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The New England Journal of Medicine

Review Article
Current Concepts
Volume 344:1846-1850

June 14, 2001

Number 24
The Irritable Bowel Syndrome
Brenda J. Horwitz, M.D. and Robert S. Fisher, M.D. In 1849, Cumming 1
<http://content.nejm.org/cgi/content/full/344/24/#R1>  said of the irritable
bowel syndrome, "The bowels are at one time constipated, another lax, in the
same person. How the disease has two such different symptoms I do not
profess to explain." Over the years, the unexplained gastrointestinal
symptoms of the irritable bowel syndrome have been described in various
terms, including mucous colitis, spastic colitis, nervous colon, and
irritable colon. The irritable bowel syndrome and nonulcer dyspepsia are the
most common functional gastrointestinal disorders.
The irritable bowel syndrome is defined on the basis of the recently
modified Rome criteria as the presence for at least 12 weeks (not
necessarily consecutive) in the preceding 12 months of abdominal discomfort
or pain that cannot be explained by structural or biochemical abnormalities
and that has at least two of the following three features: pain is relieved
with defecation, its onset is associated with a change in the frequency of
bowel movements (diarrhea or constipation), or its onset is associated with
a change in the form of the stool (loose, watery, or pellet-like). 2
<http://content.nejm.org/cgi/content/full/344/24/#R2>  The syndrome can be
divided into four subcategories according to whether the predominant symptom
is abdominal pain, diarrhea, constipation, or constipation alternating with
diarrhea.
Epidemiologic Features
Approximately 15 percent of U.S. adults report symptoms that are consistent
with the diagnosis of the irritable bowel syndrome 3
<http://content.nejm.org/cgi/content/full/344/24/#R3> ; the disease affects
three times as many women as men. Whether this difference reflects a true
predominance of the disorder among women or merely the fact that women are
more likely to seek medical care has not been determined. The irritable
bowel syndrome is the most common diagnosis made by gastroenterologists in
the United States 4 <http://content.nejm.org/cgi/content/full/344/24/#R4>
and accounts for 12 percent of visits to primary care providers. 5
<http://content.nejm.org/cgi/content/full/344/24/#R5>  It is estimated that
only 25 percent of persons with this condition seek medical care for it, and
studies suggest that those who seek care are more likely to have behavioral
and psychiatric problems than are those who do not seek care. 6
<http://content.nejm.org/cgi/content/full/344/24/#R6>  In addition, patients
with a diagnosis of the irritable bowel syndrome are at increased risk for
other, nongastrointestinal functional disorders such as fibromyalgia and
interstitial cystitis. 7
<http://content.nejm.org/cgi/content/full/344/24/#R7> , 8
<http://content.nejm.org/cgi/content/full/344/24/#R8>  The irritable bowel
syndrome accounts for an estimated $8 billion in direct medical costs and
$25 billion in indirect costs annually in the United States. 9
<http://content.nejm.org/cgi/content/full/344/24/#R9>
Pathophysiologic Features
Altered bowel motility, visceral hypersensitivity, psychosocial factors, an
imbalance in neurotransmitters, and infection have all been proposed as
playing a part in the development of the irritable bowel syndrome ( Figure 1
<http://content.nejm.org/cgi/content/full/344/24/#F1> ).


  <http://content.nejm.org/cgi/content/full/344/24/1846/F1>
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Figure 1. Pathophysiologic Factors in the Development of the Irritable Bowel
Syndrome.
The double-headed arrows indicate an interaction.

Altered Bowel Motility
Over the past 50 years, alterations in the contractility of the colon and
small bowel have been described in patients with the irritable bowel
syndrome. Psychological or physical stress 10
<http://content.nejm.org/cgi/content/full/344/24/#R10>  and ingestion of
food 11 <http://content.nejm.org/cgi/content/full/344/24/#R11>  may alter
the contractility of the colon. Abnormal motility of the small intestine
during fasting, such as loss of the migrating motor complex 12
<http://content.nejm.org/cgi/content/full/344/24/#R12>  and the presence of
both discrete, clustered contractions and prolonged, propagated
contractions, 13 <http://content.nejm.org/cgi/content/full/344/24/#R13>  has
been described in patients with the irritable bowel syndrome. In addition,
an exaggerated contractile response to a high-fat meal has been reported. 13
<http://content.nejm.org/cgi/content/full/344/24/#R13>  Pain is more
frequently associated with irregular motor activity of the small intestine
in patients with this syndrome than in normal controls or patients with
inflammatory bowel disease. 12
<http://content.nejm.org/cgi/content/full/344/24/#R12>
Visceral Hypersensitivity
Balloon-distention studies of the rectosigmoid 14
<http://content.nejm.org/cgi/content/full/344/24/#R14>  and the ileum 15
<http://content.nejm.org/cgi/content/full/344/24/#R15>  have shown that
patients with the irritable bowel syndrome experience pain and bloating at
balloon volumes and pressures that are significantly lower than those that
induce pain in control subjects, a phenomenon referred to as visceral
hypersensitivity. One possible explanation is that the sensitivity of
receptors in the viscus is altered through the recruitment of silent
nociceptors in response to ischemia, distention, intraluminal contents,
infection, or psychiatric factors.
There may be increased excitability of the neurons in the dorsal horn of the
spinal cord, an area rich in neurotransmitters such as catecholamines and
serotonin. Centrally, there may be differences in the way the brain
modulates afferent signals from the dorsal-horn neurons through the
ascending pathways. Functional magnetic resonance imaging 16
<http://content.nejm.org/cgi/content/full/344/24/#R16> , 17
<http://content.nejm.org/cgi/content/full/344/24/#R17>  and
positron-emission tomography 18
<http://content.nejm.org/cgi/content/full/344/24/#R18> , 19
<http://content.nejm.org/cgi/content/full/344/24/#R19>  of the brain show
different levels of activation in the thalamus and the anterior cingulate
cortex after balloon distention of the rectum in patients with the irritable
bowel syndrome, as compared with normal subjects.
These findings, although controversial, suggest a primary central defect of
visceral pain processing. Some authors have suggested that hypervigilance
rather than true visceral hypersensitivity may be responsible for the low
pain threshold in patients with the irritable bowel syndrome.
Psychosocial Factors
Psychological stress can alter motor function in the small bowel 11
<http://content.nejm.org/cgi/content/full/344/24/#R11>  and colon, 20
<http://content.nejm.org/cgi/content/full/344/24/#R20>  both in normal
subjects and in patients with the irritable bowel syndrome. Up to 60 percent
of patients seen at referral centers have psychiatric symptoms such as
somatization, depression, and anxiety, and patients with a diagnosis of the
irritable bowel syndrome are more likely to have these symptoms than are
persons who have never sought medical care for bowel problems. 21
<http://content.nejm.org/cgi/content/full/344/24/#R21> , 22
<http://content.nejm.org/cgi/content/full/344/24/#R22>  When present,
psychiatric disturbances influence overall use of health care services and
the ability to cope with symptoms. The presence or absence of a history of
abuse in childhood (sexual, physical, or both) is correlated with the
severity of symptoms in patients with the irritable bowel syndrome. 23
<http://content.nejm.org/cgi/content/full/344/24/#R23>  It has even been
proposed that experiences early in life may affect the central nervous
system and confer a predisposition to a state of hypervigilance.
Neurotransmitter Imbalance
Recent studies have suggested that neurotransmitters are involved in the
pathogenesis of the irritable bowel syndrome. Five percent of serotonin is
located in the central nervous system, and the remaining 95 percent is in
the gastrointestinal tract, within enterochromaffin cells, neurons, mast
cells, and smooth-muscle cells. When released by enterochromaffin cells,
serotonin stimulates extrinsic vagal afferent nerve fibers and intrinsic
enteric afferent nerve fibers, resulting in such physiological responses as
intestinal secretion and the peristaltic reflex and in such symptoms as
nausea, vomiting, abdominal pain, and bloating. 24
<http://content.nejm.org/cgi/content/full/344/24/#R24>  Preliminary evidence
suggests that patients with the irritable bowel syndrome have increased
serotonin levels in plasma and in the rectosigmoid colon. 25
<http://content.nejm.org/cgi/content/full/344/24/#R25> , 26
<http://content.nejm.org/cgi/content/full/344/24/#R26>
Other neurotransmitters that may have an important role in functional
gastrointestinal disorders include calcitonin gene–related peptide,
acetylcholine, substance P, pituitary adenylate cyclase–activating
polypeptide, nitric oxide, and vasoactive intestinal peptide. These
neurotransmitters may provide links not only between bowel contractility and
visceral sensitivity, but also between the enteric and central nervous
systems.
Infection and Inflammation
There is compelling evidence that inflammation of the enteric mucosa or
neural plexuses initiates or contributes to symptoms associated with
irritable bowel syndrome. 27
<http://content.nejm.org/cgi/content/full/344/24/#R27> , 28
<http://content.nejm.org/cgi/content/full/344/24/#R28> , 29
<http://content.nejm.org/cgi/content/full/344/24/#R29>  Mucosal inflammatory
cytokines may activate peripheral sensitization or hypermotility. Gwee et
al. reported that in patients with infectious enteritis, the presence of
hypochondriasis and stressful life events at the time of the acute infection
predicted the subsequent development of the irritable bowel syndrome. 30
<http://content.nejm.org/cgi/content/full/344/24/#R30>  To date, no single
conceptual model can explain all cases of the syndrome.
Diagnosis
After a complete history has been obtained, all patients with lower
gastrointestinal tract symptoms should undergo a complete physical
examination and laboratory testing, including a complete blood count,
blood-chemistry tests, liver-function tests, and measurement of thyrotropin.
The diagnosis of the irritable bowel syndrome is suggested when a patient's
symptoms meet the Rome criteria. In the majority of cases, there are no
abnormalities on physical examination or laboratory testing and there are no
findings suggestive of a structural disorder — so-called alarm symptoms.
Therefore, the irritable bowel syndrome can be reasonably diagnosed on the
basis of flexible sigmoidoscopy alone, in patients who are less than 50
years old, or colonoscopy, in those who are 50 or older; barium enema and
flexible sigmoidoscopy are often substituted for colonoscopy. In patients
with diarrhea, a biopsy specimen should be obtained from the mucosa of the
descending colon to rule out microscopic colitis.
If there are abnormalities on physical examination or laboratory testing or
if an alarm symptom is present, the irritable bowel syndrome is a diagnosis
of exclusion after reasonable diagnostic testing has been performed, such as
colonoscopy, computed tomographic scanning of the abdomen and pelvis, and
radiographic evaluation of the small intestine. Alarm symptoms include
evidence of gastrointestinal bleeding such as occult blood in the stool,
rectal bleeding, or anemia; anorexia or weight loss; fever; persistent
diarrhea causing dehydration; severe constipation or fecal impaction; a
family history of gastrointestinal cancer, inflammatory bowel disease, or
celiac sprue; and the onset of symptoms at the age of at least 50 years. In
1985, the American College of Physicians recommended the use of alarm
symptoms to guide treatment 31
<http://content.nejm.org/cgi/content/full/344/24/#R31> ; however, the
validity of this approach has never been established in rigorous,
randomized, prospective clinical studies.
A number of structural or metabolic disorders that are responsive to
specific treatment cause symptoms similar to those of the irritable bowel
syndrome. Lactase deficiency is a common culprit. Other such disorders
include cancer of the colon, diverticulitis, mechanical obstruction of the
colon or small intestine, inflammatory bowel disease, enteric infection,
ischemia, maldigestion or malabsorption, and endometriosis (suggested by the
presence of pelvic pain at the time of the menstrual period). In the absence
of alarm symptoms, the presence of one of these structural or metabolic
disorders is very unlikely.
Treatment
Whether the irritable bowel syndrome is diagnosed on the basis of the
history, physical examination, and laboratory tests or after extensive
testing (because of the presence of an alarm symptom), the establishment of
trust in the physician–patient relationship should be given a high priority
in order to maximize the efficacy of treatment and minimize "doctor
shopping." A diary of food intake and symptoms can be useful in identifying
foods that may be associated with symptoms of the irritable bowel syndrome.
Patients often report an exacerbation of symptoms after the consumption of
certain foods. Some patients benefit from avoiding or limiting their intake
of caffeine, alcohol, fatty foods, gas-producing vegetables, or products
containing sorbitol, such as sugarless gum and dietetic candy. The avoidance
of constipating foods and the addition of 20 to 30 g of fiber per day either
in the diet or in the form of supplements such as bran, polycarbophil, or a
psyllium derivative may help relieve constipation 32
<http://content.nejm.org/cgi/content/full/344/24/#R32> , 33
<http://content.nejm.org/cgi/content/full/344/24/#R33> , 34
<http://content.nejm.org/cgi/content/full/344/24/#R34> , 35
<http://content.nejm.org/cgi/content/full/344/24/#R35>  and may occasionally
improve diarrhea.
A rational approach to treating the irritable bowel syndrome uses the
patient's symptoms as a guide ( Table 1
<http://content.nejm.org/cgi/content/full/344/24/#T1> ). For patients in
whom the disorder is manifested predominantly as abdominal pain, a variety
of medications have been used, and several new agents are under development.
Antispasmodic agents may reduce abdominal pain or bloating through
anticholinergic pathways; in refractory cases, nitrates are occasionally
useful for direct relaxation of smooth muscles. A recent meta-analysis
suggested the effectiveness of antispasmodic agents and tricyclic compounds
in treating selected patients with the irritable bowel syndrome. 36
<http://content.nejm.org/cgi/content/full/344/24/#R36>  Unfortunately, many
of these agents are not available in the United States, and large-scale,
stand-alone studies have not been performed. Small studies have shown that
tricyclic compounds in low doses relieve unexplained abdominal pain. 37
<http://content.nejm.org/cgi/content/full/344/24/#R37>  Side effects —
sedation, dry mouth and eyes, and weight gain — limit the use of primary
tricyclic amines. Secondary tricyclic amines such as nortriptyline and
desipramine may be less likely to have side effects. 38
<http://content.nejm.org/cgi/content/full/344/24/#R38>


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Table 1. Symptom-Guided Treatment of the Irritable Bowel Syndrome.

Despite speculation that 5-hydroxytryptamine (5-HT), or serotonin, receptors
may be involved in the pathogenesis of the irritable bowel syndrome, the
results of treatment with selective serotonin-reuptake inhibitors have been
disappointing. Nevertheless, serotonin has been implicated in the modulation
of visceral nociception, especially through the 5-HT3 and 5-HT4 pathways.
Two new agents — alosetron, a 5-HT3–receptor antagonist, and tegaserod, a
5-HT4 agonist — have been shown to diminish visceral sensitivity to rectal
distention in women who have diarrhea as the predominant symptom of the
irritable bowel syndrome and in those who have constipation as the
predominant symptom, respectively. 39
<http://content.nejm.org/cgi/content/full/344/24/#R39> , 40
<http://content.nejm.org/cgi/content/full/344/24/#R40>  Fedotozine, a
kappa-opioid agonist, 41
<http://content.nejm.org/cgi/content/full/344/24/#R41>  has shown promise as
a visceral antinociceptive agent, and other kappa-opioid agonists are being
developed. Finally, in some patients who have abdominal pain that is
refractory to all these therapeutic agents, treatment with classic
analgesics such as nonsteroidal antiinflammatory agents (perhaps with an
initial trial of a cyclooxygenase-2 inhibitor) or, in extreme cases, opioid
analogues may control the pain and improve the quality of life. The
addictive potential of opioid analogues makes them the last choice for
long-term therapy.
For patients in whom diarrhea is the predominant manifestation of the
irritable bowel syndrome, classic antidiarrheal agents such as loperamide 42
<http://content.nejm.org/cgi/content/full/344/24/#R42>  and diphenoxylate
may help decrease the frequency of bowel movements and improve the
consistency of stool. In a study of women with this form of the irritable
bowel syndrome, alosetron prolonged colonic transit, reduced the frequency
of bowel movements and the urge to defecate, improved the consistency of
stool, and decreased abdominal pain. 43
<http://content.nejm.org/cgi/content/full/344/24/#R43>  However, this drug
has been removed from the market because of side effects such as severe
constipation, ischemic colitis, and bowel perforation. In cases of diarrhea
that cannot be controlled, cholestyramine has been used to bind bile acids
that may be responsible for increased secretion and decreased absorption of
water in the colon. 44
<http://content.nejm.org/cgi/content/full/344/24/#R44>  In some refractory
cases, a short course of antibiotics may reduce the diarrhea, presumably by
altering the intestinal flora. 45
<http://content.nejm.org/cgi/content/full/344/24/#R45>
For patients in whom constipation is the predominant manifestation of the
irritable bowel syndrome, consumption of fiber may alleviate constipation
and related symptoms such as abdominal pain, tenesmus, and dyschezia. 32
<http://content.nejm.org/cgi/content/full/344/24/#R32>  Constipation can
also be safely treated with osmotic laxatives such as nonabsorbable
carbohydrates (lactulose and sorbitol), milk of magnesia or magnesium
citrate, or a polyethylene glycol solution. Two new classes of compounds,
aminoguanidine indoles such as tegaserod and benzofurans such as
prucalopride, act specifically on 5-HT4 receptors. These agents shorten the
transit time in the colon and small intestine, increase the frequency of
bowel movements, and increase the softness of stools. 46
<http://content.nejm.org/cgi/content/full/344/24/#R46> , 47
<http://content.nejm.org/cgi/content/full/344/24/#R47> , 48
<http://content.nejm.org/cgi/content/full/344/24/#R48> , 49
<http://content.nejm.org/cgi/content/full/344/24/#R49>  Studies of
prucalopride have been suspended because of concern about tumorigenic
effects in animals. Derivatives of anthraquinones (senna and cascara), which
act as strong laxatives, may be used as a last resort, but their use is
limited by the frequent development of tachyphylaxis. The question of
whether anthraquinones and their derivatives damage the enteric nervous
system has not been resolved.
Although many pharmacologic agents have been used to treat the irritable
bowel syndrome, few have been tested in controlled, double-blind studies
with adequate statistical power. The doses of some commonly used agents are
shown in Table 2 <http://content.nejm.org/cgi/content/full/344/24/#T2> .


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Table 2. Dosage Guidelines for Drugs Commonly Used to Treat the Irritable
Bowel Syndrome.

The interaction between psychosocial factors and the genesis of all forms of
the irritable bowel syndrome is poorly understood. The most provocative
observations in this respect are that persons with the syndrome who seek
care are those in whom the syndrome is accompanied by a psychiatric disorder
and that the syndrome may develop in patients who have both infectious
gastroenteritis and a psychiatric disorder. The potential benefits of
supportive therapy, relaxation exercises, hypnosis, cognitive behavioral
therapy, and psychodynamic interpersonal psychotherapy are well recognized.
50 <http://content.nejm.org/cgi/content/full/344/24/#R50>
The irritable bowel syndrome is a common disorder that has a pronounced
effect on the quality of life and that accounts for a large proportion of
health care costs. Common pitfalls in diagnosing and treating this disorder
include unnecessary repetition of tests, failure to establish trust in the
physician–patient relationship, and failure to provide the patient with
realistic expectations regarding the efficacy of medications. A concise
diagnostic evaluation and prompt institution of symptom-guided therapy can
help alleviate the pain and suffering experienced by patients with the
irritable bowel syndrome.

Source Information
From the Gastroenterology Section and the Functional Gastrointestinal
Diseases Center, Temple University School of Medicine, Philadelphia.
Address reprint requests to Dr. Fisher at the Gastroenterology Section,
Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140.
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.