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  • Gastroenterology 2016;150:13931407

    Bowel Disorders

    BOWEL

    Brian E. Lacy,1 Fermn Mearin,2 Lin Chang,3 William D. Chey,4 Anthony J. Lembo,5

    Magnus Simren,6 and Robin Spiller7

    1Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; 2Institute ofFunctional and Motor Digestive Disorders, Centro Mdico Teknon, Barcelona, Spain; 3David Geffen School of Medicine atUCLA, Los Angeles, California; 4University of Michigan Health System, Ann Arbor, Michigan; 5Beth Israel Deaconess MedicalCenter, Harvard Medical School, Boston, Massachusetts; 6Institute of Medicine, Department of Internal Medicine and ClinicalNutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and 7Cantab, University of Nottingham,United Kingdom

    Functional bowel disorders are highly prevalent disordersfound worldwide. These disorders have the potential toaffect all members of society, regardless of age, sex, race,creed, color, or socioeconomic status. Improving our un-derstanding of functional bowel disorders (FBD) is critical,as they impose a negative economic impact to the globalhealth care system in addition to reducing quality of life.Research in the basic and clinical sciences during the pastdecade has produced new information on the epidemi-ology, etiology, pathophysiology, diagnosis, and treatmentof FBDs. These important findings created a need to revisethe Rome III criteria for FBDs, last published in 2006. Thisarticle classifies the FBDs into 5 distinct categories: irri-table bowel syndrome, functional constipation, functionaldiarrhea, functional abdominal bloating/distention, andunspecified FBD. Also included in this article is a new sixthcategory, opioid-induced constipation, which is distinctfrom the functional bowel disorders (FBDs). Each disorderwill first be defined, followed by sections on epidemiology,rationale for changes from prior criteria, clinical evalua-tion, physiologic features, psychosocial features, andtreatment. It is the hope of this committee that this newinformation will assist both clinicians and researchers inthe decade to come.

    Keywords: Abdominal Pain; Bloating; Distension; Constipation;Diarrhea; Functional Bowel Disorders; Irritable BowelSyndrome.

    unctional bowel disorders (FBD) are a spectrum of

    Abbreviations used in this paper: BSFS, Bristol Stool Form Scale; CBC,complete blood count; CC, chronic constipation; DD, dyssynergicdefecation; FAB, functional abdominal bloating; FAD, functional abdom-inal distention; FBD, functional bowel disorder; FC, functionalconstipation; FDr, functional diarrhea; FODMAP, fermentable oligosac-charides, disaccharides, monosaccharides, and polyols; GI, gastrointes-tinal; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome;IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowelsyndrome with diarrhea; IBS-M, irritable bowel syndrome with con-stipation and diarrhea; IBS-U, irritable bowel syndrome unclassified; OIC,opioid-induced constipation.

    Most current article

    2016 by the AGA Institute0016-5085/$36.00

    http://dx.doi.org/10.1053/j.gastro.2016.02.031

    Fchronic gastrointestinal (GI) disorders characterizedby predominant symptoms or signs of abdominal pain,bloating, distention, and/or bowel habit abnormalities (eg,constipation, diarrhea, or mixed constipation and diarrhea).The FBDs can be distinguished from other GI disordersbased on chronicity (6 months of symptoms at the time ofpresentation), current activity (symptoms present withinthe last 3 months), frequency (symptoms present, onaverage, at least 1 day per week), and the absence ofobvious anatomic or physiologic abnormalities identified byroutine diagnostic examinations, as deemed clinicallyappropriate. The FBDs are classified into 5 distinct cate-gories: irritable bowel syndrome (IBS), functional con-stipation (FC), functional diarrhea (FDr), functional

    abdominal bloating/distention, and unspecified FBD(Table 1). Also included in this article is a new sixth cate-gory, opioid-induced constipation (OIC), which is distinctfrom the FBDs by having a specific etiology that can producesimilar symptoms as FC. Clinically, OIC can overlap with FCand so is included in this article, as clinicians may need toevaluate both concurrently and may use different treat-ments. This classification scheme is designed to assist bothresearchers and clinicians; however, it is important toacknowledge that significant overlap exists between thesedisorders, and these disorders should be thought of asexisting on a continuum, rather than discrete disorders(Figure 1). As these disorders exist on a continuum, it maynot always be possible to confidently separate them. Usingevidence from the scientific literature and a consensus-based approach, the 2016 working team has revised theRome III diagnostic criteria and updated the clinical evalu-ation and treatment for all FBDs.

    C1. Irritable Bowel SyndromeDefinition

    IBS is an FBD in which recurrent abdominal pain isassociated with defecation or a change in bowel habits.Disordered bowel habits are typically present (ie, con-stipation, diarrhea, or a mix of constipation and diarrhea), asare symptoms of abdominal bloating/distention. Symptomonset should occur at least 6 months before diagnosis andsymptoms should be present during the last 3 months.

    http://crossmark.crossref.org/dialog/?doi=10.1053/j.gastro.2016.02.031&domain=pdfhttp://dx.doi.org/10.1053/j.gastro.2016.02.031

  • Table 1.Functional Gastrointestinal Disorders

    C. Functional bowel disordersC1. Irritable bowel syndromeC2. Functional constipationC3. Functional diarrheaC4. Functional abdominal bloating/distensionC5. Unspecified functional bowel disordersC6. Opioid-induced constipation

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    EpidemiologyThe world-wide prevalence of IBS is 11.2% (95% con-

    fidence interval: 9.8%12.8%) based on a meta-analysis of80 studies involving 260,960 subjects.1 The incidence of IBSis estimated to be 1.35%1.5%, based on 2 separate lon-gitudinal population studies lasting 10 and 12 years.2,3

    Prevalence rates are higher for women than for men;younger people are more likely to be affected than thoseolder than age 50 years.1

    C1. Diagnostic Criteriaa for Irritable Bowel Syndrome

    Recurrent abdominal pain, on average, at least 1 day perweek in the last 3 months, associated with 2 or more ofthe following criteria:

    Figuandimpoexistabdocom

    1. Related to defecation

    2. Associated with a change in frequency of stool

    re 1. Conceptual framework to explain FBDs. The FBDs areunspecified FBD (U-FBD). Although often thought of as ertant to acknowledge that significant overlap exists betweing on a continuum, rather than as in isolation. This figure iminal pain, in contrast to a patient with FC or FDr, whomon symptoms frequently reported by patients with any FB

    3. Associated with a change in form (appearance) ofstool

    aCriteria fulfilled for the last 3 months with symptomonset at least 6 months before diagnosis.

    Rationale for Changes From Previous CriteriaIn contrast to the Rome III criteria, the term discomfort

    has been eliminated from the current definition and diag-nostic criteria because not all languages have a word fordiscomfort, it has different meanings in different lan-guages, and the term is ambiguous to patients. One study ofIBS patients found that patients exhibited wide variations intheir understanding of this term.4 Another study demon-strated that in 4 of 5 cases, the same individual would bediagnosed with IBS regardless of which descriptor wasused.5

    The current definition involves a change in the fre-quency of abdominal pain, stating that patients should havesymptoms of abdominal pain at least 1 day per week duringthe past 3 months. This is in contrast to Rome III criteria,which defined IBS as the presence of abdominal pain (anddiscomfort) at least 3 days per month. The requirement foran increase in the frequency of abdominal pain is based ondata from the Report on Rome Normative GI symptomsurvey.6

    classified into 5 distinct categories: IBS, FC, FDr, FAB/FAB,xisting as completely separate and discrete disorders, it isen these disorders. These disorders should be thought of asllustrates that a patient with IBS (right) will have symptoms ofdoes not have abdominal pain. Bloating and distention areD.

  • May 2016 Bowel Disorders 1395

    The phrase improvement with defecation was modi-fied in the current definition to related to defecation as alarge subset of IBS patients do not have an improvement inabdominal pain with defecation, but instead report aworsening. Similarly, the word onset was deleted fromcriteria 2 and 3 of the Rome III definition, as not all IBSpatients report the onset of abdominal pain directly coin-ciding with a change in stool frequency or form.

    BOWEL

    Clinical EvaluationThe diagnosis of IBS requires a thoughtful approach,

    limited diagnostic tests, and careful follow-up. The goal ofdiagnostic criteria is to provide a readily useable frameworkthat can be easily applied, recognizing that no single test andno single definition are perfect.7 Because a number of con-ditions have symptoms that can mimic IBS (eg, inflamma-tory bowel disease [IBD], celiac disease, lactose and fructoseintolerance, and microscopic colitis), limited testing may berequired to accurately distinguish these disorders. However,for the majority of patients, when diagnostic criteria for IBSare fulfilled and alarm features are absent, the need fordiagnostic tests should be minimal.8 Using the criteria out-lined here, clinicians should make a positive diagnosis of IBSbased on symptoms and limited testing; performing a bat-tery of tests in all patients suspected of having IBS is notwarranted. The diagnosis of IBS should be made based onthe following 4 key features: clinical history; physicalexamination; minimal laboratory tests; and, when clinicallyindicated, a colonoscopy or other appropriate tests.

    The diagnosis of IBS begins with a careful history.Abdominal pain must be present; the absence of abdominalpain precludes the diagnosis of IBS. Pain can be presentanywhere throughout the abdomen, although it is morecommon in the lower abdomen. A history of disorderedbowel habits (eg, constipation or diarrhea or both) shouldbe identified, along with their temporal association withepisodes of abdominal pain (see Diagnostic Criteria forIrritable Bowel Syndrome Subtypes). Unpredictable bowelpattern (3 different stool form types/week) reinforces thediagnosis of IBS in the diarrhea subtype (IBS-D).9 Anincreasing number of consecutive days without a bowelmovement is associated with the diagnosis of constipation-predominant (IBS) (IBS-C).10 Abnormal stool frequency(>3 bowel movements/day and

  • Figure 2. (A) The BSFS is auseful tool to evaluatebowel habit. The BSFS hasbeen shown to be a reli-able surrogate marker forcolonic transit.19 (B) IBSsubtypes should beestablished according tostool consistency, usingthe BSFS. IBS subtyping ismore accurate whenpatientshaveat least4daysof abnormal bowel habitsper month. Bowel habitsubtypes should be basedon BSFS for days withabnormal bowel habits.

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    abnormalities, patients should not be on any type of medi-cation used to treat bowel habit abnormalities (eg, evalua-tion should occur off laxatives and off antidiarrheal agents).For clinical trials, the IBS subtype should be based on 14days of daily diary reports.12 Figure 2 illustrates a 2-dimensional display of the 4 possible IBS subtypes.

    IBS patients frequently report that symptoms areinduced or exacerbated by meals, although these symptomsare not specific enough to be included in IBS diagnosticcriteria. A variety of other GI (ie, dyspepsia) and non-GIsymptoms (ie, migraine headaches, fibromyalgia, intersti-tial cystitis, dyspareunia) are frequently present in IBSpatients; the presence of these concomitant symptoms lendsfurther support to the diagnosis.1316 The presence of alarmfeatures (a positive family history of colorectal cancer, rectal

    bleeding in the absence of documented bleeding hemor-rhoids or anal fissures, unintentional weight loss, or anemia)does not improve the performance of IBS diagnosticcriteria.17,18 However, it is reasonable to include them in adirected review, as one study showed that the absence ofalarm symptoms reduced the likelihood of organic diseasein subjects with IBS-D symptoms.19 Patients should bequestioned about their diet, with special attention paid tothe ingestion of dairy products, wheat, caffeine, fruits, veg-etables, juices, sweetened soft drinks, and chewing gum,because these can mimic or exacerbate IBS symptoms.Lastly, a brief psychosocial review should be performed.

    A physical examination should be performed in everypatient evaluated for IBS. This reassures the patient andhelps to exclude an organic etiology. The presence of ascites,

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    hepatosplenomegaly, or an abdominal mass warrantsfurther evaluation. An anorectal examination is mandatoryto identify anorectal causes of bleeding, evaluate anorectaltone and squeeze pressure, and identify dyssynergicdefecation.

    The third step in the diagnosis of IBS is to performlimited laboratory studies, if not previously performed. Acomplete blood count (CBC) should be ordered, as thefinding of anemia or an elevated white blood cell countwarrants further investigation. A C-reactive protein or fecalcalprotectin should be measured, as a systematic review andmeta-analysis showed that these tests are helpful inexcluding IBD in patients with symptoms suggestive ofnonconstipated IBS.20 If inflammatory markers are mildlyelevated, but the probability of IBD is low, then tests shouldbe remeasured before performing colonoscopy (if no otherindication for colonoscopy exists).21 Inflammatory markers,including fecal calprotectin, may not be useful in patientswith constipation symptoms. Routine thyroid tests are notindicated in all patients, but can be checked if clinicallywarranted. Serologic tests for celiac disease should be per-formed in patients with IBS-D and IBS-M who fail empirictherapy. Upper gastrointestinal endoscopy with duodenalbiopsies should be performed if serologic tests for celiacdisease are positive or if clinical suspicion is high; duodenalbiopsies can also be used to identify tropical sprue, whichcan mimic IBS symptoms.22 Stool analysis (bacteria, para-sites, and ova) may be useful if diarrhea is the mainsymptom, especially in developing countries where infec-tious diarrhea is prevalent.

    A screening colonoscopy is indicated in patients 50 yearsand older in the absence of warning signs (45 years inAfrican Americans), based on national recommendations.Colonoscopy is also indicated for the presence of alarmsymptoms or signs, a family history of colorectal cancer andpersistent diarrhea that has failed empiric therapy. Biopsiesof different segments of the colon may be required inpatients with chronic diarrhea to rule out microscopiccolitis.23 Bile acid malabsorption may be the cause ofpersistent, watery diarrhea in some patients.24 If empirictherapy fails, scintigraphic evaluation (75SeHCAT test) orpostprandial serum C4 (7a-hydroxy-4-cholesten-3-one) orfibroblast growth factor 19 are diagnostic options, althoughnone are currently widely available. Breath tests to rule outcarbohydrate malabsorption may be useful in some patientswith IBS symptoms and persistent diarrhea.

    Physiologic FeaturesIBS is a multifactorial disorder with a complex patho-

    physiology. Factors that increase the risk of developing IBSinclude genetic, environmental, and psychosocial factors.Factors that trigger the onset or exacerbation of IBS symp-toms include a prior gastroenteritis, food intolerances,chronic stress, diverticulitis, and surgery.25 The resultingpathophysiologic mechanisms are variable and patientindependent, and include altered GI motility, visceralhyperalgesia, increased intestinal permeability, immuneactivation, altered microbiota, and disturbances inbraingut function (Figure 2).

    Psychosocial FeaturesPsychological disturbance is associated with IBS, espe-

    cially in patients who seek medical care,26 and psychosocialfactors affect outcome.27 Regardless of care-seeking status,IBS is associated with more psychiatric distress, sleepdisturbance, affective vulnerability, and over-adjustmentto the environment.28

    TreatmentIBS treatment begins by explaining the condition,

    providing reassurance as to the benign natural history, andeducating the patient about the utility and safety of diag-nostic tests and treatment options. Treatment should bebased on symptom type and severity. In research trials, thevalidated IBS symptom severity scale can be used to quan-tify symptom severity.29

    Although data are limited, lifestyle modifications thatmay improve IBS symptoms include exercise, stress reduc-tion, and attention to impaired sleep.30 Dietary fiber sup-plementation remains a cornerstone of IBS management,although its optimal use can be quite nuanced. A recentsystematic review and meta-analysis identified 12 trialscomparing fiber with control and found only a marginaldifference in the proportion of IBS patients with persistentsymptoms after any type of fiber vs the control interven-tion.31 Subgroup analysis suggested that benefits for IBSsymptoms were confined to soluble (psyllium/ispaghulahusk) and not insoluble (bran) fiber. Certain forms of fiber,and particularly bran, can exacerbate problems of abdom-inal distention and flatulence.32

    Dietary restriction of gluten may improve symptoms insome IBS patients. Two small prospective studies in IBSpatients, in which celiac disease was carefully excluded,demonstrated global symptom improvement.33,34 DietaryFODMAP (fermentable oligosaccharides, disaccharides,monosaccharides, and polyols) restriction is associated withreduced fermentation and significant symptom improve-ment in some IBS patients.35 In a randomized, controlled,single-blind cross-over trial, 30 IBS patients who had notpreviously tried dietary manipulation reported significantreduction in overall gastrointestinal symptom scorescompared with those on a standard Australian diet.36 Add-ing a gluten-free diet to IBS patients already on a lowFODMAP diet does not offer additional benefit.37 Anotherrecent comparative effectiveness study concluded that a lowFODMAP diet and standardized traditional teaching from adietitian yielded similar results in IBS patients.38

    Several peripherally acting agents are available to treatIBS-C symptoms (Table 2). A randomized controlled trial(RCT) of polyethylene glycol (PEG) vs placebo demonstratedimprovements in stool frequency, stool consistency, andstraining, but not abdominal pain or bloating during the 4-week study.39 Lubiprostone is a luminally acting prostonethat selectively activates type 2 chloride channels.40,41 In 2large, placebo-controlled, randomized studies lubiprostone(8 mg twice daily) resulted in significantly higher overallsymptom response compared with placebo during 12 weeksof treatment.42 A subsequent 52-week extension study

  • Table 2.Therapeutic Options for Irritable Bowel Syndrome Based on Predominant Symptom

    Symptom Therapy Dose

    Diarrhea Opioid agonists Loperamide; 24 mg; when necessaryTitrate up to 16 mg/d

    Diet Low/no gluten; low FODMAPBile salt sequestrants cholestyramine (9 g bidtid)

    colestipol (2 g qdbid)colesevelam (625 mg qdbid)

    Probiotics Multiple products availableAntibiotics Rifaximin, 550 mg po tid 14 d5-HT3 antagonists Alosetron (0.51 mg bid)

    Ondansetron (48 mg tid)Ramosetron 5 mg qd

    Mixed opioid agonists/antagonists Eluxadoline, 100 mg bidConstipation Psyllium up to 30 g/d in divided doses

    PEG 1734 g/dChloride channel activators Lubiprostone, 8 mg bidGuanylate Cyclase C agonists Linaclotide 290 mg qd

    Abdominalpain

    Smooth muscle antispasmodics dicycylomine (1020 mg qdqid)

    Otilonium (4080 mg bidtid)Mebeverine (135 mg tid)

    Peppermint oil Enteric-coated capsules, 250750 mg, bidtid

    Tricyclic antidepressants Desipramine (25100 mg qhs), amitriptyline (1050 mg qhs)

    SSRIs paroxetine (1040 mg qd)sertraline (25100 mg qd)citalopram (1040 mg qd)

    Chloride channel activators Lubiprostone 8 mg bidGuanylate cyclase C agonists Linaclotide 290 mg qd5-HT3 antagonists Alosetron 0.51.0 mg bid

    SSRI, selective serotonin reuptake inhibitor; qhs, at bedtime.

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    identified the most common adverse events as nausea anddiarrhea.43 Linaclotide is a 14-amino acid peptide that actsas a guanylate cyclase C agonist. In 2 large phase 3 trials,linaclotide was found to be more effective than placebo atimproving bowel and abdominal symptoms in IBS-Cpatients.4446 A 6-month, double-blind, placebo-controlledphase 3 trial utilized a combined end point, which requiredimprovement of 30% from baseline in mean daily worstabdominal pain score, as well as an increase of 1 completespontaneous bowel movement from baseline for 6 and 12weeks. Linaclotide proved superior to placebo in 12- and26-week studies. Diarrhea was the most commonly reportedadverse event with linaclotide. A second guanylate cyclase Cagonist, plecanatide, is currently in development.47 A smallpilot study showed that supplementation of bile acids usingsodium chenodeoxycholic acid may improve IBS-C symp-toms in some patients.48

    Loperamide, a synthetic peripheral m-opioid receptoragonist that decreases colonic transit, and increases waterand ion absorption, is commonly used to treat IBS-Dpatients. In one small placebo RCT, loperamide improvedstool consistency, pain, urgency, and subjective overallresponse.49 In another study, loperamide improved stoolconsistency, reduced bowel frequency, and reduced in-tensity of pain, although it increased nightly abdominal

    pain.50 There is increasing evidence to support a role forbile acids in the pathophysiology of IBS-D.24 In small pilotstudies, bile acid sequestrants (eg, colesevelam and coles-tipol) improved stool passage and stool consistency.51,52

    Antispasmodics are used to treat abdominal pain andspasms in all IBS subtypes. A meta-analysis involving 12different antispasmodics found this class of drugs to besuperior to placebo for the prevention of recurrent IBSsymptoms.31 A recent meta-analysis found peppermint oil,which also has antispasmodic properties, to be significantlysuperior to placebo for global improvement of IBS symp-toms and improvement in abdominal pain. Heartburn wasthe most common adverse effect.53

    Probiotics may benefit IBS patients through multiplemechanisms.54 Bifidobacterium infantis 35624 led to sig-nificant improvements in abdominal pain/discomfort,bloating/distention, and/or bowel movement difficultycompared with placebo in 2 randomized, placebo-controlledtrials conducted in IBS patients.55,56 A recent meta-analysisthat included 43 clinical trials using different productsfound probiotics to offer benefits for global IBS symptoms,pain, bloating, and flatulence.57

    The US Food and Drug Administration approved rifax-imin, a nonabsorbable antibiotic, for the treatment of IBS-D.In 2 large clinical trials, 2 weeks of treatment with rifaximin

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    550 mg 3 times daily in patients with nonconstipated IBSresulted in significantly more patients reporting adequaterelief of global IBS symptoms and bloating during the first 4weeks of follow-up.58 Improvement in symptoms relative toplacebo persisted for the 10-week follow-up period, eventhough a gradual loss of symptom response was noted.Repeat treatment with rifaximin appears to offer similarefficacy to an initial course of therapy. Patients with IBS-Dwho relapsed during an 18-week follow-up period weremore likely to respond to retreatment with rifaximincompared with placebo.59

    Alosetron, a highly selective 5-HT3 antagonist, is effectiveat relieving pain and reducing stool frequency and rectalurgency in women with IBS-D.31,40 Alosetron is approvedwith restrictions in the United States for women with severeIBS-D beginning at 0.5 mg twice daily. Uncommon adverseevents include ischemic colitis and constipation, 0.95 and0.36 cases per 1000 patient-years, respectively.60 The 5-HT3antagonists ondansetron and ramosetron also appear effec-tive in the treatment of IBS-D.61,62

    Eluxadoline is a novel mixed m-receptor agonist/d-opioidreceptor antagonist that has been developed as a treatmentfor patients with IBS-D.63 In 2 large phase 3 trials involving>2,400 IBS-D patients, a greater percentage of eluxadoline-treated patients (75 and 100 mg oral once daily) werecombined responders (both abdominal pain and diarrhea)during weeks 112 or 126 compared with patients onplacebo. The most common adverse events were nausea(8%), constipation (8%), and abdominal pain (5.0%). Asmall number of patients experienced sphincter of Oddidysfunction or self-limited pancreatitis. All of these patientshad a history of cholecystectomy or significant ethanolconsumption. Eluxadoline should be used at the lower doseand with careful monitoring in these patients.64

    Tricyclic antidepressant agents appear effective intreating IBS symptoms.65 In a 2-month trial of IBS-Dpatients, 10 mg of amitriptyline significantly improved over-all IBS symptoms and reduced the frequency of loose stool andfeelings of incomplete defecation, and led to a completeresponse (defined as loss of all symptoms).66 A recent sys-tematic review and meta-analysis summarized the efficacydata for selective serotonin reuptake inhibitors. Seven trialswere included, demonstrating benefits of selective serotoninreuptake inhibitors over placebo for overall IBS symptoms.65 Anumber of clinical characteristics, including the predominantstool complaint, thepresenceof insomnia, or comorbidanxiety,can influence the choice of antidepressant in an individual IBSpatient. Few data are available on the use of selective norepi-nephrine reuptake inhibitors in IBS.

    Disodium cromoglycate, a mast cell stabilizer, mayimprove symptoms in some IBS-D patients.67 Two recentappropriately powered, high-quality RCTs demonstrated nosignificant efficacy of mesalazine vs placebo in IBS-D.68,69

    Fecal microbiota transplantation, herbal therapies, andcomplementary therapies are also potential treatments,however, these have not been rigorously studied. RCTs haveconsistently failed to show benefit of acupuncture comparedwith sham acupuncture.70 The efficacy of psychological/behavioral therapies including cognitive behavioral therapy

    and hypnotherapy is discussed in detail in the article onpsychological therapies.

    Psychological and behavioral treatments relates tohelping patients control and reduce pain and discomfort andare seen as ancillary to or augmenting medical treatments.Treatments include cognitive behavioral therapy, hypnosis,and various relaxation methods to reduce muscle tensionand autonomic arousal believed to aggravate GI symptoms.A large number of studies in IBS confirm the values of thesetreatments and are discussed in detail in this issue (Bio-psychosocial Aspects of Functional GastrointestinalDisorders).

    C2. Functional ConstipationDefinition

    FC is a functional bowel disorder in which symptoms ofdifficult, infrequent, or incomplete defecation predominate.Patients with FC should not meet IBS criteria, althoughabdominal pain and/or bloating may be present but are notpredominant symptoms. Symptom onset should occur atleast 6 months before diagnosis, and symptoms should bepresent during the last 3 months.

    EpidemiologyFew studies have evaluated the incidence and preva-

    lence of FC. Most studies have focused on patients withchronic constipation (CC), who may or may not meet strictcriteria for FC. One study reported onset rates of 40/1000person-years when patients were resurveyed a median of14.7 months after the initial survey.71 Using modified RomeII criteria, a community study identified a 12-year cumula-tive incidence of constipation of 17.4%.72 In adults, themean prevalence rate of CC is approximately 14%, withrates that range from 1.9% to 40.1%.73 Self-report rates ofconstipation are generally higher compared with use ofRome criteria. Risk factors for FC include female sex,reduced caloric intake, and increasing age.74,75

    C2. Diagnostic Criteriaa for Functional Constipation

    1. Must include 2 or more of the following:b

    a. Straining during more than one-fourth (25%)of defecations

    b. Lumpy or hard stools (BSFS 12) more thanone-fourth (25%) of defecations

    c. Sensation of incomplete evacuation more thanone-fourth (25%) of defecations

    d. Sensation of anorectal obstruction/blockagemore than one-fourth (25%) of defecations

    e. Manual maneuvers to facilitate more than onefourth (25%) of defecations (eg, digital evacu-ation, support of the pelvic floor)

    f. Fewer than 3 spontaneous bowel movementsper week

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    2. Loose stools are rarely present without the use oflaxatives

    3. Insufficient criteria for irritable bowel syndrome

    aCriteria fulfilled for the last 3 months with symptomonset at least 6 months prior to diagnosis.

    bFor research studies, patients meeting criteria for OICshould not be given a diagnosis of FC because it isdifficult to distinguish between opioid side effects andother causes of constipation. However, clinicians recog-nize that these 2 conditions might overlap.

    Rationale for Changes From Previous CriteriaThe following points highlight notable changes from the

    Rome III criteria. It is now specified that abdominal painand/or bloating may be present but are not predominantsymptoms (ie, the patient does not meet criteria for IBS).This supports the concept that FC and IBS-C are disordersthat exist on a continuous spectrum.

    Clinical EvaluationFC can be diagnosed by both subjective and objective

    (measurable) variables. A survey study of patients with CCdetermined that the most frequent symptoms were strain-ing (79%), hard stools (71%), abdominal discomfort (62%),bloating (57%), infrequent bowel movements (57%), andfeelings of incomplete evacuation after a bowel movement(54%).76 When necessary, objective tests can be performedand these measures of stool frequency, daily stool weight(10% in 3 months), rectalbleeding (in the absence of documented bleeding hemor-rhoids or anal fissures), and a family history of colon cancer(or familial polyposis syndromes) should be elicited. A longduration of symptoms refractory to conservative measuresis suggestive of an FBD. By contrast, the new onset of con-stipation might indicate a structural disease.31 It is impor-tant to identify DD because it has a distinct pathophysiologyand is more likely to respond to specific treatments. DD canbe suspected by using specific questionnaires and by per-forming a thorough physical examination, although objec-tive measures are often required (discussed later).78,79

    A physical examination should exclude central nervoussystem disorders and spinal lesions. The abdomen should beexamined for distention, hard stool in a palpable colon, or amass. A careful rectal examination is essential. The peri-neum should be observed both at rest and after the patientstrains as if to have a bowel movement. A digital rectalexamination can identify a fecal impaction, anal stricture, orrectal mass. Inappropriate contraction of the puborectalismuscle and/or anal sphincter during simulated evacuationis consistent with DD.78,79

    A CBC should be obtained if not recently performed.Thyroid-stimulating hormone and serum calcium should beperformed when clinically indicated. All patients aged olderthan50years (45years andolder inAfricanAmericans) shouldhave a screening colonoscopy based on national recommen-dations. The presence of alarm symptoms or a family history ofcolorectal cancer should prompt earlier intervention.

    Testing for slow colonic transit and/or DD is neitherrequired nor justified in all patients. Patients who do notrespond to reasonable trials of empiric therapy should un-dergo diagnostic evaluation to identify physiological sub-groups. Radiopaque markers can be used to evaluate colonictransit; this is inexpensive, simple and safe.80,81 A radio-isotope technique involves less radiation than x-ray studiesand may provide more information,82 although it is avail-able in very few centers. Anorectal manometry and balloonexpulsion testing may help identify DD.83 Defecography maydetect anatomic etiologies, such as intussusception andrectocele with stool retention, as well as inability to relaxthe puborectalis or decrease the anorectal angle withstraining, features typical of DD.84 Electromyography andpudendal nerve latency testing are adjunctive techniques(see section on Anorectal Disorders).

    Physiologic FeaturesSimilar to IBS, symptoms of FC arise due to a variety of

    pathophysiologic processes. Several studies suggest

  • Table 3.Therapeutic Options for Functional Constipation

    Drug Dose

    Psyllium Up to 30 mg/d in divided dosesPEG 1734 g/dChloride channel activators Lubiprostone, 24 mg bidGuanylate cyclase C agonists Linaclotide 145 mg qdPrucalopride 24 mg/d

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    constipation shows familial clustering.85,86 Data supportinga direct genetic cause are sparse.87,88 Limited data frompediatric studies raise the possibility that lifestyle factors inchildhood (low fiber intake, low fluid intake, and ignoringthe call to stool) may play a role in the development ofconstipation.8993 Two studies have shown that high fiberintake reduced the risk of constipation.75,94 Regular exerciseis associated with a significantly reduced risk of con-stipation.75,95,96 Small RCTs have shown that there is nobenefit in increasing fluid intake in those who are hydratednormally.97

    Transit studies in constipated subjects show disparateresults, with slow colonic transit in some patients butnormal transit in others.98100 In those with delayed transit,variations exist with regard to which colonic segment isaffected.101,102 Most FC patients do not have evidence ofvisceral hypersensitivity when evaluated by rectal barostattesting, although some have rectal hyposensitivity.103

    Autonomic dysfunction, morphologic changes in the myen-teric and submucosal plexus, and reduced neurotransmitterlevels (eg, VIP, NO, 5-HT) have been demonstrated in somepatients with slow transit constipation.103108 Confocal mi-croscopy studies and pathology specimens from patientswith slow-transit constipation undergoing colectomy haveshowed reduced numbers of interstitial cells of Cajal.109111

    Psychosocial FeaturesThere is no specific psychological feature or personality

    that is associated with constipation, but constipationreporting, stool output, and gut dysmotility may be affectedby personality, stress, and early toilet training.112 Patientswith severe constipation and normal intestinal transit oftenhave increased psychological distress, and may have mis-perceptions about their bowel frequencies.112,113 In addi-tion, abnormal illness behavior is more common in patientswith chronic constipation compared with nonpatients.114

    Constipation behavior can be learned in early life; delib-erate suppression of defecation leads to reduced stool fre-quency and weight and increased transit time.115

    TreatmentTreatment should begin by educating the patient about

    FC, eliminating medications (prescription, over-the-counter,complementary) that can cause or worsen constipation,asking the patient to maintain a diet that contains anadequate amount of fiber, scheduling routine bathroom timeafter the morning or evening meal, and elevating the feetwith a foot stool or using a toilet that is lower to the ground.If symptoms persist, empiric therapy can be initiated in theabsence of warning signs. If empiric therapy fails after anappropriate clinical trial (ie, 48 weeks), then physiologicaltesting should be considered to identify the underlyingdisorder and initiate the most appropriate treatment.

    Empiric therapy should begin with a fiber supplement(Table 3).116 Insoluble, nonfermentable fiber acceleratestransit by increasing stool biomass leading to direct stimu-lation of secretion and motility. Soluble, more fermentableforms of fiber may accelerate transit via hydrophilic

    properties and the osmotic effects of fermentation by-products. Total fiber intake of 2030 g/d is recom-mended, although dose-dependent bloating, distention, andflatulence can affect tolerability and compliance. Consti-pated patients with severely delayed colon transit and/orobstructed defection are less likely to improve withfiber.31,77

    Prospective RCTs dictating the choice of therapy after apatient fails fiber therapy are not available. However, os-motic agents are often used next, given their safety, cost,and efficacy.31,73,117,118 Osmotic laxatives (eg, lactulose,lactitol, mannitol, and sorbitol) are not absorbed by thesmall intestine; ingestion causes net water and electrolytesecretion, resulting in reduced stool viscosity and increasedfecal biomass with secondary effects on peristalsis.113115

    Side effects include dose-dependent abdominal crampingand bloating.115 PEG, another osmotic agent, has beenevaluated in high-quality RCTs of up to 6 months.116 PEG issuperior to placebo and lactulose in adults and child-ren.119123 Adverse effects of PEG include distention anddiarrhea. Saline laxatives, including magnesium citrate,magnesium sulfate, and sodium and disodium phosphate,induce movement of water into the small intestine andcolon. RCTs evaluating the efficacy of these agents have notbeen performed; they should be used cautiously in theelderly and avoided in those with renal impairment.124

    Stimulant laxatives (diphenylmethane derivatives, eg,bisacodyl, sodium picosulfate, and conjugated anthraqui-none derivatives, eg, cascara sagrada, aloe, and senna)decrease water absorption and stimulate intestinal motilityand prostaglandin release.125127 RCTs have demonstratedclinical benefits for stool frequency and other constipation-associated symptoms with bisacodyl and sodium picosulfatein patients with CC.128,129 The most common side effects areabdominal pain and diarrhea.128,129

    Two pro-secretory agents (secretagogues) improvesymptoms of CC. In 4 week, RCTs of patients with CC,lubiprostone (24 mg twice daily with food) proved superiorto placebo at increasing stool frequency, improving stoolconsistency and reducing straining and overall constipationsymptoms.130132 Nausea and diarrhea were the mostcommon adverse events. In 12-week RCTs, linaclotide (145mg once daily) was more effective than placebo at increasingstool frequency, improving stool consistency, straining, andoverall constipation symptoms.133 The most commontreatment-associated side effect was diarrhea. Plecanatide,another guanylate cyclase C agonist, at 3 mg once daily, mayalso be effective for FC.134

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    Elobixibat is a nonabsorbed, small molecule that inhibitsileal bile acid transporters. Still under development at thistime, elobixibat improves stool frequency and other con-stipation associated symptoms in patients with CC. The mostcommonly reported adverse events have been dose-dependent abdominal pain and diarrhea.135137

    5-HT4 receptor agonists stimulate peristalsis and accel-erate gastrointestinal transit.138140 Tegaserod, a highlyselective, partial 5-HT4 receptor agonist, was found superiorto placebo at improving stool frequency and other con-stipation associated symptoms.141,142 Tegaserod was with-drawn from the United States and most other markets in2007 due to concerns involving possible cardiovascularadverse events. Prucalopride is a dihydrobenzofur-ancarboxamide derivative with greater selectivity for the5-HT4 receptor compared with other 5-HT4 agonists. RCTshave reported that prucalopride (14 mg daily) improvesCC symptoms, including stool frequency, stool consistency,and straining. The most common adverse events of head-aches, nausea, and diarrhea tended to occur within 24 hoursof initiating treatment and were often transient.143,144

    Prunes (50 g or roughly 6 prunes twice daily)145 and hempseed extract (7.5 g twice daily) improved stool frequency andconstipation severity during separate 8-week trials.146 A sys-tematic review that included the results of 5 RCTs concludedthat probiotics may increase stool frequency and improvestool consistency in patients with CCorganisms studiedincluded Bifidobacterium lactis DN-173 010, Lactobacilluscasei Shirota, and Escherichia coli Nissle 1917.147

    C3. Functional DiarrheaDefinition

    Functional diarrhea (FDr) is an FBD characterized byrecurrent passage of loose orwatery stools. Patientswith FDrshould not meet criteria for IBS although abdominal painand/or bloating may be present, but are not predominantsymptoms. Recurrent passage of loose or watery stool onsetshould have occurred at least 6 months before diagnosis andsymptoms should be present during the last 3 months.

    EpidemiologyThe incidence and prevalence of FDr have not been well

    investigated. Using a matched, casecontrol approach, theincidence of FDr was estimated at 5 per 100,000 patient-years, and a preceding infectious gastroenteritis was a sig-nificant risk factor.148 Reported prevalence rates for FDrrange from 1.5% to 17%.149153

    C3. Diagnostic Criteriona for Functional Diarrhea

    Loose or watery stools, without predominant abdominalpain or bothersome bloating, occurring in >25% ofstools.b

    aCriterion fulfilled for the last 3 months with symptomonset at least 6 months before diagnosis

    bPatients meeting criteria for diarrhea-predominant IBSshould be excluded

    Rationale for Changes From Previous Criteria

    Changes from Rome III criteria include removing the

    term mushy, as this was felt to be redundant, and specifyingthat abdominal pain and/or bloating may be present but arenot predominant symptoms (ie, patients do not meetcriteria for IBS). In addition, 75% of stools being loose hasbeen changed to >25% based on data from the RomeNormative GI symptom survey.6

    Clinical EvaluationThe diagnosis of FDr should be made based on 3 key

    features: clinical history; physical examination; and limiteddiagnostic tests. The evaluation should start with a carefulhistory. Diarrhea should be defined by stool form, not fre-quency, as stool consistency correlates well with colontransit.11 IBS should be excluded (see section on IBS). Astool diary incorporating the BSFS (Figure 2) helps to verifystool consistency and excludes pseudodiarrhea.154 A dietaryhistory should be taken to exclude lactose and fructosemalabsorption, and the ingestion of excess amounts of fiberor poorly absorbed carbohydrates. Alarm features, such asunintentional weight loss, diarrhea awakening the patient,recent antibiotic use, hematochezia (in the absence ofdocumented bleeding hemorrhoids or anal fissures), high-volume diarrhea (>250 mL/d), very frequent bowelmovements (>610 per day), evidence of malnutrition, or afamily history of colorectal neoplasia, celiac disease, or in-flammatory bowel disease, should prompt furtherinvestigation.155,156

    The physical examination of a patient with FDr should benormal. A careful anorectal examination should be per-formed to assess anal sphincter tone (especially importantin patients with incontinence), and to identify a mass,fissure, or hemorrhoidal disease (especially important in apatient with hematochezia).

    A CBC and C-reactive protein should be checked in allpatients with chronic diarrhea. A thyroid profile can beperformed if there is clinical suspicion of hyperthyroidism.Serologic tests for celiac disease should be checked in thosethat fail empiric therapy (and consider esophagogas-troduodenoscopy with duodenal biopsies if antibody testsare positive or if clinical suspicion is high). Stool analysis(bacteria, parasites, and ova) should be performed inendemic areas, and fecal calprotectin should be checked ifclinical suspicion for an inflammatory process is high.Giardiasis and tropical sprue should be excluded in theappropriate clinical setting.

    For patients with persistent symptoms, stool specimenscan be analyzed for fecal elastase-1 and fat to identify amalabsorptive process; a negative test should minimize theneed for further diagnostic studies.157 Colonoscopy shouldbe considered in those who have failed empiric therapy, inthose with alarm symptoms, and in all patients older thanage 50 years for screening purposes (older than age 45years in African Americans) based on national recommen-dations. When performed, random biopsies should beobtained from both the right and left colon to rule outmicroscopic colitis. Bile acid malabsorption, which is an

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    often overlooked diagnosis in patients with longstandingdiarrhea, can be identified, when available, by using75SeHCAT.158 Breath tests can identify carbohydratemalabsorption, but if not available, then dietary exclusionof the suspected carbohydrate (eg, 34 weeks) isrecommended.

    Physiologic FeaturesSimilar to other FBDs, no single pathophysiological ab-

    normality can explain the cause of FDr in every patient.Rather, a number of diverse mechanisms seem to contributeto symptom generation, including altered GI motility,braingut disturbances, genetic and environmental factors,prior infections, and psychosocial factors.159 Genetic studiesin FDr patients have not been performed. One study reportedthat fasting and postprandial colonic propagating contrac-tions are increased in FDr, while a small pilot study showednormal left colonic tone during fasting and a reduced dura-tion of increased tone postprandially.160,161 Similar to IBS, aprior infection can lead to post-infectious FDr.162,163

    Psychosocial FeaturesThere are few data on psychological features in FDr

    patients. While anxiety often accompanies IBS, few dataapply specifically to FDr. Acute stress accelerates colonictransit in humans and animals,164 but the relevance of thisfinding to chronic stress, and to FDr patients, is uncertain.

    TreatmentFew studies have evaluated specific treatments for FDr

    patients. Data from studies in patients with other conditionslike IBS-D tend to be extrapolated to the treatment ofpatients with FDr. Dietary interventions and fiber supple-mentation have not been evaluated. Loperamide, a m-opioidagonist, improves stool frequency and consistency, as wellas urgency and incontinence, in patients with FDr andIBS-D.49,50,165 Cholestyramine (4 g twice daily) is effectiveand safe for short-term treatment of patients with FDrpresumably secondary to bile acid malabsorption.166 Pro-biotics, antibiotics, and 5-HT3 antagonists may all improvediarrhea symptoms but have not been tested specifically inFDr patients.

    C4. Functional AbdominalBloating/DistensionDefinition

    Functional abdominal bloating (FAB)/distention (FAD)is characterized by symptoms (subjective) of recurrentabdominal fullness, pressure, or a sensation of trapped gas(FAB), and/or measurable (objective) increase in abdominalgirth (FAD). Patients should not meet criteria for otherFBDs, although mild abdominal pain and/or minor bowelmovement abnormalities may coexist. Symptom onsetshould be at least 6 months before diagnosis and the pre-dominant symptom (bloating or distention) should be pre-sent during the last 3 months.

    FAB and FAD should be classified as a single entity(functional abdominal bloating/distention) although theyencompass 2 different symptoms/signs. These conditionsmay exist independently, although they frequently coincidein the same individual. The distinct nature of these disor-ders is demonstrated by research showing that only 50%60% of patients with bloating have abdominal distentionand the correlation between abdominal bloating and anincrease in abdominal girth is poor.167,168 Further researchmay allow FAB and FAD to be considered separate entities.

    EpidemiologyThe incidence of functional bloating has not been evalu-

    ated in large prospective studies. The prevalence of bloatingis better described. A large (n 2510) telephone survey of USadults reported that 15.9% had symptoms of bloating ordistention in themonth before the interview.169Womenweremore likely to report bloating than men (19.2% vs 10.5%) torate their bloating as severe (23.8% vs 13%). Two other largeprospective studies of US adults identified similar prevalencerates of bloating (21% and 19%).170,171 Patients with FGIDsare more likely to report co-existing symptoms of bloating,especially those with IBS-C and FC.172177

    Rationale for Changes From Previous CriteriaThe current definition includes the addition of the

    phrase abdominal fullness, pressure or a sensation oftrapped gas to reflect commonly reported symptoms. FADhas been added as a separate diagnosis. This addition helpsdistinguish subjective sensations of bloating from theobjective finding of an increase in abdominal girth seen inpatients with FAD. The change in definition also reflects theuse of new technologies (eg, abdominal plethysmography)and a new understanding of the pathophysiology ofdistention. FAD is typically seen in conjunction with FAB,although it can occur independently. A further change fromthe Rome III criteria is the acknowledgment that FAB/FADpatients may also report symptoms of mild abdominal painand/or minor bowel movement abnormalities.

    C4. Diagnostic Criteriaa for Functional AbdominalBloating/Distension

    Must include both of the following:

    1. Recurrent bloating and/or distention occurring,on average, at least 1 day per week; abdominalbloating and/or distention predominates overother symptoms.b

    2. There are insufficient criteria for a diagnosis ofirritable bowel syndrome, functional constipation,functional diarrhea, or postprandial distresssyndrome.

    aCriteria fulfilled for the last 3 months with symptomonset at least 6 months prior to diagnosis.

    bMild pain related to bloating may be present as well asminor bowel movement abnormalities.

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    Clinical Evaluation

    FAB/FAD should be diagnosed based on the following 3

    key features: clinical history, physical examination, andlimited diagnostic studies.

    The evaluation of a patient with abdominal bloatingand/or distention should begin with a careful history, whichincludes the onset of symptoms, the relationship to diet (eg,wheat, dairy, fructose, fiber, nonabsorbable sugars) andbowel habits, and the presence of symptoms suggestive ofother FGIDs. Alarm features, such as anemia and uninten-tional weight loss, should be assessed, as these symptomsmay be evidence of a malabsorptive process. Patients withFAB/FAD typically report a worsening of symptoms as theday progresses, particularly after meals, but alleviation ofsymptoms overnight.178,179 Diurnal worsening of bloating isfrequently accompanied by increased girth.180

    During the physical examination, bloating (subjective)and distention (objective) should be differentiated andexplained to the patient. The term abdominal distentionshould be reserved for patients who show a visible increasein abdominal girth. Evidence of a partial bowel obstructionor organomegaly warrants further evaluation. A pelvic ex-amination should be performed when appropriate.

    Validated guidelines for the evaluation of bloating do notexist. Many clinicians favor empiric therapy in the absence ofwarning signs. Alternatively, limited testingmay be useful. Anabdominal x-ray can evaluate for possible obstruction. A CBCshould be performed if there are warning signs of anemia.Serologic tests can be used to identify celiac disease. If theclinical suspicion for celiac disease is high, or if serologicaltest are positive, an upper endoscopy with duodenal biopsiesshould be performed. Small intestinal bacterial overgrowthcan be evaluated by culturing the jejunal aspirate or by per-forming a breath test, preferably with glucose.181

    Physiologic FeaturesThe pathophysiology of bloating remains incompletely

    understood, in part, because the etiopathophysiology variesfrom patient to patient. Potential causes include visceralhypersensitivity, abnormal intestinal gas transit, impairedevacuation of rectal gas, colonic fermentation, small intes-tine bacterial overgrowth, and gut microbiota alterations.75

    The pathophysiology of abdominal distention is betterunderstood due to innovations in technology, includingabdominal inductance plethysmography, a novel techniquethat can measure abdominal distention. An abnormal vis-cerosomatic reflex involving the diaphragm and theabdominal wall muscles seems to be responsible for thesymptom of distention in many FGID patients.182 The pre-cise etiology of this reflex is unknown; one study of IBSpatients identified a relationship with rectal hypo-sensitivity.183 Slow intestinal transit may contribute todistention in some patients.184

    Psychosocial FeaturesQuestionnaire studies evaluating the psychosocial fea-

    tures of patients with functional abdominal bloating/distention have not been published.

    TreatmentFew therapeutic trials have been conducted in patients

    with FAB/FAD. Most studies have evaluated abdominalbloating in patients with other FGIDs (Tables 2 and 3).Simethicone, an anti-foaming agent, was reported toimprove the frequency and severity of gas, distention, andbloating in one small old study of patients with uppergastrointestinal symptoms.185 a-Galactosidase improvedsymptoms of gas and bloating in healthy volunteers fed ahigh-fat meal.186 In 2 separate 4-week trials, peppermint oilresulted in a significant decrease in abdominal distentioncompared with placebo.187,188 Lubiprostone improvedsymptoms of bloating in 2 phase 2 studies in IBS-C patients(8 mg twice daily) compared with placebo.42 Similarly,linaclotide also improved bloating symptoms in the phase 3studies for chronic idiopathic constipation133 andIBS-C.4446 In CC patients with predominant symptoms ofbloating, linaclotide showed a significant improvement inbloating symptoms.189 Desipramine, in conjunction withcognitive behavioral therapy, resulted in an improvement inbloating, although the effects of desipramine alone remainunclear.190 A small, crossover-trial with citalopram showedan improvement in the number of days without bloating at 3and 6 weeks.191 In a study of 28 patients with abdominalbloating, intravenous neostigmine caused immediate clear-ance of infused jejunal gas compared with placebo.192

    However, in patients with IBS and bloating, pyridostig-mine provided only minimal improvement in bloating.193

    C5. Unspecified Bowel DisordersDefinition

    In some cases, a patient may not fulfill diagnostic criteriafor any of the 4 specific FBDs categories, in which case thepatient should be considered to have an unspecified FBD.

    C5. Diagnostic Criteriona for Unspecified FunctionalBowel Disorder

    Bowel symptoms not attributable to an organic etiologythat do not meet criteria for IBS or functional con-stipation, diarrhea, or abdominal bloating/distentiondisorders.

    aCriterion fulfilled for the last 3 months with symptomonset at least 6 months before diagnosis.

    C6. Opioid-Induced ConstipationOpioid-induced bowel disorders refers to a spectrum of

    disorders that develop secondary to the actions of opioidson the GI tract and the central nervous system. As opiate usehas increased, so has the recognition that these agents havea number of adverse effects on the GI tract. It is the opinionof this committee that opioid-induced effects on the GI tractshould not be considered a distinct FGID, but rather shouldbe categorized as an opioid-induced adverse effect. There is,however, frequently overlap between these disorders. Forexample, FC may overlap with, or exacerbate, OIC (and vice

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    versa). For that reason, it is important to recognize one ofthe most common opioid-induced bowel disorders, OIC,which is the focus of this section.

    DefinitionOIC can be defined as a change, when initiating opioid

    therapy, from baseline bowel habits and defecation patterns,that is characterized by any of the following: reduced bowelfrequency; development or worsening of straining; a senseof incomplete evacuation; or a patients perception ofdistress related to bowel habits.194 The occasional patientmay also develop fecal impaction with overflow inconti-nence, while others may report symptoms compatible withoverlapping opioid-induced bowel disorders (eg, reflux,nausea, bloating).

    C6. Diagnostic Criteria for Opioid-Induced Constipation

    1. New, or worsening, symptoms of constipationwhen initiating, changing, or increasing opioidtherapy that must include 2 or more of thefollowing:

    a. Straining during more than one-fourth (25%)of defecations

    b. Lumpy or hard stools (BSFS 12) more thanone-fourth (25%) of defecations

    c. Sensation of incomplete evacuation more thanone-fourth (25%) of defecations

    d. Sensation of anorectal obstruction/blockagemore than one-fourth (25%) of defecations

    e. Manual maneuvers to facilitate more than one-fourth (25%) of defecations (eg, digital evacu-ation, support of the pelvic floor)

    f. Fewer than three spontaneous bowel move-ments per week

    2. Loose stools are rarely present without the use oflaxatives

    EpidemiologyThe prevalence of OIC is 41% in patients with chronic

    noncancer pain taking opioids, based on a systematic reviewof 8 placebo-controlled studies.195 In a study of cancerpatients taking opioids for pain, the incidence of con-stipation was approximately 94%.196

    Clinical EvaluationThe diagnosis of OIC should be made based on the

    following 3 key features: clinical history, physical examination,and limited diagnostic tests. The first step in the diagnosis ofOIC is to ascertain the relationship of constipation symptomswith the use of opioids to determine whether a temporalrelationship exists (see diagnostic criteria). If a temporal

    relationship exists, then the clinician should identify the type,severity, and frequency of constipation symptoms (eg,reduced stool frequency, straining, sense of incomplete evac-uation, hard stools). The presence of alarm features, such asunintentionalweight loss (>10% in3months), rectal bleeding(in the absence of documented bleeding hemorrhoids or analfissures), and a family history of colon cancer (or familialpolyposis syndromes) should be elicited. A physical exami-nation should be performed to determine whether an organicproblem exists to account for symptoms; a careful anorectalexamination can identify structural issues and DD. Few dataare available regarding the clinical utility of tests in patientswith suspected OIC. If clinically indicated, simple laboratorytests (eg, CBC, complete metabolic profile, serum calcium andthyroid-stimulating hormone) are reasonable, while anabdominal x-ray (kidney, ureter, and bladder) can identifyfecal impaction and the level of stool burden. Patients agedolder than 50 years (45 years and older in African Americans)should have a screening colonoscopy based on national rec-ommendations, as should patients with warning signs (eg,anemia, hematochezia not thought due to hemorrhoidalbleeding or fissures, and a family history of colorectal cancer).

    Physiologic FeaturesThe 3 classes of opioid receptors in the GI tract (m, k, and

    d) are all G-proteincoupled receptors that reduce acetyl-choline release.197 OIC develops when GI tract opioidreceptors are activated by oral opioids leading to a decreasein propulsive activity; an increase in nonpropulsive con-tractions; a decrease in pancreatic, biliary, and gastric se-cretions; and an increase in anal tone. These physiologicchanges may lead to the symptoms of constipationdescribed previously.

    Psychosocial FeaturesAlthough not as extensively studied as IBS or functional

    constipation, patients with OIC report a significant reductionin quality of life.198,199 One-third of patients treated withopioids missed or decreased the dose of prescribed opioidsdue to GI side effects; this can further reduce quality of life.198

    TreatmentThe initial treatment of OIC is similar in many ways to

    the treatment of FC. Laxatives are recommended for boththe prophylaxis and management of OIC in patients withcancer by the European Association for Palliative Care.200

    Lubiprostone, a chloride channel activator, is FDAapproved for the treatment of OIC in adults with noncancerpain.201

    Additional treatment options for patients with OICinvolve the use of opioid receptor antagonists that blockopioid actions either centrally or peripherally, therebyminimizing or preventing the negative effects of opioids onintestinal secretion and colonic propulsion.202 Naloxone andnalbuphine are 2 medications classified as centrally activeagents. Because these agents cross the bloodbrain barrier,they may precipitate opioid withdrawal symptoms.203,204 Acombination product of an opioid antagonist (naloxone) and

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    an opioid agonist (oxycodone) is available in Europe and hasreceived approval for patients with severe pain.

    Peripherally acting m-opioid receptor antagonists blockopioid receptors in the GI, but not central, receptors and thusdo not lead to symptoms of withdrawal. Three agents arenow available. Subcutaneous methylnaltrexone is approvedfor OIC in patients with chronic noncancer pain and forpatients with advanced illness receiving palliative care whohave had an inadequate response to laxative therapy.205,206

    The European Association for Palliative Care guidelinesrecommend subcutaneous methylnaltrexone as a second-linetreatment option for OIC in patients with chronic cancer painwhen traditional laxatives are not effective.200 Alvimopan,available in the United States but not in Europe, is aperipherally acting m-opioid receptor antagonist indicatedonly for preventing or shortening the course of postoperativeileus after bowel resection and is therefore available forhospital use only.207 It is not currently approved for use inOIC in either Europe or the United States. Naloxegol, an oralPEGylated derivative of naloxone, was approved by the FDAfor the treatment of OIC in adult patients with noncancerpain in September 2014.208 Naloxegol was approved by theEuropean Medicines Agency for the treatment of OIC, butwithout the limitation of restricting use to noncancer painpatients. Another peripherally acting m-opioid receptorantagonist, Naldemedine, has successfully completed earlyclinical trials at the time of this publication.

    Supplementary MaterialNote: The first 50 references associated with this article areavailable below in print. The remaining references accom-panying this article are available online only with the elec-tronic version of the article. Visit the online version ofGastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/j.gastro.2016.02.031.

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    Reprint requestsAddress requests for reprints to: Brian E. Lacy, PhD, MD, Division ofGastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, 1Medical Center Drive, Lebanon, New Hampshire 03755. e-mail:[email protected]; fax: (603) 650-5225.

    Conflicts of interestThe authors disclose no conflicts.

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