Comparative Effect of Trimebutine and Probiotics on Functional Abdominal Pain Disorders (FAPD) in Children: Randomized Clinical Trial (RCT)
Phase: PHASE1
Conditions: Functional Abdominal Pain Syndrome, Functional Gastrointestinal Disorders, Irritable Bowel Syndrome Variant of Childhood
Sponsor: Universidad de Colima

SCHOOL OF MEDICINE
MASTER OF MEDICAL SCIENCES
RESEARCH PROTOCOL
EFFECT OF TRIMEBUTINE AND PROBIOTICS ON
FUNCTIONAL ABDOMINAL PAIN IN CHILDREN:
RANDOMIZED CLINICAL TRIAL
PRESENTS:
PABLO HERNAN SANDOVAL-VILLASEÑOR, M.D.
ADVISORS:
CLINICAL ADVISOR:
CARMEN ALICIA SÁNCHEZ-RAMÍREZ, D.Sc.
METHODOLOGICAL ADVISOR:
FABIÁN ROJA-LARIOS, D.Sc.
COLIMA, MÉXICO, JANUARY 9TH 2024

INDEX
SUMMARY:...........................................................................................................................3
INTRODUCTION...................................................................................................................4
THEORETICAL FRAMEWORK........................................................................................... 5
1. Abdominal pain in the pediatric patient....................................................................... 5
2. Functional Gastrointestinal Disorders (FGID)............................................................. 5
2.1. Definition............................................................................................................ 5
2.2. Epidemiology:.....................................................................................................5
23. Etiology:...............................................................................................................6
2.4. Classification:..................................................................................................... 6
3. Functional Abdominal Pain Disorders (FAPD)............................................................ 7
3.1. Definition............................................................................................................ 7
3.2. Epidemiology......................................................................................................7
3.3. Etiology...............................................................................................................7
3.4. Pathophysiology.................................................................................................8
3.5. Classification and diagnosis (Rome IV Criteria).................................................8
3.6. Treatment......................................................................................................... 10
4. Trimebutine in the treatment of Functional Abdominal Pain Disorders (FAPD)........ 10
4.1. Pharmacokinetics.............................................................................................10
4.2. Pharmacodynamics..........................................................................................10
4.3. Clinical trials..................................................................................................... 11
5. Effect of probiotics in the treatment of Functional Abdominal Pain Disorders (FAPD)..
11
5.1. Pharmacokinetics and pharmacodynamics...................................................... 11
5.2. Probiotic strains and doses for the treatment of FAPD in pediatrics................ 12
JUSTIFICATION................................................................................................................. 14
Magnitude..................................................................................................................... 15
Transcendence..............................................................................................................15
Feasibility/Viability.........................................................................................................15
Vulnerability...................................................................................................................16
PROBLEM STATEMENT....................................................................................................17
METHODOLOGICAL DESIGN...........................................................................................17
Research question...................................................................................................... 17
Goals............................................................................................................................ 17
General....................................................................................................................17
Specific....................................................................................................................17
Hypothesis...................................................................................................................18
Material and methods................................................................................................. 19
Study design............................................................................................................19
Study universe.........................................................................................................19
Study timing.............................................................................................................19
1

Selection criteria......................................................................................................19
Inclusion criteria.................................................................................................19
Exclusion criteria............................................................................................... 19
Elimination criteria............................................................................................. 19
Variables..................................................................................................................20
Independent variables....................................................................................... 20
Dependent variables..........................................................................................20
Intervening variables......................................................................................... 20
Sampling method.................................................................................................... 21
Evaluation instruments............................................................................................21
Study headquarters.................................................................................................21
Sample size.............................................................................................................21
Methodological description......................................................................................22
Statistical analysis and data interpretation..............................................................24
ETHICAL CONSIDERATIONS........................................................................................... 26
FINANCING........................................................................................................................ 27
SCHEDULE OF ACTIVITIES..............................................................................................28
BIBLIOGRAPHIC REFERENCES......................................................................................29
ANNEXES...........................................................................................................................33
Annex 1. Informed consent........................................................................................... 33
Annex 2. Questionnaire for pediatric digestive symptoms, format for parents..............35
Annex 3. Questionnaire for pediatric digestive symptoms, self-report.......................... 47
Annex 4. Scoring instructions for the Questionnaire for Pediatric Digestive Symptoms,
Rome Version IV (QPGS-RIV)...................................................................................... 59
Annex 5. PedsQL 3.0 - Gastrointestinal Symptoms Module. Report from parents of
young children...............................................................................................................60
Annex 6. PedsQL 3.0 - Gastrointestinal Symptoms Module. Children's report.............65
Annex 7. PedsQL 3.0 - Gastrointestinal Symptoms Module. Teen Report................... 70
Annex 8. Weekly medication report (4 to 10 years)...................................................... 75
Annex 9. Weekly medication report (10 to 18 years old)...............................................77
Annex 10. Letter of no conflict of interest......................................................................79
Annex 11. Checklist (CONSORT reporting guidelines) for randomized clinical trials(40).
80
Annex 12. Turnitin Similarity Report..............................................................................83
Annex 13. Probation of approval of tutors.....................................................................84
Annex 14. Bioethics Committee Approval of the School of Medicine........................... 85
2

ABSTRACT:
Objective: To evaluate the efficacy of trimebutine and probiotics in Functional Abdominal
Pain Disorders (FAPD) in children. Introduction: FAPD are common in children and lack
well-researched treatments. Their etiology is multifactorial, involving both medical and
psychosocial factors. Materials and methods: A double-blind, randomized clinical trial will
be conducted with 82 children aged 4 to 18 years. Participants will be assigned to one of
three
groups:
trimebutine/probiotics,
probiotics/placebo,
or
trimebutine/placebo.
Measurements will be taken at baseline, 4 weeks, and 8 weeks. Results: … Discussion: …
KEYWORDS:
Randomized clinical trial, placebo, double-blind, abdominal pain, trimebutine, probiotics,
lactobacillus rhamnosus GG.
3

INTRODUCTION
Functional Gastrointestinal Disorders (FGID) represent a set of diseases that affect the
gastrointestinal (GI) system without a present organic cause, they are characterized by
chronic or recurrent symptoms such as abdominal pain, abdominal distension, changes in
bowel habits and bowel movement dysfunction. (1,2).
Within the FGID, there are Functional Abdominal Pain Disorders (FAPD) where abdominal
pain is the common symptom, present in the pediatric population, and with a prevalence
that can vary depending on age, gender and geographic region, affecting approximately
one in four children and adolescents, with a higher prevalence in Latin America(3).
The etiology of FGID and FAPD is complex and multifactorial, involving the interaction of
genetic, environmental and psychosocial factors. At a pathophysiological level, they may
be related to alterations in the motility of the GI system, visceral hypersensitivity,
alterations in the intestinal barrier and changes in the communication between the central
nervous system and the enteric nervous system(4,5).
The management of FAPD is individualized and multidisciplinary, including changes in diet,
pharmacological and psychological therapies(6,7). Among pharmacological therapies,
trimebutine, a modulator of intestinal motility, has been shown to be effective in reducing
abdominal pain and stool frequency in children with irritable bowel syndrome (IBS)(8). On
the other hand, probiotics have shown beneficial effects in the treatment of FAPD in
pediatric patients(9).
Despite the high prevalence of FGID and FAPD in the pediatric population, research on
these disorders at a global and national level is scarce, so it is necessary to investigate
effective treatments for this population, which is why it is proposes the following thesis
work, which aims to evaluate the effectiveness of trimebutine and probiotics in the
treatment of FAPD in pediatric patients.
4

THEORETICAL FRAMEWORK
1. Abdominal pain in the pediatric patient
Abdominal pain is a common symptom in children. Due to evolution, the pain can be acute
or recurrent. Acute abdominal pain can be due to both gastrointestinal and extraintestinal
causes; Recurrent abdominal pain can be due to various causes, but only 5 to 10% of
cases are of organic origin, while the majority are due to some functional disorder(1). A
meta-analysis by Korterink et al. found that the global prevalence of recurrent abdominal
pain in children in Western countries is 13.5%(2). The prevalence of abdominal pain can
vary depending on age, gender and geographical region, being more common in girls and
school-age boys(10).
In the case of functional gastrointestinal disorders (FGID), it is believed that alteration in
the motor function of the gastrointestinal tract, visceral hypersensitivity, and dysfunction in
communication between the central nervous system and the enteric nervous system may
contribute to abdominal pain ( eleven).
2. Functional Gastrointestinal Disorders (FGID)
2.1. Definition
Functional gastrointestinal disorders (FGID) are a group of diseases that affect the
gastrointestinal (GI) system and have no identifiable organic cause. These conditions are
characterized by chronic or recurrent symptoms, such as abdominal pain, bloating,
changes in bowel habits, and bowel movement dysfunction. FGIDs are common in the
pediatric population and can affect the quality of life of children and their families(2).
2.2. Epidemiology:
FGIDs frequently affect children and adolescents around the world; it is estimated that up
to 20% of school-aged children experience symptoms related to FGIDs, although rates
vary depending on the population and study methodology(12). Some studies have
reported prevalence rates of up to 50%, in specific populations of children with chronic
abdominal symptoms(13). FGIDs have been shown to be more common in girls than in
boys and tend to increase in prevalence with age. Risk factors for developing FGID include
a family history of functional GI disorders, history of GI infections, psychosocial factors
such as stress and anxiety, as well as early exposure to adverse life events(14).
5

23. Etiology:
The etiology of FGID is complex and multifactorial; it is believed to involve an interaction
between genetic, environmental and psychosocial factors. At a pathophysiological level,
FGIDs may be related to alterations in the motility of the GI system, visceral sensitivity,
intestinal barrier function and communication between the central nervous system and the
enteric nervous system(5).
Studies have identified multiple factors that may contribute to the development of FGID in
children,
including
genetic
predisposition,
gut
microbiota
dysbiosis,
low-grade
inflammation, alterations in the secretion and absorption of fluids and electrolytes in the
intestine, and abnormalities in the function of the enteric nervous system and in pain
modulation(15).
2.4. Classification:
FGIDs are classified according to the Rome IV pediatric criteria, classified according to
age; in children under five years of age (neonates and young children) such as infant
regurgitation, rumination syndrome, cyclic vomiting syndrome, infant colic, functional
diarrhea, infant dyschezia and functional constipation; and in patients 5 to 18 years (older
child and adolescent) as cyclic vomiting syndrome, functional nausea and vomiting,
rumination
syndrome,
aerophagia,
functional
dyspepsia,
irritable
bowel
syndrome,
abdominal migraine, functional abdominal pain not otherwise specified , functional
constipation and non-retentive fecal incontinence, as seen in the following Table 1(16,17).
Table 1. GFR according to Rome IV Pediatric Criteria
Neonate and young child (< 5 years)
Older child and adolescent (4 to 18 years)
G1
Infant regurgitation
H1
Functional nausea and vomiting
disorders
G2
Rumination syndrome
H1a
Cyclic vomiting syndrome
G3
Cyclic vomiting syndrome
H1b
Functional nausea and vomiting
G4
Infant colic
H1c
Rumination syndrome
G5
Functional diarrhea
H1d
Aerophagia
G6
Infant dyschezia
H2
Functional abdominal pain
disorders (FAPD)
G7
Functional constipation
H2a
Functional dyspepsia
6

H2b
Irritable bowel syndrome (IBS)
H2c
abdominal migraine
h2d
Functional abdominal pain not
otherwise specified
H3
Functional defecation disorders
H3a
Functional constipation
H3b
Non-retentive fecal incontinence
* Adapted from Blesa-Baviera, 2017(17).
3. Functional Abdominal Pain Disorders (FAPD)
3.1. Definition
Functional abdominal pain disorders (FAPD) in children and adolescents are a group of
disorders in which patients experience abdominal pain without an apparent organic cause.
These disorders fall under the general classification of functional gastrointestinal disorders
(FGID) and are based on the Rome IV diagnostic criteria(10,12). FAPDs include functional
dyspepsia (FD), irritable bowel syndrome (IBS), abdominal migraine (AM), and abdominal
pain not otherwise specified (FAD-NEOM)(18).
3.2. Epidemiology
The prevalence of FAPD varies depending on the population studied and the diagnostic
criteria used. According to the Rome IV criteria, the global prevalence of FAPD in children
and adolescents ranges between 13.5% and 20.7%(2,19). IBS is the most common, with a
prevalence of 8.8%, followed by FD with a prevalence of 5.8% and FAP-NOS with a
prevalence of 1.1%(2). FDAD are more common in girls than in boys and tend to be more
frequent during adolescence(19,20).
3.3. Etiology
The
etiology
of
FAPD
is
multifactorial
and
may
involve
genetic,
environmental,
psychological and pathophysiological factors. Alterations in the motor function of the
gastrointestinal tract, visceral perception, and intestinal barrier function have been
identified in patients with FAPD. Psychological factors, such as stress and anxiety, can
also influence the onset and course of FAPD(4,21).
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3.4. Pathophysiology
Visceral hyperalgesia leading to disability is shown to be the end result of sensitizing
medical factors overlaid on a background of genetic predisposition and early life events
(Figure 1)(5).
Figure 1.Etiopathogenesis and summary pathophysiology of FAPD.
*Adapted from Thapar, et al., 2020(5).
3.5. Classification and diagnosis (Rome IV Criteria)
FAPD are classified according to the Rome IV criteria into four main subtypes with
diagnostic criteria as seen in Table 2(5,16):
Table 2. Diagnostic Criteria for Functional Abdominal Pain Disorders (FAPD)
H2a. Functional
dyspepsia (FD)
You must have one or more of the following symptoms at least
four days a month, for at least two months prior to diagnosis:
1.
Postprandial fullness.
2.
Early satiety.
3.
Epigastric
pain
or
heartburn
not
associated
with
defecation.
4.
After
appropriate
medical
evaluation,
the
symptoms
cannot be attributed to another condition.
H2b. Irritable
bowel syndrome
(IBS)
You must meet all of the following:
1.
Abdominal pain at least four days per month associated
with one or more of the following, for at least two months
prior to diagnosis:
a.
Related to defecation.
b.
Changes in defecation frequency.
c.
Changes in the shape or appearance of bowel
movements.
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2.
In children with constipation, the pain does not resolve
with its resolution.
3.
After
appropriate
medical
evaluation,
the
symptoms
cannot be attributed to another condition.
Subtypes:IBS with constipation, IBS with diarrhea, IBS with
constipation and diarrhea, undefined IBS.
H2c. Abdominal
migraine (AM)
You must do all of the following at least twice in the six months
before diagnosis:
1.
Paroxysmal episodes of periumbilical, midline or diffuse
abdominal pain, lasting an hour or more, this being the
most important symptom.
2.
Episodes separated by weeks to months.
3.
The pain is disabling and interferes with normal activity.
4.
Symptoms and stereotyped patterns in each individual
patient.
5.
The pain is associated with two or more of the following:
anorexia, nausea, vomiting, headache, photophobia, and
paleness.
6.
After
appropriate
medical
evaluation,
the
symptoms
cannot be attributed to another condition.
H2d. Abdominal
pain not otherwise
specified
(FAD-NEOM)
You must do all of the following at least 4 times a month for at
least 2 months prior to diagnosis:
1.
Episodic or continuous abdominal pain that does not
occur
only during physiological events (e.g., eating,
menstruation).
2.
Insufficient criteria for IBS, DF or MA.
3.
After
appropriate
medical
evaluation,
the
symptoms
cannot be attributed to another condition
*Adapted from Menninga, et al., 2016(16).
In the diagnostic approach to functional abdominal pain disorders, it is important to identify
the presence of alarm data, which can guide us to an organic origin of abdominal pain
(Table 3)(1).
Table 3. Warning signs and symptoms in children with recurrent abdominal pain.
Family history of inflammatory bowel disease, celiac disease, or peptic ulcer
Persistent pain in the right upper or right lower quadrant
Dysphagia
Odynophagia
Persistent vomiting
gastrointestinal bleeding
nocturnal diarrhea
Arthritis
Perianal disease
Unintentional weight loss
9

Growth arrest
Delayed puberty
Unexplained fever
* Adapted from Sánchez-Ramírez, 2023(1).
3.6. Treatment
The management of FAPD is multidisciplinary and individualized, since the effectiveness of
interventions can vary between patients. Treatment may include changes in diet,
pharmacological therapies and psychological therapies(6,7).
1.
Changes
in
the
diet:
inclusion
of
fiber,
reduction
in
fat
intake
and
the
implementation
of
a
diet
low
in
FODMAPs
(Fermentable
Oligo-,
Di-,
Monosaccharides and Polyols)(22,23).
2.
Pharmacological therapies: antispasmodics (trimebutine), tricyclic antidepressants,
probiotics and laxatives to treat the symptoms of FAPD(24,25).
3.
Psychological therapies: cognitive-behavioral therapy, hypnotherapy and relaxation
therapy, can be beneficial in the management of FAPD, especially in patients with
psychological factors that contribute to their symptoms(26,27).
4. Trimebutine in the treatment of Functional Abdominal Pain Disorders
(FAPD)
4.1. Pharmacokinetics
Trimebutine is a drug with variable oral bioavailability, ranging from 30% to 100%. After
oral administration, it is rapidly absorbed from the gastrointestinal tract and reaches its
maximum plasma concentration in approximately 1-2 hours. Trimebutine is primarily
metabolized in the liver, and its metabolites are excreted via the kidneys and bile. The
elimination half-life of trimebutine is approximately 6 hours, allowing it to be administered
in multiple doses throughout the day. As a general rule, a dose of 10-15 mg/kg/day, divided
into 2 or 3 doses per day, has been suggested(28).
4.2. Pharmacodynamics
Trimebutine is a gastrointestinal motility modulator that acts on μ-, κ-, and δ-opioid
receptors, primarily in the gastrointestinal tract. Trimebutine also interacts with calcium and
potassium channels in intestinal smooth muscle cells, contributing to its motility-regulating
10

action. In addition, trimebutine has an antispasmodic effect on gastrointestinal smooth
muscle and improves the coordination of peristalsis in the intestine, which may be useful in
the treatment of functional abdominal pain and other gastrointestinal disorders(29).
4.3. Clinical trials
There are few studies evaluating the effects of trimebutine and FAPDs; a double-blind,
placebo-controlled study showed that trimebutine was effective in reducing abdominal pain
and stool frequency in children with irritable bowel syndrome (IBS)(8). A prospective study
showed that trimebutine significantly relieved abdominal pain and improved quality of life in
children with functional dyspepsia(30). Furthermore, it was found that trimebutine was
effective in the treatment of functional constipation in children, improving the frequency of
bowel movements and reducing abdominal pain(31).
5. Effect of probiotics in the treatment of Functional Abdominal Pain
Disorders (FAPD)
5.1. Pharmacokinetics and pharmacodynamics
Probiotics are live microorganisms that, when administered in adequate quantities, provide
health benefits to the host(32). The pharmacokinetics and pharmacodynamics of probiotics
vary widely depending on the strain used, the dose, and the mode of administration.
Probiotics are generally not absorbed systemically and exert their effects locally in the
gastrointestinal tract. Probiotics can interact with the intestinal microbiota, intestinal
mucosa and the immune system, which can lead to changes in gastrointestinal function,
inflammation and immunity(33).
Changes
in
the
intestinal
microbiota
can
occur
through
modification in function,
composition (dysbiosis) or interactions between the microbiota and the host. These
changes develop in the first years of life, reaching a stable microbial population in the
second year and a profile similar to the adult around 4 years old. The use of probiotics
could improve the intestinal microbial population, increase mucus secretion, and prevent
the destruction of tight junction proteins by decreasing the number of lipopolysaccharides
(LPS). When LPS binds to endothelial cells with toll-like receptors (TLR 2, 4), dendritic
cells (DCs) and macrophages are activated, and inflammatory markers are increased.
Additionally, a decrease in gut dysbiosis and gut leakage following probiotic therapy may
minimize
the development of inflammatory biomarkers and attenuate unnecessary
11

activation of the immune system. In turn, probiotics enhance the differentiation of T cells
against Th2 and the development of Th2 cytokines, such as IL-4 and IL-10 (36).
5.2. Probiotic strains and doses for the treatment of FAPD in pediatrics
Studies have shown that certain strains of probiotics may be effective in treating functional
abdominal pain disorders in pediatric patients. Some probiotic strains that have shown
beneficial effects include Lactobacillus rhamnosus GG (LGG), Lactobacillus reuteri DSM
17938, and Bifidobacterium infantis 35624(34–35).
L. rhamnosus HN001 in human intestinal cells interacts with TLR-9 and suppresses the
NF-kB
inflammatory
pathway
through
inhibition
of
TLR-4.
L.
reuteri
exerts
an
anti-inflammatory action, increasing Treg cell activation and IL-10 levels. The overall effect
is a significant decrease in the proinflammatory cascade with inhibition of the proliferation
of surrounding T cells. Specific strains of probiotics can negatively or positively stimulate
NK cells: L. rhamnosus GG and L. reuteri DSM 17938 inhibit the activation of T cells and
NK cells and the release of IFN-y. The different interaction between probiotics, DCs and
NK cells clearly reveals how each strain can differently modulate the immune system and
inflammatory responses; The NK/CD balance is complex and probiotics could be used to
exert beneficial effects (Figure 3)(36).
12

Figure 3.Main immunomodulatory pathways of probiotics in the intestine.
*Adapted from Cristofori, et al., 2021(36).
The effect of probiotics may be mediated by their metabolites, such as short-chain fatty
acids
(SCFAs),
particularly
propionate,
acetate
and
butyrate,
which
may
exert
anti-inflammatory effects. SCFAs are produced by bifidobacteria, lactobacilli, and various
commensal bacteria. These metabolites exert their action by binding to specific receptors
on intestinal epithelial cells. In this way, the NF-kB pathway, the suppression of Treg cells
and the production of proinflammatory cytokines by neutrophils and macrophages are
inhibited; consequently, the inflammatory state is prevented and an anti-inflammatory
effect is produced (36).
13

The effective doses of these probiotics vary, but in general, the doses used in clinical
studies range from 1x109 to 3x109 colony-forming units (CFU) per day(37–38). In a
meta-analysis carried out by Gordon M., et., on the use of probiotics for the management
of FAPD, low evidence was found with an I2 = 70%(9).
14

JUSTIFICATION
Magnitude
Functional Gastrointestinal Disorders (FGID) are common in children and adolescents,
which justifies the need to investigate effective treatments for this population. A recent
meta-analysis and systematic review examined the prevalence of FGID in children and
adolescents according to the Rome IV criteria, finding an overall prevalence of 23%. The
most common disorders were functional constipation (FE) with a prevalence of 12%,
followed by functional dyspepsia (FD) (5%) and irritable bowel syndrome (IBS) (3%). The
prevalence of FGID was higher in the Americas, with 23.67% (21.2 - 26.2%)(3).
These epidemiological data demonstrate that FGIDs, including Functional Abdominal Pain
Disorders (FAPD), are a major concern in pediatric health, affecting approximately one in
four children and adolescents. Furthermore, the higher prevalence in the Americas
suggests that countries in this region, including Mexico, could especially benefit from
additional research in this field.
Transcendence
Research on FAPD in pediatric patients worldwide and nationally is scarce. This is
problematic, as the effectiveness and safety of treatments used in adults cannot always be
directly extrapolated to children due to differences in physiology and drug metabolism. This
lack is even more worrying considering that trimebutine, a medication that could be
promising for these disorders, has not yet been studied in depth in the context of FAPD in
children. Furthermore, at a time when the use of probiotics is gaining popularity as an
adjuvant treatment, it is crucial to evaluate their efficacy and safety in this vulnerable
population. Carrying out a clinical trial that investigates the effectiveness of trimebutine and
probiotics in the treatment of FAPD in children would be transcendental. This would not
only increase the amount of research in Mexico on this topic, but will also provide valuable
information on appropriate treatment in children. Additionally, the study results could help
doctors make decisions, which could improve the quality of life for affected children and
their families.
Feasibility/Viability
There are few studies in children on FAPD, however, some studies have investigated the
effectiveness of trimebutine and probiotics in the treatment of FAPD in children.
15

Conducting the clinical trial is also feasible due to the availability of trimebutine and
probiotics on the market and the prevalence of FAPDs in the pediatric population.
Furthermore, the design of the randomized clinical trial would allow an effective
comparison between the groups treated with trimebutine, probiotics and the control group,
which will provide solid and reliable information on the effectiveness of the proposed
treatments.
Vulnerability
The implementation of the clinical trial in Colima will offer a valuable opportunity to
examine the effectiveness of trimebutine and probiotics in the treatment of FAPD in
pediatric patients, however, the compliance of parents with respect to the treatment
prescribed by the patient must be taken into account. doctor. Adherence to treatment may
be a critical factor in the effectiveness of the intervention and, therefore, it is essential to
evaluate it in the context of the study. With the information obtained, strategies could be
developed to improve treatment adherence and optimize results in the management of
FAPD in the pediatric population.
16

PROBLEM STATEMENT
ADFTs in the pediatric population represent an insufficiently explored area of ​research
despite their high prevalence, being mainly alarming given that treatments in adults are not
necessarily extrapolated to the pediatric population due to differences in physiology and
drug metabolism. , so its effectiveness and safety in children have not yet been
conclusively established.
Therefore, this study seeks to address these gaps in the literature by evaluating the
efficacy of trimebutine compared to probiotics in the treatment of FAPDs in pediatric
patients in reducing abdominal pain. The findings could have significant implications in
clinical practice by providing empirical data that could guide the treatment of ADD in the
pediatric population, improving their quality of life.
METHODOLOGICAL DESIGN
Research question
What is the effect of trimebutine and probiotics on Functional Abdominal Pain Disorders in
pediatric patients?
Goals
General
To evaluate the effect of treatment with trimebutine and probiotics in the treatment of
Functional Abdominal Pain Disorders (FAPD) in pediatric patients.
Specific
1.
To identify the prevalence of Functional Gastrointestinal Disorders (FGID) in
pediatric patients according to the Rome IV criteria.
2.
To measure the prevalence of Functional Abdominal Pain Disorders (FAPD) in
pediatric patients according to the Rome IV criteria.
3.
To determine the effectiveness of treatments with trimebutine and probiotics in
reducing pain in pediatric patients with FAPD.
4.
To evaluate the impact of treatments with trimebutine and probiotics on the quality
of life of pediatric patients with FAPD.
17

5.
To assess the safety and tolerability of treatments with trimebutine and probiotics in
the treatment of FAPD in pediatric patients.
6.
Identify the factors associated with the presentation of FAPD in pediatric patients.
Hypothesis
Hi: The efficacy of treatment with trimebutine is greater against probiotics in the treatment
of Functional Abdominal Pain Disorders (FAPD) in pediatric patients.
H0: The efficacy of treatment with trimebutine and probiotics is equal in the treatment of
Functional Abdominal Pain Disorders (FAPD) in pediatric patients.
Ha: The effectiveness of probiotic treatment is greater than trimebutine in the treatment of
Functional Abdominal Pain Disorders (FAPD) in pediatric patients.
Ha2: There is a greater reduction in pain with combined treatment in Functional Abdominal
Pain Disorders (FAPD) in pediatric patients.
18

Material and methods
Study design
Placebo-controlled, randomized, double-blind clinical trial (patient/legal guardians, principal
investigator).
Study universe
Children from 4 to 18 years old who attend pediatric consultation.
Study timing
January to December 2024.
Selection criteria
Inclusion criteria
○
Pediatric patients from 4 to 18 years old.
○
Meet the Rome IV criteria for any of the Functional Abdominal Pain
Disorders (Functional Dyspepsia, IBS, Abdominal Migraine, or Functional
Abdominal Pain Not Otherwise Specified)
○
Having signed the informed consent by the parents or legal guardians of the
minor.
Exclusion criteria
○
Patients who present abdominal pain of organic cause.
○
Immunosuppressed patients.
○
Patients with previous hypersensitivity to the study drug.
Elimination criteria
○
Voluntary withdrawal from the study.
○
Patients not adherent to treatment (less than 80%)
○
Patients who are participating in another study simultaneously.
○
Patients who are being treated by another doctor simultaneously.
19

Variables
Independent variables
Variable
Operational definition
Guy
Scale
Treatment
Patient who received
treatment with
trimebutine/probiotics,
trimebutine/placebo,
probiotics/placebo
Qualitative
nominal
polytomous
Trimebutine/probiotics
Trimebutine/placebo
Probiotics/placebo
Dependent variables
Variable
Operational
definition
Guy
Scale
Functional Abdominal
Pain Disorders (FAPD)
Rome IV Criteria
Qualitative
nominal
polytomous
Functional dyspepsia (FD)
Irritable bowel syndrome
(IBS)
Abdominal migraine (AM)
Abdominal pain not
otherwise specified
(DAF-NEOM)
Abdominal pain intensity
Subjective feeling of
discomfort or discomfort
in the abdominal region.
Continuous
quantitative
4 to 10 years: Wong-Baker
Pain Scale
10 to 18 years: Visual
analogue scale (VAS)
score
Quality of life
State of complete
physical, mental and
social well-being.
Continuous
quantitative
Score obtained 0 - 100 with
the PedsQL 4.0 scale
(Pediatric Quality of Life
Inventory) Generic Core
Scales.
Intervening variables
Variable
Operational definition
Guy
Scale
Age
Chronological
age
in
months
Continuous
quantitative
48 to 216
months
Sex
Sex
corresponding
to
your phenotype
Dichotomous
nominal qualitative
Man
Women
Scholarship
Maximum
educational
level achieved.
Ordinal qualitative
Preschool
Primary
20

Secondary
Baccalaureate
BMI
Measurement of weight
in relation to height
Continuous
quantitative
WHO
percentiles for
age.
Medicines
Drugs other than
trimebutine and
probiotics that could
have an impact on
gastrointestinal function
or the perception of
abdominal pain.
Nominal qualitative
List of indicated
medications
(free text box)
Sampling method
Probabilistic, random, stratified sampling (Irritable Bowel Syndrome, Functional Dyspepsia,
Abdominal Migraine and FAD-NEOM) and simple random sampling to form groups A
(trimebutine/probiotics), B (trimebutine/placebo) and C (probiotics/placebo).
Evaluation instruments
Rome IV criteria for pediatric patients 4-10 years (See Annex 2); Rome IV criteria for
pediatric patients 10-18 years (See Annex 3)(3); PedsQL 3.0 Gastrointestinal Symptoms
Module (Appendices 5-7); Weekly medication reports and Visual Analogue Scale (VAS) for
those over 10 years of age and the Wong-Baker Faces Scale for children under 10 years
of age (Appendixes 8-9).
Study headquarters
Private pediatric consultation (Dr. Carmen Alicia Sánchez Ramírez and associated
pediatric doctors)
Sample size
The Fleiss formula was used to calculate the general sample size N, adjusting N for each
stratum using its prevalence, taking into account the 4 strata (Irritable Bowel Syndrome,
Functional Dyspepsia, Abdominal Migraine and FAD-NOS) with prevalences of 8.8, 5.8,
1.1 and 1.1% respectively, and 3 treatment groups (trimebutine, probiotics and placebo)
with efficacy in reducing pain intensity of 94.9 and 50.0%, respectively. (8,9,39).
21

𝑛=
(𝑍α/2​ +𝑍β)
2 × (𝑝1(1−𝑝1)+𝑝2​ (1−𝑝2)) × 𝐷𝐸𝐹𝐹​
(𝑝1−𝑝2​ )
2
= 1.96 (for a significance level ofα=0.05)
𝑍α/2 
= 1.64 (for a statistical level of1−β=0.95)
𝑍β
p1= 0.949 (trimebutine efficacy)
p2= 0.5 (probiotic efficacy)
= 1 (completely randomized design effect)
𝐷𝐸𝐹𝐹
= = =
𝑛= (1.96 +1.64)
2 × (0.949(0.051)+0.5(0.5)) × 1​
(0.949−0.5​)
2
(3.6)
2 × (0.048399+0.25) × 1​
(0.449 )
2
12.96 × 0.298399​
0.201601
3.8722944​
0.201601
n = 19.22 = 20 per treatment group.
The sample size n is adjusted according to the prevalence of each stratum with the
formula:𝑛𝑖​ = 𝑛 ×
𝑤𝑖
∑𝑤𝑖​ ​
=
10.48
= 11 x 3 (trimebutine/probiotics, trimebutine/placebo and
𝑛𝑆𝐼𝐼​ = 20 ×
8.8
16.8 ​
probiotics/placebo) = 33 20% (additional margin of adherence to treatment) = 40 for the
IBS stratum.±
= 6.90 = 7 x 3 = 21 20% = 26 for the DF stratum.
𝑛𝐷𝐹​ = 20 ×
5.8
16.8 ​
±
= 1.31 = 2 x 3 = 6 20% = 8 for the MA stratum.
𝑛𝑀𝐴​ = 20 ×
1.1
16.8 ​
±
= 1.31 = 2 x 3 = 6 20% = 8 for the DAF-NEOM stratum.
𝑛𝐷𝐴𝐹−𝑁𝐸𝑂𝑀​ = 20 ×
1.1
16.8 ​
±
N = 82.
Methodological description
The protocol will be subject to review by the Bioethics Committee of the School of
Medicine of the Universidad de Colima, as well as the Research Committee and the
Research Ethics Committee of the Hospital Regional Universitario de Colima. Once
approval is obtained, a placebo-controlled, randomized, double-blind clinical trial will be
carried out, based on the CONSORT guidelines (Annex 11)(40). This trial involves the
participation of both pediatric patients aged 4 to 18 years, their legal guardians, their
treating physician, and the principal investigator.
22

Patients will be selected from among those who attend private consultation and who meet
the Rome IV criteria for any of the Functional Abdominal Pain Disorders. Patients who
meet these criteria will be invited to participate in the study. Before any intervention is
performed, the purpose and procedures of the study will be explained to patients and their
legal guardians. If they decide to participate, they will be asked to sign a letter of informed
consent and the minor's assent. Patients will be selected through probabilistic sampling
stratified into 4 (Irritable Bowel Syndrome, Functional Dyspepsia, Abdominal Migraine and
FAD-NOS), until the desired sample size of 82 participants is reached. Once the
participants are selected, they will be assigned by simple random sampling to one of the
three groups: trimebutine/probiotic, probiotic/placebo or trimebutine/placebo, each group
consisting of at least 20 participants. The initial diagnosis will be made using the Rome IV
Criteria Questionnaires for pediatric patients (Annexes 2-4), the quality of life will be
evaluated with PedsQL 3.0 Gastrointestinal Symptoms Module (Annexes 5-7), the intensity
of pain with the Scale Visual Analogue (VAS) for those over 10 years of age and the
Wong-Baker Faces Scale for children under 10 years of age (Appendixes 8-9). Patients
will be prescribed the treatment corresponding to their assigned group and will undergo
clinical follow-up at 4 and 8 weeks. During these follow-up consultations, the Rome IV
Criteria Questionnaires and scales will be administered again to evaluate the evolution of
patients' symptoms, as well as their response to treatment. Any patient who requests
voluntary withdrawal, those with less than 80% adherence to treatment (assessed by
counting the medication in the container and weekly medication reports, annexes 8-9), and
those who are participating in another study or are being treated by another doctor
simultaneously.
The data obtained in each consultation (initial, at 4 weeks and at 8 weeks) will be recorded
in an Excel spreadsheet for subsequent statistical analysis.
Figure 2.Methodological description
23

* Own elaboration.
Statistical analysis and data interpretation
The statistical analysis will be carried out using IBM SPSS Statistics 26. Descriptive
statistics will be used with measures of central tendency, presenting the results in tables
and graphs.
To determine if the data follow a normal distribution, the Kolmogorov-Smirnov and
Shapiro-Wilk tests will be applied. The measurements will be analyzed in 3 groups
(trimebutine, probiotics and control) and at 3 times (0, 4 and 8 weeks). For the categorical
intervening variables such as sex and education, the chi-square test (X2) will be used. For
continuous variables such as age and BMI, the Mann-Whitney U test will be applied,
expecting statistically significant differences with p < 0.05.
24

If the data follow a normal distribution, repeated measures ANOVA will be used to
compare the means of the 3 groups (trimebutine/probiotics, trimebutine/placebo, and
probiotics/placebo). The McNemar test or sign test will be taken into account as a
secondary analysis to evaluate changes within each group over time (0, 4 and 8 weeks). If
the data do not follow a normal distribution, non-parametric tests such as the Friedman
test will be used.
If a statistically significant difference is found in repeated measures ANOVA or in the
Friedman test, post hoc tests will be performed to identify specific differences between
groups and times. If necessary, correlation tests such as Pearson or Spearman will be
used to evaluate the relationships between different variables within the study.
25

ETHICAL CONSIDERATIONS
In accordance with the international principles of Ethics for research on human beings
established in the Declaration of Helsinki and the Nuremberg Code. In national documents
such as NOM-012-SSA3-2012, the General Health Law in its articles 100 and 101 of
chapter V, Research for Health, in the Regulations of the General Health Law on Research
for Health (DOF 04-02-2014), where article 17, section I, establishes that this research is
classified as research with minimal risk, as it is a research study with commonly used
medications, wide therapeutic range, authorized for its sale, using the established
indications, doses and routes of administration, which is why informed consent is
necessary (Annex 1), a letter of no conflict of interest (Annex 10) and approval by an
Ethics and Research Committee will be necessary. .
Furthermore, according to article 15 of the same Regulation, considering a protocol with an
experimental design in human beings, which includes several groups, random selection
methods will be used to obtain an impartial assignment of the participants in each group
and the pertinent measures will be taken to avoid any risk or damage to the research
subjects, as well as the privacy of the individual subject of research, identifying themselves
only when the results require it and they authorize it as established in article 16 of this
same Regulation.
Likewise, it will be carried out in accordance with Chapter III, Research on Minors or
Incapacitated Children, respecting articles 34 to 37 of the Regulations of the General
Health Law on Health Research, requiring the consent of the minor, when the mental
capacity and psychological state of the minor allow it, providing appropriate information for
the understanding of the minor, based on this, the research is classified as risky and with
the probability of direct benefit for the minor or the incapable, in accordance with article 38,
position that the risk is justified by the importance of the benefit that the minor will receive
by receiving the treatment, and the benefit is equal to or greater than other alternatives
already established for diagnosis and treatment, according to fractions I and II.
This protocol will be submitted for evaluation and approval by the Research Committee
and the Research Ethics Committee of the Hospital Regional Universitario de Colima.
Likewise, it will be registered in the Clinical Trials database of the US Department of
Health and Human Services. The participants and those responsible for the research
protocol undertake to safeguard the information confidentially, as well as guarantee the
rights of the subjects. study.
26

FINANCING
Human Resources
1.
Principal researcher: Pablo Hernan Sandoval Villaseñor, Master's Student in
Medical Sciences, Universidad de Colima.
2.
Thesis advisors: Dr. C. Carmen Alicia Sánchez Ramírez, Dr. C. Fabián Rojas
Larios.
Physical resources
Resource type
Unit
Amount
Cost per unit
Cost
Computer
Part
1
$0 (Personal use)
$0
EPSON L4150
printer
Part
1
$0 (Personal use)
$0
Black ink for
EPSON 504
printer
Part
1
$250
$250
Sheets
Pack of 500
sheets
5
$200
$1000
Pens
Box with 12
pieces
2
$70
$140
Trimebutin
tablets 200 mg
(Espabion)
Box with 40
tablets
39 (28 tablets
per patient, 26
patients, 2
consultations)
$94.0
$3572
Trimebutin
suspension 20
mg/ml
(Espabion)
Bottle with 100
ml
26 (4 bottles per
patient, 13
patients, 2
consult)
$150.0
$3900
Probiotics
Lactobacillus
rhamnosus GG
Box with 10
envelopes of 1.5
gr
157 (28
envelopes per
patient, 28
patients, 2
consultations)
$250 (approx.)
$39250
Placebo
Box with 28
microcrystalline
cellulose tablets
8 mm 250 mg.
56 (28 tablets
per patient, 28
patients, 2
consultations)
$0 (Faculty of Chemical
Sciences)
$0
Totall
$48,112
MXN
27

SCHEDULE OF ACTIVITIES
ACTIVITY
PROGRAMMED CALENDAR MONTHS
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
1. Modifications to the
research protocol
2. Evaluation and
authorization of the
protocol by an Ethics
and Research
Committee
3. Pilot test of
evaluation and informed
consent instrument
4. Sample of patients
and randomization of
study groups (G1 and
G2) and control
5. Follow-up 4 weeks
start of treatment study
groups (G1, G2) and
control.
6. Follow-up 8 weeks
start of treatment study
groups (G1, G2) and
control
7. Analysis of results
8. Writing conclusions
and discussion
9. Dissemination of
results, publication of
article and obtaining a
degree
28

BIBLIOGRAPHIC REFERENCES
1.
Sánchez-Ramirez
CA.
Abdominal
pain
in
the
pediatric
patient.
In:
Cruz-Palacios
A,
Remes-Troche J, Roesch-Dietlen F, Yamamoto-Furusho JK, editors. Emerging topics in
gastroenterology. Mexico: Permanyer; 2023. p. 57–60.
2.
Korterink Judith J. AND Diederen KANDBMAANDTMM. Epidemiology of Pediatric Functional
Abdominal Pain Disorders: A Meta-Analysis. PLoS One [Internet]. 2015 Aug;10(5):1–17.
Available in:https://doi.org/10.1371/journal.pone.0126982
3.
V. CA, . CJ, . MP, . E, . EA, . M. Utility of the Rome IV questionnaires in Spanish to identify
functional gastrointestinal disorders in pediatrics. Working group of the Latin American Society
of Gastroenterology, Hepatology and Pediatric Nutrition (SLAGHNP). Acta Gastroenterol
Latinoam
[Internet].
2019;49:260–97.
Available
in:https://www.redalyc.org/articulo.oa?id=199361721018
4.
Simrén M, Törnblom H, Palsson Olafur S and Van Oudenhove L, Whitehead WE, Tack J.
Cumulative Effects of Psychological Distress, Visceral Hypersensitivity, and Abnormal Transit
on
Patient-reported
Outcomes
in
Irritable
Bowel
Syndrome.
Gastroenterology.
2019
Apr;157(2):391–402.e2.
5.
Thapar N, Benninga MA, Crowell MD, Di Lorenzo C, Mack I, Nurko S, et al. Pediatric functional
abdominal
pain
disorders.
Nat
Rev
Dis
Primers
[Internet].
2020;6(1):89.
Available
in:https://doi.org/10.1038/s41572-020-00222-5
6.
Horvath A, Dziechciarz P, Szajewska H. Systematic Review of Randomized Controlled Trials:
Fiber Supplements for Abdominal Pain-Related Functional Gastrointestinal Disorders in
Childhood.
Ann
Nutr
Metab
[Internet].
2012
Aug
10;61(2):95–101.
Available
in:https://doi.org/10.1159/000338965
7.
Chumpitazi BP, Kearns GL, Shulman RJ. Review article: the physiological effects and safety of
peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders.
Aliment
Pharmacol
Ther
[Internet].
2018;47(6):738–52.
Available
in:https://onlinelibrary.wiley.com/doi/abs/10.1111/apt.14519
8.
Karabulut GS, Beşer OF, Erginöz E, Kutlu T, Cokuğraş Fügen Ç and Erkan T. The Incidence of
Irritable Bowel Syndrome in Children Using the Rome III Criteria and the Effect of Trimebutine
Treatment. J Neurogastroenterol Motil. 2013 Jan;19(1):90–3.
9.
Gordon M WCS V, Akobeng AK. Probiotics for management of functional abdominal pain
disorders in children. Cochrane Database of Systematic Reviews [Internet]. 2023;(2). Available
in:https://doi.org//10.1002/14651858.CD012849.pub2
10. Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Childhood
Functional
Gastrointestinal
Disorders:
Child/Adolescent.
Gastroenterology
[Internet].
29

2016;150(6):1456-1468.e2.
Available
in:https://www.sciencedirect.com/science/article/pii/S0016508516001815
11. Khrizman M, Pakalnis A. Management of Pediatric Migraine: Current Therapies. Pediatr Ann
[Internet].
2018;47(2):e55–60.
Available
in:https://journals.healio.com/doi/abs/10.3928/19382359-20180129-02
12. Saps
M,
Velasco-Benitez
CA,
Langshaw
AH,
Ramirez-Hernández
CR. Prevalence of
Functional Gastrointestinal Disorders in Children and Adolescents: Comparison Between
Rome III and Rome IV Criteria. J Pediatr. May 2018;199:212–6.
13. Koppen IJN, Nurko S, Saps M, Di Lorenzo C, Benninga MA. The pediatric Rome IV criteria:
what's new? Expert Rev Gastroenterol Hepatol [Internet]. 2017 Mar 4;11(3):193–201. Available
in:https://doi.org/10.1080/17474124.2017.1282820
14. Chiou E, Nurko S. Management of functional abdominal pain and irritable bowel syndrome in
children and adolescents. Expert Rev Gastroenterol Hepatol [Internet]. 2010;4(3):293–304.
Available in:https://doi.org/10.1586/egh.10.28
15. Koppen
IJN,
Saps
M,
Lavigne
JV,
Nurko
S,
Taminiau JAJM, Di Lorenzo C, et al.
Recommendations for pharmacological clinical trials in children with functional constipation:
The Rome foundation pediatric subcommittee on clinical trials. Neurogastroenterol Motil. Jan
2018;30(4):e13294.
16. Benninga MA, Faure C, Hyman PE, St James Roberts I, Schechter NL, Nurko S. Childhood
Functional Gastrointestinal Disorders: Neonate/Toddler. Gastroenterology. February 2016;
17. Blesa-Baviera L. Pediatric functional digestive disorders. Rome IV Criteria. In: Pediatrics
Update Course 2017. Madrid: Lúa Ediciones; 2017. p. 99–114.
18. Devanarayana NM, Rajindrajith S. Irritable bowel syndrome in children: Current knowledge,
challenges and opportunities. World J Gastroenterol. 2018 Jun;24(21):2211–35.
19. van Tilburg MAL, Hyman PE, Walker L, Rouster A, Palsson OS, Kim SM, et al. Prevalence of
functional gastrointestinal disorders in infants and toddlers. J Pediatr. 2014 Dec;166(3):684–9.
20. Chumpitazi BP, Weidler EM, Lu DY, Tsai CM, Shulman RJ. Self-Perceived Food Intolerances
Are Common and Associated with Clinical Severity in Childhood Irritable Bowel Syndrome. J
Acad Nutr Diet. Jun 2016;116(9):1458–64.
21. Van Oudenhove L, Levy RL, Crowell MD, Drossman DA, Halpert AD, Keefer L, et al.
Biopsychosocial
Aspects
of
Functional
Gastrointestinal
Disorders:
How
Central
and
Environmental Processes Contribute to the Development and Expression of Functional
Gastrointestinal Disorders. Gastroenterology [Internet]. 2016;150(6):1355-1367.e2. Available
in:https://www.sciencedirect.com/science/article/pii/S0016508516002183
30

22. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces
symptoms of irritable bowel syndrome. Gastroenterology. 2013 Sep;146(1):67–75.e5.
23. Newlove-Delgado TV, Martin AE, Abbott RA, Bethel A, Thompson-Coon J, Whear Rebecca
and Logan S. Dietary interventions for recurrent abdominal pain in childhood. Cochrane
Database Syst Rev. March 2017;3(3):CD010972.
24. Ford AC, Quigley EMM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, et al. Efficacy of prebiotics,
probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation:
systematic review and meta-analysis. Am J Gastroenterol. 2014 Jul;109(10):1562, 1547–61;
maybe 1546.
25. Chumpitazi BP, Cope JL, Hollister EB, Tsai CM, McMeans AR, Luna RA, et al. Randomized
clinical trial: gut microbiome biomarkers are associated with clinical response to a low
FODMAP diet in children with the irritable bowel syndrome. Aliment Pharmacol Ther [Internet].
2015;42(4):418–27. Available in:https://onlinelibrary.wiley.com/doi/abs/10.1111/apt.13286
26. Rutten JMTM, Reitsma JB, Vlieger AM, Benninga MA. Gut-directed hypnotherapy for functional
abdominal pain or irritable bowel syndrome in children: a systematic review. Arch Dis Child.
2012 Dec;98(4):252–7.
27. Palsson OS, Whitehead WE. Psychological treatments in functional gastrointestinal disorders:
a primer for the gastroenterologist. Clin Gastroenterol Hepatol. 2012 Oct;11(3):208–16; quiz
e22–3.
28. Brunton LL, Knollman BC. Goodman & Gilman: The pharmacological bases of therapeutics
[Internet]. 13th ed. Vol. 1, Goodman & Gilman: The pharmacological bases of therapeutics,
14e.
New
York,
NY:
McGraw-Hill
Education;
2022.
Available
at:
accessmedicina.mhmedical.com/content.aspx?aid=1192578587
29. Costa VA, Ovalle Hernández AF. Role of antispasmodics in the management of irritable bowel
syndrome.
Rev
Colomb
Gastroenterol
[Internet].
2019
Oct
7;34(3):269–76.
Available
in:https://revistagastrocol.com/index.php/rcg/article/view/309
30. Nijevitch AA, Akhmadeeva EN, Sataev VU, Idrisov B. Efficacy of Trimebutine Maleate in the
Treatment
of
Functional
Dyspepsia
in
Childhood.
Journal
of Nepal Pediatric Society.
2013;33(2):158–62.
31. Kountouras J, Gavalas E, Papaefthymiou A, Tsechelidis I, Polyzos SA, Bor S, et al.
Trimebutine Maleate Monotherapy for Functional Dyspepsia: A Multicenter, Randomized,
Double-Blind Placebo Controlled Prospective Trial. Medicine (B Aires) [Internet]. 2020;56(7).
Available in:https://www.mdpi.com/1648-9144/56/7/339
31

32. Vandenplas Y, Hauser B, Salvatore S. Functional Gastrointestinal Disorders in Infancy: Impact
on
the
Health
of
the
Infant
and
Family.
Pediatr
Gastroenterol
Hepatol
Nutr.
2019
Apr;22(3):207–16.
33. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. The International Scientific
Association for Probiotics and Prebiotics consensus statement on the scope and appropriate
use of the term probiotic. Nat Rev Gastroenterol Hepatol [Internet]. 2014;11(8):506–14.
Available in:https://doi.org/10.1038/nrgastro.2014.66
34. Dryl R, Szajewska H. Probiotics for management of infantile colic: a systematic review of
randomized controlled trials. Arch Med Sci. Feb 2017;14(5):1137–43.
35. Francavilla R, Miniello V, Magistà AM, De Canio A, Bucci N, Gagliardi F, et al. A randomized
controlled trial of Lactobacillus GG in children with functional abdominal pain. Pediatrics. 2010
Nov;126(6):e1445–52.
36. Cristofori, F., Dargenio, VN, Dargenio, C., Miniello, VL, Barone, M., & Francavilla, R. (2021).
Anti-Inflammatory and Immunomodulatory Effects of Probiotics in Gut Inflammation: A Door to
the Body. Frontiers in Immunology, 12.https://doi.org/10.3389/fimmu.2021.578386
37. Romano C, Ferrau' V, Cavataio F, Iacono G, Spina M, Lionetti E, et al. Lactobacillus reuteri in
children
with
functional
abdominal
pain
(FAP).
J
Paediatr
Child
Health
[Internet].
2014;50(10):E68–71.
Available
in:https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1754.2010.01797.x
38. Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, O'Mahony L, et al. Efficacy of an
encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome.
Am J Gastroenterol. 2006 Jul;101(7):1581–90.
39. Rodríguez VM V, O VAM, Hernández JR, G FH, R AN. Sampling and sample size: a practical
guide for health personnel conducting research [Internet]. El Cid Editor; 2003. Available
in:https://books.google.com.mx/books?id=3H3RMgEACAAJ
40. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated
guidelines for reporting parallel group randomized trials. BMJ. 2010;340:c869. Published 2010
Mar 23.https://doi.org/10.1136/bmj.c869
32

ANNEXES
Annex 1. Informed consent.
LETTER OF INFORMED CONSENT
Research
project
name:EFFECT
OF
TRIMEBUTINE
VS
PROBIOTICS
ON
FUNCTIONAL
ABDOMINAL PAIN IN CHILDREN: RANDOMIZED CLINICAL TRIAL
Dear parents:
The main objective of this work is to include all children who come for consultation due to recurrent
abdominal pain. If you decide to have your child participate in this research, the staff will:
a) Carry out a general evaluation of your health status.
b) Provide pediatric consultation and provide the appropriate medication if applicable.
c)
Take necessary data from the patient for research purposes.
d) Monitor the patient and the effect of the administered medications.
This work consists of evaluating the effectiveness of medications used for Functional Abdominal Pain
Disorders in the pediatric population, such as pharmacological therapies such as antispasmodics
(trimebutine) or probiotics, using a group of patients with placebo, so you should know that Your child
may be given any of these medications, but it will have no impact on their health or well-being.
If your child participates, the highly trained doctors who are consulting you will ask you some
questions to know your child's health history and will prescribe one of the medications, which must be
administered in the dose, frequency and duration indicated until your subsequent appointment, to
re-evaluate your child on the signs and symptoms they have presented during treatment and observe
if there has been improvement.
All the information you provide about your child's health will be confidential and if you wish, you may
withdraw your child from this study at any time you decide, without this affecting the care that is always
provided. has been provided by health services. Medical treatment will be provided by the treating
doctor, and in case of damages that warrant it, directly caused by the research and if there are
additional expenses, these will be absorbed by the research budget. HOWEVER, WE CANNOT
PROMISE
THAT
YOU.
YOU
WILL RECEIVE SOME ADDITIONAL BENEFIT FROM YOUR
PARTICIPATION IN THIS STUDY.
Children as human beings have rights. By participating in this work, you as a tutor must make use of,
among others, the following rights:
1.
Be informed of the nature and purpose of this work.
2.
Receive a detailed explanation of the procedures that will be performed on your child and any
medications used.
3.
Receive a description of any reasonable inconvenience or risk that may arise.
4.
Receive an explanation of any reasonable benefit that could benefit you.
33

5.
Receive information about any alternative measures, as well as medications or other types of
treatments that could be useful for the minor, as well as the relative benefits and risks they
entail.
6.
Be informed of the treatment options if they are available, if complications occur.
7.
That you have the opportunity to ask any questions regarding the work or the procedures
involved.
8.
Be instructed that acceptance in this research can be withdrawn at any time and without
detriment or harm to the minor.
9.
Be given a copy of this consent, signed and dated.
10. That you have the opportunity to decide about your acceptance or refusal to participate in this
work, without the intervention of any force, fraud, lies, pressure, coercion or undue influence on
your decision.
Your signature indicates that you have read and understood the content of this letter, that you have
asked the questions you considered appropriate and they have been answered appropriately, that you
agree for your child to participate, based on the information received and that you have been given a
copy of this consent
Patient's full name
Name of parent or guardian
Signature of parent or guardian
Current date
Witness name 1
Witness name 2
Witness address 1
Witness address 2
Page 2 of 2
34

QPGS-IV 2020
Annex 2. Questionnaire for pediatric digestive symptoms, format for parents.
QUESTIONNAIRE FOR PEDIATRIC DIGESTIVE
SYMPTOMS, ROME VERSION IV (QPGS-RIV)
(Adapted from the Pediatric Digestive Symptoms Questionnaire,
Walker, Caplan-Dover and Rasquin-Weber, 2000)
FORM FOR PARENTS AND
REPRESENTATIVES (CHILDREN
BETWEEN 4 AND 10 YEARS OF AGE)
Your child's full name
Name of parent or guardian
Date
Signature of parent or guardian
INSTRUCTIONS:
This questionnaire is about the digestive system (esophagus, stomach, small intestine and colon) and
problems that your child may have with them. Some problems may exist in your child and others may not.
Please answer all questions to the best of your ability.
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
35

QPGS-IV 2020
If you have any questions, the research staff will be happy to answer them.
Section A.
Pain and discomfort above the navel
The shaded area in the drawing below shows the area above from the navel were some children may feel
pain or discomfort. Some terms used to describe the discomfort are: “belly pain”, “nausea”, “bloated belly”,
“full belly” or “not being hungry after eating a small amount”.
The questions in this section are about pain or discomfort above the belly button that your child has had in
the past month. Children may have pain and discomfort in more than one area of ​the tummy. In other
sections of the questionnaire, we will ask about the areas around or below the belly button.
A1. In the past month, how many days has your child felt pain or discomfort above the navel? (although it
didn't last long)
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
A2. In the past month, how many days has your child felt burning or burning above the navel? (although it
didn't last long)
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
A3. In the past month, on how many days has your child felt nauseous or bothered by feeling very full after a
normal meal?
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
36

QPGS-IV 2020
A4. In the past month, how many days was his child not able to finish his meal because he felt too full?
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
If you answered NEVER to questions 1, 2, 3 and 4, please go to Section B (page 5)
TO 5. When your child feels discomfort or discomfort above the navel (pain, discomfort, burning, fullness,
etc.), have they had any of the following discomforts? (You can choose more than one option):
A5a. Stomach more swollen than usual
___ No Yes
A5b. Nausea (feeling like vomiting)
___ No Yes
A5c. Belching
___ No Yes
A6. When your child feels discomfort or discomfort above the navel:
A6a. Does it get worse when eating?
___ No Yes
A6b. Does it improve when eating?
___ No Yes
A7. How long has your child had discomfort or discomfort above the navel (pain, soreness, burning, fullness,
etc.)?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
A8. In the past month, when your child had pain or discomfort above the belly button, how often did she have
it at the same time as pooping?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
A9. In the past month, when your child had pain or discomfort above the belly button, how often was his or
her poop softer or more liquid than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
A10. In the past month, when your child had pain or discomfort above the belly button, how often was his or
her poop harder or in chunks than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
37

QPGS-IV 2020
A11. In the past month, when your child had pain or discomfort above the belly button, how often did she
poop more times than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
A12. In the past month, when your child had pain or discomfort above the belly button, how often did she
poop fewer times than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
38

QPGS-IV 2020
Section b.
Pain and discomfort in the belly button, around the belly button, or below the belly
button
The shaded area in the drawing below shows the navel area,around the navel and below the navel were
some children may feel pain or discomfort. Sometimes this discomfort is less intense than real pain. Some
terms used are: “stomach pain” or “belly pain”.
B1. In the past month, on how many days did your child feel pain or discomfort in the belly button, around the
belly button, or below the belly button?
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
If you answered NEVER, please go to Section C (page 8)
B2a. Does your child feel pain or discomfort in the navel, around the navel, or below the navel only
when he eats or after eating?
●
No
●
Yeah
B2b. For Girls Only: Do you feel pain or discomfort in your belly button, around your belly button, or
below your belly button only when you have your period?
●
No
●
Yeah
●
Her first menstruation has not yet arrived
B3. How long has your child had pain or discomfort in the belly button, around the belly button, or below the
belly button?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
B4. In the past month, when your child had pain or discomfort in the belly button, around the belly button, or
below the belly button, how often did she have it at the same time as pooping?
●
Never
●
From time to time
●
Sometimes
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
39

QPGS-IV 2020
●
Most of the time
●
Always
B5. In the past month, when your child had pain or discomfort in the belly button, around the belly button, or
below the belly button, how often was his or her poop softer or more liquid than normal?
​
Never
​
From time to time
​
Sometimes
​
Most of the time
​
Always
B6. In the past month, when your child had pain or discomfort in the belly button, around the belly button, or
below the belly button, how often was his or her poop harder or in chunks than normal?
​
Never
​
From time to time
​
Sometimes
​
Most of the time
​
Always
B7. In the past month, when your child had pain or discomfort in the belly button, around the belly button, or
below the belly button, how often did she poop more times than usual?
​
Never
​
From time to time
​
Sometimes
​
Most of the time
​
Always
B8. In the past month, when your child had pain or discomfort in the belly button, around the belly button, or
below the belly button, how often did your child poop less than usual?
​
Never
​
From time to time
​
Sometimes
​
Most of the time
​
Always
B9. Is your child taking medication for constipation or hard poop?
●
No
●
Yeah
●
I don't know
B9a. If yes, how often does your pain or discomfort in your belly button, around your belly button, or
below your belly button get better when you take the medications?
​
Never
​
From time to time
​
Sometimes
​
Most of the time
​
Always
B10. Has your child ever had to stop doing the activities she was doing due to very intense abdominal pain
around the navel?
●
No (if this is your answer, please go to Section C, page 8)
●
Yeah
B10a. How long do these episodes of severe abdominal pain last?
●
less than 1 hour
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
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QPGS-IV 2020
●
1-2 hours
●
3-4 hours
●
Most of the day
●
All day
B10b. In the last 6 months: How often did your child have these episodes of severe abdominal pain?
●
1 time
●
2 times
●
3 to 5 times
●
6 or more times
B10c. During that episode of severe abdominal pain, did your child have any of the following?
1. Lack of appetite
___ No Yes
2. Nausea (feeling like vomiting)
___ No Yes
3. Vomiting
___ No Yes
4. Paleness
___ No Yes
5. Headache
___ No Yes
6. Annoyance with light
___ No Yes
B10d. When severe pain around the belly button is relieved, how long does it take before the severe
abdominal pain returns?
●
several minutes
●
Several hours
●
Several days
●
Several weeks
●
Several months
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
41

QPGS-IV 2020
Section C.
Bowel movements (“poop”, “poop”, “doing 2”)
In this section we will ask about bowel movements. There are many words to define bowel movements:
“poop”, “poop”, “doing 2”. Your family can use other words to talk about poop.
C1. In the past month, how often has your child pooped?
●
2 times a week or less
●
3 to 6 times a week
●
Once a day
●
2 to 3 times a day
●
More than 3 times a day
C2. Look at the scale above and answer: what was your child's poop like last month?
●
Type 1
●
Type 2
●
Type 3
●
Type 4
●
Type 5
●
Type 6
●
Type 7
●
Variable: not always the same
C2a. If, according to the scale on the previous page, your child's poop is type 1 or type 2, how long
has he/she been type 1 or type 2?
●
Less than a month
●
1 month
●
2 or more months
●
Their poop is usually not hard.
C3. Last month, did it hurt your child's poop?
___ No Yes
C4. In the past month, has your child pooped so big that it clogged the toilet? ___ No Yes
Copyright 2016. The Rome Foundation. All Rights Reserved.
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QPGS-IV 2020
C5. Some people poop despite having a bathroom available. They do this by tensing their bodies or crossing
their legs. In the past month, while at home, how often has your child tried to hold in poop?
●
Never
●
1 to 3 times a month
●
Once a week
●
Several times a week
●
Every day
C6. Has a doctor or nurse when examining your child told you that she has a lot of poop inside?
●
No
●
Yeah
C7. In the past month, how often has your child got poop on his/her underwear?
●
Never (if you answered never, please go to Section D)
●
Less than once a month
●
1 to 3 times a month
●
Once a week
●
Many times a week
●
Every day
C7a. When her son/daughter stained her underwear, how badly did she stain it?
●
With pints of poop (not with poop)
●
With a small amount of poop (less than a poop)
●
With a lot of poop (a complete poop)
C7b. How long has your child stained their underwear?
●
less than 1 month
●
1 month
●
2 months
●
3 to 11 months
●
One year or more
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
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QPGS-IV 2020
Section D.
Nausea and vomiting
This section asks about the symptoms of nausea or vomiting. Nausea is when your child feels sick to their
stomach or feels like they are going to “take food back.” There are many words for nausea, such as “upset
stomach,” “feeling dizzy,” or “being sick to your stomach.” Your family may use a special word when you talk
about nausea.
D1. In the past 2 months, how often did your child have nausea or vomiting?
●
Never (if you answered never, please go to question 5)
●
1 to 3 times a month.
●
Once a week
●
2 times a week
●
More than 2 times a week, but not every day.
●
Every day
D2. How long has your child felt nauseated or wanted to vomit?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
D3. Does nausea start after eating?
___ No Yes
D4. When your child has nausea, he or she has:
1. Vomiting
___ No Yes
2. Belly pain
___ No Yes
4a. If your child has nausea and belly pain at the same time, which one bothers you more?
●
Nausea
●
Stomachache
The next questions are about vomiting.Vomiting is when food returns to your mouth from your stomach
and comes out through your mouth. There may be other ways to call vomiting and your family may call it
differently.
D5. In the past month, how often did your child vomit?
●
Never (if you answered never, please go to question 8)
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
D6. How long has your child been vomiting?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
D7. Does your child ever force himself to vomit (for example, by sticking a finger down his throat)?
●
Never
●
From time to time
●
Sometimes
Copyright 2016. The Rome Foundation. All Rights Reserved.
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QPGS-IV 2020
●
Many times
●
Always
D8. In the last 6 months: How many times did your child vomit continuously (“non-stop”) for 2 or more hours?
●
Never (if you answered never, please go to question 8)
●
Once
●
2 times
●
3 times
●
4 or more times
D8a. How long has your child had these episodes of frequent vomiting (“that doesn't stop”)?
●
A month or less
●
2 - 3 months
●
4 - 5 months
●
6 or more months
D8b. When your child vomits often (“it doesn't stop”), does she feel nauseous, feel sick to her
stomach, or feel like vomiting?
●
No
●
Yeah
D8c. When that episode of continuous vomiting stops, how long does it take before this continuous
vomiting (“that doesn't stop”) is repeated?
●
several minutes
●
Several days
●
Several weeks
●
Several months
D9. In the past month, how often did your child put food back in his/her mouth after eating?
●
Never (if you answered never, please continue to Section E)
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
D9a. If food comes back into your mouth, does it happen within the first hour after eating?
___ No Yes
D9b. Does food return to your mouth when you are sleeping?
___ No Yes
D9c. Do you usually feel nauseous or vomit when you put food back in your child's mouth?
___ No Yes
D9d. What does your child usually do when food is returned to his or her mouth?
___ Swallows it ___ Spits it out
Section E.
Other symptoms
E1. In the last 2 months, without trying on purpose, how often has your child burped over and over again?
●
Never
●
1 to 3 times a month
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QPGS-IV 2020
●
Once a week
●
Many times per week
●
Every day
E2. In the last 2 months, how often did your child fart a lot?
●
Never
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
E3. In the past 2 months, how often did your child have a larger than normal belly during the day?
●
Never
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
E4. In the past 2 months, how often has your child swallowed more air than normal? (You may or may not
hear noise when swallowing.)
●
Never
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
Thank you so much!
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
46

QPGS-IV 2020
Annex 3. Questionnaire for pediatric digestive symptoms, self-report.
QUESTIONNAIRE FOR PEDIATRIC DIGESTIVE
SYMPTOMS, ROME VERSION IV (QPGS-RIV)
(Adapted from the Pediatric Digestive Symptoms Questionnaire,
Walker, Caplan-Dover and Rasquin-Weber, 2000)
FORMAT FOR CHILDREN AND
TEENAGERS (10 YEARS OF AGE
AND OLDER)
Your full name
Name of parent or guardian
Date
Signature of parent or guardian
INSTRUCTIONS:
This questionnaire is about your digestive system (esophagus, stomach, small intestine and colon) and
problems you may have with it. You may have some problems and not others.
Please answer all questions to the best of your ability.
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
47

QPGS-IV 2020
If you have any questions, the research staff will be happy to answer you.
Section A.
Pain and discomfort above the navel
The shaded area in the drawing below shows the area above the belly button where some children may feel
pain or discomfort. Some terms used to describe the discomfort are: “tummy pain”, “tummy pain”, “nausea”,
“swollen belly”, “full belly” or “not being hungry after eating a small amount”.
The questions in this section are about pain and discomfort above the navel that you have had in the past
month. Children may have pain and discomfort in more than one area of ​the belly. In other sections of the
questionnaire, we will ask you about the areas around or below the belly button.
A1. In the past month, how many days have you felt pain or discomfort above your belly button? (although it
didn't last long).
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
A2. In the past month, how many days have you felt burning or burning above your navel? (although it didn't
last long).
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
A3. In the past month, after a normal meal, how many days have you felt very full or nauseous or with your
belly more swollen than usual?
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
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QPGS-IV 2020
A4. In the past month, how many days were you not able to finish your meal because you felt too full?
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
If you answered NEVER to questions 1, 2, 3 or 4, please go to Section B (page 5)
TO 5. When you feel discomfort or discomfort above the navel (pain, discomfort, burning, fullness, etc.), have
you had any of the following discomforts? (You can choose more than one opcion):
to. Belly more inflated than usual
___ No Yes
b. Nausea (feeling like vomiting)
___ No Yes
c. Belching
___ No Yes
A6. When you feel discomfort or discomfort above the navel:
to. Does it get worse when eating?
___ No Yes
b. Does it improve when eating?
___ No Yes
A7. How long have you had discomfort or discomfort above your belly button (pain, soreness, burning,
fullness, etc.)?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
A8. In the past month, when you had pain or discomfort above your belly button, how often did you have it at
the same time as pooping?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
A9. In the past month, when you had pain or discomfort above your belly button, how often was your poop
softer or more liquid than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
A10. In the past month, when you had pain or discomfort above your belly button, how often was your poop
harder or in chunks than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
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Updated Oct 21
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QPGS-IV 2020
A11. In the past month, when you had pain or discomfort above your belly button, how often did you poop
more times than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
A12. In the past month, when you had pain or discomfort above your belly button, how often did you poop
fewer times than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
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QPGS-IV 2020
Section b.
Pain and discomfort in the belly button, around the belly button, or below the belly
button
The shaded area in the drawing below shows the area of ​the belly button, around the belly button, and below
the belly button where some people may feel pain or discomfort. Sometimes this discomfort is less intense
than real pain. Some terms used are: “stomach pain” or “belly pain”.
B1. In the past month, on how many days did you feel pain or discomfort in your belly button, around your
belly button, or below your belly button?
●
Never
●
1 day
●
2 days
●
3 days
●
4 days
●
5 or more days
If you answered NEVER, please go to Section C (page 8)
B2a. Do you feel pain or discomfort in your belly button, around your belly button, or below your belly
button only when you eat or after eating?
●
No
●
Yeah
B2b. For Girls Only: Do you feel pain or discomfort in your belly button, around your belly button, or
below your belly button only when you have your period?
●
No
●
Yeah
●
I haven't gotten my first period yet.
B3. How long have you had pain or discomfort in your belly button, around your belly button, or below your
belly button?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
B4. In the past month, when you had pain or discomfort in your belly button, around your belly button, or
below your belly button, how often did you have it at the same time as pooping?
●
Never
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QPGS-IV 2020
●
From time to time
●
Sometimes
●
Most of the time
●
Always
B5. In the past month, when you had pain or discomfort in your belly button, around your belly button, or
below your belly button, how often was your poop softer or more liquid than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
B6. In the past month, when you had pain or discomfort in your belly button, around your belly button, or
below your belly button, how often was your poop harder or in chunks than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
B7. In the past month, when you had pain or discomfort in your belly button, around your belly button, or
below your belly button, how often did you poop more times than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
B8. In the past month, when you had pain or discomfort in your belly button, around your belly button, or
below your belly button, how often did you poop less than usual?
●
Never
●
From time to time
●
Sometimes
●
Most of the time
●
Always
B9. Are you taking medication for constipation or hard poop?
●
No
●
Yeah
●
I don't know
B9a. If yes, how often does your pain or discomfort in your belly button, around your belly button, or
below your belly button get better when you take the medications?
​
Never
​
From time to time
​
Sometimes
​
Most of the time
​
Always
B10. Have you ever, due to severe abdominal pain around the navel, had to stop doing the activities you
were doing?
●
No (if this is your answer, please go to Section C, page 8)
●
Yeah
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QPGS-IV 2020
B10a. How long does this intense abdominal pain last because you stopped the activities you were
doing?
●
less than 1 hour
●
1-2 hours
●
3-4 hours
●
Most of the day
●
All day
B10b. In the last 6 months: How often does that intense abdominal pain occur due to which you
stopped the activities you were doing?
●
1 time
●
2 times
●
3 to 5 times
●
6 or more times
B10c. During that episode of severe abdominal pain, did you have any of the following?
1. Lack of appetite
___ No Yes
2. Nausea (feeling like vomiting)
___ No Yes
3. Vomiting
___ No Yes
4. Paleness
___ No Yes
5. Headache
___ No Yes
6. Annoyance with light
___ No Yes
B10d. When the severe pain around the belly button passes, how long does it take before that
severe abdominal pain recurs?
●
several minutes
●
Several hours
●
Several days
●
Several weeks
●
Several months
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Updated Oct 21
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QPGS-IV 2020
Section C.
Bowel movements (“poop”, “poop”, “doing 2”)
In this section we will ask about bowel movements. There are many words to define bowel movements:
“poop”, “poop”, “doing 2”. Your family can use other words to talk about poop.
C1. In the past month, how often have you pooped?
●
2 times a week or less
●
3 to 6 times a week
●
Once a day
●
2 to 3 times a day
●
More than 3 times a day
C2. Look at the scale above and answer: What was your poop like in the last month?
●
Type 1
●
Type 2
●
Type 3
●
Type 4
●
Type 5
●
Type 6
●
Type 7
●
Variable: not always the same
C2a. If according to the scale on the previous page, your poop is type 1 or type 2, how long has it
been type 1 or type 2?
●
Less than a month
●
1 month
●
2 or more months
●
My poop is usually not hard.
C3. Last month, did it hurt when you pooped?
___ No Yes
C4. In the past month, have you had poop so big that it clogged the toilet? ___ No Yes
C5. Some children hold in poop despite having a bathroom available. They do this by tensing up or crossing
their legs. In the past month, while at home, how often did you try to hold back pooping?
●
Never
●
1 to 3 times a month
Copyright 2016. The Rome Foundation. All Rights Reserved.
Updated Oct 21
54

QPGS-IV 2020
●
Once a week
●
Several times a week
●
Every day
C6. Has a doctor or nurse examined you and said that you have a lot of poop inside?
●
No
●
Yeah
C7. In the past month, how often have you gotten poop on your underwear?
●
Never (if you answered NEVER, please go to Section D, page 10)
●
Less than once a month
●
1 to 3 times a month
●
Once a week
●
Many times a week
●
Every day
C7a. When you have stained your underwear, how much have you stained it?
●
With pints of poop (not with poop)
●
With a small amount of poop (less than a poop)
●
With a lot of poop (a complete poop)
C7b. How long have you been staining your underwear?
●
less than 1 month
●
1 month
●
2 months
●
3 to 11 months
●
One year or more
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Updated Oct 21
55

QPGS-IV 2020
Section D.
Nausea and vomiting
The next questions are about nausea.Nausea is that feeling of wanting to vomit. There are several ways to
refer to “nausea,” such as feeling sick to your stomach, feeling dizzy, and having a stomach ache. Your
family may use other words for nausea.
D1. In the past two months, how often did you feel nauseated or feel like vomiting?
●
Never (if you answered NEVER, please continue to question D5)
●
Less than once a month
●
1 to 3 times a month
●
Once a week
●
Many times a week
●
Every day
D2. Since when do you feel nauseated or feel like vomiting?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
D3. Does nausea start after eating?
___ No Yes
D4. When you have nausea, you have:
1. Vomiting
___ No Yes
2. Belly pain
___ No Yes
D4a. If you have nausea and belly pain at the same time, which one bothers you more?
●
Nausea
●
Stomachache
The next questions are about vomiting.Vomiting is when food returns to your mouth from your stomach
and comes out through your mouth. There may be other ways to call vomiting and your family may call it
differently.
D5. In the past month, how often did you vomit?
●
Never (if you answered NEVER, please continue to question D8)
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
D6. Since when have you been vomiting?
●
A month or less
●
2 months
●
3 months
●
4 to 11 months
●
One year or more
D7. Do you ever force yourself to vomit (for example, by putting your fingers in your mouth to make yourself
vomit)?
●
Never
●
From time to time
●
Sometimes
●
Many times
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56

QPGS-IV 2020
●
Always
D8. In the last 6 months: How many times did you have continuous vomiting (“that doesn't stop”) for 2 or
more hours?
●
Never (if you answered NEVER, please go to question D9)
●
Once
●
2 times
●
3 times
●
4 or more times
D8a. How long have you been having these episodes of frequent vomiting (“that doesn't stop”)?
●
A month or less
●
2 - 3 months
●
4 - 5 months
●
6 or more months
D8b. When you vomit frequently (“that doesn't stop”), do you feel nauseated or feel like vomiting?
●
No
●
Yeah
D8c. When that episode of vomiting stops, how long does it take before it happens again?
●
several minutes
●
Several days
●
Several weeks
●
Several months
D9. In the past month, how often did food return to your mouth after eating?
●
Never (if you answered NEVER, please continue to Section E, page 12)
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
D9a. If food comes back into your mouth, does this usually happen within the first hour after eating?
___ No Yes
D9b. Does food return to your mouth when you are sleeping?
___ No Yes
D9c. Do you usually feel nauseous or vomit when food is returned to your mouth?
___ No Yes
D9d. What do you usually do when food is returned to your mouth?
___ You swallow it ___ You spit it out
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Updated Oct 21
57

QPGS-IV 2020
Section E.
Other symptoms
E1. In the past two months, how often did you accidentally burp over and over again?
●
Never
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
2. In the past two months, how often did you fart a lot?
●
Never
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
3. In the past two months, how often did your belly feel more swollen than usual during the day?
●
Never
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
4. In the past two months, how often did you swallow more air than usual? (you may or may not hear noise
when swallowing)
●
Never
●
1 to 3 times a month
●
Once a week
●
Many times per week
●
Every day
Thank you so much!
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Updated Oct 21
58

PedsQL
Annex
4.
Scoring
instructions
for the Questionnaire for Pediatric Digestive
Symptoms, Rome Version IV (QPGS-RIV).
H2. Abdominal pain disorders
H2a. Abdominal dyspepsia:Functional dyspepsia is diagnosed if the child qualifies for postprandial distress
syndrome or epigastric pain syndrome or both.
H2a1. Postprandial distress syndrome
●
(A3) Fullness "4 days a month" or more often, OR
●
(A4) Satiety "4 days a month" or “more often”, AND
●
(A7) The duration of pain or discomfort in the upper abdomen is "2 months" or more.
H2a2. Epigastric pain syndrome
●
(A1) upper abdominal pain “4 days a month” or “more often,” OR
●
(A2) heartburn "4 days a month" or “more often”, AND
●
(A7) The duration of pain or discomfort in the upper abdomen is "2 months" or more, AND
●
(A8) Not related to a bowel movement: "Never" or "Once in a while", AND
●
(A9-12) Not associated with changes in stool form or frequency: "Never or "Occasionally"
H2b. Irritable bowel syndrome
●
(B1 or A1) Abdominal pain "4 days a month” or more frequently, AND
●
(B3 or A7) Abdominal pain lasts "2 months" or longer, AND
●
(B2a) Not exclusively associated with eating ("No"), AND
●
(B2b) For girls, not exclusively associated with menstruation ("No" or "Not applicable"), AND
●
[At least one (A8-A12) or (B4-B8) intestinal symptoms "Sometimes" or more frequently], AND
●
(B9) For those who use laxatives (B9 is “Yes”), the question (B9a) Elimination of symptoms with laxatives
should be answered “Never”, “Once in a while” or “Sometimes” (i.e. NO answered “The most of the time" or
"Always").
H2c. abdominal migraine
●
(B10) Severe pain causing restriction in daily activities ("Yes"), AND
●
(B10a) The pain lasts 1 hour or more, AND
●
(B10b) In the last 6 months, 2 or more episodes of severe pain, AND
●
(B10c) Two or more of the following during pain episodes:
●
No appetite, Ó
●
Nausea, OR
●
Vomiting, OR
●
Pale skin, Ó
●
Headache, OR
●
Light sensitive eyes
●
(B10d) Pain episodes are separated by several weeks or more.
H2d. Abdominal pain not otherwise specified (FAD-NEOM)
●
Lower abdominal location
●
(B1 or A1) Abdominal pain "4 days a month" or “more often”, AND
●
(B3 OR A7) Abdominal pain lasts "2 months" or longer, AND
●
(B2a) The pain is not exclusively associated with eating ("No"), AND
●
(B2b) In girls, pain is not exclusively associated with menstruation ("No" or "Not applicable"), AND
●
Does not meet criteria for other functional gastrointestinal disorders associated with abdominal pain (e.g.,
functional dyspepsia, IBS, abdominal migraine).
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59

PedsQL
Annex 5. PedsQL 3.0 - Gastrointestinal Symptoms Module. Report from parents of
young children
Name:___________________________________
Date:_____ / _____ / ________
PedsQLTM
Gastrointestinal Symptoms Module
Version 3.0
REPORT FROM PARENTS OF YOUNG CHILDREN (ages 5-7)
INSTRUCTIONS
On the next page is a list of things that could be a problem for your child.
Please tell us, by circling each answer, how much of a problem each thing has been for
your child in the last month:
0If it's never a problem
1Yes it is almost never a problem
2Yes sometimes it is a problem
3Yes it is often a problem
4Yes it is almost always a problem
There are not correct or incorrect answers.
If you do not understand any question, please ask for help.
In the last month, how much of a problem has this been for your child…?
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PedsQL
STOMACH PAIN (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You feel pain in your stomach
0
1
2
3
4
2. They give you stomach pains
0
1
2
3
4
3. Your stomach hurts
0
1
2
3
4
4. You wake up at night with stomach pain
0
1
2
3
4
5. Your stomach turns
0
1
2
3
4
6. You have an upset stomach
0
1
2
3
4
STOMACH DISCOMFORT WHEN EATING
(problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. When you eat, your stomach turns
0
1
2
3
4
2. When you eat, you feel sick to your stomach
0
1
2
3
4
3. Your stomach hurts when you eat
0
1
2
3
4
4. You feel a heavy stomach when you eat
0
1
2
3
4
5. As soon as you start eating, you feel full.
0
1
2
3
4
FOOD AND DRINK LIMITS (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You can't eat some foods
0
1
2
3
4
2. You can't drink some drinks
0
1
2
3
4
3. You can't eat what you want
0
1
2
3
4
4. You can't drink what you want
0
1
2
3
4
5. You can't eat some foods because they upset
your stomach.
0
1
2
3
4
6. He can't eat the foods his friends eat
0
1
2
3
4
DIFFICULTY SWALLOWING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You find it difficult to swallow food
0
1
2
3
4
2. It hurts when you swallow
0
1
2
3
4
3. Food gets stuck as it passes by
0
1
2
3
4
ACIDITY AND REFLUX (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You feel a burning sensation in your throat
0
1
2
3
4
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PedsQL
2. You feel pain in your stomach
0
1
2
3
4
3. Food returns to your mouth after eating
0
1
2
3
4
NAUSEA AND VOMITING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You feel like vomiting
0
1
2
3
4
2. You feel like vomiting when you eat
0
1
2
3
4
3. You feel like vomiting after eating
0
1
2
3
4
4. Vomit
0
1
2
3
4
GASES AND SWELLING (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. Your stomach feels full of gas (farts)
0
1
2
3
4
2. Your stomach feels very full
0
1
2
3
4
3. Your stomach swells and becomes hard
0
1
2
3
4
4. It has a lot of gases
0
1
2
3
4
5. Expels a lot of gases
0
1
2
3
4
6. You feel like you have gas in your stomach
0
1
2
3
4
7. Your stomach makes noises
0
1
2
3
4
CONSTIPATION (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You still feel full after having pooped
0
1
2
3
4
2. You feel like you're not done after you've
pooped.
0
1
2
3
4
3. You feel like you can't get your stool to come
out completely.
0
1
2
3
4
4. It's painful when you poop
0
1
2
3
4
5. Your stools are hard
0
1
2
3
4
6. Your stool is lumpy or chunky
0
1
2
3
4
7. You have to use a lot of force to be able to
poop.
0
1
2
3
4
8. Poop gets stuck when you have a bowel
movement
0
1
2
3
4
9. Your butt hurts after you poop.
0
1
2
3
4
10. Poop takes a long time to come out
0
1
2
3
4
11. He has to work hard to get the poop out.
0
1
2
3
4
12. He doesn't want to poop because it hurts.
0
1
2
3
4
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PedsQL
13. Spends a lot of time on the toilet pooping
0
1
2
3
4
14. Your stomach hurts when you poop.
0
1
2
3
4
BLOOD IN Stool (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. There is blood on the toilet paper after he
poops.
0
1
2
3
4
2. There is blood in your stool
0
1
2
3
4
DIARRHEA (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You need to be near a bathroom very often
0
1
2
3
4
2. He has to run to the bathroom to poop
0
1
2
3
4
3. You feel like you're always in the bathroom
pooping.
0
1
2
3
4
4. He wakes up at night to poop
0
1
2
3
4
5. The stools are watery
0
1
2
3
4
6. He poops in his underwear accidentally.
0
1
2
3
4
7. You have to evacuate many times
0
1
2
3
4
CONCERN ABOUT POOPING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. He worries about pooping his pants.
0
1
2
3
4
2. You are worried about not making it to the
bathroom on time.
0
1
2
3
4
3. You worry about hurting yourself when you
poop.
0
1
2
3
4
4. You are worried about having to use the
bathroom at school
0
1
2
3
4
5. He worries about pooping his pants at school.
0
1
2
3
4
CONCERN ABOUT STOMACH PAIN
(problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. You are worried about your stomach pain
0
1
2
3
4
2. You are worried about getting a stomachache
at school.
0
1
2
3
4
MEDICINES (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. It is hard for him/her to take his/her
0
1
2
3
4
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PedsQL
medications
2. You forget to take your medicines
0
1
2
3
4
3. It is hard for him/her to swallow his/her
medicines
0
1
2
3
4
4. He doesn't like having to take his medicine all
the time.
0
1
2
3
4
COMMUNICATION (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. It is hard for him/her to tell doctors and nurses
how he/she feels
0
1
2
3
4
2. It is hard for him/her to ask doctors and nurses
some questions
0
1
2
3
4
3. It is hard for him/her to explain his/her illness to
other people.
0
1
2
3
4
4. It is hard for him/her to explain his/her illness to
his/her friends.
0
1
2
3
4
5. It is hard for him/her to talk about his/her
illness with his/her parents.
0
1
2
3
4
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PedsQL
Annex 6. PedsQL 3.0 - Gastrointestinal Symptoms Module. Children's report
Name:___________________________________
Date:_____ / _____ / ________
PedsQLTM
Gastrointestinal Symptoms Module
Version 3.0
CHILDREN REPORT (ages 8-12)
INSTRUCTIONS
On the next page is a list of things that could be a problem for you.
Please tell us, by circling or crossing out each answer, depending on how much trouble
each thing has caused you in the last month:
0If it's never a problem
1Yes it is almost never a problem
2Yes sometimes it is a problem
3Yes it is often a problem
4Yes it is almost always a problem
There are not correct or incorrect answers.
If you do not understand any question, please ask for help.
In the last month, how much of a problem has this been for you…?
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65

PedsQL
STOMACH PAIN (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I feel pain in my stomach
0
1
2
3
4
2. I feel sore in my stomach
0
1
2
3
4
3. My stomach hurts
0
1
2
3
4
4. I wake up at night with a stomach ache
0
1
2
3
4
5. My stomach turns
0
1
2
3
4
6. I have an upset stomach
0
1
2
3
4
STOMACH DISCOMFORT WHEN EATING
(problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. When I eat, my stomach turns
0
1
2
3
4
2. When I eat, I feel sick to my stomach
0
1
2
3
4
3. My stomach hurts when I eat
0
1
2
3
4
4. I feel heaviness in my stomach when I eat
0
1
2
3
4
5. As soon as I start eating, I feel full.
0
1
2
3
4
FOOD AND DRINK LIMITS (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I can't eat some foods
0
1
2
3
4
2. I can't have some drinks
0
1
2
3
4
3. I can't eat what I want
0
1
2
3
4
4. I can't drink what I want
0
1
2
3
4
5. I can't eat some foods because they upset my
stomach.
0
1
2
3
4
6. I can't eat the foods my friends eat
0
1
2
3
4
DIFFICULTY SWALLOWING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I find it difficult to swallow food
0
1
2
3
4
2. It hurts when I swallow
0
1
2
3
4
3. Food gets stuck when it passes by
0
1
2
3
4
ACIDITY AND REFLUX (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
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PedsQL
1. I feel burning in my throat
0
1
2
3
4
2. I have chest pain or discomfort
0
1
2
3
4
3. My food returns after eating
0
1
2
3
4
NAUSEA AND VOMITING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I feel like vomiting
0
1
2
3
4
2. I feel like vomiting when I eat
0
1
2
3
4
3. I feel like vomiting after eating
0
1
2
3
4
4. Vomiting
0
1
2
3
4
GASES AND SWELLING (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. My stomach feels full of gas
0
1
2
3
4
2. My stomach feels very full
0
1
2
3
4
3. My stomach swells and becomes hard
0
1
2
3
4
4. I have a lot of gas (belching)
0
1
2
3
4
5. I expel a lot of gas (farts)
0
1
2
3
4
6. I feel like I have gas in my stomach
0
1
2
3
4
7. My stomach makes noises
0
1
2
3
4
CONSTIPATION (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I still feel full after pooping
0
1
2
3
4
2. I feel like I'm not done after pooping.
0
1
2
3
4
3. I feel like I can't get the poop to come out
completely.
0
1
2
3
4
4. It hurts when I poop
0
1
2
3
4
5. My stools are hard
0
1
2
3
4
6. My stool is lumpy
0
1
2
3
4
7. I have to use a lot of force to poop.
0
1
2
3
4
8. My poop gets stuck
0
1
2
3
4
9. My butt hurts after pooping.
0
1
2
3
4
10. It takes a long time for the poop to come out
0
1
2
3
4
11. I have to try really hard to poop.
0
1
2
3
4
12. I don't want to poop because it hurts.
0
1
2
3
4
13. I spend a lot of time on the toilet pooping.
0
1
2
3
4
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PedsQL
14. My stomach hurts when I poop.
0
1
2
3
4
BLOOD IN Stool (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. There is blood on the toilet paper after I poop.
0
1
2
3
4
2. There is blood in my poop
0
1
2
3
4
DIARRHEA (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I need to be near a bathroom very often
0
1
2
3
4
2. I have to run to the bathroom to poop.
0
1
2
3
4
3. I feel like I'm always in the bathroom pooping.
0
1
2
3
4
4. I wake up at night to poop.
0
1
2
3
4
5. My stools are watery
0
1
2
3
4
6. I accidentally poop in my underwear.
0
1
2
3
4
7. I have to poop a lot
0
1
2
3
4
CONCERN ABOUT POOPING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I worry about pooping my pants.
0
1
2
3
4
2. I worry about not getting to the bathroom on
time.
0
1
2
3
4
3. I worry about hurting myself when I poop.
0
1
2
3
4
4. I worry about having to use the bathroom at
school
0
1
2
3
4
5. I worry about pooping my pants at school.
0
1
2
3
4
CONCERN ABOUT STOMACH PAIN
(problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I am worried about my stomach pain
0
1
2
3
4
2. I worry that my stomach will hurt at school.
0
1
2
3
4
MEDICINES (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. It is hard for me to take my medicines
0
1
2
3
4
2. I forget to take my medicines
0
1
2
3
4
3. It is hard for me to swallow my medicines
0
1
2
3
4
4. I don't like having to take my medicine all the
0
1
2
3
4
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68

PedsQL
time.
COMMUNICATION (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. It is hard for me to tell doctors and nurses how
I feel.
0
1
2
3
4
2. It is hard for me to ask doctors and nurses
some things.
0
1
2
3
4
3. It is hard to explain my illness to other people
0
1
2
3
4
4. It is hard to explain my illness to my friends
0
1
2
3
4
5. It is hard to talk about my illness with my
parents
0
1
2
3
4
PedsQL 3.0 Reproduction without permission is prohibitedCopyright © 1998 JW Varni, Ph.D. All rights reserved
PedsQL-3.0_GIS-Module-PC_AU3.0_spa-ES_nonMapi
69

PedsQL
Annex 7. PedsQL 3.0 - Gastrointestinal Symptoms Module. Teen Report
Name:___________________________________
Date:_____ / _____ / ________
PedsQLTM
Gastrointestinal Symptoms Module
Version 3.0
TEEN REPORT (ages 13-18)
INSTRUCTIONS
On the next page is a list of things that could be a problem for you.
Please tell us, by circling or crossing out each answer, depending on how much trouble
each thing has caused you in the last month:
0If it's never a problem
1Yes it is almost never a problem
2Yes sometimes it is a problem
3Yes it is often a problem
4Yes it is almost always a problem
There are not correct or incorrect answers.
If you do not understand any question, please ask for help.
In the last month, how much of a problem has this been for you…?
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PedsQL-3.0_GIS-Module-PC_AU3.0_spa-ES_nonMapi
70

PedsQL
STOMACH PAIN (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I feel pain in my stomach
0
1
2
3
4
2. I feel sore in my stomach
0
1
2
3
4
3. My stomach hurts
0
1
2
3
4
4. I wake up at night with a stomach ache
0
1
2
3
4
5. My stomach turns
0
1
2
3
4
6. I have an upset stomach
0
1
2
3
4
STOMACH DISCOMFORT WHEN EATING
(problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. When I eat, my stomach turns
0
1
2
3
4
2. When I eat, I feel sick to my stomach
0
1
2
3
4
3. My stomach hurts when I eat
0
1
2
3
4
4. I feel heaviness in my stomach when I eat
0
1
2
3
4
5. As soon as I start eating, I feel full.
0
1
2
3
4
FOOD AND DRINK LIMITS (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I can't eat some foods
0
1
2
3
4
2. I can't have some drinks
0
1
2
3
4
3. I can't eat what I want
0
1
2
3
4
4. I can't drink what I want
0
1
2
3
4
5. I can't eat some foods because they upset my
stomach.
0
1
2
3
4
6. I can't eat the foods my friends eat
0
1
2
3
4
DIFFICULTY SWALLOWING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I find it difficult to swallow food
0
1
2
3
4
2. It hurts when I swallow
0
1
2
3
4
3. Food gets stuck when it passes by
0
1
2
3
4
ACIDITY AND REFLUX (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I feel burning in my throat
0
1
2
3
4
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PedsQL-3.0_GIS-Module-PC_AU3.0_spa-ES_nonMapi
71

PedsQL
2. I have chest pain or discomfort
0
1
2
3
4
3. My food returns after eating
0
1
2
3
4
NAUSEA AND VOMITING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I feel like vomiting
0
1
2
3
4
2. I feel like vomiting when I eat
0
1
2
3
4
3. I feel like vomiting after eating
0
1
2
3
4
4. Vomiting
0
1
2
3
4
GASES AND SWELLING (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. My stomach feels full of gas
0
1
2
3
4
2. My stomach feels very full
0
1
2
3
4
3. My stomach swells and becomes hard
0
1
2
3
4
4. I have a lot of gas (belching)
0
1
2
3
4
5. I expel a lot of gas (farts)
0
1
2
3
4
6. I feel like I have gas in my stomach
0
1
2
3
4
7. My stomach makes noises
0
1
2
3
4
CONSTIPATION (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I still feel full after pooping
0
1
2
3
4
2. I feel like I'm not done after pooping.
0
1
2
3
4
3. I feel like I can't get the poop to come out
completely.
0
1
2
3
4
4. It hurts when I poop
0
1
2
3
4
5. My stools are hard
0
1
2
3
4
6. My stool is lumpy
0
1
2
3
4
7. I have to use a lot of force to poop.
0
1
2
3
4
8. My poop gets stuck
0
1
2
3
4
9. My butt hurts after pooping.
0
1
2
3
4
10. It takes a long time for the poop to come out
0
1
2
3
4
11. I have to try really hard to poop.
0
1
2
3
4
12. I don't want to poop because it hurts.
0
1
2
3
4
13. I spend a lot of time on the toilet pooping.
0
1
2
3
4
14. My stomach hurts when I poop.
0
1
2
3
4
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PedsQL-3.0_GIS-Module-PC_AU3.0_spa-ES_nonMapi
72

PedsQL
BLOOD IN Stool (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. There is blood on the toilet paper after I poop.
0
1
2
3
4
2. There is blood in my poop
0
1
2
3
4
DIARRHEA (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I need to be near a bathroom very often
0
1
2
3
4
2. I have to run to the bathroom to poop.
0
1
2
3
4
3. I feel like I'm always in the bathroom pooping.
0
1
2
3
4
4. I wake up at night to poop.
0
1
2
3
4
5. My stools are watery
0
1
2
3
4
6. I accidentally poop in my underwear.
0
1
2
3
4
7. I have to poop a lot
0
1
2
3
4
CONCERN ABOUT POOPING (problems
with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I worry about pooping my pants.
0
1
2
3
4
2. I worry about not getting to the bathroom on
time.
0
1
2
3
4
3. I worry about hurting myself when I poop.
0
1
2
3
4
4. I worry about having to use the bathroom at
school
0
1
2
3
4
5. I worry about pooping my pants at school.
0
1
2
3
4
CONCERN ABOUT STOMACH PAIN
(problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. I am worried about my stomach pain
0
1
2
3
4
2. I worry that my stomach will hurt at school.
0
1
2
3
4
MEDICINES (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. It is hard for me to take my medicines
0
1
2
3
4
2. I forget to take my medicines
0
1
2
3
4
3. It is hard for me to swallow my medicines
0
1
2
3
4
4. I don't like having to take my medicine all the
time.
0
1
2
3
4
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73

PedsQL
COMMUNICATION (problems with...)
Never
Hardly
ever
Sometim
es
Often
Almost
always
1. It is hard for me to tell doctors and nurses how
I feel.
0
1
2
3
4
2. It is hard for me to ask doctors and nurses
some things.
0
1
2
3
4
3. It is hard to explain my illness to other people
0
1
2
3
4
4. It is hard to explain my illness to my friends
0
1
2
3
4
5. It is hard to talk about my illness with my
parents
0
1
2
3
4
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74

Annex 8. Weekly medication report (4 to 10 years)
●
It is important to take medications as directed by your doctor.
●
Make sure your child (patient) does not miss any doses.
●
Inform your doctor immediately if you experience any side effects caused by taking a medication.
●
Make sure the doctor is aware of any additional supplements, vitamins, or over-the-counter
medications the patient takes.
Name:
Contain
er:
#
Start date:
//
End date:
//
Mark with a check mark (✔) the days on which you took the medication.
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Indicate with a check mark (✔) if in the last 7 days you had any of the following reactions
within the next 2 hours of taking the medication.
Dry mouth
Indigestion
Constipation
Diarrhea
Nausea
Urticaria
Headache
Dream
Fatigue
Dizziness
Shaking chills
Bad breath
Others: ________________________________________________________
Contain
er:
#
Start date:
//
End date:
//
Mark with a check mark (✔) the days on which you took the medication.
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
75

Indicate with a check mark (✔) if in the last 7 days you had any of the following reactions
within the next 2 hours of taking the medication.
Dry mouth
Indigestion
Constipation
Diarrhea
Nausea
Urticaria
Headache
Dream
Fatigue
Dizziness
Shaking chills
Bad breath
Others: ________________________________________________________
Wong-Baker FACES® Pain Scale.
Choose the face that best describes how your child feels now.
0
It does not hurt
2
It hurts a little
4
It hurts a little
more
6
It hurts even
more
8
It hurts much
10
The worst pain
Choose the face that best describes the worst pain your child had during the last 7 days.
0
It does not hurt
2
It hurts a little
4
It hurts a little
more
6
It hurts even
more
8
It hurts much
10
The worst pain
Mark with an X the exact place where you have pain now. If you have pain in more than one place, mark '1',
'2', '3', etc., starting with '1' for the most painful place.
76

Annex 9. Weekly medication report (10 to 18 years old)
●
It is important to take medications as directed by your doctor.
●
Make sure your child (patient) does not miss any doses.
●
Inform your doctor immediately if you experience any side effects caused by taking a medication.
●
Make sure the doctor is aware of any additional supplements, vitamins, or over-the-counter
medications the patient takes.
Name:
Contain
er:
#
Start date:
//
End date:
//
Mark with a check mark (✔) the days on which you took the medication.
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Indicate with a check mark (✔) if in the last 7 days you had any of the following reactions
within the next 2 hours of taking the medication.
Dry mouth
Indigestion
Constipation
Diarrhea
Nausea
Urticaria
Headache
Dream
Fatigue
Dizziness
Shaking chills
Bad breath
Others: ________________________________________________________
Contain
er:
#
Start date:
//
End date:
//
Mark with a check mark (✔) the days on which you took the medication.
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
77

Indicate with a check mark (✔) if in the last 7 days you had any of the following reactions
within the next 2 hours of taking the medication.
Dry mouth
Indigestion
Constipation
Diarrhea
Nausea
Urticaria
Headache
Dream
Fatigue
Dizziness
Shaking chills
Bad breath
Others: ________________________________________________________
Visual Analogue Scale (VAS) of Pain.
Put a check on the line to show how you feel now.
Without
pain
Severe pain
Put a mark on the line to show the worst pain you had during the last 7 days.
Without
pain
Severe pain
Mark with an X the exact place where you have pain now. If you have pain in more than one place, mark '1',
'2', '3', etc., starting with '1' for the most painful place.
78

Annex 10. Letter of no conflict of interest
Colima, Col., October 25, 2023
Dr. Gabriel Ramirez Patiño
Director of the Hospital Regional Universitario de Colima
No conflict of interest letter
Hereby, I, C. Pablo Hernan Sandoval Villaseñor, Principal Investigator, student of the Master's
Degree in Medical Sciences at the School of Medicine of the Universidad de Colima, and the thesis
advisors Mr. C. Fabián Rojas Larios, Medical Specialist A, assigned to the Teaching, Training and
Research Unit, and Dr. C. Carmen Alicia Sánchez Ramírez, Medical Specialist in Pediatrics,
External Associate Researcher, we declare that we have no conflict of interest in relation to the
research protocol titled "EFFECT OF TRIMEBUTINE VS PROBIOTICS ON FUNCTIONAL
ABDOMINAL PAIN IN CHILDREN: RANDOMIZED CLINICAL TRIAL."
We confirm that we do not have any financial, personal or professional relationships with other
people or organizations that could inappropriately influence our work. We have not received any
funding to carry out this study, which was carried out with our own funds.
We undertake to inform the Research Committee (IC) and the Ethics and Research Committee
(CEI) of any change in the study protocol or in the situation of the researchers that may give rise to
a conflict of interest. We appreciate your attention and remain at your disposal for any additional
information you may require.
Sincerely,
_______________________________
________________________
_______________________________
C. Pablo Hernan Sandoval
Villaseñor
D. in C. Fabián Rojas
Larios
D. in C. Carmen Alicia
Sánchez Ramírez
Principal investigator
Methodological advisor
Clinical advisor
79

Annex 11. Checklist (CONSORT reporting guidelines) for randomized clinical
trials(40).
Instructions to authors:Complete this checklist by entering the page numbers from your
manuscript where readers will find each of the items listed below. Your article may not currently
address all the items on the checklist. Please modify your text to include the missing information. If
you are certain that an item does not apply, please write "N/A" and provide a short explanation.
Upload
your
completed
checklist
as
an
extra
file
when
you
submit
to
a
journal
(https://www.goodreports.org/reporting-checklists/consort/).
Section
Item number
☑
P
Title and summary
1a. Qualification
It is identified as a randomized clinical trial in the
title.
●
1
1 B. Summary
Structured summary of the trial design, methods,
results and conclusions.
●
SUMMARY:PEN
D
Introduction
2a. Background
Scientific
background
and
explanation
of
the
fundamentals.
●
THEORETICAL
FRAMEWORK
2b. Goals
Specific objectives or hypotheses.
●
Goals
Methods
3a. Trial design
Description
of
trial
design
(such
as
parallel,
factorial), including allocation rate.
●
Study design
3b. Trial design
Major changes in methods after the start of the
trial (such as eligibility criteria), with reasons.
●
N/A
4a. Participants
Eligibility criteria for participants.
●
Selection
criteria
4b. Participants
Environments
and
locations
where
data
was
collected.
●
Study universe
5. Interventions
Experimental and control interventions for each
group with sufficient details to allow replication,
including
how
and
when
they
were
actually
administered.
●
Variables
6a. Results
Fully defined pre-specified primary and secondary
outcome measures, including how and when they
were assessed.
●
PEND
6b. Results
Any change in the results of the trial after its start,
with its reasons.
●
N/A
7a. Sample size
How the sample size was determined.
●
Sample size
7b. Sample size
Where
applicable,
explanation
of
any
interim
analysis and stopping guidelines.
●
N/A
80

Section
Item number
☑
P
8a. Randomization:
generation.
Method used to generate the random assignment
sequence.
●
Sampling
method
8b. Randomization:
generation.
Type of randomization; details of any restrictions
(such as blocking and block size).
●
Sampling
method
9. Randomization:
allocation hiding
mechanism
Mechanism used to implement the randomization
sequence (such as sequentially numbered bins),
describing
any
steps
taken
to
conceal
the
sequence until interventions were assigned.
●
Methodological
description
10. Randomization
implementation
Who
generated the allocation sequence, who
enrolled
participants,
and
who
assigned
participants to the interventions.
●
Methodological
description
11a. Masking
If done, who was blinded after assignment to
interventions (e.g., participants, care providers,
those assessing outcomes) and how.
●
Methodological
description
11b. Masking
If applicable, description of the similarity of the
interventions.
●
N/A
12a. Statistical methods
Statistical methods used to compare groups for
primary and secondary outcomes.
●
Statistical
analysis and
data
interpretation
12a. Statistical methods
Methods for additional analyses, such as subgroup
analyzes and adjusted analyses.
●
Statistical
analysis and
data
interpretation
Results
13a. Participant flowchart
For each group, the number of participants who
were
randomized,
received
the
intended
treatment, and were analyzed for the primary
outcome.
●
Methodological
description
13b. Participant flowchart
For
each
group,
losses
and exclusions after
randomization, along with the reason.
●
Methodological
description
14 to. Recruitment
Dates that define the contracting and monitoring
periods.
●
SCHEDULE OF
ACTIVITIES
14b. Recruitment
Why the trial ended or was stopped.
●
N/A
15. Reference data
A table showing the baseline demographic and
clinical characteristics of each group.
●
PEND.
16. Participants analyzed
For
each
group,
number
of
participants
(denominator)
included
in
each
analysis
and
whether the analysis was performed by originally
assigned groups.
●
PEND.
17a. Results and
estimation
For each primary and secondary outcome, the
results for each group and the estimated effect
size and its precision (such as the 95% confidence
interval).
●
PEND.
81

Section
Item number
☑
P
17b. Results and
estimation
For binary results, presentation of absolute and
relative effect sizes is recommended.
●
PEND.
18. Auxiliary analyzes
Results of any other analyzes performed, including
subgroup
analyzes
and
adjusted
analyses,
distinguishing prespecified from exploratory.
●
PEND.
19. Adverse effects
Any major damage or unwanted effects in each
group (for specific guidance, see CONSORT for
damage).
●
PEND.
Discussion
20. Limitations
Limitations of the trials, addressing sources of
possible
bias,
imprecision
and,
if
relevant,
multiplicity of analyses.
●
PEND.
21. Generability
Generalizability (external validity, applicability) of
the trial findings.
●
PEND.
22. Interpretation
Interpretation consistent with the results, weighing
benefits and harms, and considering other relevant
evidence.
●
PEND.
Other information
23. Registration
Registration number and name of the trial record.
●
PEND.
24. Protocol
Where the full trial protocol can be accessed, if
available.
●
PEND.
25. Financing
Sources of financing and other types of support
(such as the provision of medicines), role of
funders.
●
FINANCING
* Adapted from Schulz, et al., 2010(40).
The CONSORT checklist is distributed under the terms of the Creative Commons Attribution
License CC-BY. This checklist can be completed online using https://www.goodreports.org/, a tool
made by the EQUATOR Networkin collaboration with Penelope.ai
82

Annex 12. Turnitin Similarity Report
83

Annex 13. Bioethics Committee Approval of the School of Medicine
84