A randomised 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 4-18
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 randomised 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-NOS (not
otherwise specified), 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:
1. to establish the percentage of children with functional abdominal pain
becoming pain free with laxative therapy, in comparison with placebo therapy.

Secondary objective:
2. to establish the decrease of the pain intensity in children with functional
abdominal pain with laxative therapy, in comparison with placebo therapy.
3. to establish if laxative therapy is effective in all functional abdominal
pain disorders, including functional dyspepsia and IBS-D.

A multicenter double blind randomized placebo controlled trial.

Children (age 4,0 -18,0 years of age) presenting in a hospital (secondary care)
because of functional abdominal pain. The prevalence of chronic abdominal pain
in this age group is 10-15% as established in schoolchildren in many countries;
chronic abdominal pain is a frequent reason for outpatient visits.

4.2 Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. age 4-18 years;
2. fulfilling the Rome IV criteria for functional abdominal pain disorders,
with exception of the criterion for IBS-patients that the pain does not resolve
with resolution of the constipation.

4.3 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.
5. diagnosis *functional constipation* according to the Rome IV criteria.

Macrogol 4000, generic form, 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 guided by 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).
This dosage, which differs from the advised dosage in the Dutch
*Kinderformularium*, is within the limits of the recent guideline on
constipation of the Nederlandse Vereniging voor Kindergeneeskunde (*Richtlijn
Obstipatie bij kinderen van 0 tot 18 jaar*, update 2015, p.107: table 5.5.2)
(22), which advises 1-1,5 g/kg/day as starting dosage for disimpaction. After
disimpaction, the dosage should be adjusted which will be guaranteed by the
above mentioned instructions.
Maltodextrin, 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
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 when the diagnosis functional abdominal pain has been 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 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 insufficient.
Absorption of water by the fecal mass can cause distension of the bowel, with
increase of pain as a result. However, this is the first step in the laxative
process, which therefore is inevitable. The risk is negligible. Allergic
reactions are very rare.