Gut 1999;45(Suppl II):II43–II47
`
`II43
`
`Functional bowel disorders and functional
`abdominal pain
`
`W G Thompson, G F Longstreth, D A Drossman, K W Heaton, E J Irvine,
`S A Müller-Lissner
`
`Abstract
`The Rome diagnostic criteria for the
`functional bowel disorders and functional
`abdominal pain are used widely in re-
`search and practice. A committee consen-
`sus approach, including criticism from
`multinational expert reviewers, was used
`to revise the diagnostic criteria and
`update diagnosis and treatment recom-
`mendations, based on research results.
`The terminology was clarified and the
`diagnostic criteria and management rec-
`ommendations were revised. A functional
`bowel disorder (FBD) is diagnosed by
`characteristic symptoms for at least 12
`weeks during the preceding 12 months in
`the absence of a structural or biochemical
`explanation. The irritable bowel syn-
`drome,
`functional abdominal bloating,
`functional constipation, and functional
`diarrhea are distinguished by symptom-
`based diagnostic criteria. Unspecified
`FBD lacks criteria for the other FBDs.
`Diagnostic testing is individualized, de-
`pending on patient age, primary symptom
`characteristics, and other clinical and
`laboratory features. Functional abdomi-
`nal pain (FAP) is defined as either the
`FAP syndrome, which requires at least six
`months of pain with poor relation to gut
`function and loss of daily activities, or
`unspecified FAP, which lacks criteria for
`the FAP syndrome. An organic cause for
`the pain must be excluded, but aspects of
`the patient’s pain behavior are of primary
`importance. Treatment of the FBDs relies
`upon confident diagnosis, explanation,
`and reassurance. Diet alteration, drug
`treatment, and psychotherapy may be
`beneficial, depending on the symptoms
`and psychological features.
`(Gut 1999;45(Suppl II):II43–II47)
`
`Keywords: functional bowel disorder; functional
`constipation; functional diarrhea; irritable bowel
`syndrome; functional abdominal pain; functional
`abdominal bloating; Rome II
`
`The functional bowel disorders and functional
`abdominal pain are common and cause much
`suVering. As these entities are identified by
`symptoms and patient care is highly individual-
`ized, a symptom-based classification has great
`importance, particularly for use in clinical trials
`(table 1).
`The 1998 Working Team assessed the termi-
`nology and results of relevant clinical research
`in order
`to revise the diagnostic criteria,
`
`Table 1 Functional gastrointestinal disorders
`
`A. Esophageal disorders
`A1. Globus
`A2. Rumination syndrome
`A3. Functional chest pain of presumed esophageal origin
`A4. Functional heartburn
`A5. Functional dysphagia
`A6. Unspecified functional esophageal disorder
`B. Gastroduodenal disorders
`B1. Functional dyspepsia
`B1a. Ulcer-like dyspepsia
`B1b. Dysmotility-like dyspepsia
`B1c. Unspecified (non-specific) dyspepsia
`B2. Aerophagia
`B3. Functional vomiting
`C. Bowel disorders
`C1. Irritable bowel syndrome
`C2. Functional abdominal bloating
`C3. Functional constipation
`C4. Functional diarrhea
`C5. Unspecified functional bowel disorder
`D. Functional abdominal pain
`D1. Functional abdominal pain syndrome
`D2. Unspecified functional abdominal pain
`E. Biliary disorders
`E1. Gall bladder dysfunction
`E2. Sphincter of Oddi dysfunction
`F. Anorectal disorders
`F1. Functional fecal incontinence
`F2. Functional anorectal pain
`F2a. Levator ani syndrome
`F2b. Proctalgia fugax
`F3. Pelvic floor dyssynergia
`G. Functional pediatric disorders
`G1. Vomiting
`G1a. Infant regurgitation
`G1b. Infant rumination syndrome
`G1c. Cyclic vomiting syndrome
`G2. Abdominal pain
`G2a. Functional dyspepsia
`G2b. Irritable bowel syndrome
`G2c. Functional abdominal pain
`G2d. Abdominal migraine
`G2e. Aerophagia
`G3. Functional diarrhea
`G4. Disorders of defecation
`G4a. Infant dyschezia
`G4b. Functional constipation
`G4c. Functional fecal retention
`G4d. Non-retentive fecal soiling
`
`comment further on diagnosis, and summarize
`treatment recommendations.
`
`C. Functional bowel disorders
`is a
`A functional bowel disorder
`(FBD)
`functional gastrointestinal disorder with symp-
`toms attributable to the mid or lower gastro-
`intestinal tract, including the irritable bowel
`syndrome (IBS), functional abdominal bloat-
`ing,
`functional constipation,
`functional di-
`arrhea, and unspecified functional bowel
`disorder.
`Subjects with a FBD may be divided into the
`following groups:
`
`Abbreviations used in this paper: FBD, functional
`bowel disorder; IBS, irritable bowel syndrome; FAPS,
`functional abdominal pain syndrome.
`
`Chair, Committee on
`Functional Bowel
`Disorders and
`Functional Abdominal
`Pain, Multinational
`Working Teams to
`Develop Diagnostic
`Criteria for Functional
`Gastrointestinal
`Disorders (Rome II),
`Emeritus Professor of
`Medicine,
`University of Ottawa,
`Canada
`W G Thompson
`
`Co-Chair, Committee
`on Functional Bowel
`Disorders and
`Functional Abdominal
`Pain, Multinational
`Working Teams to
`Develop Diagnostic
`Criteria for Functional
`Gastrointestinal
`Disorders (Rome II),
`Kaiser Permanente,
`San Diego, CA, USA
`G F Longstreth
`
`Division of Digestive
`Diseases,
`University of North
`Carolina, Chapel Hill,
`NC, USA
`D A Drossman
`
`Department of
`Medicine,
`University of Bristol,
`Bristol, UK
`K W Heaton
`
`Department of
`Medicine,
`McMaster University,
`Ontario, Canada
`E J Irvine
`
`Department of
`Medicine,
`Park-Klinik,
`Weissensee, Berlin,
`Germany
`S A Müller-Lissner
`
`Correspondence to:
`W Grant Thompson, MD,
`7 Nesbitt Street, Nepean,
`Ontario K2H 8C4, Canada.
`
`Bausch Health Ireland Exhibit 2051, Page 1 of 5
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`II44
`
`Tlwmpso11, Longstreth, Drossman, et al
`
`(1) non-patients: those who have never sought
`health care for the FBD;
`(2) patients: those who have sought care for the
`FBD; (a) incident cases: those who have
`sought care for the FBD for the first time in
`the past year; (b) prevalent cases: those who
`have ever sought care for the FBD.
`Symptoms of a FBD must have been present
`for 12 weeks or more within the past 12
`months; the 12 weeks need not be consecutive.
`The diagnosis always presumes the absence of
`a structural or biochemical explanation for the
`symptoms.
`The Working Team changed the definitions
`of IBS, functional abdominal bloating and
`functional constipation from a "disorder" to
`"disorders" to acknowledge multiple patho(cid:173)
`physiologic possibilities. For IBS, "discomfort"
`was added to "pain" to broaden symptom
`description, and "distension" was deleted.
`To clarify how discomfort and pain are tem(cid:173)
`porally related to a change in frequency and
`form of stool, "onset" was added to the relevant
`symptom features. The symptom criteria for
`IBS were changed (a) by designating the non(cid:173)
`pain-related, the second part of the previous
`criteria, as nonessential due to their poor clus(cid:173)
`tering in factor analyses' 2; (b) their lesser
`prevalence in men3; and (c) the partial duplica(cid:173)
`tion in the retained, pain-related criteria.
`Furthermore, these symptoms were clarified by
`replacing the term "altered" with "abnormal."
`The criteria for functional constipation were
`expanded due to the overlap between it and the
`functional anorectal disorders (see Functional
`disorders of the anus and rectum) .
`
`Ct. Irritable bowel syndrome
`IBS comprises a group of functional bowel dis(cid:173)
`orders in which abdominal discomfort or pain
`is associated with defecation or a change in
`bowel habit, and with features of disordered
`defecation.
`Surveys of Western populations have re(cid:173)
`vealed IBS in 15-20% of adolescents and
`adults, with a higher prevalence in women; the
`prevalence is variable in other populations.•
`IBS has a chronic relapsing course and overlaps
`with
`other
`functional
`gastrointestinal
`disorders. 5 It accounts for high direct medical
`expenses6 and indirect costs, including absen(cid:173)
`teeism from work. 5
`
`DIAGNOSTIC CRITERIA
`At least 12 weeks, which need not be
`consecutive, in the preceding 12 months of
`abdominal discomfort or pain that has two
`of three features:
`(1) Relieved with defecation; and/or
`(2) Onset associated with a change in
`frequency of stool; and/or
`(3) Onset associated with a change in form
`(appearance) of stool.
`
`The following symptoms cumulatively sup(cid:173)
`port the diagnosis of IBS:
`• abnormal stool frequency (for research pur(cid:173)
`poses "abnormal" may be defined as >3/day
`and <3/week);
`
`Table 2 Supportive symptoms of the irritable bowel
`syndrome
`
`1. Fewer than three bowel movements a week
`2. M ore than three bowel m ovements a day
`3. Hard or Jumpy stools
`4. Loose (mushy) or watery stools
`5. Straining d uring a bowel movement
`6. Urgency (having to rush to have a bowel movement)
`7. Feeling of incomplete bowel movement
`8 . Passing mucus (white material) during a bowel movement
`9. Abdominal fullness, bloating or swelling
`Diarrhea-predominam
`1 or more of 2, 4 , or 6 and none of 1, 3, or 5
`Cotisa"pa.tion-predomitiant
`1 or more of 1, 3, or 5 and none of 2, 4 , or 6
`
`• abnormal stool form (lumpy/hard or loose/
`watery stool);
`• abnormal stool passage (straining, urgency,
`or feeling of incomplete evacuation);
`• passage of mucus;
`• bloating or feeling of abdominal distension.
`These symptoms can be used to subclassify
`patients with predominant diarrhea or consti(cid:173)
`pation for entry into clinical trials (table 2).
`
`DIAG NOSTIC COMMENTS
`is
`The validity of the symptom criteria
`supported by patient studies/ 7 8 factor analy(cid:173)
`ses on non-patients' 2 and Jong term patient
`follow up. 9 The history may also reveal
`postprandial symptom exacerbation, 10 and oc(cid:173)
`casionally, incontinence and nocturnal pain.
`Symptom worsening during menses and other
`features can falsely suggest a gynecologic
`explanation for "chronic pelvic pain." " Other
`non-gastrointestinal somatic symptoms are
`common. 5 Colonic transit time can be esti(cid:173)
`mated by rating self-reported stool appearance
`according to a stool form scale.12 Fever, rectal
`bleeding, or weight Joss require consideration
`of another disorder. 13 Abdominal examination
`reveals no abnormality. Large bowel structural
`examination is recommended to support a
`symptom-based diagnosis. The choice of such
`examinations should be guided by the age and
`gender of the patient, the nature and duration
`of symptoms, and other factors. 8 1
`•
`
`TREATMENT RECOMMENDATIONS
`A confident diagnosis, explanation, and reas(cid:173)
`surance are vital therapeutic tools. A graded,
`multicomponent approach is advised, depend(cid:173)
`ing on the dominant symptoms, their severity
`and psychosocial factors.• Although rigorous
`therapeutic trials are scarce, popular therapy
`includes the use increased dietary fiber such as
`wheat bran or bulking agents for constipation,
`Joperimide or diphenoxylate for diarrhea, and
`anticholinergic/antispasmodic agents or low(cid:173)
`dose antidepressants for pain.• Psychological or
`behavioral treatments may help some patients.
`
`C2. Functional abdominal bloating
`Functional abdominal bloating comprises a
`group of functional bowel disorders which are
`dominated by a feeling of abdominal fullness or
`bloating and without sufficient criteria for
`another functional gastrointestinal disorder.
`Few studies adequately separate bloating
`from IBS and other functional disorders, but it
`occurs in about 15% of community-based
`
`Bausch Health Ireland Exhibit 2051, Page 2 of 5
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`Fu11ctio11al bowel disorders and fwzctional abdominal pain
`
`Il45
`
`populations, usually with a female predomi(cid:173)
`nance. •s 16
`
`DIAGNOSTIC CRITERIA
`At least 12 weeks, which need not be
`consecutive, in the preceding 12 months of:
`(1) Feeling of abdominal fullness, bloating,
`or visible distension; and
`(2) Insufficient criteria for a diagnosis of
`functional dyspepsia, IBS, or other
`functional disorder.
`
`DIAGNOSTIC COMMENTS
`Functional bloating is usually absent on awak(cid:173)
`ening and worsens throughout the day. It may
`be intermittent and related to ingestion of spe(cid:173)
`cific foods. Excessive burping or farting may be
`present, but these are not necessarily related to
`the bloating. Diarrhea, weight loss, or nutri(cid:173)
`tional deficiency should alert the physician to
`investigate for another disorder.
`
`TREATMENT RECOM,\U!NDATIONS
`There is no proved effective therapy for
`functional bloating, and its cause is unknown,
`so only education and reassurance are recom(cid:173)
`mended. The common practice of restricting
`certain "gas-forming" foods may be beneficial
`but even patients with confirmed lactase
`deficiency can drink 250 ml milk with no or
`negligible bloating. 17
`
`C3. Functional constipation
`Functional constipation comprises a group of
`functional disorders which present as persist(cid:173)
`ent difficult, infrequent or seemingly incom(cid:173)
`plete defecation.
`Constipation occurs in up to 20% of popula(cid:173)
`tions, depending on demographic factors, sam(cid:173)
`pling and the definition used. It is more
`common in women and is usually found to
`increase with age.5 18
`
`DIAGNOSTIC CRITERIA
`At least 12 weeks, which need not be
`consecutive, in the preceding 12 months of
`two or more of:
`(1) Straining in> 1/4 defecations;
`(2) Lumpy or hard stools in > 1/4 defeca(cid:173)
`tions;
`(3) Sensation of incomplete evacuation in
`> 1/4 defecations;
`(4) Sensation of anorectal obstruction/
`blockade in > 1/4 defecations
`(5) Manual maneuvers to facilitate > 1/4
`defecations (e.g., digital evacuation,
`support of the pelvic floor); and/or
`(6) <3 defecations/week.
`Loose stools are not present, and there are
`insufficient criteria for IBS.
`
`DIAGNOSTIC COMMENTS
`The physician should clarify what the patient
`means by constipation, as patients describe it in
`various ways. 19 Many, if not most patients actu(cid:173)
`ally have the rectal symptoms of IBS with or
`without lumpy stools. 20 Evaluation of the
`
`patient's general health, psychological status,
`use of constipating medications, dietary fiber
`intake, and medical illnesses (e.g., hypo(cid:173)
`thyroidism) is important. In patients who do
`not respond to fiber supplementation, meas(cid:173)
`urements of whole gut transit time21 and
`anorectal function22 may be indicated to place
`them in a physiological subgroup.
`
`TREATMENT RECOMMENDATIONS
`Dietary fiber increases fecal bulk by providing
`indigestible matter and promoting fecal water
`holding and bacterial proliferation. 23 Other
`useful bulking agents include psyllium, methyl(cid:173)
`cellulose, and calcium polycarbophil. Severely
`constipated patients may respond to polyethe(cid:173)
`lene glycol solution.24 Otherwise, stimulant
`laxatives such as bisacodyl, sodium picosul(cid:173)
`phate, or sennosides may be tried. Specific
`treatment for patients in the anorectal dysfunc(cid:173)
`tion subgroup is discussed in Functional disor(cid:173)
`ders of the anus and rectum.
`
`C4. Functional diarrhea
`Functional diarrhea is continuous or recurrent
`passage ofloose (mushy) or watery stools with(cid:173)
`out abdominal pain.
`A British population survey of stool form (a
`scale previously validated against symptoms
`) revealed liquid stools were
`and transit time'2
`the predominant type described by 5.3% of
`men and 4.3% ofwomen. 25 Liquid stools were
`more common in women under 50 years of age
`than in older women.
`
`DIAGNOSTIC CRITERIA
`At least 12 weeks, which need not be
`consecutive, in the preceding 12 months of:
`(1) Liquid (mushy) or watery stools;
`(2) Present >3/4 of the time; and
`(3) No abdominal pain.
`
`DIAGNOSTIC COMMENTS
`Pseudodiarrhea (frequent defecation and ur(cid:173)
`gency with solid stools) must be distinguished
`from diarrhea. Chronic diarrhea without pain
`is caused by many diseases indistinguishable by
`history, which should be excluded by diagnos(cid:173)
`tic testing. Basic evaluation includes routine
`blood and stool tests plus sigmoidoscopy with
`biopsy. Features atypical for a functional disor(cid:173)
`der (e.g., large volume stools, rectal bleeding,
`nutritional deficiency, and weight loss) call for
`more extensive studies of intestinal structure
`and function-for example, radiography, duo(cid:173)
`denal biopsy, and serum hormone assay.
`
`TREATMENT RECOMMENDATIONS
`Discussion of possible psychosocial factors,
`symptom explanation, and reassurance are
`important. Restriction of foods which seem
`provocative may help. Empiric antidiarrheal
`therapy (e.g., diphenoxylate or loperimide) is
`usually effective, especially if taken prophylac(cid:173)
`tically, such as before meals. The occasional
`patient responds to cholestyramine. Fortu(cid:173)
`nately, spontaneous remissions are common.26
`
`Bausch Health Ireland Exhibit 2051, Page 3 of 5
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`II46
`
`Tlwmpso11, Longstreth, Drossman, et al
`
`CS. Unspecified functional bowel
`disorder
`
`An unspecified functional bowel disorder is
`defined as functional bowel symptoms that
`do not meet criteria for the previously
`defined categories.
`
`D. Functional abdominal pain
`Functional abdominal pain describes continu(cid:173)
`ous, nearly continuous, or frequently recurrent
`pain localized in the abdomen but poorly
`related to gut function.
`Functional abdominal pain is divided into
`two categories.
`
`D1. Functional abdominal pain
`syndrome
`Functional abdominal pain syndrome (FAPS),
`also called "chronic idiopathic abdominal
`pain" or "chronic functional abdominal pain,"
`describes pain for at least six months that is
`poorly related to gut function and is associated
`with some loss of daily activities.
`FAPS occurs in 1.7% of people, mainly
`women, and is associated with significant
`absenteeism from work and physician visits. 5
`Over time, patients with FAPS tend to have
`many specialist referrals, diagnostic tests and
`major abdominal and pelvic operations. 27
`
`DIAGNOSTIC CRITERIA
`At least six months of:
`(1) Continuous or nearly continuous ab(cid:173)
`dominal pain; and
`(2) No or only occasional relation of pain
`with physiological events (e.g., eating,
`defecation or menses); and
`(3) Some loss of daily functioning; and
`(4) The pain is not feigned (e.g., malinger(cid:173)
`ing); and
`(5) Insufficient criteria for other functional
`gastrointestinal disorders that would
`explain the abdominal pain.
`
`DIAGNOSTIC COMMENTS
`Aspects of the patient's pain behavior are of
`primary importance. 27 Typically, the pain is
`described in emotional or bizarre terms,
`involves a large anatomic area, is associated
`with other painful symptoms, and is part of a
`continuum of painful experiences over many
`years. Usually, patients urgently report pain as
`extremely intense, and they request many diag(cid:173)
`nostic studies or surgery, focus primarily on the
`illness, and relentlessly seek pain relief and
`validation that the pain is "organic." They often
`ignore or deny a role for psychosocial contribu(cid:173)
`tions and absolve personal responsibility for
`self-management, while placing high expecta(cid:173)
`tions for relief on the physician. Pain behavior
`may diminish when the patient is distracted or
`not aware of being observed. A spouse or par(cid:173)
`ent may be so affected by the patient's illness as
`to report the history. Requests for narcotics are
`common. FAPS may co-exist with a structural
`
`disease (e.g., chronic pancreatitis) or FBD
`(e.g., IBS). The observation of a lack auto(cid:173)
`nomic arousal, eye closure during abdominal
`examination, and diminished pain behavior
`with stethoscope application to the abdomen
`are typical. Multiple abdominal scars are com(cid:173)
`mon.
`
`TREATMENT RECOMMENDATIONS
`Management depends on an effective doctor(cid:173)
`including reasonable
`patient relationship,27
`goals, regular appointments and, in some cases,
`concurrent psychological treatment. Analge(cid:173)
`sics are ineffective, and narcotics should be
`avoided. Concurrent depression should be
`treated. Low doses of antidepressants can
`reduce pain as well as insomnia. Anxiolytic
`therapy, if used at all, should be limited in
`duration. Various types of psychotherapy have
`been tried without critical evaluation. A multi(cid:173)
`disciplinary pain management program may be
`the most promising approach. 28
`
`D2. Unspecified functional abdominal
`pain
`
`Unspecified functional abdominal pain is
`functional abdominal pain which fails to
`meet criteria for FAPS (Dl).
`
`1 Whitehead WE, Crowell MD, Bosmajian L, et al. Existence
`of irritable bowel syndrome supported by factor analysis of
`symptoms in two community samples. Gasrroenterology
`1990;98:336-40.
`2 Taub E, Cuevas JL, Cook EW, el aL Irritable bowel
`syndrome defined by factor analysis. Dig Dis Sci 1995;40:
`2647-55.
`3 Thompson WG. Gender differences in irritable bowel
`symptoms. Eur J Gasrroenurol Hepatol 1997;9:299-302.
`4 Drossman DA, Whitehead WE, Camilleri M . Irritable
`bowel syndrome. A technical review for practice guideline
`development. Gastroenterology 1997;112:2120-37.
`5 Drossman DA, Li Z, Andruzzi E, el al. U.S. householder
`survey of functional gastrointestinal disorders: prevalence,
`sociodemography and health impact. Dig Dis Sci 1993;38:
`1569-80.
`6 Talley NJ, Gabriel SE, Harmsen WS, ei aL Medical costs in
`oommunity subjects with irritable bowel syndrome. Gastro(cid:173)
`et1urology 1995;109:1736-41.
`7 Manning AP, Thompson WG, Heaton KW, ei al. Towards
`positive diagnosis of the irritable bowel syndrome. BMJ
`1978;ii:653-54.
`8 Longstreth GF. Irritable bowel syndrome. Diagnosis in the
`managed care era. Dig Dis Sci 1997;42:1 105-1 I.
`9 Harvey RF, Mauad EC, Brown AM. Prognosis in the irrita(cid:173)
`ble bowel syndrome. A 5-year prospective study. La11cei
`1987;i:963-5.
`10 Chaudhary NA, Truelove SC. The irritable colon syn(cid:173)
`drome. QJMed 1962;31:307- 22.
`11 Longstreth GF. Irritable bowel syndrome and chronic pelvic
`pain. Obsu, GyneoolSurv 1994;49:505-7.
`12 O'Donnell LJD, Vitjee J, Heaton KW. Detection of pseudo(cid:173)
`diarrhea by simple clinical assessment of intestinal transit
`rate. BMJ 1990;300:439-40.
`13 Kruis W, Thieme CH, Weinzieri M, et al. A diagnostic score
`for the irritable bowel syndrome. Its value in the exclusion
`of organic disease. Gasrroem.ero/ogy 1984;87: l- 7.
`14 Camilleri M, Prather CM. The irritable bowel syndrome. A
`review and a practical approach to management. Anti Intern
`Med 1992;116:1001-8.
`15 Johnsen R, Jacobsen BK, Forde OH. Association between
`symptoms of irritable colon and psychological and social
`conditions and lifestyle. BMJ 1986;292: 1633- 5.
`16 Kay L, Jorgensen T, Jensen KR. The epidemiology of irrita(cid:173)
`ble bowel syndrome in a random population. Prevalence,
`incidence, nawral history and risk factors. J lncern Med
`1994;236:23-30.
`17 Suarez FL, Savaiano DA, Levin MD. A oomparison of
`symptoms after the consumption of milk or lactose(cid:173)
`hydrolyzed milk by people with self-reported severe lactose
`intolerance. N E11gl J Med 1995;333: 1-4.
`18 Everhart JE, Go VL, Johannes RS, ei al. A longitudinal sur(cid:173)
`vey of self-reported bowel habits in the United States. Dig
`Dis Sci l 989;34: 1153-{;2.
`19 Sandler RS, Drossman DA. Bowel habits in young adults
`not seeking health care. Dig Dis Sci 1987;32:841-5.
`
`Bausch Health Ireland Exhibit 2051, Page 4 of 5
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`Functional bowel disorders and functional abdominal pain
`
`II47
`
`20 Probert CSJ, Emmett PM, Cripps HA, et al. Evidence for
`the ambiguity of the term constipation: the role of irritable
`bowel syndrome. Gut 1994;35:1455–8.
`21 van der Sijp JRM, Kamm MA, Nightingale JMD, et al.
`Radioisotope determination of regional colonic transit in
`severe constipation. Comparison with radiopaque markers.
`Gut 1993;34:402–8.
`22 Wald A, Camara BJ, Freimanis MG, et al. Contribution of
`evacuation proctography and anorectal manometry to the
`evaluation of adults with constipation and defecatory diY-
`culty. Dig Dis Sci 1990;25:481–7.
`23 Voderholzer WA, Schatke W, Muhldorfer BE, et al. Clinical
`response to dietary fiber treatment of chronic constipation.
`Am J Gastroenterol 1997;92:95–8.
`
`24 Klauser AG, Muhldorfer BE, Voderholzer WA, et al.
`Polyethylene glycol 4000 for slow transit constipation. Z
`Gastroenterol 1995;33:5–8.
`25 Heaton KW, Radavan J, Cripps H, et al. Defecation
`frequency and timing, and stool
`form in the general
`population: a prospective study. Gut 1992;33:818–24.
`26 Afzalpurkar RG, Schiller LR, et al. The self-limited nature of
`chronic idiopathic diarrhea. N Engl J Med 1992;327:1849–
`52.
`27 Drossman DA. Chronic functional abdominal pain. Am J
`Gastroenterol 1996;91:2270–81.
`28 Kames LD, Rapkin AJ, NaliboV BD, et al. EVectiveness of
`an interdisciplinary pain management program for the
`treatment of chronic pelvic pain. Pain 1990;41:41–6.
`
`For further information and updates on Rome II,
`visit our website at:
`www.romecriteria.org
`
`Bausch Health Ireland Exhibit 2051, Page 5 of 5
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`