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CURRENT MECHANISMS OF ACTION IN TREATMENT OF
CHRONIC CONSTIPATION AND IRRITABLE BOWEL SYNDROME*
—
I
Lucinda A. Harris, MS, MD†
ABSTRACT
Patients with chronic constipation and irritable
bowel syndrome (IBS) have a variety of potential
treatment options. Treatment typically begins with
lifestyle changes and fiber supplementation. The
predominant lifestyle changes are alteration of fluid
intake, dietary modification, and physical activity.
Laxatives constitute the second line of therapy.
Patients can avail themselves of various emollient,
osmotic, and stimulant laxatives. Among all the laxative agents, the strongest supporting evidence is for
lactulose and polyethylene glycol. These conventional therapies have highly variable rates of therapeutic success. Most patients cope with their symptoms
and are less than completely satisfied with therapy.
Newer therapies have provided additional options
that may help improve symptom relief and patient
satisfaction. The 5-HT4 serotonin agonist tegaserod
has demonstrated efficacy for chronic constipation
and constipation-predominant IBS and is approved
for treatment of men and women with chronic constipation and for women with IBS. The chloride
channel activator lubiprostone recently was
approved for treatment of constipation in men and
women. The 5-HT3 antagonist alosetron has
approval for treatment of diarrhea-predominant IBS
in women. A host of investigational agents are in
various stages of evaluation and clinical development, many of which represent new approaches to
treatment of chronic constipation and IBS.
(Adv Stud Med. 2006;6(4A):S237-S242)
*This article is based on a roundtable symposium held
in Montreal, Quebec, Canada, on September 9, 2005.
†Senior Associate Consultant, Division of Gastroenterology
and Hepatology, Mayo Clinic, Scottsdale, Arizona.
Address correspondence to: Lucinda A. Harris, MS, MD,
Senior Associate Consultant, Division of Gastroenterology and
Hepatology, Mayo Clinic, 13400 East Shea Boulevard,
Scottsdale, AZ 85259. E-mail: [email protected].
Johns Hopkins Advanced Studies in Medicine
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n considering treatment options for chronic
constipation, physicians should keep in mind
the profile of a “typical” patient. Typically, the
patient is female more often than male and has
been symptomatic for more than 10 years.
The majority of patients have tried lifestyle changes,
fiber, and over-the-counter laxatives before seeking
care. They manage their condition with several therapies. Most often, they are referred to the gastroenterologist by a primary care physician. A key point is
that the typical patient copes with his or her constipation but is not completely satisfied with the treatment that is available, and therefore, a great deal of
room exists for improvement.
The American College of Gastroenterology (ACG)
Chronic Constipation Task Force has evaluated the
many therapies available for chronic constipation in
terms of the evidence available to support their use and
their ability to alleviate constipation.1 Therapies were
given a grade of A, B, or C depending on the level of
evidence available to support their use. The Table lists
the 4 levels of evidence, that were identified.1
Understanding the strength of a particular recommendation provides a context for evaluating available
therapies for constipation and making treatment decisions that best meet the needs of our patients.
CURRENT THERAPY FOR CHRONIC CONSTIPATION
TRADITIONAL APPROACHES
In most cases, the discussion of therapeutic options
for chronic constipation begin with lifestyle factors
and fiber supplements.2 Much has been made of the
role that lifestyle changes can play in the management
of chronic constipation, but the reality is that these
interventions, such as increased fluid intake, dietary
modification, and exercise, have limited support. The
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data indicate that fluid intake is helpful only in
patients who are clinically dehydrated. Most patients
think dietary modification plays a major role in management of constipation, but the evidence shows that
diet works in a select group of patients—namely those
individuals whose diets are woefully deficient in fiber.
Much like diet, exercise often is viewed by patients as
quite helpful to bowel function, but available data suggest that exercise has limited beneficial effects on gastrointestinal function, with 2 possible exceptions.
First, increasing physical activity in sedentary elderly
patients can improve bowel function, and second,
marathon runners often have diarrhea.
After lifestyle factors, the next step in therapeutic
decision making usually involves the use of fiber.
When the ACG reviewed available therapies, sufficient
evidence existed to give psyllium a Grade B recommendation. Psyllium has been shown to increase stool
bulk and decrease transit time. The same may be true
for products, such as calcium carbophil, methylcellulose, and bran, but the data supporting their use range
from limited to nonexistent.
The second major category of treatments is comprised of laxatives, which can be divided into 3 categories: emollient, osmotic, and stimulant. Emollient
laxatives include docusate sodium and docusate calcium.
The ACG found enough evidence to give emollient laxatives a Grade B recommendation. An emollient may
help soften stool, but evidence is lacking to support its
use as sole therapy for chronic constipation. If fiber and
stool softeners fail to improve constipation, the next
therapeutic tier is often osmotic laxatives, which include
milk of magnesia, citrate of magnesia, nonabsorbed sugars (ie, sorbitol and lactulose), and polyethylene glycol
(PEG), which is a nonabsorbed polymer. Osmotic agents
increase stool bulk and intestinal fluid volume. Overall,
the evidence supporting the use of most of these agents
was only of Grade B quality. Exceptions were lactulose
and PEG, which received a Grade A recommendation
for treating constipation. Lactulose works primarily by
creating an osmotic load. Many patients experience a
great deal of abdominal discomfort and gas as side effects
of this agent. PEG also creates an osmotic load, but is
approved by the US Food and Drug Administration
(FDA) only for the short-term treatment of constipation
(ie, <2 weeks). When patients do not improve with
emollient or osmotic laxatives, stimulant laxatives are
often the next course of action. Stimulant laxatives
decrease water absorption and may influence the pro-
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duction or activity of kinases, adenosine triphosphatases,
and prostaglandins to stimulate the intestine and promote bowel motility. These agents include senna, ricinoleic acid (castor oil), bisacodyl, and cascara. The ACG
found evidence to support only a Grade B recommendation for stimulant laxatives.
The ACG did not evaluate other therapies for constipation, such as enemas (ie, tap water, phosphate, or
mineral oil) or suppositories (ie, glycerin), which also
are used with some frequency in the management of
chronic constipation.
To summarize, laxative therapy in the treatment of
chronic constipation is of variable efficacy and often
has not been thoroughly evaluated, as reflected in the
ACG’s preponderance of Grade B recommendations
for most of these medications. Laxatives are generally
recommended for short-term use, and they can cause
side effects that limit their effectiveness, including
bloating, cramping, diarrhea, and metabolic disturbances (ie, hypercalcemia, hyperphosphatemia,
hyponatremia, and hypokalemia).3-5
Overall, the conventional or traditional approaches
to treatment of chronic constipation result in variable
treatment responses. Treating constipation is not just
about the frequency of bowel movements and most
therapies have not been evaluated for their ability to
treat the constellation of constipation symptoms, such
as straining or bloating.
Table. Systematic Review of Chronic Constipation
in North America
Levels of Evidence/Grading of Recommendations
– Level I
• Data based on high-quality, randomized, placebocontrolled studies.
• Grade A recommendation
– Level II
• Data based on intermediate-quality, randomized,
controlled trials
• Grade B recommendation
– Level III
• Data based on nonrandomized studies
• Grade C recommendation
– Level IV
• Data based on case controls or anecdotal experience
• Grade C recommendation
Adapted with permission from Brandt et al. Am J Gastroenterol.
2005;100:S5-S22.1
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PROCEEDINGS
Current treatment options for constipation have
several limitations. In some instances, they can actually worsen constipation symptoms, such as bloating,
gas, cramping, and abdominal pain or colic. Some of
the treatments are associated with potential complications that include diarrhea, hypovolemia, and metabolic disturbances. Other potential adverse effects
include interference with concomitant drug absorption, structural changes in the gut mucosa, and abuse
potential. Conventional therapies for chronic constipation also tend to have a diminished therapeutic
effect over time.6-12
Not surprisingly, many patients are not satisfied
with available treatments for constipation. When
asked to rate their satisfaction with treatment, between
33% and 50% of patients with constipation say they
are not satisfied with their current treatments. The reasons for dissatisfaction tend to have more to do with
lack of efficacy than with side effects.13,14
OTHER TREATMENT OPTIONS
Fortunately, newer treatment options for chronic
constipation have become available or are being developed. One in particular, tegaserod, received a Grade A
recommendation from the ACG. A serotonergic agent,
tegaserod is a 5-HT4 agonist that has US FDA
approval for treatment of chronic constipation and
constipation-predominant IBS (IBS-C). Tegaserod is a
new class of compounds, called an aminoguanidine
indole—a partial 5-HT4 agonist—which works
through the 5-HT4 receptor to stimulate the peristaltic
reflex and accelerate oral-cecal transit.15
Tegaserod is indicated for treatment of men and
women with chronic constipation. The recommended
dosage is 6 mg orally, twice daily, 30 minutes before
meals. Tegaserod is recommended for men and women
aged 65 or younger for chronic constipation. No dose
adjustment is required for older age, mild hepatic
impairment, or mild-to-moderate renal impairment.16
In 2 pivotal clinical studies involving patients with
chronic constipation, tegaserod was compared to
placebo with respect to complete spontaneous bowel
movements (CSBM) over 12 weeks. Patients treated
with tegaserod had significantly more CSBMs.
Notably, in 1 of these trials, patients were followed
after the drug was withdrawn, and it is important to
note that once the drug was withdrawn, the number of
CSBMs also decreased. Patients also had decreased
straining and greater global relief of symptoms.17,18
Johns Hopkins Advanced Studies in Medicine
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Tegaserod has proven to be a safe drug to use for
treatment of chronic constipation. It causes more diarrhea compared to placebo, but the diarrhea tends to
occur during the first week of treatment and often
resolves with continued therapy. The incidence of
headache, including migraine, is similar between
tegaserod and placebo.
Previously, the use of the agent cisapride, a combined 5-HT4 and 5-HT3 agonist, caused some concern related to the potential for induction of cardiac
arrhythmias. That has not been the case with
tegaserod. Tegaserod also can be safely used in conjunction with selective serotonin reuptake inhibitors
(SSRI).19 This drug requires no dosage adjustment
when used with other medications, and no clinically
relevant drug interactions have been identified.
Other medications for chronic constipation consist
largely of therapies developed for other indications (eg,
colchicine and misoprostol). These are generally
reserved for severely constipated patients and carry
with them several potentially serious side effects.
For selected patients with severe colonic inertia,
surgery is an option. To be a surgical candidate for
chronic constipation, a patient must meet stringent
criteria, including clear failure of other forms of medical therapy.
Agents that are being investigated as potential therapies for constipation include the chloride channel activator, lubiprostone. Granted US FDA approval in early
2006 for the treatment of chronic idiopathic constipation, lubiprostone works on the chloride channel on the
apical side of the mucosal epithelial cell to increase fluid
in the stool, allowing for more spontaneous bowel
movements, which reduces abdominal pain, discomfort, and bloating and softens the stool. Other investigational agents for constipation are the combination
5HT4 agonists and 5HT3 antagonists, renzapride and
mosapride, and the opioid antagonists, methylnaltrexone and alvimopan. Lastly, neurotropic factors, which
stimulate nerve activity or growth, have been evaluated
as therapy for chronic constipation. Neurotrophin-3
was originally evaluated as a treatment for Alzheimer’s
disease and Parkinson’s disease. Patients treated with the
agent often developed diarrhea, which led to investigation of the agent as a treatment for constipation.
Neurotrophin-3 appears to increase transit time,
although the explanation for the effect remains unclear.
For patients with constipation as a result of pelvic
floor dyssynergia, 2 types of training have been evaluat-
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ed: anorectal biofeedback and simulated defecation. The
former approach has been evaluated more thoroughly
and has achieved success rates ranging from 48% to
62%.
TREATMENT OF IRRITABLE BOWEL SYNDROME
Management of IBS often has focused on specific
symptoms, such as abdominal pain, bloating, and diarrhea or constipation. In general, patients have not
achieved global relief of their complaints with such a
symptom-driven approach. One recent survey of more
than 5000 patients with IBS showed that 80% of the
patients were receiving traditional medications, but
only 14% were completely satisfied with their treatment. Satisfaction with relief of specific symptoms varied between 10% and 19%.20
The ACG conducted a systematic review of IBS
diagnosis and treatment in North America and provided graded recommendations, similar to those
assigned in the review of therapies for constipation.
Essentially, the review identified evidence that could
support no more than a Grade B recommendation for
most of the therapies used to treat IBS, indicative of
intermediate-quality, randomized controlled trials
with plus/minus statistical significance. The review
encompassed the most widely used IBS therapies,
including bulking agents, antispasmodics, behavioral
therapy, and tricyclic antidepressants (TCA; Figure).21
Again tegaserod has been given a Grade A recommendation for the treatment of IBS-C. For patients
with IBS, the treatment has US FDA approval only for
women at a dosage of 6 mg twice daily, taken 30 minutes before breakfast and dinner for a 4-to-6 week period. For patients who respond to this as an IBS therapy,
an additional 4 to 6 weeks of treatment can be considered. Efficacy data for tegaserod in IBS treatment have
come primarily from 2 clinical trials.22,23 Results of
those trials showed that tegaserod effectively relieved
global and individual IBS symptoms, including
abdominal pain/discomfort, bloating, and constipation. Efficacy was maintained over 3 months. The
time to relief was rapid, beginning as early as day 1 for
the symptom of constipation and within the first week
for abdominal pain/discomfort. Symptom relapse with
discontinuation of the drug was seen in the trials.
Another trial demonstrated that when the drug is used
for 12 weeks and then stopped for 4 weeks, symptoms
are relieved when the drug is reinstituted.24
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The 5-HT3 antagonist alosetron slows gut function
to increase water absorption. It also decreases chloride
secretion and also seems to affect mechanoelastic properties of the colon by increasing compliance.25 The
drug is indicated only for women with severe diarrheapredominant IBS who have chronic symptoms for at
least 6 months and who have failed conventional therapy. The safety and efficacy of the drug in men was not
shown in the initial pivotal phase III clinical trials.26
However a recent analysis of the data have shown a
beneficial effect in men but not to the same extent as
in women.27 Alosetron still has US FDA approval only
for women, and the starting dosage is 0.5 mg daily to
be slowly titrated as necessary up to 1 mg once or twice
daily. In general, treatment should stop if the condition does not respond to 1 mg twice daily. Alosetron is
currently under a restricted use program, requiring
physician attestation to a proficiency in treating IBS.
Additionally patients must be educated with regard to
potentially serious side effects of the drug, because of
adverse events reported after the drug’s initial US FDA
approval. These events included chronic constipation
and serious complications of constipation (eg, ileus,
bowel obstruction, fecal impaction, colonic perforation, or toxic megacolon) in 1 in 1000 patients and
ischemic colitis (≤1 in 1000).28
Figure. ACG Recommendations for the Treatment of IBS:
Traditional Approaches
Bulking agents:
Not more effecitve than placebo
Antispasmodics:
Insufficient data
All Grade B
recommendations:
Intermediate quality
RCTs +/statistical significance
Tricyclic
antidepressants:
Not more effective
than placebo,
may improve
abdominal pain
Behavioral therapy:
May be more effective
than placebo
ACG = American College of Gastroenterology; IBS = irritable bowel syndrome;
RCT = randomized controlled trials.
Reprinted with permission from American College of Gastroenterology Functional
Gastrointestinal Disorders Task Force. Am J Gastroenterol. 2002;97:S1-S5.21
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Tricyclic antidepressants and SSRIs have been used
in the treatment of IBS. Antidepressants likely exert
their beneficial effects by several different mechanisms.
They can have a central modulating effect on pain perception; they may modulate gut action, locally at the
gut level or centrally; and lastly, they may exert their
effects by treating underlying psychological disturbances, such as anxiety, depression, or somatization.
Adherence and persistence with therapy have a strong
influence on the success of treatment and data are
stronger for TCAs than SSRIs.29,30
Drugs under investigation for IBS include the 5-HT3
antagonist and 5-HT4 agonist renzapride, the chloride
channel activator lubiprostone, the 5-HT3 antagonist
cilanestron, the benzodiazepine dextofisopam, and the
neurokinin-3 antagonist talnetant.
Other agents under investigation as therapy for IBS
include probiotics, particularly bifidobacteria,31 antibiotics, particularly rifaxamin,32 alternative therapies (ie,
peppermint oil and herbal therapies), and nonpharmacologic therapies that include hypnosis, acupuncture, and cognitive behavioral therapies.
CONCLUSIONS
Most therapies for chronic constipation have
Grade B recommendations, which reflect less-thanoptimal supporting evidence. A select few, such as
PEG, lactulose, and tegaserod, have Grade A recommendations. Most therapies have side effects that limit
their use. A similar situation exists with respect to therapies for IBS. Tegaserod and alosetron are among the
very few that have strong supporting evidence that warrant Grade A recommendations. Although several
newer therapies work at serotonergic receptor sites, drug
development is expanding to look at a variety of potential receptors sites. The therapeutic field for chronic
constipation and IBS remains wide open for the addition of better tolerated, more effective therapies.
DISCUSSION
Dr Kalloo: Why should you ever use a Grade B
drug? Why not just go straight to a Grade A drug?
Dr Harris: I don’t think that giving a drug Grade
A or B recommendation is a reason to give therapy.
The real reason for the grading is to determine the
level of evidence available that supports the use of a
particular therapy and to point out that perhaps we do
Johns Hopkins Advanced Studies in Medicine
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need to have better studies and more data about the
efficacy of a particular therapy. I think that many of
the drugs are useful. Patients have found them useful
for individual symptom relief. Unfortunately, we don’t
have enough drugs that deal with global symptoms of
relief of the abdominal pain, discomfort, change in
bowel function, and bloating of patients with IBS. I
think that’s also the other important point to understand—that the drugs that are given a Grade A recommendation usually offer more global relief of IBS or
chronic constipation symptoms but the Grade A or B
recommendation is not the reason for deciding
whether to use it.
Dr Lembo: I feel exactly the same way. I think the
lack of data doesn’t mean the data are negative.
Dr Kalloo: Isn’t it interesting that the lack of data
seems to involve medications that have been around
for a long time?
Dr Lembo: Right, because the studies haven’t been
well conducted in large numbers. That’s why they’ve
received a lower grade.
Dr Talley: That applies to all of our older medications. Think about digoxin. We didn’t really understand its role in heart failure until quite recently, in
terms of the lack of decent clinical trials early on. But
it does work and, in fact, we all knew that. It just took
a long time to show it with the evidence.
Dr Kalloo: Amy, do you ever go with a Grade A
drug first?
Dr Foxx-Orenstein: I go with lifestyle modification first, such as encouraging breakfast each morning
to stimulate the gastrocolic reflex and morning bowel
activity. I also may recommend a drug, depending on
the severity of the condition and what they’ve been
through before. I’ll almost always try to incorporate
lifestyle changes to facilitate bowel activity.
Dr Kalloo: There are some extreme therapies, such
as colchicine and surgery, used for chronic constipation. When do you decide on these nontraditional but
more extreme drugs or surgery?
Dr Lembo: The patients fail other therapies. These
are very refractory, usually very slow-transit patients
who have failed all other medical therapies, usually in
combination.
Dr Chang: I only send a patient for surgery for
colonic inertia, not for IBS-C.
Dr Foxx-Orenstein: Surgery is absolutely the last
resort.
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