Policy makers: The recommendation can be adapted as apolicy in most situations.

� Conditional (weak) recommendationsB Patients: The majority of people in this situation would want

the suggested course of action, but many would not. Deci-sion aids are useful in helping patients make decisionsconsistent with their values and preferences.

B Clinicians: Examine a summary of the evidence to help pa-tients make a decision that is consistent with their ownvalues and preferences (shared decision making).

B Policy makers: There is a need for substantial debate andinvolvement of stakeholders.

NOTE. Reprinted with permission from Sultan et al.2

2 Weinberg et al Gastroenterology Vol. -, No. -

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

AGASECTION

3. Should PEG Laxatives Be Used inPatients With IBS-C?

There are several trials examining the use of PEG laxa-tives in patients with chronic constipation; however, there isonly one RCT evaluating the use of PEG solution for treatingpatients with IBS-C. This 4-week trial did not show abeneficial effect of PEG laxatives on IBS-related globalsymptom relief. However, these results should be inter-preted with caution due to sparse data, methodological is-sues, and short follow-up. A large body of indirect evidence(showing efficacy of PEG laxatives for chronic constipationand for bowel lavage before colonoscopy) shows that laxa-tives are effective in increasing the frequency of bowelmovements. Therefore, PEG laxatives may be useful in pa-tients with IBS-C for specific symptom relief or as adjunctivetreatment. Notably, there are few reported adverse effectsand the cost is very low.

The AGA suggests using laxatives (over no drugtreatment) in patients with IBS-C. (Conditionalrecommendation; Low-quality evidence)

4. Should Rifaximin Be Used in PatientsWith IBS-D?

Pooled data from 2 RCTs showed a small but beneficialeffect based on the combination of improvement inabdominal pain plus improvement in stool consistency (FDAresponse) in patients treated with rifaximin. ThreeRCTs demonstrated an improvement in IBS-related global

PGL 5.2.0 DTD � YGAST59331_proof �

symptoms. Additionally, these studies showed small im-provements in abdominal pain and bloating, although thesewere of uncertain clinical significance. It is important tonote that patients were treated for 2 weeks only and there isno evidence to support repetitive treatment. Although sideeffects were minimal, the cost of treatment for many pa-tients may be quite high. At present, rifaximin is notapproved by the FDA for the treatment of IBS-D.

The AGA suggests using rifaximin (over no drugtreatment) in patients with IBS–D. (Conditionalrecommendation; Moderate-quality evidence)

5. Should Alosetron Be Used in PatientsWith IBS-D?

Based on pooled data from multiple RCTs, patientstreated with alosetron had improvement in abdominal painand IBS-related global symptoms. Also, postmarketing datafrom an observational study suggested only rare occur-rences of harm. The overall quality of the evidence wasmoderate (due to downgrading for inconsistency). Whenlimited to consideration of abdominal pain improvement asthe primary outcome, the quality of the evidence is greater(high). Several important caveats should be noted; alosetronis only FDA approved for use in women, and because ofconcerns about idiopathic, non–dose-dependent ischemiccolitis (approximately 1 case/1000 patient-years), the drugwas voluntarily withdrawn from the market and subse-quently reintroduced only under a specific physician-basedrisk management program.

The AGA suggests using alosetron (over no drugtreatment) in patients with IBS-D to improve globalsymptoms. (Conditional recommendation; Moderateevidence)

6. Should Loperamide Be Used inPatients With IBS-D?

Available data investigating the use of loperamide spe-cifically for the treatment of patients with IBS-D, as opposedto symptomatic relief of diarrhea for other disease states, isvery limited. Two older RCTs that in the aggregate enrolled42 patients failed to show a significant benefit in globalrelief of IBS-related symptoms. However, the quality of ev-idence from these trials was deemed very low due tomethodological concerns and sparse data. There is, how-ever, a large body of indirect evidence from a variety ofother settings that shows the efficacy of loperamide inreducing stool frequency. Therefore, because of low cost,wide availability, and minimal adverse effects, loperamidecan be viewed as a useful adjunct to other IBS-D therapies.

The AGA suggests using loperamide (over no drugtreatment) in patients with IBS-D. (Conditionalrecommendation; Very low-quality evidence)

24 September 2014 � 2:53 pm � ce

240

4

3

- 2014 AGA Section 3

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

AGASE

CTION

7. Should Tricyclic Antidepressants BeUsed in Patients With IBS?

A systematic review of multiple RCTs of 6- to 12-weekduration showed a modest improvement in global reliefand abdominal pain in patients treated with tricyclic anti-depressants, although the overall body of evidence was lowquality. Tricyclic antidepressants are a low-cost option fortreatment of symptoms in patients with IBS; however, theyshould be used with caution in patients at risk for prolon-gation of the QT interval. In some patients, mild sedationmay be a beneficial effect.

The AGA suggests using tricyclic antidepressants(over no drug treatment) in patients with IBS.(Conditional recommendation; Low-quality evidence)

8. Should Selective Serotonin ReuptakeInhibitors Be Used in Patients With IBS?

Pooled estimates from 5 RCTs of 6- to 12-week durationshowed no improvement in global relief symptoms. Also, 4RCTs of 6- to 12-week duration showed no improvement inabdominal pain. The risk of important adverse effects isminimal.

The AGA suggests against using selective serotoninreuptake inhibitors for patients with IBS. (Condi-tional recommendation; Low-quality evidence)

9. Should Antispasmodics Be Used inPatients With IBS?

A meta-analysis of 22 RCTs showed significantimprovement in IBS-related global symptoms. Studies alsoshowed modest improvement in abdominal pain symptomswith minimal risk of important adverse effects. The overallquality of evidence was low due to methodological limita-tions, heterogeneity, and publication bias. Notably, the re-ported data were based on continuous use, not as neededuse, and not all antispasmodics studied are currentlyavailable in the United States.

The AGA suggests using antispasmodics (over nodrug treatment) in patients with IBS. (Conditionalrecommendation; Low-quality evidence)

SummaryIBS is the most common diagnosis in clinical gastroen-

terology. It is estimated that approximately 10% to 15% ofthe general adult population is affected. Using the GRADEframework, this guideline offers 9 recommendations aboutpharmacological therapy for IBS-C and IBS-D. For thisreview, the important role of nonpharmacological therapies,including dietary and lifestyle modification, was notconsidered.

PGL 5.2.0 DTD � YGAST59331_proof �

Despite the large number of published studies, in mostcases our recommendations are weak because either (1) thequality of the available data and/or (2) the balance of risksand benefits for a particular therapy do not overwhelminglysupport its use. In one case, alosetron for IBS-D, ourrecommendation is conditional, reflecting additional limi-tations based on FDA requirements. Given the growing focuson the need to show the comparative effectiveness of ther-apeutic alternatives, it is important to note that essentiallyno studies exist in this area comparing commonly usedtherapies with each other. Further, there are no substantialdata comparing combinations of various therapies withplacebo or with each other. Because no IBS therapy is uni-formly effective, many patients describe a history of avariety of treatments alone or in combination. The presentguideline is unable to address this important and frequentchallenge of clinical care.

Recognizing these and other limitations, the re-commendations included here represent a rigorous,evidence-based summary of extensive literature describingpharmacological therapy for IBS. Review of this guidelineplus the associated technical review hopefully will promoteeffective shared decision making with patients for thiscommon, chronic set of symptoms.

24 S

References

1. American Gastroenterological Association. AGA Institute

clinical practice guideline development process. January2013. http://www.gastro.org/practice/medical-position-statements/aga-institute-clinical-practice-guideline-development-process.

2. Sultan S, Falck-Ytter Y, Inadomi JM. The AGA Instituteprocess for developing clinical practice guidelines partone: grading the evidence. Clin Gastroenterol Hepatol2013;11:329–332.

3. Institute of Medicine. Clinical practice guidelines we cantrust. Washington, DC: Institute of Medicine, 2011.

4. Chang L, Lembo T, Sultan S. American Gastroenterolog-ical Association technical review on the pharmacologicalmanagement of irritable bowel syndrome. Gastroenter-ology 2014;147: xxx–xxx. Q

AcknowledgmentsThe Clinical Guidelines Committee included Steven L. Flamm (NorthwesternFeinberg School of Medicine, Chicago, IL), Lauren Gerson (California PacificMedical Center, San Francisco, CA), Ikuo Hirano (Northwestern UniversitySchool of Medicine, Chicago, IL), Joseph K. Lim (Yale Liver Center, YaleUniversity School of Medicine, New Haven, CT), Geoffrey C. Nguyen (MountSinai Hospital Centre for Inflammatory Bowel Disease, University of Toronto,Toronto, Ontario, Canada), Joel H. Rubenstein (Veterans Affairs Center forClinical Management Research and Division of Gastroenterology, Universityof Michigan Medical School, Ann Arbor, MI), Siddharth Singh (Division ofGastroenterology and Hepatology, Mayo Clinic, Rochester, MN), NeilStollman (University of California San Francisco, Northern CaliforniaGastroenterology Consultants, San Francisco, CA), Santhi S. Vege (PancreasGroup, Division of Gastroenterology and Hepatology, Mayo Clinic,Rochester, MN), and Yu-Xiao Yang (Division of Gastroenterology, PerelmanSchool of Medicine at the University of Pennsylvania, Philadelphia, PA).

Conflicts of interestAll members were required to complete a disclosure statement. Thesestatements are maintained at the American Gastroenterological AssociationInstitute headquarters in Bethesda, Maryland, and pertinent disclosures arepublished with the report. Dr. Stollman has received research support fromFuriex Pharmaceuticals for a study involving an investigational drug for IBS-D Q.

eptember 2014 � 2:53 pm � ce

360