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CHRONIC CONSTIPATION:
MECHANISMS OF ACTION AND EFFECTIVE TREATMENT
—
T
Lucinda A. Harris, MS, MD*
ABSTRACT
This is an exciting time in the treatment of
functional gastrointestinal (GI) disorders because
of our rapidly evolving understanding of the
mechanism of action of these illnesses and their
treatment. In this article, chronic constipation
(CC), which is one of the most common functional disorders of the gut, is discussed. Although not
life-threatening, CC can profoundly and negatively affect quality of life and is associated with
a significant economic burden of direct and
indirect annual healthcare costs. In the United
States alone, estimates from several years ago
placed the annual cost of laxatives to treat constipation at $800 million. Possible causes of CC
range from psychologic disorders to dysfunctions of GI motility, though most patients do not
have an identifiable explanation for their constipation. Recent research indicates that constipation most likely results from abnormalities of
myenteric neurons or pacemaker function,
defects in neurotransmitters, or incoordination
of the muscles of the pelvic floor or anorectum,
and may be influenced by environmental factors
or chronic stress. In this article, the symptoms of
CC are reviewed and the safety and efficacy of
traditional, novel, and emerging therapies are
examined. Because of the overlap in symptoms,
many of the treatments discussed in this review
also apply to patients with constipation-predominant irritable bowel syndrome.
(Adv Stud Med. 2005;5(10B):S965-S976)
*Senior Associate Attending, Division of Gastroenterology,
Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
Address correspondence to: Lucinda A. Harris, MD,
Division of Gastroenterology, Mayo Clinic, Scottsdale,
13400 East Shea Blvd, Scottsdale, AZ 85259. E-mail:
[email protected].
Advanced Studies in Medicine
n
he definition of constipation differs
among individuals affected with the disorder, their physicians, and the professional medical organizations that provide
guidelines for treatment. Research reveals
that 50% of patients define constipation by the symptoms reported most often: infrequent, difficult, or
incomplete evacuation; the passage of hard stool; or
the unproductive urge to defecate.1-3 Most clinicians
define constipation simply as fewer than 3 bowel
movements per week,1-3 but both the Rome II
Functional Gastrointestinal Disorders Coordinating
Committee4 and the American College of
Gastroenterology (ACG) Chronic Constipation (CC)
Task Force5 have published current guidelines for diagnosis and treatment that are more specific.
Rome II criteria for CC specify that during the preceding 12 months symptoms must have occurred for at
least 12 (not necessarily consecutive) weeks. In addition,
more than 25% of defecations must be characterized by
2 or more of the following symptoms: lumpy or hard
stools, straining, a sensation of incomplete evacuation or
anorectal obstruction, the need for a manual maneuver
to evacuate the rectum, and/or fewer than 3 defecations
per week. It is essential that no organic disease, irritable
bowel syndrome (IBS), or loose stools be present.4
However the ACG CC Task Force members concluded
that this definition was rather onerous for primary care
clinicians because many patients who self-report CC do
not meet these criteria.6 The Task Force proposed a
broader definition of the disorder that includes the most
common symptoms of self-reported constipation (infrequent stools, difficult defecation [straining, incomplete
evacuation, hard or lumpy stools, prolonged time for
defecation], or both)5 and states that a combination of
those symptoms should have been present for at least 3
of the prior 12 months.7 The ACG CC Task Force rec-
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ognized that CC is associated with a significant decrease
in quality of life8 and that, because there are no symptom-based criteria that identify subtypes of CC such as
colonic inertia or defecatory disorders, those subtypes
may occur concomitantly in individual patients. In its
definition of CC, the Task Force also recognized that
abdominal discomfort or bloating usually is minimally
present in patients with CC and that the symptoms of
CC often are difficult to differentiate from those of IBS.
PATHOGENESIS AND PATHOPHYSIOLOGY
In his article in this monograph, Dr Camilleri
addresses the pathogenesis and pathophysiology of CC
and IBS. In summary, the clinical causes of CC can be
divided into 3 primary categories: extracolonic constipation, mechanical constipation, and functional constipation.9 In patients with extracolonic constipation the
function of the colon and/or rectum is affected by exogenous factors such as dietary habits (eg, low fiber intake,
anorexia); medications (eg, antidepressants, anticholinergics, antihypertensives, opioids, iron supplements, aluminum- or calcium-based antacids); metabolic,
endocrine, neurologic, or connective-tissue disorders; or
trauma such as spinal cord injury.9 Mechanical constipation is caused by a physical anomaly of the colon and/or
rectum (ie, anal stenosis, rectal prolapse, rectocele, the
colonic effects of diverticular disease). Functional constipation is classified as 1 of 3 entities: constipation-predominant IBS (C-IBS) characterized by abdominal
discomfort and bloating10; slow-transit constipation, in
which fewer than 3 bowel movements per week are produced without either the urge to defecate or abdmominal pain; or a defecatory disorder of the pelvic floor or
anal sphincter, in which patients must strain excessively
and may rely on manual maneuver to defecate.9 Within
any one person slow-transit constipation, defecatory disorder, and C-IBS may coexist.5
CHRONIC CONSTIPATION: FALLACIES AND FOLKLORE
CC is a widespread disorder of the gut that has
been long misunderstood.11 Before various treatments
are presented, it is important to briefly review the
myths about constipation, which influence prescribing
practices, patients’ perceptions of CC, and compliance
with therapy. Misconceptions about the benefits of
fiber consumption and fluid intake will be discussed in
the treatment section of this article.
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THE TOXIC GUT
Many patients (and even some healthcare providers)
believe that toxins produced by undigested food in the
gut are systemically absorbed and produce a wide variety
of adverse health-related symptoms, from lassitude to
hypertension to various cancers.12,13 The need for a “daily
bowel movement” is a widespread myth to which the
regular use by many individuals of laxatives or cleansing
techniques ranging from herbal teas to enemas can be
attributed. To date, however, no single such toxin has
been identified, and the prompt relief of many nonspecific symptoms of idiopathic constipation probably
results from a mechanical rather than systemic effect.
Another common myth states that in some individuals,
CC is caused by a colon that is too long or “kinked” and
that surgical intervention might be helpful. Other than
for the treatment of volvulus or severe refractory colonic
inertia, surgery does not play a role in the treatment of
constipation, and no valid studies correlate colonic
length with transit.11
THE EFFECT OF HORMONES
Sex hormones and GI hormones have been long
hypothesized to influence intestinal transit. Sex hormones do not appear to exert a major effect on bowel
function during the menstrual cycle, although the looser
stools often seen on the first day of menses may be related to the local action of prostaglandins produced on the
first day of menstruation.14 However, progesterone may
be responsible for the slower colonic transit that occurs
during pregnancy.15 Xiao et al have suggested the possibility that down-regulation of contractile G proteins and
up-regulation of inhibitory G proteins, likely caused by
overexpression of progesterone receptors, may be a cause
of slow-transit CC in women.16 Women with severe idiopathic constipation seem to exhibit a reduction in steroid
hormones, which may result from alterations in the
hepatic circulation of those hormones and/or their
breakdown by the intestine.17 The role of GI hormones
such as motilin, glucagon, and pancreatic polypeptide is
less clear. Alterations in hormone levels have been found
in people with severe idiopathic constipation, but the
differences in primary and secondary changes in those
levels must be further elucidated.11 In individuals without the clinical features of hypothyroidism, the role of
thyroid dysfunction in CC is minimal.11
THE HAZARDS OF LONG-TERM LAXATIVE USE
The myth that the long-term use of laxatives caus-
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es enteric neuronal damage, impairs the function of
the colon, and creates laxative dependency often leads
patients to fear treatment with a laxative medication
when it is required. Recent reviews11,18 examining this
misconception and the literature that created it show
that such concern is unfounded. However, laxatives
can cause electrolyte disturbances and abdominal discomfort and must therefore be appropriately selected
and prescribed in correct doses.
THE INCREASED RISK OF COLORECTAL CANCER
FROM ANTHRAQUINONE USE
Also common is the misperception that
anthraquinone cathartic use increases the risk of colorectal cancer. That impression results from a meta-analysis by Sonnenberg and Muller,19 who examined the
colorectal cancer risk associated with cathartic use and
constipation in 14 case-controlled studies. The analysis
of those investigators revealed a statistically significant
pooled odds ratio of 1.46 for cathartics and 1.48 for constipation, and their review of the data on dietary factors
such as the consumption of fat, alcohol, meat, and lowresidue foods revealed relative risks ranging from 2 to 4.19
It thus appears much more likely that the risk associated
with anthraquinone laxatives reflects the effect of diet. A
subsequent population-based, case-controlled investigation confirmed that constipation and not laxative use
was the significant risk factor for colorectal cancer.20
TREATMENT
Before treatment for constipation is initiated, the clinician must obtain the patient’s complete medical history
and perform a thorough physical examination (especially
important is a rectal examination to assist in excluding
patients with defecatory disorders). When patients with
CC present without alarm symptoms (Table 1), the recommendation from the ACG CC Task Force is to initiate empiric treatment without diagnostic testing (Grade
C recommendation).5 The ACG CC Task Force6 also
recently reviewed many available laxative treatments and
classified those therapies as Grade A, B, or C according to
the quality of the studies supporting their use. The ACG
grades of laxative treatment are similar to those developed
by the American College of Gastroenterology Functional
Gastrointestinal Disorders Task Force on the management of IBS in North America.10
ACG Grade A recommendations for the treatment
of CC are based on Level I evidence, which represents
Advanced Studies in Medicine
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data obtained from high-quality randomized controlled
trials (RCTs). Grade B recommendations are based on
intermediate-quality RCTs (Level II evidence), and
Grade C recommendations are based on Level III-V evidence (primarily observational studies). Where applicable, the ACG grades are discussed in this article, but it is
important to note that only North American literature
(United States and Canada) was reviewed in determining
the levels of evidence. Those grades should be used as
guidelines to assist the clinician in choosing therapies for
the treatment of CC but are not meant to prohibit treatment with any of the agents graded.
The goals of treatment for patients with CC, then,
are to restore normal bowel function and relieve symptoms by accelerating colonic transit time, stimulating
gut motility, facilitating defecation, and/or promoting
secretion by the intestinal mucosa. Discussed below
are treatments commonly used to do so, such as traditional therapies including lifestyle changes, laxatives
and enemas, pelvic floor retraining, and surgery; novel
therapies including tegaserod; and emerging therapies.
Traditional and novel pharmacotherapeutic agents for
the treatment of CC are listed in Table 2, and emerging therapies are featured in Table 3.
LIFESTYLE CHANGES
Although public perception holds that diet, fluid,
and exercise influence constipation, most studies
demonstrate only limited support of that view.21-24
Analysis of available data indicates that a low-fiber diet is
a contributing factor to CC in only a select group of
individuals.25 Because increasing natural fiber intake
increases bloating and flatulence,26 patients’ acceptance
of this recommendation is limited. Clinicians often rec-
Table 1. Alarm Signs and Symptoms in Patients
With Chronic Constipation*
Acute onset of constipation in older individuals
Overt or occult blood in stool
Weight loss ≥10 lb
Anemia
Family history of colon cancer or inflammatory bowel disease
*The list above is not all-inclusive; the suggested signs and symptoms are
based on guidelines from the American College of Gastroenterology
Chronic Constipation Task Force.5
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ommend that individuals with constipation increase their fluid intake, but studies do not demonstrate that this
increases stool bulk or colon transit
time,23 even if the fluids consumed are
hyperosmolar.27 Only in the setting of
clinical dehydration is increasing fluid
intake helpful in treating CC.11 With the
exception of especially vigorous activity
such as marathon running,28 exercise
exerts no proven benefit in ameliorating
CC in young, healthy patients.21,22,24,29,30
In older adults, the cause of constipation
may be multifactorial; etiologic factors
include medication, diet, and inactivity.
However, evidence for physical inactivity as a risk factor for CC in older persons
does exist.31,32 Despite the fact that
changes in lifestyle and diet have not
been validated in controlled trials, those
measures often are recommended as
treatment for both CC and IBS before
pharmacologic therapy is considered.6,33
LAXATIVES
Bulking agents: Initial treatment for
the patient with CC who seeks clinical
assessment often involves the use of a
bulk-forming supplement such as psyllium (ispaghula husk, Metamucil®,
Konsyl®), calcium polycarbophil
(Perdiem® Fiber Therapy, FiberCon®),
methylcellulose (Citrucel®), carboxymethylcellulose, or bran. Those
agents have been approved by the US
Food and Drug Administration (FDA)
for the treatment of occasional constipation6; however, only psyllium has been
shown to increase stool frequency.34,35
Bulking agents retain water in and
increase the solid content of the stool
but, like high-fiber foods, they may produce gas and bloating. The ACG CC
Task Force, citing the fact that studies
often were of short duration or suboptimal design or revealed conflicting
results, applied a Grade B recommendation to bulking agents for the treatment
of constipation.6,36,37 These agents also
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Table 2. Agents for the Treatment of Chronic Constipation and
Constipation-Predominant Irritable Bowel Syndrome*
Class
Laxatives
Bulking agents
Stool softeners
(emollients)
Osmotics
Stimulants
(irritants)
Brand Name
Psyllium
Methylcellulose
Calcium polycarbophil
Metamucil, Konsyl
B
Citrucel
B
FiberCon, Equalactin,
B
Perdiem Fiber Therapy
Docusate sodium
Docusate calcium
Mineral oil
Magnesium hydroxide
Magnesium citrate
Sodium phosphate
Lactulose
B
B
B
B
Colace
Surfak
No brand name
Milk of Magnesia
Citroma
Fleet Phospho-Soda
Cephulac, Kristalose,
Enulose
Polyethelene glycol (PEG) MiraLax
Sorbitol
No brand name
Mannitol
No brand name
Cascara sagrada
Senna
Ricinoleic acid
Diphenylmethane
derivatives
Nature’s Remedy
Perdiem, Senokot
Castor oil
Dulcolax, Correctol
Enemas and suppositories
Innovative-use
agents
Sodium phosphate
Visicol
monobasic monohydrate +
sodium phosphate dibasic
anhydrous
Misoprostol
Various brand names
Bethanechol
Various brand names
Colchicine
Various brand names
Prokinetic agents
(5-HT4 agonists ) Tegaserod
Alternative
treatments
ACG Grade†
Generic Name
Herbal supplements
Combination laxatives
lubricants (in adults)
‡
‡
A
A
‡
‡
B
B
B
B
‡
‡
Off-label use
Off-label use
Off-label use
Zelnorm
A
Various commercial
brands
C§
ACG = American College of Gastroenterology; 5-HT4 = 5-hydroxytryptoamine4.
*Adapted from: Harris L, Chang L. The functional bowel spectrum. In: Wallace DJ, Clauw DJ, eds.
Textbook of Fibromyalgia and Other Non-Neuropathic Pain Syndromes. Philadelphia, Pa: Lippincott,
Williams & Wilkins; 2005.
†Grade A, recommendations supported by 2 or more Level 1 trials without conflicting evidence from other
Level 1 trials; Grade B, recommendations based on evidence from a single Level I trial or recommendations
based on evidence from 2 or more Level I trials with conflicting evidence from other Level I trials or supported by evidence from 2 or more Level II trials; Grade C, recommendations based on Level III-V evidence.
‡Insufficient studies available to judge safety and effectiveness.
§Applies only to herbal laxatives; other alternative therapies have not yet been evaluated.
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Table 3. Emerging Therapies* for the Treatment of
Chronic Constipation and ConstipationPredominant Irritable Bowel Syndrome
Class
Generic Name
Brand Name
Prokinetic agents
(5-HT4 agonists )
Prucalopride
No brand name
Combination
Mosapride
No brand name
Renzapride
No brand name
Chloride-channel
activators
Lubiprostone
No brand name
Nonspecific opioid
antagonists
Methylnaltrexone
No brand name
Mu-opioid antagonists
Alvimopan
Entereg
5-HT4 agonist5-HT3 antagonists
*All agents are not yet FDA approved and await further study.
received a Grade B designation from the American
College of Gastroenterology Functional Gastrointestinal
Disorders Task Force as treatment for IBS.10
Because of flaws in study design, an accurate assessment of the efficacy of bulking agents cannot be made.
In addition, adverse effects such as an increased risk of
mechanical obstruction of the esophagus or colon or
an anaphylactic reaction have been associated with the
use of those agents.26 When bulking agents fail, stool
softeners may be added or other laxatives may be used.
Stool softeners (emollients): Stool softeners (emollients), which are thought to be inferior to psyllium in
managing the symptoms of CC,6 act primarily as detergents to soften stools. The most common agents available as stool softeners in the United States are docusate
calcium (Surfak) and docusate sodium (Colace). Those
medications, which are FDA approved for the treatment
of occasional constipation, received a Grade B recommendation from the ACG CC Task Force.6
Mineral oil, which also exerts an emollient effect, was
not evaluated by the ACG Task Force because no RCTs of
that agent have been conducted in adults. RCTs in the
pediatric population demonstrate that mineral oil is more
effective than senna-based laxatives and less effective than
osmotic laxatives in producing more frequent and softer
stools as treatment for CC.5 Adverse effects of mineral oil
include lipoid pneumonia, anal seepage, malabsorption of
fat-soluble vitamins, and foreign-body reactions in tissue.38
The ACG CC Task Force has designated a Grade C
recommendation for the use of herbal supplements (eg,
Advanced Studies in Medicine
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aloe), lubricants (eg, mineral oil) in adult patients, or
combination laxatives (eg, psyllium plus senna) because
no published RCTs on the efficacy of those therapies
exist in the United States in patients with CC.5
Osmotic laxatives: Osmotic laxatives, which
increase stool bulk and the volume of water in the
small and large intestine, often require 1 to 2 days to
produce a full result. Osmotics are of 3 types: saline laxatives (magnesium hydroxide [milk of magnesia], magnesium citrate, magnesium sulfate, sodium phosphate,
etc), nonabsorbed sugars (solutions of lactulose
[Cephulac, Kristalose®, Enulose], sorbitol, or mannitol),38 or polyethylene glycol (PEG, MiraLax), which is a
large polymer with osmotic activity. FDA approval of
those agents for the treatment of CC is variable.
Lactulose is approved for the treatment of constipation,
but magnesium hydroxide is approved for only occasional use. PEG can be used for 2 weeks or fewer in the
treatment of CC. Both PEG and lactulose received a
Grade A recommendation from the ACG CC Task
Force, but a Grade B recommendation was applied to
magnesium hydroxide because of insufficient data on the
effect of that agent in patients with CC.6
Lactulose and sorbitol have been shown to be similarly effective, but in 1 trial that compared those agents,
lactulose was more likely to produce nausea.33,39 As a
treatment for constipation, PEG has been shown to be
somewhat more effective than lactulose and to cause
fewer adverse effects, although both agents have been
reported to cause abdominal bloating, flatulence, and
abdominal cramps.9,29 Osmotic laxatives also have been
associated with multiple electrolyte abnormalities
(hypermagnesemia, hyperphosphatemia, hypercalcemia,
hyponatremia, hypokalemia), hypovolemia, and diarrhea,6,26 and for those reasons may be contraindicated in
patients with renal insufficiency or cardiac dysfunction.29,40 In addition, magnesium toxicity has been associated with the use of magnesium hydroxide.38 When
overused, osmotic laxatives can cause dehydration.41
Stimulant (irritant) laxatives: Stimulant (irritant)
laxatives, which increase the frequency of intestinal
contractions, include over-the-counter remedies
such as cascara sagrada (Nature’s Remedy), senna
(Perdiem, Senokot), ricinoleic acid (castor oil,
Castor), and derivatives of diphenylmethane
(Correctol, Dulcolax).42 Those agents, which are
believed to exert a direct effect on mucosal transport
and motility, have been approved by the FDA for the
treatment of occasional constipation,6 but insuffi-
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cient evidence exists about their effectiveness in the management of CC. As a result, stimulant laxatives have
received a Grade B recommendation from the ACG Task
Force.6 Diphenylmethane derivatives include bisacodyl,
picosulfate, and phenolphthalein (which has been withdrawn from the US market). Bisacodyl is a diacetic acid
ester, picosulfate is a disulfuric acid semiester, and phenolphthalein consists of free diphenolic groups. The
mechanism of all stimulant laxatives involves conversion
to free diphenolic groups.
Phenolphthalein is no longer available in the United
States because it was associated with an increased risk of
carcinogenesis (an assumption that remains unproven
and probably is incorrect). Bisacodyl, which is more
potent than phenolphthalein, is thought to inhibit water
absorption in the colon and small bowel by exerting an
effect on kinases, prostaglandins, and (possibly) adenosine triphosphatase. Picosulfate, which seems to exert a
direct effect on colonic bacteria, is transformed to the
same active molecule as that of bisacodyl.42
Stimulant laxatives exert their effect within hours after
ingestion but should be taken infrequently9 because they
can cause flatulence, abdominal pain, and metabolic disturbances and may be overused.43 Other adverse effects
associated with stimulant-laxative use abound.
Diphenylmethane derivatives can cause abdominal
cramping, Stevens-Johnson syndrome, fixed drug eruptions, protein-losing enteropathy, hepatotoxicity, and
reactions similar to those produced by lupus erythematosus.29,40,42 Long-term use of any stimulant laxative can
cause diarrhea and resultant hypokalemia, hyponatremia,
and dehydration,41 and some investigators associate radiographic changes in the colon with the use of those
agents.40,43 As discussed previously, however, neurologic
damage is unlikely to be caused by this class of drug.
ENEMAS AND SUPPOSITORIES
Enemas are of different types: phosphate, mineral
oil, tap water, and soap suds. The mechanism of action
varies with the type of enema used. Suppositories can
be osmotic (bisacodyl) or more lubricating (glycerine).
Glycerine suppositories are thought to exert an osmotic effect and also may act as a local irritant. This group
of agents, which was not evaluated or even mentioned
by the ACG CC Task Force, is thought to be useful in
the management of patients with fecal impaction of
the rectosigmoid colon.44 Adverse effects include
mechanical trauma from placement and (with phosphate enemas) hyperphosphatemia. Soap suds enemas
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can be severely irritating to the lining of the intestine
and generally are not recommended.
INNOVATIVE-USE AGENTS
A variety of other agents (sodium phosphate compounds, misoprostol, bethanechol, colchicine) have been
prescribed as innovative treatments for CC in certain
populations. Those therapies often are limited in their
application because of their unfavorable adverse effect
profile. At the time of this writing, only sodium phosphate compounds remain the focus of ongoing investigation for the treatment of constipation.
Sodium phosphate monobasic monohydrate + sodium
phosphate dibasic anhydrous: A combination of lowdose sodium phosphate monobasic monohydrate plus
sodium phosphate dibasic anhydrous (Visicol) was
shown in an open-label, multicenter, 4-week, phase 4
study to provide relief of constipation in patients with
C-IBS and CC. Benefit was achieved in subjects
receiving the 4- or 8-tablet regimen of sodium phosphate as opposed to those receiving placebo. The treatment was well tolerated in general (particularly in the
low-dose group) and promptly relieved constipation
(usually within the first week of treatment), a benefit
that persisted during the 28-day period of therapy.45
This combination drug currently is approved by the
FDA for bowel cleansing before colonoscopy. Sodium
phosphate laxatives, like osmotic laxatives, can cause
electrolyte disturbances. Because of this and the fact
that phosphate may be more readily absorbed than
magnesium, this laxative is contraindicated in patients
with renal insufficiency and cardiac dysfunction.
Misoprostol: Because misoprostol often causes diarrhea when prescribed to treat acid peptic disorders, it has
been used to treat severe constipation that is refractory to
other therapy.38 Adverse effects (nausea, diarrhea,
abdominal pain, increased risk of spontaneous abortion)
have limited the use of this drug. Some studies have
shown, however, that 50% of patients with severe CC
benefit from treatment with misoprostol.38,42,46
Bethanechol: The cholinergic agent bethanechol
increases gastric motility and tone and can improve
diminished rhythmic peristalsis. Older research indicates that bethanechol 25 mg to 50 mg, when administered 3 or 4 times daily, ameliorates constipation
caused by tricyclic antidepressant use.38,47 However, it
also is associated with hypersalivation, nausea, vomiting, and dizziness, and those adverse effects have limited the usefulness of bethanechol.
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Colchicine: Although the exact mechanism of action
of colchicine is unknown, this agent seems to act as a
mucosal toxin. It is used primarily in the treatment of
acute gout and may produce diarrhea as an adverse
effect. A double-blind, placebo-controlled, randomized,
crossover study of colchicine was performed in a small
group of patients with CC.48 A dose of 0.6 mg 3 times
daily was used for a 4-week treatment period. Patients
reported reduced transit time, an increased number of
bowel movements, and no particularly adverse effects.
However, colchicine can cause neutropenia, aplastic anemia, and neuromyopathy. Less severe side effects include
alopecia, rash, nausea, vomiting, and abdominal pain.
The use of colchicine or misoprostol usually is reserved
for patients with severe constipation that is refractory to
other therapy because the desired result of treatment
with those agents is, in essence, an adverse reaction to the
drug. Both drugs are contraindicated in pregnancy.
PROKINETIC AGENTS (5-HT4 AGONISTS)
Tegaserod: Tegaserod (Zelnorm®) currently is the
only 5-hydroxytryptamine4 (5-HT4) agonist approved
by the FDA for the treatment of CC. A partial agonist
of the 5-HT4 (serotonin) presynaptic receptors in the
enteric nervous system (Figure 1), tegaserod exerts several beneficial effects in those who suffer from CC. It
may decrease visceral hypersensitivity, stimulates the
peristaltic reflex, increases colonic motility, and acts on
intestinal chloride secretion, thus facilitating the transport of fluid into the lumen of the colon and improving stool consistency and frequency.6,49-51 Studies have
shown that this agent also is effective in improving the
frequency of complete spontaneous defecation and that
it decreases straining.6 Approved by the FDA to treat
CC in men and women younger than 65 years,
tegaserod received a Grade A recommendation from the
ACG CC Task Force.6 The American College of
Gastroenterology
Functional
Gastrointestinal
Disorders Task Force applied a Grade A recommendation to tegaserod for the treatment of C-IBS, but its use
is restricted to women with that disorder.10
The mechanism of action of tegaserod is limited to
the periphery by a unique design: Its molecular structure replicates that of the serotonin molecule but has
been altered by the addition of a hydrophilic “tail”
that restricts passage across the blood-brain barrier. As
an aminoguanidine indole, tegaserod does not
obstruct cardiac potassium channels and is thus
thought not to potentiate cardiac arrhythmia.52
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In a recent review of therapies for CC, Ramkumar
and Rao found that Grade A evidence similar but not
equivalent to that of the ACG CC Task Force grading
system supported the use of tegaserod for the treatment of constipation.33 The grades those authors cited
were based on 2 large, multinational, randomized,
double-blind, placebo-controlled studies53,54 indicating
that tegaserod was a safe, effective, and tolerable therapy that was superior to placebo for the treatment of
CC in those under age 65. Treated subjects experienced significant improvement in the frequency of
complete spontaneous bowel movements, total spontaneous bowel movements, global satisfaction with
bowel habits, and straining to defecate. Mild, transient
diarrhea occurred significantly more often in the
tegaserod-treated group but usually resolved without
additional therapy.53,54 Other reported adverse effects
of treatment include headache and nausea, but in general, the safety profile of that agent is favorable.
According to the results of several studies, serious
sequelae were no more likely to occur with tegaserod
treatment than with placebo, and tegaserod induced
neither clinically relevant drug interactions nor electrocardiographic abnormalities.55-57 New prescribing
recommendations from the FDA include a “precaution” stating that ischemic colitis has occurred in
patients treated with this drug, but according to information gathered from clinical trials and postmarketing
Figure 1. Role of Serotonin in Gastrointestinal Function
5-HT4 receptor
5-HT1p receptor
5-HT3 receptor
Signals to CNS
(visceral sensation)
Motor neurons
(contraction)
Signals to ENS
Motor neurons
(relaxation)
Myenteric
plexus
Submucosa
5-HT (serotonin)
Mucosa
CNS = central nervous system; ENS = enteric nervous system.
Data from Grider, et al. Gastroenterology. 1998;115:370 and Gershon M. Rev
Gastroenterol Dis. 2003;3:S25.
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surveillance, the likelihood that tegaserod produces
that adverse effect is minimal.6,58
EMERGING TREATMENTS
Although safe and effective therapies do exist for the
treatment of occasional constipation, the need for
improvement in the treatment of CC is evident.
Pharmacologic agents that increase peristalsis by their
effect on serotonergic receptors are under investigation.
Other receptor sites targeted pharmacologically in individuals with CC include opioid receptors and chloride
channels, which work via different mechanisms. Newer
pharmacotherapeutic agents effective at those receptors
and the combination 5-HT4 agonist-5-HT3 antagonists
renzapride and mosapride are reviewed below.
5-HT4 agonists—prucalopride: The drug prucalopride, a benzofurancarboxamide and a full agonist at 5HT4 receptors,52 once was thought to be a promising
agent in the treatment of CC. The results of 2 large
RCTs revealed that when compared with placebo, daily
doses of prucalopride 2 mg or 4 mg produced a modest
benefit in patients who had characterized themselves as
having “severe” or “very severe” CC. Over 12 weeks of
therapy, treatment with prucalopride increased the number of complete spontaneous bowel movements from a
median of 0 per week to 3 per week in 29% of study
patients.52,59 However, studies of prucalopride were suspended because of concern about the development of
cardiac arrhythmias in treated patients.52 It is unlikely
that this drug will be marketed in the United States, but
its development underscores the importance of the 5HT4 receptor as a target for drug therapy.
Combination 5-HT4 agonist–5-HT3 antagonists—
mosapride, renzapride: Mosapride citrate, a novel selective 5-HT4 receptor agonist–5-HT3 receptor antagonist, enables acetylcholine release from enteric
cholinergic neurons but does not block potassium
channels or D2 dopaminergic receptors.60 In a small
trial of patients with Parkinson’s disease, 10 men and 4
women (mean age, 67 years) with constipation (a
bowel movement fewer than 3 times per week or difficult defecation) were treated with 15 mg daily of
mosapride citrate for 3 months. Treatment was well tolerated by all but 1 patient, who terminated participation
in the study because of epigastric discomfort. The
remaining 13 patients reported a subjective improvement in the frequency of bowel movements and difficult
defecation. The investigators concluded that mosapride
alleviated several symptoms of constipation in subjects
S972
with Parkinson’s disease without inducing serious adverse
effects. This agent awaits further study.
Renzapride is another promising therapy that may be
used for the treatment of CC and C-IBS. This agent,
which functions as both a 5-HT3 antagonist and a 5HT4 agonist, has been tested in clinical trials in men and
women with C-IBS. Its presumed mechanism of action
is the activation of 5-HT4 receptors in cholinergic neurons that stimulate contractions, and the 5-HT3 antagonist activity of this agent also may decrease visceral
sensation. In a recent trial of its effects in patients with
C-IBS, renzapride improved stool consistency and
increased the frequency of bowel movements but provided no overall relief of abdominal pain and discomfort.61 In a randomized, double-blind, parallel-group,
2-week study of 48 patients with C-IBS and normal or
slow baseline colonic transit but without pelvic outlet
obstruction, renzapride was associated with an improvement in bowel function scores and accelerated colonic
transit, although small-bowel transit and gastric emptying were not affected.62,63 In that study, the renzapridetreated subjects exhibited an acceleration of colonic
transit and an improvement in bowel function scores,
although gastric emptying and small-bowel transit were
not affected. Like many evolving agents for the treatment of CC, renzapride also awaits further study.
Chloride-channel activators—lubiprostone: Lubiprostone (RU 0211) is an orally administered novel
bicyclic fatty acid64,65 undergoing development for the
treatment of CC, postoperative ileus, and C-IBS.64 By
activating a chloride channel on the apical side of
epithelial cells lining the gut (the driver of intestinal
fluid secretion), lubiprostone increases fluid to the
small intestine, which in turn increases overall fluid
content in the colon (Figure 2). The greater amount of
fluid in the intestine promotes spontaneous bowel
movements; reduces abdominal discomfort, pain, and
bloating; and softens the stool.64 In addition, chloridechannel activators show promise in the ability to repair
mucosal barrier function following ischemic injury, an
effect that appears to result from reduction in paracellular permeability via changes to the tight junction following CIC-2 channel activation.66,67
Two phase 3, multicenter, double-blind, placebocontrolled studies have shown that lubiprostone, when
compared with placebo, was significantly more effective
in providing relief from the symptoms of CC (Figure
3).56,57 Both male and female patients meeting Rome II
criteria for CC were included in the study. At a dose of
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Advanced Studies in Medicine
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ways that transmit pain to the central nervous system.
A study by Paulson and colleagues indicated that alvimopan reversed the opioid-induced inhibition of gastrointestinal transit without affecting analgesia.80 Mild
to moderate adverse events, which were bowel-related,
occurred during the first week of treatment, but therapy with alvimopan generally was well tolerated.
Figure 2. The Role of Chloride Channels in
Intestinal Transport
Ion Transport
Chloride
Intestinal
lumen
Sodium
Water
Chloridechannel
CI-
Tight
junction
Na+
Epithelial
K+
Na+ pump
K+ channel
K+
Na+
CI- K+
Na+ H20
Chloride channels located on
the apical surface of the
epithelial cells are a driving
force for intestinal fluid
secretion.
1. As negatively charged chloride ions actively enter the
lumen via chloride channels,
2. positively charged sodium
ions passively diffuse
through the intracellular
spaces to balance chloride,
3. allowing water to follow
passively into the lumen.
Na+-K+-2CI
cotransporter
Figure 3. Effect of Lubiprostone on Chronic
Constipation*
Multi-center, parallel-group, double-blind,
placebo-controlled study
7
Entry
<3 BM/wk
+
Rome II
N = 242
Bowel Movements/wk
24 mg twice daily highly significant statistical improvements were seen, not only in the global assessments of
treatment effectiveness and constipation severity but also
in that patients experienced an increase in spontaneous
bowel movements. Secondary measures of frequency and
consistency of spontaneous bowel movements were also
significantly improved. The most common adverse
effects of treatment were headache, diarrhea, and nausea.67 Nausea occurred in approximately 30% of patients.
Although more common in the treatment than the control group, the number of patients in either group who
withdrew from the study because of nausea was limited.
The new drug application for the use of lubiprostone in
the treatment of CC, under review at the FDA at the
time of this writing, includes the results of 3 long-term
safety studies, 2 of which are 12-month assessments.68-70
Peripheral opioid antagonists—methylnaltrexone and
alvimopan: Opioids administered as long-term analgesics
for patients with cancer or during and after surgery can
cause constipation or postoperative ileus.69 Although
blocking peripheral opioid receptors in the bowel is the
ideal mechanism for ameliorating opioid-induced constipation, most opioid antagonists (eg, naloxone) cross
the blood-brain barrier, reverse analgesia, and result in
opioid withdrawal.71 N-methylnaltrexone bromide
(methylnaltrexone), the first peripheral opioid receptor
antagonist, is a quaternary derivative of naltrexone,
which is a pure opioid antagonist.72,73 Because methylnaltrexone does not cross the blood-brain barrier,72-74 it may
block the adverse effects of opioids that are primarily
mediated by peripherally located receptors73,75,76 and preserve centrally mediated analgesia. It is presumed to act
as an antinociceptive and to disrupt the antimotility
effects of opioids.77 Research indicates that in healthy
individuals, intravenous or oral methylnaltrexone
reversed opioid-induced inhibition of bowel motility
without affecting analgesia and, in patients receiving
long-term opioid therapy, reduced (with minimal
adverse effects) the delay in oral-cecal transit and evoked
laxation in all subjects without evoking withdrawal
symptoms.78 Other investigators suggest that subcutaneous methylnaltrexone may also be useful in treating
opioid-induced constipation.73
Alvimopan, a novel peripherally acting mu-opioid
antagonist, is currently being evaluated for the treatment of acute postoperative ileus and reversal of the
delayed gastrointestinal and colonic transit caused by
opioid therapy.79 Mu-opioid receptors are located in
the enteric nervous system and on nociceptive path-
[ITT population]
P=.0001
P=.0017
6
P=.0002
P=.0002
5
4
3
2
Placebo
Lubiprostone 48µgýĦ24µg x 2/day)
1
0
Baseline
Week 1
Week 2
Week 3
Week 4
• Onset of action was within 24 hours in the majority of subjects
• Most common adverse events were nausea (31%), diarrhea, and headache
• 9 subjects taking lubiprostone withdrew due to adverse events
*Reprinted with permission from Johanson JF, Gargano MA, Holland PC,
Patchen ML, Ueno R. Phase III efficacy and safety of RU-0211, a novel chloride channel activator, for the treatment of constipation. Gastroenterology.
2003;124(4, suppl 1):A48.
S973
REVIEW
NONPHARMACOLOGIC TREATMENTS
Pelvic floor retraining (biofeedback): For patients with
evidence of pelvic floor dysfunction (PFD), biofeedback
is a behavioral approach of varying effectiveness in the
treatment of CC. Via manometry or electromyography,
patients with PFD learn techniques for the relaxation of
the pelvic floor muscles and the anal sphincter, which
enables the expulsion of stool. Although good results are
obtained from biofeedback in many medical centers, the
effectiveness of the training depends on the availability of
qualified personnel. Success rates have varied from 48%
to 75%.9,38 Anal disorders, such as fissures or a tender
puborectalis muscle, also may limit participation, and
patients must exhibit some degree of rectal perception to
benefit from biofeedback training. The cost of the technique may also be prohibitive.52,44
Surgery: Surgery is rarely required and should be
reserved only for the most refractory cases of CC. The
procedure of choice is subtotal colectomy with ileorectal anastomosis (in patients with megarectum, the rectum also is removed). In some individuals, ileostomy is
performed. Ten percent of patients who undergo
surgery for CC experience postoperative ileus and
mechanical small- bowel obstruction. Postsurgical
diarrhea is common but tends to resolve over time in
most cases.38,44 A limited number of patients with outlet obstruction also may require surgery to correct a
large rectocele or repair rectal prolapse.38 Patients with
a high rate of postoperative bowel obstruction in addition to PFD, small-bowel dysmotility, or severe
abdominal pain are not candidates for the surgical
treatment of CC.
Colonic electrical stimulation: Three types of colonic
electrical stimulation, a nondrug treatment for CC, are
currently under development. The electric stimulation
of sacral nerve function is used as therapy for urinary
and fecal incontinence, and patients so treated exhibited an increase in the sensory threshold for desire to
defecate as well as an increase in the frequency of the
sensation of the need to defecate.81 Another approach,
which has been tested only in a canine model, involves
using microprocessor-controlled sequential electric
stimulation to induce peristalsis.82 This technique
appears to be successful but awaits further study.
Fajardo and colleagues demonstrated that in patients
with spinal cord injury, electric stimulation of the
abdominal wall muscles reduced (by half ) the time
necessary for a bowel movement and also decreased the
time required for bowel care.83
S974
CONCLUSION
CC and C-IBS are among the most prevalent and
enduring GI diagnoses in North America. Most often
identified by primary care physicians and gastroenterologists, these common disorders of the gut impose
a substantial burden of healthcare costs and can negatively affect quality of life and productivity. Research has
shown that nonpharmacologic and pharmacologic therapies designed to address each patient’s specific symptoms are most effective in the management of CC, the
causes of which may range from abnormalities in myenteric neuron function, defects in neurotransmitters, and
incoordination of pelvic-floor or anorectal muscles to
environmental factors and chronic stress. A more complete understanding of those etiologic mechanisms will
enable the development of a new generation of superior
therapeutic agents, which even now are the subject of
ongoing analysis and research.
ACKNOWLEDGEMENT
Dr Harris would like to thank Jane Vail for her assistance in the development of this manuscript.
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