Document Sample
					 Gastroenterol Clin N Am 36 (2007) 665–685

Irritable Bowel Syndrome: Current
Approach to Symptoms, Evaluation,
and Treatment
Elizabeth J. Videlock, BS, Lin Chang, MD*
Center for Neurovisceral Sciences and Women’s Health, Division of Digestive Diseases,
David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System,
CURE Building 115, Room 223, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA

   rritable bowel syndrome (IBS) is a common functional gastrointestinal (GI)
   disorder. It has a very high prevalence, estimated to be 10% to 20% in the
   general population [1]. IBS accounts for significant health care costs with
annual direct and indirect costs estimated at $1.35 billion and at least $200 mil-
lion, respectively [2]. IBS patients use more health care services than the general
population, even for non–GI-related concerns [3,4].
   This article provides clinicians with a current, concise, and evidence-based
review of the symptoms, diagnostic evaluation, and treatment of IBS. A clear
understanding of recommended diagnostic and therapeutic approaches leads
to greater patient satisfaction and reduced health care costs.

Gastrointestinal Symptoms
The main symptom of IBS is chronic or recurrent abdominal pain or discom-
fort associated with altered bowel habits. The new Rome III criteria for the di-
agnosis of IBS were published in 2006 and are listed in Box 1 [1]. The following
are not part of the diagnostic criteria but are considered supportive symptoms:
abnormal stool frequency (<3 bowel movements per week or >3 bowel move-
ments per day); abnormal stool form (lumpy-hard stool or loose-watery stool);
defecation; straining; urgency; a feeling of incomplete evacuation; and passing
mucus and bloating.
   The previous Rome II classification of IBS subtype was based on a combina-
tion of symptoms including stool frequency and form, and defecation-related
symptoms. This classification was suboptimal because it was not evidence-
based and because there was inconsistency with regard to the correct sub-
classification of patients with frequent hard stools or infrequent watery stools.
Furthermore, cluster analysis and symptom studies have shown that stool

*Corresponding author. E-mail address: (L. Chang).

0889-8553/07/$ – see front matter                               Published by Elsevier Inc.
666                                                                 VIDELOCK & CHANG

 Box 1: The symptom-based Rome III criteria for the diagnosis of IBS
 These criteria should be filled for the last 3 months with symptom onset at least 6
   months before diagnosis.
 Recurrent abdominal pain or discomforta at least 3 days per month in the last 3
   months that is associated with two or more of the following:
     Improvement with defecation
     Onset associated with a change in frequency of stool
     Onset associated with a change in form (appearance) of stool
  Discomfort means an uncomfortable sensation not described as pain.

frequency is within normal range for most IBS patients [1]. Based on more re-
cently published studies characterizing the bowel habits of the IBS subgroups
[5–7], stool form was found to be the best predictor of predominant bowel habit
in IBS. Furthermore, stool form is a better reflection of intestinal transit time.
For these reasons, stool form rather than frequency determines classification
according to Rome III. The subtype classification is illustrated in Fig. 1.
   The category of alternating IBS (IBS-A) should be reserved for patients with
bowel habits that have changed over time (eg, weeks to months). Patients with
both diarrhea and constipation that may alternate within hours or days were
classified as IBS-A according to Rome II, but should now be referred to as
IBS-M. The prevalence of IBS-D, IBS-C, and IBS-M are similar, but IBS-M
is the subtype most frequently encountered in primary care. Patients change

Fig. 1. The Rome III classification for subtyping IBS by bowel habit predominance. Patients
are classified as IBS with constipation (IBS-C) if !25% of stools are hard or lumpy and
<25% are loose (mushy) or watery. IBS with diarrhea (IBS-D) describes patients with !25%
of stools loose or watery and <25% hard or lumpy. Mixed IBS (IBS-M) describes patients
with !25% of stools hard and lumpy and !25% of stools loose or watery. IBS patients are
unsubtyped (IBS-U) if not enough stools are abnormal to meet criteria for any other subtype.
IRRITABLE BOWEL SYNDROME                                                    667

subtypes frequently, with 29% moving from IBS-C to IBS-D within 1 year [8].
Because of this symptom instability, the terms ‘‘IBS with diarrhea’’ and ‘‘IBS
with constipation’’ are preferred over the previously used terms of ‘‘diarrhea-
and constipation-predominant IBS’’ [8].
  IBS-C and IBS-D patients have different symptom profiles, with IBS-C
patients reporting more overall symptoms (both lower and upper abdominal
pain) and particularly bloating [9]. Symptoms of IBS and functional dyspepsia
overlap significantly and respond similarly to treatment. It has been argued that
they are different manifestations of one condition [10].

Extraintestinal Symptoms and Comorbid Disorders
IBS patients make more health care visits and incur more health care costs
than non-IBS patients. More than half of additional visits and additional costs
are for non-GI concerns [11]. Non-GI symptoms that are more common in
IBS than controls include the following (prevalence): headache (23%–45%);
back pain (27%–81%); fatigue (36%–63%); myalgia (29%–36%); dyspareunia
(9%–42%); urinary frequency (21%–61%) and other urinary symptoms; and
dizziness (11%–27%) [11]. IBS patients with comorbid somatic disorders (eg,
fibromyalgia) report more severe IBS symptoms and lower health-related qual-
ity of life (HRQOL) [11]. Common comorbid GI and other somatic disorders
are listed in Table 1.
   Although it seems that these comorbid disorders and IBS may have distinct
contributing factors to their pathophysiology, there are common themes that
are mostly related to psychologic symptoms and stress reactivity [11]. Stress
is defined as acute threats to the homeostasis of an organism, be they real
(physical) or perceived (psychologic). Sustained, threatening life events (psy-
chosocial stressors) predict symptom exacerbation in established IBS patients
[12–14], and the development of IBS symptoms in asymptomatic individuals
following a gastroenteric infection (postinfectious IBS) [13,15]. Stress-induced
changes in pain modulation (hyperalgesia) and cognitive processes (hypervigi-
lance toward viscerosomatic stimuli) may play a key role in the pain and
discomfort characteristic of these disorders. Although these mechanisms may
be shared, they may be more specifically related to one particular stimulus
depending on the condition. For example, IBS patients may have developed
persistent symptom-specific anxiety from previously threatening visceral stim-
uli (eg, food or GI infection), whereas fibromyalgia patients have symptom-
specific anxiety to somatic stimuli (eg, muscle injury). These threatening
events, which are attached to their symptoms, may be involved in the develop-
ment of anticipatory or anxiety-related responses [16] related to symptom
recurrence. Symptom-specific anxiety can amplify the perception of visceral
and somatic afferent input to the brain, thereby contributing to pain-related
symptoms. A recently developed reliable, validated scale called the Visceral
Sensitivity Index measures GI-specific anxiety (ie, fear of visceral sensations)
and may be useful for clinical assessment, treatment outcome studies, and
mechanistic studies of the role of anxiety in IBS presentation [17]. In addition,
668                                                                     VIDELOCK & CHANG

Table 1
Comorbidity with irritable bowel syndrome
                                                                        % Prevalence of the
                                           % Prevalence of IBS in       disorder in patients with
Disorder                                   patients with the disorder   IBS
  Gastroesophageal reflux                   47                           46.5
  Functional dyspepsia                     28–47                        28–57
Other somatic
  Fibromyalgia                             32–77                        28–65
  Chronic fatigue syndrome                 35–92                        14a
  Chronic pelvic pain                      29–79                        35a
  Temporomandibular joint                  64a                          16a
  Interstitial cystitis                    30.2a                        —
    Based on results of only one study [11].

a path analysis demonstrated that GI-specific anxiety mediates the relationship
between general psychologic distress measures and GI symptom severity. The
Visceral Sensitivity Index was related to GI, but not non-GI, symptom severity
   There is a higher prevalence of psychiatric disorders in the IBS population
than in controls. This is true in the community (prevalence of 18%) [19]; in
clinics (prevalence of 40%–60%) [20]; and in referral centers (prevalence with
lifetime history of 94%) [19]. Although comorbidity is highest in the health
care–seeking population, the prevalence in IBS nonpatients (ie, individuals
who have not sought health care for their IBS symptoms) is greater than
that seen in the general population, which suggests that psychiatric disorders
influence health care seeking, but are not the primary cause. Somatization dis-
order deserves special mention. The diagnostic criteria for somatization disor-
der, a psychiatric disorder that is characterized by multiple medically
unexplained symptoms, include a history of multiple pain symptoms; GI symp-
toms; sexual dysfunction or pain; and pseudoneurologic symptoms, such as
weakness or urinary retention [21]. There is a high degree of overlap between
IBS and somatization disorder, and patients with IBS who meet criteria for so-
matization disorder have more psychiatric comorbidity, more severe symp-
toms, and are less responsive to treatment [22]. Although IBS patients with
somatization disorder do not have increased numbers of health care visits com-
pared with IBS, they do incur more expenditures, which suggests both that so-
matization disorder is an important factor in health care use by IBS patients and
that increased health care use may be mediated by physicians [23].
Symptom Severity
There are no consensus criteria that have been established to determine sever-
ity of IBS. This is caused in part by the large number of factors that influence
IRRITABLE BOWEL SYNDROME                                                      669

severity and the wide gap between patient and physician perceptions of sever-
ity. Current research suggests that a multidimensional view of illness severity is
more useful than one that is based on GI symptom intensity. Factors that are
important to consider when assessing severity are HRQOL, psychosocial fac-
tors, health care use behaviors, disability, and the overall degree to which
the illness affects the patient’s life [24,25]. A preliminary report identified sev-
eral predictors for patient-assessed ‘‘overall severity of GI symptoms’’ [26]. The
predictors included multiple symptoms, such as ratings of abdominal pain and
discomfort (pain, bloating); defecation-related symptoms (straining, urgency);
and illness-related anxiety (‘‘something serious is wrong with my body’’).
More recent epidemiologic data suggest a prevalence of severe or very severe
IBS ranging from 3% to 69%, which is higher than previously thought [24].

Gender Differences
Gender differences in IBS are difficult to measure because most research partic-
ipants are female; however, differences have been shown both in prominent
symptoms and in the response to treatment. Although in the community the
ratio of women to men with IBS is estimated to be 2:1, this difference is
even greater in the health care–seeking population, with women leading men
by an estimated ratio of 2 to 4:1 [27]. A recently published study, however,
found equal prevalence of men and women with IBS in newly developing
Asian countries [28]. Compared with men with IBS, women with IBS report
greater overall IBS symptom severity, intensity of abdominal pain and bloating,
impact of symptoms on daily life, and lower HRQOL [29,30]. It is not known,
however, if this is caused by differences in the sensation of pain, cognitive re-
sponse to pain, or reporting bias [27]. Women also report more extraintestinal
symptoms, such as nausea, urinary urgency, and dyspareunia, and are more
likely to report symptoms of constipation and bloating [31–35].
   Symptoms in women vary according to the menstrual cycle, with increased
reporting of GI symptoms in the late luteal and menses phases when compared
with the midfollicular phase [36]. In particular, women report looser stools and
more GI symptoms just before and during menses and rectal sensitivity has
been shown to be greater in women with IBS in menses compared with women
with IBS in other phases of the menstrual cycle [37].
   With regard to gender differences in IBS treatment, serotonergic agents, such
as the 5-hydroxytryptamine (HT)3 antagonist alosetron, seem to have a more
robust effect in women with IBS-D than in men [38,39]. This difference could
be related to small sample sizes, differences in drug metabolism, or the interac-
tion between serotonin and estrogen [27] but is likely related to a combination
of gender-based differences in peripheral and central mechanisms.

The diagnosis of IBS is symptom-based because there are not yet diagnostic
biomarkers for IBS. The symptom-based Rome III criteria had a sensitivity
of 0.707 and a specificity of 0.878 in the validation sample of 328 patients
670                                                            VIDELOCK & CHANG

who had received a clinical diagnosis of IBS [40]. Although the presence of ‘‘red
flag’’ or alarm signs and symptoms may indicate a need for further diagnostic
work-up, it is not recommended that patients with red flag symptoms be ex-
cluded from the diagnosis of IBS. On average, IBS patients report the presence
of at least 1.65 red flag symptoms [41]. Nocturnal symptoms (40%) and onset
over the age of 50 (32%) were most common alarm signs. Alarm signs and
symptoms include the following:

      Age !50
      Unintentional weight loss
      Family history of GI malignancy
      Severe unrelenting large-volume diarrhea
      Fevers, chills, recent travel to endemic region
      Nocturnal symptoms
      Relevant findings on physical examination (arthritis, skin lesions, lymphadenop-
         athy, abdominal mass)

   Historically, IBS has been a diagnosis of exclusion, but current best evidence
suggests that a battery of diagnostic tests is not necessary because the prevalence
of organic disease is not increased in the population with symptoms of IBS with-
out alarm features, and the positive predictive value of such tests remains small
[42,43]. Diagnostic tests are likely unnecessary, including blood tests, stool tests,
lactulose breath tests, abdominal imaging, and colonic imaging; however, fur-
ther research on the use of diagnostic testing is warranted. Diagnostic tests
may reveal incidental findings or findings that are not related to the symptoms
of IBS. Additionally, a negative finding on colonoscopy is not associated with an
increased sense of reassurance in patients with IBS [44]. There are several sce-
narios in which diagnostic testing is recommended: (1) stool ova and parasite
testing for patients who have recently traveled to endemic regions or for immu-
nocompromised individuals, (2) colonoscopy in patients over 50 years of age for
colon cancer screening, and (3) testing in patients who have not improved de-
spite symptom-based treatment. There is good evidence that serologic testing
for celiac disease followed by endoscopic biopsy confirmation of positive results
is a cost-effective strategy in North American IBS-D patients [45].
   Small bowel bacterial overgrowth has been theorized to play a role in the
symptoms of IBS. Although some studies have shown an increased prevalence
of small bowel bacterial overgrowth in IBS as diagnosed by a lactulose breath
test [46,47], the use of this diagnostic tool is limited by the lack of evidence that
treatment of small bowel bacterial overgrowth with antibiotics leads to long-
term abatement of IBS symptoms.
   Testing for lactase deficiency is not generally recommended because true lac-
tose malabsorption is not well-correlated with reported lactose intolerance [48]
and because lactose restriction has not been shown to improve IBS symptoms
[49,50]. This is likely because lactose intolerance coexists with IBS but is not
the predominant cause of symptoms.
IRRITABLE BOWEL SYNDROME                                                      671

Patient-Centered Care
A good health care provider–patient relationship is the cornerstone of effective
care of IBS. The quality of this relationship has been shown to improve patient
outcomes [51]. Elements of a good provider-patient relationship include a non-
judgmental patient-centered interview, a careful and cost-effective evaluation,
inquiry into the patient’s understanding of the illness, patient education, and
involvement of the patient in treatment decisions [6]. Because IBS is a chronic
disease, it is important to assess specific reasons for the current visit, which may
differ among patients (eg, concern about cancer, worsening pain, lack of re-
sponse to treatment, and so forth) [52]. An intrinsic part of the clinical assess-
ment is the psychosocial interview, which is usually quite relevant in IBS
patients. Because IBS patients may have stress-related symptoms or comorbid
psychologic symptoms, the psychosocial interview may uncover previously
unexpressed associated symptoms and concerns that could be contributing to
the patient’s illness severity, daily functioning, and health-related outcome.
Addressing psychosocial factors may improve health status and treatment
response [53].

Many patients report an inconsistent symptom response to certain foods, and
a 1- to 2-week food and symptom diary can aid in careful analysis of potential
food triggers. Although most patients cannot completely control symptoms
through diet alterations alone, diet-related exacerbations may be minimized.
Common food triggers include high-fat foods, raw fruits and vegetables, and
caffeinated beverages.
   There is some evidence that the symptoms of IBS are related to a visceral hy-
persensitivity to low-grade immune reactivity that does not cause symptoms in
the general population. A group in the United Kingdom conducted a random-
ized controlled trial of food elimination based on IgG levels. IBS patients were
given either a list of foods to which they had increased levels of IgG or
a sham diet of similar foods to eliminate. Twenty-eight percent of patients adher-
ing to the true diet had global improvement of symptoms versus 16.7% on sham
diets. This difference was statistically significant and corresponds to a number-
needed-to-treat of 9. A larger percentage of patients who fully adhered to the diet
had improved symptoms (54% versus 15% of strict adherers to the sham diet),
corresponding to a number-needed-to-treat of 2.5. Additionally, resumption of
the regular diet caused a worsening of symptoms in a greater percentage of those
following the true diet than the control diet. There was not a significant effect on
HRQOL. It has been suggested, however, that the effect seen in this study was
a result of diet alone regardless of IgG levels. IgG levels have not been shown to
be predictive of food intolerance and a large percentage of patients in the true
diet treatment group eliminated milk and wheat, which are known to affect
symptoms in IBS [54,55]. Modification of diet may affect symptoms regardless
of whether or not there is true food intolerance.
672                                                          VIDELOCK & CHANG

Pharmacologic Agents
In 2002, the American College of Gastroenterology (ACG) Functional Gastro-
intestinal Disorders Task Force published a comprehensive systematic review
on the treatment of IBS [56]. In a subsequent publication in 2005, Schoenfeld
[57] updated and expanded on the ACG’s review. The section of this article
focusing on pharmacologic treatment summarizes these findings, taking into ac-
count high-quality trials that have since been published (Table 2).
Bulking Agents
Bulking agents include psyllium, methylcellulose, corn fiber, calcium polycar-
bophil, and ispaghula husk. Fiber supplementation has often been used as ini-
tial management of IBS; however, the ACG Functional Gastrointestinal
Disorders Task Force evaluated randomized, placebo-controlled treatment tri-
als for IBS and found that none of the trials of bulking agents were of high qual-
ity [56]. A meta-analysis showed a small, but significant improvement with
soluble fiber (psyllium, ispahula, calcium polycarbophil), but not with insoluble
fiber (corn, wheat bran) [58]. This meta-analysis is limited by the inclusion of
results from divergent studies and the extrapolation of end points [57]. Fiber
may increase stool frequency in IBS-C, but it is not clear whether this is
well-correlated with relief of pain or other symptoms. Additionally, bulking
agents in quantities that are therapeutic can cause adverse effects including
bloating and abdominal pain and discomfort, and it may be helpful to recom-
mend a gradual initiation of the dose to minimize side effects, particularly in
those who have relatively little fiber in their diets or those with predominant
bloating [57].

Antidiarrheal Agents
The use of antidiarrheal agents has shown no benefit for global IBS symptoms
or abdominal pain [56,57]. Loperamide seems to be effective at prolonging in-
testinal transit time and improving stool consistency in IBS-D. These agents
may be very useful in some IBS-D patients to manage stool urgency, frequency,
and fecal incontinence. They can be used on a more regular basis in patients
with more frequent symptoms or on an as-needed basis. It is often useful for
patients to use antidiarrheals prophylactically before leaving the house,
a long car trip, a meal, or a stressful event. This can decrease both the diarrhea
and the anticipatory stress often felt by patients before a known symptom

Osmotic laxatives are available over the counter and are widely used in the
treatment of IBS-C and chronic constipation. Although no randomized, con-
trolled studies have shown efficacy of laxatives in IBS, they may be useful in
treating the constipation symptoms in those with IBS-C. Osmotic laxatives,
such as polyethylene glycol or magnesium-containing products, are generally
safe and well tolerated. Polyethylene glycol can be easily titrated by the patient,
allowing adjustment in stool frequency and consistency as symptoms vary.
IRRITABLE BOWEL SYNDROME                                                              673

Table 2
Agents available to treat irritable bowel syndrome by predominant symptom
Drug class         Generic name           Dose
Bulking agents     Psyllium               1–3 Tbsp qd             First-line treatment for
                                                                     constipation. Start
                                                                     with 4 g/d,
                                                                     gradually increase
                                                                     over 2–3 weeks to
                                                                     20–25 g/d
                   Methylcellulose        1–3 Tbsp qd
                   Polycarbophil          2–4 tablets qd
Osmotic            Milk of magnesia       1–2 Tbsp qd to bid
                   Magnesium citrate      6–12 oz
                   Sodium phosphate       1 tspn in 8 oz fluid
                   Lactulose              1–2 Tbsp qd–bid
                   Polyethylene glycol    17 g in 8 oz fluid
                   Sorbitol               1–2 Tbsp qd–bid
Stimulants         Cascara sagrada        325 mg or 1 tspn qhs
                   Senna                  187-mg tablets;
                                            1–2 tablets qhs
                   Riconleic acid         1–2 Tbsp qd
                   Diphenylmethane        10 mg 1–2 tablets
                     derivatives            qhs or 1 suppository
Emollients         Docusates              100 mg; 1–3 tablets
                   Mineral oil            1 tsp–1 Tbsp qhs
5-HT4 agonist      Tegaserod              6 mg bid               Available only through
                                                                 restricted-use program
Drug class         Generic name
Antidiarrheals     Loperamide             1 tablet qid            Use prophylactically
                                                                    (start at 1 per day
                                                                    but can use up to 8
                                                                    per day)
                   Diphenoxylate          1–2 tablets tid
Binding agents     Cholestyramine         1 g bid to qid
5-HT3 antagonist   Alosetron              0.5 mg–1 mg             For women with severe
                                            qd–bid                  IBS-D who have
                                                                    failed conventional
                                                                    therapy. Available
                                                                    only through
Tricyclic          Amitriptyline          10–150 mg qhs           Very sedating
                   Doxepin                10–150 mg qhs           Very sedating
                                                                (continued on next page)
674                                                                              VIDELOCK & CHANG

Table 2
                     Imipramine                    10–150     mg   qhs
                     Clomipramine                  25–100     mg   qhs
                     Trimipramine                  10–150     mg   qhs
                     Desipramine                   10–150     mg   qhs           Most empiric evidence
                                                                                   for efficacy. Less
                                                                                   sedation and
                     Nortriptyline                 10–150 mg qhs                 Least sedating
Antispasmodics       Hyoscamine sulfate            0.125 mg sl/po qid
                                                     prn, 0.375 mg po
                     Dicyclomine                   10 mg po bid
                     Propantheline                 15 mg tid a.c. and 30
                        hydrochloride                mg qhs
                     Clidinium þ                   5–10 mg tid–qid
                     Hyoscamine þ                  1–2 tablets tid–qid
                        scopolamine þ
                        atropine þ
TCAs                 See above                     See above
SSRIs                Fluoxetine                    10–40 mg qd                   Long half-life; less
                                                                                   withdrawal effects
                     Citalopram                    20 mg qd                      Less side effects and
                                                                                   drug interactions
                     Paroxetine                    20–50 mg qd                   Short half-life; more
                                                                                   likely withdrawal
                                                                                   effects. Greater
                                                                                   effect; use in IBS-D
                     Sertraline                    25–100 mg qd                  Requires dose ranging
                     Escitalopram                  10 mg qd                      Less side effects and
                                                                                   drug interactions
SNRIs                Venlafaxine                   37.5–75 mg bid–tid
                     Duloxetine                    40–60 mg qd                   FDA approved for
                                                                                   depression and
                                                                                   diabetic neuropathy.
                                                                                   Unlabeled uses
                                                                                   include chronic pain
                                                                                   fibromyalgia, stress
                                                                                   Ongoing open
                                                                                   labeled trial for IBS.
5-HT4 agonist        Tegaserod                     See above
Antibiotics          Rifaximin                     400 mg tid
Probiotics           Bifidobacterium infantis       1 tablet qd
                     VSL # 3                       1 packet bid
Abbreviations: a.c., before meals; bid, twice daily; g, grams; mg, milligrams; oz, ounces; qd, daily; qhs, at
night; qid, four times daily; Tbsp, tablespoon; tid, three times daily; tspn, teaspoon.
IRRITABLE BOWEL SYNDROME                                                         675

Lactulose and sorbitol may also increase stool frequency, but are often associ-
ated with the side effects of bloating or cramping in IBS patients. Stimulant lax-
atives, such as senna, cascara, or bisacodyl, are useful on an intermittent basis
for refractory constipation, although frequently cause cramping, loose stools,
and urgency.

Antispasmodics work either by a direct effect on intestinal smooth muscle (eg,
mebeverine, pinaverine) or by their anticholinergic or antimuscarinic proper-
ties (eg, dicyclomine, hyoscyamine). A meta-analysis evaluated 23 randomized
clinical trials (RCTs) and reported a significantly higher global improvement
with drug versus placebo (56% versus 38%) and a greater pain improvement
(53% versus 41%) [59]. The ACG systematic review, however, evaluated 18
English-language RCTs assessing the efficacy of antispasmodic agents [56].
This review concluded that there is little evidence for the efficacy of antispas-
modics for global relief of IBS symptoms [57]. Most of these studies have short
duration, small sample sizes, and suboptimal quality. Of three higher-quality
RCTs [60–62], only one showed a significant difference between placebo and
treatment (dicyclomine), but this was using a dose high enough to cause 15%
of the treatment group to withdraw from the study because of adverse effects com-
pared with no withdrawals in the placebo group [62]. Side effects of these agents
include dry mouth, constipation, urinary retention, and visual disturbances.
Serotonergic Agonist or Antagonists
Tegaserod is a selective 5-HT4 partial agonist that stimulates gut transit and
may also have an effect on visceral sensation [63,64]. Tegaserod was approved
by the Food and Drug Administration (FDA) for the treatment of IBS-C in
women and more recently has been approved for the treatment of chronic
constipation in men and women under the age of 65. On March 30, 2007, how-
ever, Novartis Pharmaceuticals suspended marketing of Zelnorm (tegaserod)
because of important safety information. This suspension occurred at the
request of the FDA because of the incidence of cardiovascular ischemic events be-
ing significantly higher with Zelnorm treatment than with placebo treatment (13
per 11,614 [0.11%] with Zelnorm and 1 per 7031 [0.01%] with placebo [P ¼ .024]).
   Several large and well-designed trials have shown tegaserod to be more effec-
tive than placebo in improving symptoms of IBS-C [65–68]. More recent stud-
ies have shown that tegaserod remains as effective with repeated use (after
a treatment-free interval) as it is in initial therapy, and there is no rebound effect
(worsening of symptoms after treatment withdrawal) [69,70]. In addition to
improving IBS-C symptoms, tegaserod has been proved to improve outcomes
related to productivity and work impairment [71].

Alosetron is a 5-HT3 receptor antagonist that is currently available under a re-
stricted use program and is approved only for women with severe IBS-D who
676                                                          VIDELOCK & CHANG

have failed conventional therapy. This restriction is because of the occurrence
of GI-related adverse events including ischemic colitis and serious complica-
tions of severe constipation. These events occurred at a rate of 1.1 per 1000
patient years for ischemic colitis and 0.66 per 1000 patient years for serious
complications of constipation [72]. A recent systematic review concluded that
there is a significantly increased rate of ischemic colitis among alosetron-using
patients compared with placebo-using patients (0.15% versus 0.0%), but no sig-
nificant difference in the rate of serious complications of constipation. All of the
alosetron-using patients with ischemic colitis had a reversible colopathy without
long-term sequelae and most cases occurred within the first month of treatment
[73]. The restriction notwithstanding, alosetron has been proved efficacious in
seven placebo-controlled trials with over 3000 patients with nonconstipation
IBS. Five of the seven studies showed relief of abdominal pain or discomfort
and two showed relief of urgency [72]. There is a recently published
placebo-controlled long-term study that demonstrated significant efficacy of
alosetron compared with placebo over a treatment period of 48 weeks [74].
Alosetron is not FDA-approved for the treatment of IBS-D in men, but one trial
did show an increased rate of relief from symptoms during 8 weeks of treat-
ment with 1 mg alosetron twice a day (53%) compared with placebo (40%)
[39]. Alosetron significantly reduced stool consistency scores indicating more
formed stools; however, no significant effects of alosetron were seen with
regard to the other secondary symptom end points.

Tricyclic antidepressants
The rationale of using antidepressants in IBS is that these agents may alter pain
perception by a central modulation of visceral afferents, treat comorbid psycho-
logic symptoms, and alter GI transit. Different classes of antidepressants likely
act by different combinations of mechanisms. Tricyclic antidepressants are the
best studied, and are often used at low doses, because their major impact in IBS
may be more associated with an analgesic effect rather than treatment of
psychologic symptoms. A systematic review found that none of the seven
randomized placebo-controlled trials evaluating the effect of tricyclic antide-
pressants in the treatment of IBS were of high quality because of relatively
small sample sizes and poorly defined primary and secondary end points
[56]. A large randomized 12-week placebo-controlled trial, which evaluated
the efficacy of desipramine in treating moderate to severe functional bowel
disorders, conducted by Drossman and colleagues [75], however, was pub-
lished subsequent to the systematic review. Desipramine was shown to have
statistically significant benefit over placebo in the per protocol analysis, which
included only those patients who completed treatment (responder rate 73%
versus 49%), but not in the intention-to-treat analysis. The lack of benefit in
the intention-to-treat analysis may have been related to a significant drop out
rate primarily because of symptom side effects. This study also found that
the patients most likely to improve with desipramine were patients with
IRRITABLE BOWEL SYNDROME                                                     677

IBS-D, no depression, and mild to moderate symptoms. The most common
side effects associated with tricyclic antidepressants include dry mouth, consti-
pation, and drowsiness. Often initiating the drug at the lowest available dose
and increasing it gradually can minimize adverse events while trying to achieve
a therapeutic effect (eg, starting dose of 10 mg at bedtime and increasing up to
75 mg if needed). In patients who have coexistent sleep disturbances, amitrip-
tyline may be a good choice because it has a greater sedative effect caused by its
more potent antihistaminic effects. Desipramine and nortriptyline are less
sedating. If a tricyclic antidepressant is used in IBS-C, desipramine should be
considered because it has less anticholinergic effects and is less constipating
than the other tricyclic antidepressants.
Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors are commonly used to treat IBS even
though there have been relatively few placebo-controlled trials. Preliminary
evidence suggests that selective serotonin reuptake inhibitors have an effect
on overall HRQOL, symptom frequency, and abdominal pain, and these
effects seem to be independent of effects on mood. A RCT of paroxetine in
IBS patients who failed therapy with a high-fiber diet showed a greater increase
in overall well-being with paroxetine than placebo [76]. This was true for
depressed and nondepressed participants [76]. Fluoxetine was evaluated in
44 patients with IBS-C and was more effective than placebo in decreasing
the frequency of symptoms including abdominal discomfort and bloating
and increasing frequency of bowel movements and improving consistency of
stool [77]. A controlled crossover study of citalopram in 23 nondepressed
IBS patients showed an improvement in abdominal pain, bloating, and overall
well-being [78]. There is more evidence for the efficacy of tricyclic antidepres-
sants as analgesics, but tricyclic antidepressants are not as well tolerated as
selective serotonin reuptake inhibitors. Large, high-quality trials are needed
to evaluate the effectiveness of selective serotonin reuptake inhibitors in IBS;
however, in patients with severe IBS, treatment with selective serotonin reup-
take inhibitors may be helpful and has been shown to be cost-effective when
compared with routine care [79]. Combined serotonin-norepinephrine reuptake
inhibitors, such as venlaxifine and duloxetine, may have possible beneficial
effects in IBS but further studies are needed.
Small bowel bacterial overgrowth has been theorized to play a role in IBS
and is supported by an abnormal lactulose breath test in most IBS patients
[46,47]. Rifaximin is an antibiotic that has very low systemic absorption and
broad-spectrum activity against gram-positive and gram-negative aerobes and
anaerobes. In a randomized, double-blind placebo-controlled trial, 400 mg of
rifaximin given three times per day for 10 days was superior to placebo in improv-
ing global symptoms (mean improvement of 36.4% versus 21%) and bloating (but
not abdominal pain, diarrhea, or constipation). The effects were present through-
out the 10-week follow-up of the study. Although difficult to evaluate in a small
678                                                           VIDELOCK & CHANG

sample (N ¼ 87), adverse effects were uncommon and included nausea and
abdominal pain [80]. Future studies including an ongoing multicenter RCT
will likely provide more information on the efficacy of this antibiotic treatment
in IBS.
Probiotics are hypothesized to work by several mechanisms. These include
a shift from a proinflammatory to an anti-inflammatory cytokine profile, the
reduction of bile acid delivery to the colon, and alteration of motility [81]. A
trial of probiotics comparing either Bifidobacterium infantis (B infantis) or Lactoba-
cillus salivarius with placebo in 75 patients with IBS over a 12-week treatment
period showed a significant reduction in abdominal pain and discomfort, bloat-
ing, and difficulty with bowel movements with B infantis but not with L salivarius
[82]. IBS patients were found to have a decreased blood interleukin-10/interleu-
kin-12 ratio indicative of a proinflammatory, Th-1 state. Normalization of this
ratio occurred in patients who received B infantis but not in those taking L sal-
ivarius or placebo. A larger study (N ¼ 362) from the same group further eval-
uated B infantis in a capsule formulation in women with IBS seen in a primary
care setting. A dose of 1 Â 108 colony-forming units given once a day over
4 weeks significantly reduced specific symptoms of IBS and global assessment
compared with placebo or lower doses of B infantis. A higher dose of B infantis
was not observed to be beneficial, but this may have been caused by problems
with dissolution of the capsule [83].
    Data from placebo-controlled trials also exists for VSL# 3, a probiotic that is
a combination of three species of Bifidobacteria, four species of Lactobacilli, and
Streptococcus salivarius ssp. thermophilus. VSL#3 decreased flatulence but did not
show clinical efficacy for overall relief of IBS symptoms [84,85]. Another pro-
biotic mixture (Lactobacillus rhamnosus GG, L rhamnosis LC705, Bifidobacterium
breve Bb99, and Propionibacterium freudenreichii ssp. shermanii JS) was effective in
reducing IBS symptoms overall, but when the effect on individuals symptoms
was analyzed, there was only a statistically significant reduction of borborygmi,
and HRQOL was not significantly improved [86].
Novel Drugs in Development for Irritable Bowel Syndrome
There are a number of drugs in various phases of drug development that are
being studied for the treatment of IBS. Many of these agents have novel mech-
anisms of action. Drugs undergoing phase III clinical trials for IBS include the
chloride channel activator lubiprostone and the 5-HT4 agonist–5-HT3 antago-
nist renzapride. Lubiprostone is a FDA-approved treatment of chronic consti-
pation in men and women that was demonstrated to be efficacious at a dose
of 24 lg twice daily in improving stool frequency, stool form, and straining
[87,88]. Renzapride improved stool consistency and frequency in IBS-C pa-
tients but provided no overall relief of abdominal pain and discomfort [89]. Ca-
milleri and colleagues [90] reported that renzapride was associated with an
improvement in bowel function scores and a significant linear dose response
for colon transit in 48 IBS-C patients, but there was no significant effect on
IRRITABLE BOWEL SYNDROME                                                    679

gastric emptying and small intestinal transit. Acceleration of colon transit pos-
itively correlated with improvements in ease of passage and stool form but not
with stool frequency. Tack and colleagues [91] recently showed that a dose of
2 mg twice daily reduced overall colonic transit time and in the cecum–
ascending colon and descending colon. Other drugs in various stages of devel-
opment for IBS include a CRF1 antagonist; neurokinin antagonists; guanylate
cyclase-C agonist (linaclotide); 2,3-benzodiazepine (dextofisopam); kappa
opioid antagonist (asimadoline); serotonin noradrenergic reuptake inhibitor
(duloxetine); novel serotonergic agents; and opioid receptor agents.
Nonpharmacologic Agents
There are several psychologic treatments for which there is convincing evi-
dence of efficacy. Cognitive-behavioral therapy is a short-term, goal-oriented
form of psychotherapy that focuses on the role that thoughts play in determin-
ing behaviors and emotional responses. In IBS, the overall negative effect of
symptoms may be increased by such thoughts as ‘‘there is something wrong
with my body’’ or ‘‘what will people think if I go to the bathroom again?’’
[92] Cognitive-behavioral therapy helps patients to identify these thoughts as
they occur and to find alternative, more constructive ways to view the situa-
tion. It also helps people become aware of and be more in control of their
own autonomic physiology. Cognitive-behavioral therapy was more effective
than patient education in terms of global well-being and satisfaction with treat-
ment and no different than desipramine in one randomized controlled trial [75].
In another high-quality study, cognitive-behavioral therapy was shown to im-
prove symptoms but was no different than standard care or relaxation therapy
   Gut-directed hypnotherapy is another area in which there has been substan-
tial research. Gut-directed hypnotherapy is hypnosis that is directed toward
relaxation and control of intestinal motility by repeated suggestion of control
over symptoms followed by ego-strengthening [94]. It is difficult to compare
studies, because they have used different controls and end points and because
hypnosis is highly operator-sensitive. Yet, many have reported positive results,
and a recent systematic review [95] concluded that the evidence suggests that
hypnotherapy is effective, but warned that the studies were conducted in refer-
ral centers and the subjects for the most part had refractory IBS of a long
duration, and so the results may not apply to all clinic settings [95].
Complementary and Alternative Medicine
Because even the most effective treatments for IBS do not help all patients,
many turn to complementary and alternative medicine in search of other treat-
ment options. Furthermore, many patients prefer complementary and alterna-
tive medicine treatments because they view them as natural and time-tested. In
addition, complementary and alternative medicine treatments often provide
a more holistic approach and meaningful clinician-patient relationship than
western medicine. It is important for clinicians to have an understanding of
these treatments and whether there is any evidence for their efficacy.
680                                                                   VIDELOCK & CHANG

   Acupuncture has been a popular therapy for IBS patients. Despite the fact
that theory predicts effectiveness of a treatment modulating ascending pain
stimuli, it has not been well-studied and conclusions across studies are difficult
to make because of nonstandardized experimental and placebo treatment mo-
dalities. The authors of a recent Cochrane review concluded that acupuncture
was likely no better than sham acupuncture, but may have been better than
other controls; however, more research is required to make any recommenda-
tions because of the heterogeneity of the studies [96].
   Herbal medicine is another area of complementary and alternative medicine
in which patients express interest. Theoretically, this is more amenable to
rigorous randomized and controlled study designs, but few high-quality studies
have been published. The best evidence is for Chinese herbal medicine. Ben-
soussan and colleagues [97] showed an improvement in symptoms and global
scores over placebo for patients treated either with standard or individualized
Chinese herbal medicine. Only those who received individualized Chinese
herbal medicine treatment maintained a more sustained relief of their IBS
symptoms. Peppermint oil has smooth muscle relaxant effects and there is
some evidence that it may improve symptoms [98]. Other alternative or herbal
medicines that have been studied are extract of artichoke [99], carmint [100],
the herbal mixture STW 5 [101], and melatonin [102,103].

IBS is a prevalent and heterogeneous disorder and patient care should be focused
on reducing costs and improving patient satisfaction and HRQOL. The cultiva-
tion of a trusting and cooperative clinician-patient relationship reduces the order-
ing of unnecessary diagnostic tests and facilitates a collaborative effort of patient
and clinician to find the treatment that provides the most relief of symptoms, and
the greatest management of their illness and improvement of HRQOL.

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IRRITABLE BOWEL SYNDROME                                                                      681

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IRRITABLE BOWEL SYNDROME                                                                      685

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