A randomized controlled trial on the effect of laxative therapy in children with functional abdominal pain

Introduction
Chronic abdominal pain is a frequent complaint in children in the age of 4-16
years, with a prevalence of 10-15%. It has considerable impact on the life of
the patients and their families; quality of life (QoL) has been described to be
the same as QoL of children with inflammatory bowel disease. It is often cause
of school absenteeism (in an earlier study in The Hague 15% of the patients
with abdominal pain was absent at least once a week). Adolescents with chronic
abdominal pain tend to be more depressed and socially isolated.
Only in a minority of the patients an organic cause is found. By definition,
patients without an organic cause have the diagnosis *functional abdominal
pain*.

In some studies in adults with functional abdominal pain (particularly
irritable bowel syndrome, IBS) in several countries, the economic burden on the
society has been calculated. This appeared to be high concerning the direct
costs (doctors visits and diagnostics) as well as the indirect costs (work
absenteeism). In a recent study in The Netherlands, the costs of IBS in
children have been calculated to be ¤2500 per patient per year.

The standard therapy of functional abdominal pain (explanation, reassurance and
life style advice after exclusion of organic disease) leads to recovery in
35-50% of the patients. With hypnotherapy, the results are better: in a recent
study, 71% had at least 50% reduction of their pain score. At long term follow
up after 5 to >10 years, up to 40% of the patients still has abdominal pain.
Recently, we performed an observational study in 200 children, referred to
secondary care in the Juliana Children*s Hospital/Haga Teaching Hospital in The
Hague because of chronic abdominal pain. After exclusion of an organic cause,
all patients with functional abdominal pain had laxative therapy. Herewith 99%
of these 200 patients became pain free; they remained pain free during the
follow up period of at least 6 months (mean 18 months).
This result needs to be confirmed in a randomized placebo-controlled trial.

According to the *Rome criteria* of functional gastrointestinal disorders,
symptom clusters of functional abdominal pain are recognized: irritable bowel
syndrome (IBS), functional dyspepsia, functional abdominal pain, functional
abdominal pain syndrome and, more rarely, abdominal migraine.
Investigations into the pathophysiology are almost exclusively directed to IBS
and - less often - to functional dyspepsia. The pathophysiology of IBS is
multifactorial; stress is considered an important factor. Functional dyspepsia,
defined by upper abdominal complaints, is considered a problem of the proximal
part of the gastrointestinal tract and is treated with inhibitors of acid
secretion and prokinetics with only moderate success; in 2 publications,
indications have been found for a causal relation with constipation.
In the above mentioned study in The Hague, all children with functional
abdominal pain had laxative therapy, regardless of their presenting symptom
cluster. In that observational study, laxative therapy appeared to be
successful in nearly all patients with functional abdominal pain, regardless of
their presentation, including patients with functional dyspepsia. Remarkably,
in patients with IBS we found the same results with laxative therapy in
patients with the diarrhea type of IBS (IBS-D) as in the patients with the
constipation type of IBS (IBS-C).
If these results would be confirmed, this should have important consequences
for the therapy of functional dyspepsia (laxative therapy in stead of
inhibitors of acid secretion and prokinetics) and the therapy of IBS-D
(treatment with laxatives as in paradox diarrhea in stead of treatment with
anti-diarrhea drugs).

Rationale
1. Because of the impact of chronic abdominal pain in children and the long
term prognosis with impressive consequences for the life of the patients and
for the society, it is important to aim at optimal therapy. Literature on
laxative therapy in children with abdominal pain is extremely sparse;
controlled trials are not available. A single controlled trial in adults has
major methodological imperfections.
Therefore, the good result of the earlier observational study needs to be
confirmed in a randomized placebo-controlled trial.

2. Confirmation of the effectiveness of laxative therapy in patients with
functional dyspepsia and IBS-D would shed new light on the pathophysiology of
these disorders, and give way to a quite new therapeutic strategy for the
patients.

Primary objective: to establish the effectiveness of laxative therapy in
children with functional abdominal pain.
Secondary objective: to establish if laxative therapy is effective in all
functional abdominal pain syndromes, including functional dyspepsia and IBS-D.

A randomized placebo controlled multicenter study.

Population:
Children (age 4,0 -16,0 years of age) with the diagnosis functional abdominal
pain.

Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. age 4-16 years;
2. chronic abdominal pain since at least 2 months;
3. organic causes excluded according usual criteria.

Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
1. insufficient knowledge of the Dutch language;
2. earlier therapy with generic macrogol;
3. participation of a sibling in the study;
4. abdominal pain less than 2x per week in the diagnostic phase according to
diary.

Macrogol 4000, generic form with addition of a flavouring, is used as laxative.
Starting dosage is 20 g/day in 200 ml fluid per 10 g macrogol. In case of
insufficient result, the dosage is to be increased with 10 g/day (in extra 200
ml) every 2 days until a maximal dosage of 50 g/day (in 1000 ml fluid). This
dosage should be continued till the end of the 4 weeks intervention unless the
consistency of the stool is too loose. The dosage should be adjusted according
to the stool consistency, with help of the stool chart (adapted Bristol Stool
Form Scale). The dosage will be not be described in terms of grams, but as the
number of spoons (one spoon = 10 g macrogol).
Maltodextrin, with addition of the same flavouring, is used as placebo. This is
a fully resorbable carbohydrate, that is not to be expected to have any effect
on the motility of the bowel. Because of the caloric load, it is not ethical to
give the same dosage (in grams) as in case of macrogol, for which reason the
dosage will be described in terms of spoons instead of grams: the spoons in the
boxes of the placebo contain only 3 grams of maltodextrin. When patients need
the maximal dosage because the placebo has no laxative effect, they get 5
spoons/day = 15 g (60 kcal)/day. One spoon of maltodextrin should be solved in
50 ml water.
There is no evidence that extra water has a laxative effect, unless the child
is used to drink less fluid than recommended: in that case, the normalization
of the fluid intake by means of an extra litre of water (in case of 200 ml per
spoon of maltodextrin) could have a laxative effect. Therefore, the amount of
water is restricted to 50 ml per spoon of maltodextrin, resulting in a maximum
of 250 ml extra water/day.
The spoons and cups are packed within the boxes and are not visible from
outside. Several spoons and cups are packed within each box, to prevent that *
in case of loss of a spoon or cup * the patient has to ask for a new one and
therewith has to explain to the hospital personnel what kind of spoon or cup he
uses.

The burden associated with participation consists of some extra time needed to
explain the study after the diagnosis functional abdominal pain is made and an
extra visit for the patient to hand in the informed consent form and to give
the medication. During intervention and follow up several telephone calls will
take place.

Macrogol 4000 has a high molecular weight which makes it unabsorbable. It is a
long linear polymeric molecule to which water molecules adhere. After oral
ingestion it leads to increase of the amount of fluid in the bowel. The
intestinal fluid that is not absorbed is cause of the laxative effect.
Some complaints can result as long as defecation is still unsufficient. However
this is part of the patient's problem. The risk is negligible. Allergic
reactions are very rare.