Irritable Bowel Syndrome (cont.)
How is IBS treated?
The treatment of IBS is a difficult and unsatisfying topic because so few
drugs have been studied or have been shown to be effective in treating IBS.
Moreover, the drugs that have been shown to be useful have not been
substantially effective. This difficult situation exists for many reasons, as
follows:
- Life-threatening illnesses (for example,
cancer,
heart disease , and high blood
pressure), are the diseases that capture the public's interest and, more
importantly, research funding. IBS is not a life-threatening illness and has
received little research funding. Because of the lack of research, an
understanding of the physiologic processes (mechanisms) that are responsible for
IBS has been slow to develop. Effective drugs cannot be developed until there is
an understanding of these mechanisms.
- Research in IBS is difficult. IBS is defined by subjective symptoms,
(such as pain), rather than objective signs (for instance, the presence of
an ulcer). Subjective symptoms are more unreliable than objective signs in
identifying homogenous groups of patients. As a result, groups of patients
with IBS who are undergoing treatment are likely to contain some patients
who do not have IBS, and this may negatively affect the results of the
treatment. Moreover, the results of treatment must be evaluated on the basis
of subjective responses (such as improvement of pain). In addition to being
more unreliable, subjective responses are more difficult to measure than
objective responses (such as the healing of an ulcer).
- Different subtypes of IBS (for example, diarrhea-predominant,
constipation-predominant, etc.) are likely to be caused by different
physiologic processes (mechanisms). It also is possible, however, that the
same subtype may be caused by several different mechanisms in different
people. What's more, any drug is likely to affect only one mechanism.
Therefore, it is unlikely that any one medication can be effective in
all-even most-patients with IBS, even patients with similar symptoms. This
inconsistent effectiveness makes the testing of drugs difficult. Indeed, it
can easily result in drug trials that demonstrate no efficacy (usefulness)
when, in fact, the drug is helping a subgroup of patients.
- Subjective symptoms are particularly prone to responding to placebos
(inactive drugs, or sugar pills). In fact, in most studies, 20% to 40% of
patients with IBS will improve if they receive inactive drugs. Now, all
clinical trials of drugs for IBS require a placebo-treated group for
comparison with the drug-treated group. So, the placebo response means that
these clinical trials must utilize large numbers of patients to detect
meaningful (significant) differences in improvement between the placebo and
drug groups. Therefore, such trials are expensive to conduct.
The lack of understanding of the physiologic processes (mechanisms) that
cause IBS has meant that treatment cannot be directed at these mechanisms.
Instead, treatment usually is directed at the symptoms, which are primarily
constipation, diarrhea, and abdominal pain. These symptoms are not mutually
exclusive since patients may have abdominal pain with either constipation or
diarrhea. Moreover, periods of constipation may alternate with periods of
diarrhea. This variation in symptoms over time can make the treatment of
symptoms complex. The psychotropic drugs (antidepressants) and psychological
treatments (for example, cognitive behavioral therapy) treat hypothetical causes
of IBS (such as abnormal function of sensory nerves and the psyche) rather than
the symptoms.
Constipation
Constipation is due to the
slow transport (transit) of intestinal contents through the intestines,
primarily the colon. This slow transit may be due to either abnormal function of
the muscles of the entire colon or just the muscles of the anus and rectum.
The treatment of constipation in IBS usually begins with a trial of the
supplements and medications that are used to treat constipation of any cause. In
2002, the FDA approved tegaserod (Zelnorm),
the first drug specifically for the treatment of abdominal pain and constipation
in women with IBS. However, in March of 2007, the FDA asked Novartis to suspend sales of tegaserod (Zelnorm) in the United
States because a retrospective analysis of data by Novartis from more than
18,000 patients showed a slight difference in the incidence of cardiovascular
events (heart attacks, strokes and angina) among patients on Zelnorm compared to
placebo. The data showed that cardiovascular events occurred in 13 out of 11,614
patients treated with Zelnorm (.11%), compared to one cardiovascular event in
7,031 (.01%) placebo-treated patients. However, it is unclear whether Zelnorm
actually causes heart attacks and strokes. Doctors and scientists will be
scrutinizing the data to determine the long-term safety of Zelnorm.
The mechanism whereby
tegaserod reduces constipation is interesting. It is the contractions of the
intestinal muscles that controls transit of digesting food through the
intestine. More contractions speed transit, fewer contractions slow transit. In
constipated patients, contractions are fewer. One important factor in the
control of the contractions is serotonin. Serotonin is a chemical manufactured
by nerves in the intestine. It is released by the nerves and then travels to
other nerves where it binds to receptors on the nerves. It is, in scientific
terms, a "neurotransmitter" that allows nerves to communicate with each other.
When it binds to receptors on nerves that control the contractions of intestinal
muscles, serotonin can either promote or prevent contractions depending on the
type of receptor it binds to. Binding to some types of receptors causes
contractions, and binding to other types of receptors prevents contractions. The
serotonin 5-HT4 receptor is a receptor that prevents contractions when serotonin
binds to it. Tegaserod blocks the 5-HT4 receptor, prevents serotonin from
binding to it, and thereby increases contractions of the intestinal muscles. The
increased contractions speed the transit of digesting food. In addition,
tegaserod reduces the sensitivity of the intestinal pain-sensing nerves and can
thereby reduce the perception of pain.
In a randomized, double blind, placebo-controlled, study involving more than
1000 patients (80% women) with constipation-predominant IBS, tegaserod was found
to be more effective than placebo in increasing the frequency of stools,
relieving abdominal pain and discomfort, and decreasing the sensations of
bloating among women. (There was an insufficient number of men in the study to
draw conclusions about the effectiveness of treatment in men.) The beneficial
effects of treatment started during the first week of treatment and were
sustained throughout the 12-week period of study.
Diarrhea was the only side effect in the tegaserod study. Diarrhea usually
occurred early during treatment and resolved quickly even if the treatment was
continued. There was no effect of tegaserod on blood counts, liver and kidney
tests, electrocardiograms, blood pressure, pulse, and body weight. (A medication
similar to tegaserod, called
cisapride or Propulsid, which also promoted intestinal muscle contractions,
was withdrawn from the market due to rare but potentially fatal effects on the
electrical rhythm of the heart. So far, there have been no reports of rhythm
disturbances related to tegaserod.) Patients with major liver or kidney disease
should not take tegaserod. The safety of tegaserod to the fetus or nursing
infants has not been studied and is unknown. Therefore, pregnant or nursing
women should avoid tegaserod.
Diarrhea
The most widely studied drug for the treatment of
diarrhea in IBS is
loperamide (Imodium).
Loperamide appears to work by
inhibiting (slowing down) the contractions of the muscles of the small intestine
and colon. Loperamide is approximately 30% more effective than a placebo in
improving symptoms among patients who have diarrhea as the predominant
manifestation of their IBS. It is not clear if loperamide reduces
abdominal pain. Loperamide
can be potent and itself can cause constipation. Therefore, the dose must be
carefully adjusted and individualized for each patient. Alosetron (Lotronex)
is used to treat diarrhea and abdominal discomfort that occurs in women with
severe IBS that does not respond to other simpler treatments.
Alosetron, like
tegaserod, affects the serotonin receptors. (See the discussion above of
tegaserod.) Alosetron blocks the 5-HT3 receptor, a receptor that causes
contractions when serotonin binds to it. Alosetron, by blocking 5-HT3 receptors,
prevents serotonin from binding and thereby prevents contractions.
Alosetron was approved by the FDA in February, 2000, but was withdrawn from
the market in November, 2000, because of serious, life-threatening,
gastrointestinal side effects. In June 2002, it was approved again by the FDA
for marketing but in a restricted manner as part of a drug company-sponsored
program for managing the risks associated with treatment. Use of alosetron is
allowed only among women with severe, diarrhea-predominant, IBS who have failed
to respond to conventional treatment for IBS.
The most common side effect with alosetron is constipation. One-quarter to
one-third of patients may develop this side effect, but in only 10% (10 out of
every 100 patients) will the drug need to be stopped temporarily or permanently.
A rare side effect that has occurred with alosetron is severe intestinal
inflammation caused by poor circulation of blood ( ischemic colitis). This
complication is life-threatening, may require surgery, and has even caused death
in a small number of patients. Therefore, immediate medical attention should be
sought if the signs of ischemic colitis (rectal bleeding or a sudden worsening
of abdominal pain) occur.
Abdominal pain
The most widely studied drugs for the treatment of abdominal pain are a group
of drugs called smooth-muscle relaxants.
The gastrointestinal tract muscle is composed of a type of muscle called smooth muscle. (By contrast, skeletal muscles, such as the biceps, are composed of a type of muscle called striated muscle.) Smooth muscle relaxant drugs reduce the strength of contraction of the smooth muscles but do not affect the contraction of other types of muscles. They are used in IBS with the assumption (not proved) that strong or prolonged contractions of smooth muscles in the intestine-spasms-are the cause of pain in IBS. There are even smooth muscle relaxants that are placed under the tongue, like
nitroglycerin for angina, so that they may be absorbed rapidly. Smooth muscle relaxants are approximately 20% more effective than a placebo in reducing abdominal pain. It is not clear if smooth muscle relaxants have a beneficial effect on constipation or diarrhea.
Commonly used smooth muscle relaxants are
hyoscyamine (for example, Levsin) and
methscopolamine (for example, Pamine). Other drugs combine smooth muscle relaxants with
a sedative (for example, Donnatal),
but there is no evidence that the addition of sedatives adds to the efficacy
(effectiveness) of the treatment.
Psychotropic drugs
Patients with IBS are frequently found to be suffering from
depression, but it is unclear
if the depression is the cause of IBS, the result of the IBS, or unrelated to
the IBS. Several trials have shown that antidepressants are effective in IBS in
relieving abdominal pain and, perhaps, diarrhea. The antidepressants work in
IBS, however, at relatively low doses that have little or no effect on
depression. It is believed therefore, that they are working not by combating
depression, but in different ways (through different mechanisms). For example,
these drugs have been shown to adjust (modulate) the activity of nerves and to
have analgesic (pain-relieving) effects as well. Commonly used psychotropic
drugs include the tricyclic antidepressants,
amitriptyline (Elavil, Endep),
desipramine (Norpramine), and
trimipramine (Surmontil).
Although studies are encouraging, it is not yet clear whether the newer class of
antidepressants, the serotonin-reuptake inhibitors, such as
fluoxetine (Prozac),
sertraline (Zoloft), and
paroxetine (Paxil) are
effective.
Psychological treatments
Psychological treatments include cognitive-behavioral therapy, hypnosis,
psychodynamic or interpersonal psychotherapy, and relaxation/stress management.
They have been used in patients with IBS who are psychologically distressed to
the point that their quality of life is being impaired. A few studies have shown
that psychological treatments can reduce anxiety and other psychological
symptoms in addition to reducing IBS symptoms, particularly pain and diarrhea.
Diet
It is unclear if diet has much effect on the symptoms of IBS. Nevertheless,
patients often associate their symptoms with specific foods (such as salads,
fats, etc.). Although specific foods might worsen IBS, it is clear that they are
not the cause of IBS. The common placebo response in IBS also may explain the
improvement of symptoms in some people with the elimination of specific foods.
Dietary fiber often is
recommended for patients with IBS. Fiber probably is of benefit to IBS patients
with constipation, but it does not reduce abdominal pain. Lactose (milk sugar)
intolerance often is blamed for diarrhea-predominant IBS, but it does not cause
IBS. Because they are both common, lactose intolerance and IBS may coexist. In
this situation, restricting lactose will improve, but not eliminate the
symptoms. Lactose intolerance is
easily determined by testing the effect of lactose (hydrogen
breath testing) or trying a strict lactose elimination diet. Intolerance to
sugars other than lactose, specifically, fructose, sucrose, and sorbitol, may
cause symptoms that are similar to IBS or make IBS worse. It is unlikely,
however, that these sugars cause IBS.
Next: Is there a relationship between
IBS and small intestinal bacterial overgrowth? »
Digestion RSS