Cochrane Database of Systematic Reviews

Pharmacological interventions for recurrent abdominal pain

in childhood (Protocol)

Martin AE, Newlove-Delgado TV, Abbott RA, Bethel A, Thompson-Coon J, Nikolaou V, Logan S

Martin AE, Newlove-Delgado TV, Abbott RA, Bethel A, Thompson-Coon J, Nikolaou V, Logan S.
Pharmacological interventions for recurrent abdominal pain in childhood.
Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010973.
DOI: 10.1002/14651858.CD010973.

www.cochranelibrary.com

Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Pharmacological interventions for recurrent abdominal pain in childhood (Protocol) i

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Pharmacological interventions for recurrent abdominal pain

in childhood

Alice E Martin1 , Tamsin V Newlove-Delgado2 , Rebecca A Abbott2 , Alison Bethel2, Joanna Thompson-Coon2 , Vasilis Nikolaou3 ,
Stuart Logan2

1 Paediatrics,
Royal Devon and Exeter Hospital, Exeter, UK. 2 Peninsula CLAHRC, University of Exeter Medical School, University of
Exeter, Exeter, UK. 3 Institute of Health Research, University of Exeter Medical School, University of Exeter, Exeter, UK

Contact address: Alice E Martin, Paediatrics, Royal Devon and Exeter Hospital, Barrack Road, Exeter, England, EX2 5DW, UK.
alice.martin@doctors.org.uk.

Editorial group: Cochrane Developmental, Psychosocial and Learning Problems Group.

Publication status and date: New, published in Issue 2, 2014.

Citation: Martin AE, Newlove-Delgado TV, Abbott RA, Bethel A, Thompson-Coon J, Nikolaou V, Logan S. Pharmacological
interventions for recurrent abdominal pain in childhood. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010973.
DOI: 10.1002/14651858.CD010973.

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the effectiveness of pharmacological interventions for RAP in children of school age.

BACKGROUND
Description of the condition
Recurrent abdominal pain (RAP) is a common problem in pae-
diatric practice. It has been suggested that 4% to 25% of school-
aged children suffer from RAP that interferes with their activities
of daily living (Apley 1958; ster 1972; Faull 1986; Abu-Arafeh
1995; Williams 1996). It is regarded as a benign condition, but
it is important to note the morbidity incurred by these chil-
dren. It is hard to say the condition is truly benign consider-
ing the related school absences, hospital admissions, and appen-
dectomies for symptoms that continue (Stickler 1979; Scharff
1997; Walker 1998; Strdal 2005), sometimes even into adult-
hood (Apley 1975). Moreover, the abdominal pain is commonly
associated with other symptoms, including headaches, recurrent
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
limb pains, pallor, and vomiting (Apley 1958; Stone 1970; ster
1972; Stickler 1979; Faull 1986; Abu-Arafeh 1995; Hyams 1995).
It is increasingly recognised that RAP in children represents a
group of functional gastrointestinal disorders that have an unclear
aetiology. Children suffer either chronic or recurrent gastrointesti-
nal symptoms not explained by a structural, biochemical or in-
flammatory process. Apley first sought to define the condition in
the 1950s and suggested that at least three episodes of severe ab-
dominal pain over three months (Apley 1958), often with associ-
ated systemic symptoms but no established organic cause, fulfils
a diagnosis of RAP. Now there is international consensus with a
symptom-based classification system, the Rome III criteria, which
has specific categories for paediatric presentations (Rasquin 2006).
The categories include: functional dyspepsia, irritable bowel syn-
drome, abdominal migraine, and functional abdominal pain syn-
drome. It should be noted that the pain classification for each of
the Rome III diagnoses is defined by at least one episode per week
1
for at least two months; this varies from Apleys original defini-
tion of RAP (Apley 1958). The Rome classification is not based
on known pathophysiological differences between the conditions
but rather the collection of features for each manifestation. Thus,
it remains unclear the extent to which separating children into
these categories defines groups as distinct clinical entities that are
likely to respond differently to treatment. Nonetheless this clas-
sification has been welcomed following the historical use of di-
verse terms, some implying causation. These include: abdomi-
nal migraine (Farquar 1956; Bain 1974; Symon 1986; Hockaday
1992), abdominal epilepsy (Stowens 1970), the irritable bowel
syndrome in childhood (Stone 1970), allergic-tension-fatigue
syndrome (Speer 1954; Sandberg 1973), neurovegetative dys-
tonia (Rubin 1967; Peltonen 1970), functional gastrointestinal
disorder (Drossman 1995), and the irritated colon syndrome
(Painter 1964; Harvey 1973). The paediatric Rome criteria are an
attempt to improve the diagnosis, study, and treatment of children
with RAP (Walker 1989; Schurman 2005).
There have been several proposed causal pathways that result in
the heterogeneous presentations of chronic abdominal pain. It is
recognised that physical, emotional, and environmental factors
may contribute to cause the manifestation of unexplained abdom-
inal pain. When considering the diverse causes, it is unsurprising
that a variety of treatments have been suggested. The treatment
approaches can be grouped as pharmacological, dietary or psycho-
logical, and behavioural.
Psychosocial interventions
Many clinicians believe these conditions are affected by or orig-
inate from psychogenic factors (Friedman 1972; Raymer 1984).
Historically, authors have suggested that children with RAP come
from psychosomatic families (Osborne 1989; Walker 1989;
Robinson 1990). This is now a controversial idea although a re-
cent population-based study found that anxiety in parents added
to a specific child temperament before one year of age, which is
a strong predictor of RAP in childhood (Ramchandani 2006).
Also, in the most recent edition of the World Health Organization
(WHO) International Classification of Diseases (WHO 2010),
unexplained abdominal pain is classified as a somatoform disor-
der. Further evidence of psychological factors contributing to the
presentation of unexplained abdominal pain comes from Campo
2001, which suggested a strong association between RAP in child-
hood and anxiety in adult life. Therefore, children have received
psychological and behavioural interventions for RAP (Heinild
1959; Sank 1974; Miller 1979; Linton 1986). A variety of ap-
proaches have been used, including: behavioural and cognitive-
behavioural techniques (Sanders 1994; Scharff 1997), psychother-
apy (Vasquez 1992), family-centred approaches (Liebman 1976;
Wetchler 1992; Walker 1999), and multi-component therapies
(Finney 1989; Edwards 1991; Humphreys 2000).
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dietary interventions
Many dietary inventions have been suggested to improve the symp-
toms of RAP. These involve either excluding or reducing a food
group or specific ingredient from the diet or supplementing it and
therefore increasing its intake. The dietary interventions include
low oxalate diets (Feldman 1985), eliminating food groups, such
as dairy products (Bayless 1971; Bain 1974; Liebman 1979), some
fruits, meats or rye (Farquar 1956; Minford 1982), and taking
fibre supplements (Feldman 1985; Christensen 1986). Increased
dietary fibre may be of benefit in adults with irritable bowel syn-
drome (Rasmussen 1982; Lambert 1991). Probiotics have also
been given to children with RAP (Wilhelm 2008).
It seems likely that many children, especially those at the milder
end of the spectrum, do not present to the health care system
or only present to primary care. For these children, the principal
management is likely to be reassurance that the pain does not
represent significant organic pathology. Even in secondary care, a
large proportion of children with RAP are treated with reassurance
following investigations for treatable causes (Edwards 1994).
Description of the intervention
A range of pharmacological treatments have been tried and tested:
analgesics, dicyclomine (Edwards 1994), pizotifen (Christensen
1995; Symon 1995), herbal extracts (Zhang 1991), and many
other drugs (Bain 1974; Worawattanakul 1999). A number of
randomised controlled trials (RCTs) have reported on the use of
peppermint oil for irritable bowel syndrome in adults (Grigoleit
2005), and the results have been interpreted as suggesting it is
a beneficial intervention. However, an earlier review reached no
clear conclusion on efficacy due to poor methodological quality
of the included studies (Pittler 1998). Other possible causal fac-
tors have been postulated, including food allergies (Poley 1973),
reaction to food additives (Anonymous 1984), infectious agents
like Helicobacter pylori and parasitic infestation (Primelles 1990;
Wardhan 1993; Heldenberg 1995).
How the intervention might work
The aetiology of abdominal pain-related functional gastro-intesti-
nal disorders is unclear. It has been suggested that visceral hyper-
sensitivity (Di Lorenzo 2001; Van Ginkel 2001), autonomic dys-
function (Good 1995), and gut dysmotility may contribute, and
this may be initiated by an inflammatory, infective, traumatic or
allergic trigger (Milla 2001; Mayer 2002).
Conventional analgesics have been proposed to work by interrupt-
ing these abnormal physiological pain responses, which become
pathological. Antispamodics have been proposed to alter gut dys-
motility, including peppermint oil, which has antispasmodic ac-
tions (Hill 1991). Serotonin (5-hydroxytryptamine) agonists may
relieve symptoms by causing vasoconstriction and stimulation of
2
the release of other vasoactive substances thus inhibiting neuro- Types of interventions
genic inflammation; this has been found in migraine headaches Any pharmacological intervention compared to placebo, no treat-
(Goadsby 2000). Antidepressants treat the associated symptoms ment, waiting list or standard care.
and there is evidence of effectiveness in treating irritable bowel
syndrome in adults (Ruepert 2011).
Types of outcome measures

Why it is important to do this review

RAP in children is very common and in daily clinical practice there
is no consensus on which treatments to offer patients. Therefore,
there is an inconsistent approach. This review is important to es-
tablish if there is evidence for the effectiveness of pharmacological
interventions in children with RAP. It updates a previous review
published in 2008 (Huertas-Ceballos 2008a). Companion reviews
addressing the effectiveness of psychosocial and dietary interven-
tions for RAP are also being updated (Huertas-Ceballos 2008b;
Huertas-Ceballos 2009), so together they can guide clinicians, pa-
tients, and their families in treatment decisions.
Primary outcomes
Pain intensity, duration or frequency.
There is no standard method for measuring pain in this condi-
tion. Therefore, studies may use any validated measurement of
pain and may report the proportion of participants with signifi-
cant improvement in pain, as defined by the trial author. We ex-
pect studies to vary in their duration of post-intervention follow-
up. Therefore, we will group studies according to duration of fol-
low-up: immediate outcome measurement, short term (less than
three months), medium term (three to 12 months) and long term
(greater than 12 months).

Secondary outcomes
As measured by a validated tool:
OBJECTIVES school performance;
To determine the effectiveness of pharmacological interventions social/psychological functioning;
for RAP in children of school age. quality of daily life.

We will present all outcomes in a Summary of findings table.

METHODS
Search methods for identification of studies

Criteria for considering studies for this review

Electronic searches
We will search the following electronic databases for relevant stud-
ies:
Types of studies Cochrane Central Register of Controlled Studies
RCTs. (CENTRAL), part of the Cochrane Library;
Ovid MEDLINE;
EMBASE;
CINAHL;
Types of participants PsycINFO;
Children aged five to 18 years old with RAP or an abdominal, ERIC;
pain-related, functional gastrointestinal disorder defined by the British Education Index;
Rome III criteria. ASSIA;
RAP is defined as at least three episodes of pain interfering with AMED;
normal activities within a three month period. The Rome III cri- LILACS;
teria recognises four abdominal pain-related categories: abdom- OpenGrey (http://www.opengrey.eu/);
inal migraine, irritable bowel syndrome, functional dyspep- ClinicalTrials.gov (http://clinicaltrials.gov/);
sia, functional abdominal pain, and functional abdominal pain International Clinical Trials Registry Platform (ICTRP)
syndrome (Rasquin 2006). search portal (http://apps.who.int/trialsearch/).

Pharmacological interventions for recurrent abdominal pain in childhood (Protocol) 3

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We will adapt the following search strategy for MEDLINE (Ovid) 39 randomly.ab.
for each database as listed above. The search terms have been re- 40 trial.ab.
vised from the original Cochrane RAP reviews (Huertas-Ceballos 41 groups.ab.
2008a; Huertas-Ceballos 2008b; Huertas-Ceballos 2009); there- 42 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41
fore, searches will be run for all available years. We will use RCT 43 exp animals/ not humans.sh.
filters where appropriate and no language limits will be imposed. 44 42 not 43
We will translate any non-English language studies found in order 45 exp Child/
to be screened and considered for inclusion. 46 exp Adolescent/
1 Recurr$.tw. 47 exp Young Adult/
2 Chronic$.tw. 48 exp Students/
3 Intermittent$.tw. 49 Child$.tw.
4 Bout$1.tw. 50 Adolescen$.tw.
5 spasm$.tw. 51 Young person$.tw.
6 Transitory.tw. 52 Boy$.tw.
7 Transient.tw. 53 Girl$.tw.
8 Functional.tw. 54 teen$.tw.
9 Continu$.tw. 55 Schoolchild$.tw.
10 Paroxysmal.tw. 56 Young adult$.tw.
11 Persistent.tw. 57 Youth$.tw.
12 Idiopathic.tw. 58 P*ediatric$.tw.
13 unspecifi$.tw. 59 Student$.tw.
14 Non specifi$.tw. 60 Pupil$.tw.
15 nonspecifi$.tw. 61 Juvenile$.tw.
16 motility.tw. 62 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55
17 episod$.tw. or 56 or 57 or 58 or 59 or 60 or 61
18 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 63 32 and 44 and 62
or 14 or 15 or 16 or 17
19 exp Recurrence/
20 18 or 19
21 ((pain$ or Ache$ or Sore$ or Discomfort$ or Distress$ or Searching other resources
Cramp$ or Disorder$1 or Symptom$1 or Migraine$1 or Epilep$ We will use the Science Citation Index to locate relevant studies
or syndrome$1 or colic$) adj3 (stomach$ or abdom$ or intestin$ using the bibliographic details and authors names of relevant pa-
or viscera$ or tummy or bowel$ or belly or gastrointestinal or gi pers for forward and backward citations.
or gastric)).tw. We will contact researchers who have published studies in this field
22 exp Colic/ to ask for details of any relevant trials.
23 exp Irritable Bowel Syndrome/ or exp Colonic Diseases, Func- We will also check the bibliographies of papers retrieved to estab-
tional/ lish if all pertinent references were found in our search.
24 exp abdominal pain/ or exp dyspepsia/
25 Colonic disease$.tw
26 IBS.tw.
27 Functional dyspepsia.tw.
28 irritable bowel$.tw. Data collection and analysis
29 exp Abdomen, Acute/
30 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29
31 21 or 30
32 20 and 31 Selection of studies
33 randomized controlled trial.pt.
Two review authors (AM, TN, RA or AB) will independently
34 controlled clinical trial.pt.
screen the titles and abstracts of studies for relevance. We will ob-
35 randomi#ed.ab.
tain the full-text articles for any paper that appears to be potentially
36 placebo$.ab.
suitable for inclusion and then select them for inclusion against
37 placebo$.ab.
the agreed inclusion criteria. Any disagreements will be resolved
38 drug therapy.fs.
through discussion with a third review author (JTC).

Pharmacological interventions for recurrent abdominal pain in childhood (Protocol) 4

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data extraction and management
Two review authors (AM, TN, RA, AB or JTC) will extract data
and enter them into the Cochrane Collaborations statistical soft-
ware, Review Manager 2013. All review authors will use the same
data extraction form. We will collect the following data,
1. Study characteristics: number of participating patients,
inclusion and exclusion criteria, type of intervention and
comparison, intervention characteristics (duration, frequency,
setting), number of withdrawals.
2. Participant characteristics: sex, age, diagnosis (for example,
recurrent abdominal or syndrome defined by the Rome III
criteria).
3. Outcome measures: measurement of pain and any
secondary outcome measured.
Assessment of risk of bias in included studies
We will consider the following domains when assessing the risk of
bias in included studies:
selection bias (random sequence generation and allocation
concealment);
performance bias (blinding of participants and personnel);
detection bias (blinding of outcome assessment);
attrition bias (incomplete outcome data);
reporting bias (selective reporting);
other sources of bias.
Two review authors (AM, TN, RA, AB or JTC) will independently
assess each study. We will classify the risk of bias as low risk,
high risk or unclear risk in line with the methods detailed method in Review Manager 2013. An appropriate washout period
in the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011) (Table 1).
We will assess all included studies for other sources of bias that
may alter the estimate of treatment effect, for example differential
loss to follow-up. In cross-over studies it should be clear that the
order of receiving treatments was randomised. There should be no
assumed carry-over effects and, therefore, an adequate wash-out
period. All the data should be available at the baseline, and before
and after changing treatments. Caution is required as although
RAP is a chronic condition most patients do improve with time
(risk of period effects).
We will consider a trial as having an overall low risk of bias if most
of the above domains are assessed as a low risk of bias. We will
consider a trial as having an overall high risk of bias if several of
the above domains are assessed as high risk of bias or unclear risk
of bias.
We will use the Grading of Recommendations, Assessment, De-
velopment, and Evaluation (GRADE) approach to assess the over-
all quality of the body of evidence for a specific outcome (Higgins
2011). This will involve a consideration of within-study risk of
bias (methodological quality), directness of evidence, heterogene-
ity, precision of effect estimates, and risk of publication bias. This
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
study includes RCTs only. Although RCTs will begin as high qual-
ity evidence, they will be downgraded if most of the evidence
comes from studies with a high risk of bias.
Measures of treatment effect
We will report study results as follows:
1. for continuous data (that is, number of days of pain), we
will analyse by means and standard deviations if available or can
be calculated, and if there is no clear evidence of skewness in the
distribution. If different scales are used to measure the same
clinical outcome, we will combine the standardised mean
differences (SMDs) across the studies;
2. for dichotomous data (for example, pain improved, yes or
no), we will analyse using odds ratios (ORs).
Unit of analysis issues
If the following three types of trials are found, we will consider
their results as per the guidance in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011).
1. Cross-over trials
For cross-over trials with random allocation to period and an ap-
propriate washout period we will include the relevant effect esti-
mate within the meta-analysis, using the generic inverse variance
will vary with the interventions (including drug pharmacokinet-
ics) and outcome measurements. Considering RAP can be a stable
and chronic condition, a wash-out period of several weeks may be
sufficient.
2. Cluster-RCTs
Cluster-randomised trials randomise groups of people rather than
individuals. For each cluster-randomised trial, we will first deter-
mine whether or not the data incorporate sufficient controls for
clustering (such as robust standard errors or hierarchical linear
models). If data do not have proper controls, then we will attempt
to obtain an appropriate estimate of the datas intracluster correla-
tion coefficient (ICC). If we cannot find an estimate in the report
of the trial, then we will request an estimate from the trial report
authors. If the authors do not provide an estimate, if possible,
we will obtain one from a similar study and conduct a sensitivity
analysis to determine if the results are robust when different values
are imputed. We will do this according to procedures described
in Higgins 2011. This will prevent the meta-analysis from being
based on clustered data that have not been properly controlled.
5
3. Trials with multiple intervention groups
This is a common scenario. To avoid any unit-of-analysis errors in
the meta-analysis, we will use the following approach for a study
that could contribute multiple comparisons.
The interventions will only be analysed together if they are
clinically similar, that is testing the same class of drug. In this
situation the control group will not be split, but the intervention
groups will be combined to enable a single pair-wise comparison
for the meta-analysis. If the interventions are similar enough to
be in a single meta-analysis but not able to be combined, then
the control group will be split.
If the interventions are not similar, the data will be used in
separated meta-analyses. So a single study may contribute data to
different meta-analyses (for example if the interventions involved
eliminating different classes of drugs) and this does not require
the control group to split.
We will not perform a multiple treatment meta-analysis as the
clinical heterogeneity will make the results uninterpretable.
Dealing with missing data
In the first instance, we will contact the original investigators to
request any missing data. If it is not possible to obtain the data from
the original investigators, we will not impute values. A sensitivity
analysis may be carried out to establish if inclusion of studies with
high levels of missing data significantly alters the finding of the
review. We will collect the proportions of participants for whom
no outcome data are obtained and report them in the Risk of Bias
assessment as described above. We will explore the potential impact
of missing data on the findings of the review in the Discussion
section.
Assessment of heterogeneity
We anticipate finding considerable heterogeneity between in-
cluded studies. We will assess clinical heterogeneity by examin-
ing the distribution of relevant participant characteristics (for ex-
ample, age, definition of RAP) and study differences (for exam-
ple, concealment of randomisation, blinding of outcome assessors,
interventions or outcome measures). We will describe statistical
heterogeneity (observed variability in study results that is greater
than that expected to occur by chance) by calculating I2 (Higgins
2003). I2 describes approximately the proportion of variation in
point estimates due to heterogeneity rather than sampling error. I
2 more than 50% may indicate significant heterogeneity.
We will use Chi2 test to further assess the strength of evidence for
the heterogeneity. Any result with a P value lower than 0.10 will be
regarded as indicating significant statistical heterogeneity. We will
interpret this cautiously and use it to help quantify the impact of
heterogeneity on the results of the meta-analysis (Higgins 2003).
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Assessment of reporting biases
Publication bias
If we identify sufficient trials (at least 10), outcome data will be
used to produce a funnel plot to investigate the likelihood of overt
publication bias (Sutton 2000). Any asymmetry of the funnel plot
may indicate possible publication bias. We will explore other rea-
sons for asymmetry such as poor methodological quality or het-
erogeneity. We could also look for publication bias by comparing
the results of the published and unpublished data.
Outcome reporting bias
We will examine reports of a study to assess for selective outcome
reporting. The study will be assessed as adequate if it meets the
following criteria.
The study protocol is available and all of the studys pre-
specified (primary and secondary) outcomes that are of interest
to the review have been reported in the pre-specified way.
The study protocol is not available, but it is clear that the
published reports include all expected outcomes, including those
that were pre-specified.
Data synthesis
We will use Review Manager 2013 for statistical analysis. Two
review authors (AM, TN, RA, AB or JTC) will enter data into
Review Manager 2013 independently. We will report summary
statistics for continuous data as mean differences (MDs) or SMDs
using a random-effects model. For dichotomous data we will report
the odds ratios (ORs) using a random-effects model. We will use
a random-effects model as we anticipate significant statistical and
clinical heterogeneity.
A meta-analysis will only be carried out if it is appropriate to do so,
that is if the studies are sufficiently homogeneous. For example,
we will only carry out a meta-analysis of data from studies with
equivalent drug interventions, such as the class of drug. We are
aware that given the heterogeneity of the pharmacological options
investigated for RAP and the variety of methods to measure pain,
a meta-analysis may not be possible (DerSimonian 1986). In this
case, we will provide a narrative description of the results.
Subgroup analysis and investigation of heterogeneity
If sufficient trials are available, we will examine the following sub-
groups to explore clinical heterogeneity:
type of RAP (defined by the Rome III criteria) (Rasquin
2006);
age;
duration of follow-up: immediate outcome measurement,
short term (less than three months), medium term (three to 12
months), and long term (greater than 12 months).
6
Subgroup analysis can be misleading because the studies may not
be designed and powered to show difference within subgroups.
Therefore, we will undertake subgroup analyses with caution.
Sensitivity analysis
We will conduct primary analyses based on available data on the
outcomes of interest.
Following this, we will use a sensitivity analysis to assess the ro-
bustness of conclusions in relation to two aspects of study design.
We will assess:
1. the effect of inadequate allocation concealment, by the
removal of studies judged as high or unclear risk of bias for that
domain; and
REFERENCES
Additional references
Abu-Arafeh 1995
Abu-Arafeh I, Russell G. Prevalence and clinical features
of abdominal migraine compared with those of migraine
headache. Archives of Disease in Childhood 1995;72(5):
4137.
Anonymous 1984
Anonymous. Adverse reactions to food additives. Journal of
the Royal College of Physicians of London 1984;18(2):1156.
Apley 1958
Apley J, Naish N. Recurrent abdominal pains: a field survey
of 1000 school children. Archives of Disease in Childhood
1958;33(168):16570.
Apley 1975
Apley J. The Child with Abdominal Pains. 2nd Edition.
Oxford: Blackwell Scientific Publications, 1975.
Bain 1974
Bain HW. Chronic vague abdominal pain in children.
Pediatric Clinics of North America 1974;21(4):9911001.
Bayless 1971
Bayless TM, Huang SS. Recurrent abdominal pain due
to milk and lactose intolerance in school-aged children.
Pediatrics 1971;47(6):102932.
Campo 2001
Campo JV, Di Lorenzo C, Chappetta L, Bridge J, Colborn
K, Gartner JC, et al. Adult outcomes of pediatric recurrent
abdominal pain: do they just grow out of it?. Pediatrics
2001;108(1):e1.
Christensen 1986
Christensen MF. Recurrent abdominal pain and dietary
fiber. American Journal of Diseases in Children 1986;140(8):
7389.
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2. the effect of inadequate blinding to treatment allocation by
outcome assessors, by the removal of studies judged as high or
unclear risk of bias for that domain.
A sensitivity analysis may also be carried out to establish the effect
of missing data on the estimate of treatment effect. Therefore,
we will perform the analysis with and without the studies with
significant missing data to determine if this alters the conclusions.
ACKNOWLEDGEMENTS
We acknowledge the work done on the original review: Angela
Huertas-Ceballos, Stuart Logan, Cathy Bennett, Sarah See, Colin
Macarthur (CM), and Morris Zwi.
Christensen 1995
Christensen MF. Double blind placebo controlled trial of
pizotifen syrup in the treatment of abdominal migraine.
Archives of Disease in Childhood 1995;73(2):183.
DerSimonian 1986
DerSimonian R, Laird N. Meta-analysis in clinical trials.
Controlled Clinical Trials 1986;7(3):17788.
Di Lorenzo 2001
Di Lorenzo C, Youssef NN, Sigurdsson L, Scharff L,
Griffiths J, Wald A. Visceral hyperalgesia in children with
functional abdominal pain. Journal of Pediatrics 2001;139
(6):83840.
Drossman 1995
Drossman DA, Creed FH, Fava GA, Olden KW, Patrick
DL, Toner BB, et al. Psychosocial aspects of the functional
gastrointestinal disorders. Gastroenterology International
1995;8(2):4790.
Edwards 1991
Edwards MC, Finney JW, Bonner M. Matching treatment
with recurrent abdominal pain symptoms: an evaluation of
dietary fiber and relaxation treatments. Behavior Therapy
1991;22(2):25767.
Edwards 1994
Edwards MC, Mullins L, Johnson J, Bernardy N. Survey
of pediatricians management practices for recurrent
abdominal pain. Journal of Pediatric Psychology 1994;19(2):
24153.
Farquar 1956
Farquar HG. Abdominal migraine in children. BMJ 1956;1
(4975):10825.
Faull 1986
Faull C, Nicol AR. Abdominal pain in six-year-olds: an
epidemiological study in a new town. Journal of Child
Psychology and Psychiatry and Allied Disciplines 1986;27(2):
25160.
7
Feldman 1985
Feldman W, McGrath P, Hodgson C, Ritter H, Shipman
RT. The use of dietary fiber in the management of simple,
childhood, idiopathic, recurrent, abdominal pain. Results
in a prospective, double-blind, randomized, controlled trial.
American Journal of Diseases in Children 1985;139(12):
12168.
Finney 1989
Finney JW, Lemanek KL, Cataldo MF, Katz HP, Fuqua RW.
Pediatric psychology in primary health care: brief targeted
therapy for recurrent abdominal pain. Behavior Therapy
1989;20(2):28391.
Friedman 1972
Friedman R. Some characteristics of children with
psychogenic pain. Clinical Pediatrics 1972;11(6):3313.
Goadsby 2000
Goadsby PJ, Hargreaves RJ. Mechanisms of action of
serotonin 5-HT1B/D agonists: insights into migraine
pathophysiology using rizatriptan. Neurology 2000;55(9
Suppl 2):S814.
Good 1995
Good PA. Neurologic investigations of childhood
abdominal migraine: a combined electrophysiologic
approach to diagnosis. Journal of Pediatric Gastroenterolology
and Nutrition 1995;21(Suppl 1):S448.
Grigoleit 2005
Grigoleit HG, Grigoleit P. Peppermint oil in irritable bowel
syndrome. Phytomedicine 2005;12(8):6016.
Harvey 1973
Harvey RF, Pomare EW, Heaton KW. Effects of increased
dietary fibre on intestinal transit. Lancet 1973;1(7815):
127880.
Heinild 1959
Heinild SV, Malver E, Roelsgaard G, Worning B. A
psychosomatic approach to recurrent abdominal pain in
childhood; with particular reference to the x-ray appearances
of the stomach. Acta Paediatrica 1959;48:36170.
Heldenberg 1995
Heldenberg D, Wagner Y, Heldenberg E, Keren S,
Auslaender L, Kaufshtein M, et al. The role of Helicobacter
pylori in children with recurrent abdominal pain. American
Journal of Gastroenterology 1995;90(6):9069.
Higgins 2003
Higgins JPT, Thompson SG, Deeks JJ, Altman DG.
Measuring inconsistency in meta-analyses. BMJ 2003;327
(7414):55760.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
Hill 1991
Hills JM, Aaronson PI. The mechanism of action of
peppermint oil on gastrointestinal smooth muscle.
Gastroenterology 1991;101(1):5565.
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hockaday 1992
Hockaday JM. Is there a place for abdominal migraine as
a separate entity in the IHS classification? No!. Cephalgia
1992;12(6):3468.
Huertas-Ceballos 2008b
Huertas-Ceballos A, Macarthur C, Logan S. Psychosocial
interventions for recurrent abdominal pain (RAP) and
irritable bowel syndrome (IBS) in childhood. Cochrane
Database of Systematic Reviews 2008, Issue 1. [DOI:
10.1002/14651858.CD003014.pub2]
Huertas-Ceballos 2009
Huertas-Ceballos A, Logan S, Bennett C, Macarthur C.
Dietary interventions for recurrent abdominal pain (RAP)
and irritable bowel syndrome (IBS) in childhood. Cochrane
Database of Systematic Reviews 2009, Issue 1. [DOI:
10.1002/14651858.CD003019.pub3]
Humphreys 2000
Humphreys PA, Gevirtz RN. Treatment of recurrent
abdominal pain: components analysis of four treatment
protocols. Journal of Pediatric Gastroenterology and Nutrition
2000;31(1):4751.
Hyams 1995
Hyams JS, Treem WR, Justinich CJ, Davis P, Shoup
M, Burke G. Characterization of symptoms in children
with recurrent abdominal pain: resemblance to irritable
bowel syndrome. Journal of Paediatric Gastroenterology and
Nutrition 1995;20(2):20914.
Hyams 1998
Hyams JS, Hyman PE. Recurrent abdominal pain and
the biopsychosocial model of medical practice. Journal of
Pediatrics 1998;133(4):4738.
Lambert 1991
Lambert JP, Brunt PW, Mowat NAG, Khin CC, Lai CKW,
Morrison V, et al. The value of prescribed high fibre diets
for the treatment of the irritable bowel syndrome. European
Journal of Clinical Nutrition 1991;45(12):6019.
Liebman 1976
Liebman R, Honig P, Berger H. An integrated treatment
program for psychogenic pain. Family Process 1976;15(4):
397405.
Liebman 1979
Liebman WM. Recurrent abdominal pain in children:
lactose and sucrose intolerance, a prospective study.
Pediatrics 1979;64(1):435.
Linton 1986
Linton SJ. A case study of the behavioral treatment of
chronic stomach pain in a child. Behavioral Change 1986;3
(1):703.
Mayer 2002
Mayer EA, Collins SM. Evolving pathophysiology models
of functional gastrointestinal disorders. Gastroenterology
2002;122(7):203248.
Milla 2001
Milla PJ. Irritable bowel syndrome in childhood.
Gastroenterology 2001;120:28790.
8
Miller 1979
Miller AJ, Kratochwill TR. Reduction of frequent
stomachache complaints by time out. Behavior Therapy
1979;10(2):2118.
Minford 1982
Minford AMB, MacDonald A, Littlewood JM. Food
intolerance and food allergy in children: a review of 68
cases. Archives of Disease in Childhood 1982;57(10):7427.
Mortimer 1993
Mortimer MJ, Kay J, Jaron A. Clinical epidemiology of
childhood abdominal migraine in an urban general practice.
Developmental Medicine and Child Neurology 1993;35(3):
2438.
Osborne 1989
Osborne RB. The role of social modeling in unexplained
pediatric pain. Journal of Pediatric Psychology 1989;14(1):
4361.
Painter 1964
Painter NS, Truelove SC. Irritable bowel syndrome in
childhood. Gut 1964;5:201.
Peltonen 1970
Peltonen T. Recurrent abdominal pain. Pediatrics 1970;46
(6):973.
Pittler 1998
Pittler MH, Ernst E. Peppermint oil for irritable bowel
syndrome: a critical review and metaanalysis. American
Journal of Gastroenterology 1998;93(7):11315.
Poley 1973
Poley JR, Bhatia M. Recurrent abdominal pain: recurrent
controversy. Pediatrics 1973;52(1):1445.
Primelles 1990
Primelles D, Grass M, Campoy PE, Estrada R, Carvajal
A, Rubino de la Rosa J. Recurrent abdominal pain
in childhood: retrospective study of 150 cases [Dolor
abdominal recurrente en la infancia: estudio retrospectivo
de 150 casos]. Revista Cubana de Pediatria 1990;62(1):
1827.
Ramchandani 2006
Ramchandani P, Stein A, Hotopf M, Wiles NJ. Early
parental and child predictors of recurrent abdominal pain
at school age: results of a large population-based study.
Journal of the American Academy of Child and Adolescent
Psychiatry 2006;45(6):72936.
Rasmussen 1982
Rasmussen SN, Bondesen S, Edmund C. High fibre diet in
the treatment of the irritable bowel syndrome: a controlled
clinical investigation [Behandling af colon irritabile med
kostfiberrig diaet]. Ugeskrift for Laeger 1982;144(33):
24157.
Rasquin 2006
Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams
JS, Staiano A, et al. Childhood functional gastrointestinal
disorders: child/adolescent. Gastroenterology 2006;130(5):
1527-37.
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Rasquin-Weber 1999
Rasquin-Weber A, Hyman PE, Cucchiara S, Fleisher
DR, Hyams JS, Milla PJ, et al. Childhood functional
gastrointestinal disorders. Gut 1999;45(Suppl 2):11608.
Raymer 1984
Raymer D, Weininger O, Hamilton JR. Psychological
problems in children with abdominal pain. Lancet 1984;1
(8374):43940.
Review Manager 2013 [Computer program]
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). Version 5.2. Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration,
2013.
Robinson 1990
Robinson JO, Alverez JH, Dodge JA. Life events and family
history in children with recurrent abdominal pain. Journal
of Psychosomatic Research 1990;34(2):17181.
Rubin 1967
Rubin LS, Barbero GL, Sibinga MS. Pupillary reactivity
in children with recurrent abdominal pain. Psychosomatic
Medicine 1967;2:11120.
Ruepert 2011
Ruepert L, Quartero AO, De Wit NJ, Van Der Heijden
GJ, Rubin G, Muris JWM. Bulking agents, antispasmodics
and antidepressants for the treatment of irritable bowel
syndrome. Cochrane Database of Systematic Reviews 2011,
Issue 8. [DOI: 10.1002/14651858.CD003460.pub3]
Sandberg 1973
Sandberg DH. Additional references on the tension-fatigue
syndrome. Pediatrics 1973;51(2):3089.
Sanders 1994
Sanders MR, Shepherd RW, Cleghorn G, Woolford H.
The treatment of recurrent abdominal pain in children:
a controlled comparison of cognitive-behavioral family
intervention and standard pediatric care. Journal of
Consulting and Clinical Psychology 1994;62(2):30614.
Sank 1974
Sank LI, Bigian A. Operant treatment of a case of recurrent
abdominal pain in a 10 year old boy. Behavior Therapy
1974;5:67781.
Scharff 1997
Scharff L. Recurrent abdominal pain in children: a review
of psychological factors and treatment. Clinical Psychology
Review 1997;17(2):1456.
Schurman 2005
Schurman JV, Fiesen CA, Danda CE, Andre L, Welchert
E, Lavenbarg T, et al. Diagnosing functional abdominal
pain with the Rome II criteria: parent, child and clinician
agreement. Journal of Paediatric Gastroenterology and
Nutrition 2005;41(3):2915.
Speer 1954
Speer F. The allergic tension-fatigue syndrome. Pediatric
Clinics of North America 1954;11:102938.
9
Stickler 1979
Stickler GB, Murphy DB. Recurrent abdominal pain.
American Journal of Diseases in Children 1979;133:4869.
Stone 1970
Stone RT, Barbero GJ. Recurrent abdominal pain in
childhood. Pediatrics 1970;45(5):7328.
Stowens 1970
Stowens D. Recurrent abdominal pain. Pediatrics 1970;46
(6):9689.
Strdal 2005
Strdal, K, Nygaard E, Bentsen B. Recurrent abdominal
pain: a five-year follow-up study. Acta Paediatrica 2005;94
(2):2346.
Sutton 2000
Sutton A, Duval S, Tweedie R, Abrams K, Jones D.
Empirical assessment of effect of publication bias on meta-
analysis. BMJ 2000;320(7249):15747.
Symon 1986
Symon DNK, Russell G. Abdominal migraine: a childhood
syndrome defined. Cephalalgia 1986;6(4):2238.
Symon 1995
Symon DN, Russell G. Double blind placebo controlled
trial of pizotifen syrup in the treatment of abdominal
migraine. Archives of Disease in Childhood 1995;72(1):
4850.
Van Ginkel 2001
Van Ginkel R, Voskuijl WP, Benninga MA, Taminiau
JA, Boeckxs-taens GE. Alterations in rectal sensitivity
and motility in childhood irritable bowel syndrome.
Gastroenterology 2001;120(1):318.
Vasquez 1992
Vasquez R, Calvo M, Martinez A, Chavez P. Recurrent
abdominal pain in children [Dolor abdominal recurrente en
ninos]. Actualizaciones Pediatricas 1992;2:227.
Walker 1989
Walker LS, Greene JW. Children with recurrent abdominal
pain and their parents: more somatic complaints, anxiety,
and depression than other patient families?. Journal of
Pediatric Psychology 1989;14(2):23143.
Walker 1998
Walker LS, Guite JW, Duke M, Barnard JA, Greene JW.
Recurrent abdominal pain: a potential precursor of irritable
bowel syndrome in adolescents and young adults. Journal of
Pediatrics 1998;132(6):10105.
Walker 1999
Walker LS. The evolution of research on recurrent
abdominal pain: history, assumptions and conceptual
model. Chronic and Recurrent Pain in Children and
Adolescents. Progress in Pain Research and Management 1999;
13:14171.
Pharmacological interventions for recurrent abdominal pain in childhood (Protocol)
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Walker 2004
Walker LS, Lipani T, Greene J, Caines K, Stutts J, Polk B, et
al. Recurrent abdominal pain: symptoms subtypes based on
the Rome II criteria for pediatric functional gastrointestinal
disorders. Journal of Paediatric Gastroenterology and
Nutrition 2004;38(2):18791.
Wardhan 1993
Wardhan H, Ojha P, Kulshrestha R. Recurrent abdominal
pain in children in developing countries frequently has an
organic basis. Pediatric Surgery International 1993;8:202.
Wetchler 1992
Wetchler JL. Family treatment of a thirteen year-old with
chronic stomach pain. Journal of Family Psychotherapy 1992;
3(4):114.
WHO 2010
World Health Organization. International Classification of
Diseases (ICD). http://www.who.int/entity/classifications/
icd/ICD10Volume2_en_2010.pdf. Geneva, (accessed 23
March 2012).
Wilhelm 2008
Wilhelm SM, Brubaker CM, Varcak EA, Kale-Pradhan
PB. Effectiveness of probiotics in the treatment of irritable
bowel syndrome. Pharmacology 2008;28(4):496505.
Williams 1996
Williams K, Chambers M, Logan S, Robinson D.
Association of common health symptoms with bullying in
primary school children. BMJ 1996;313(7048):179.
Worawattanakul 1999
Worawattanakul M, Phoads JM, Lichtman SN, Ulshen
MH. Abdominal migraine: prophylactic treatment and
follow up. Journal of Pediatric Gastroenterology and Nutrition
1999;28(1):3740.
Zhang 1991
Zhang H, Luo LL, Wang Y, Sun M. Diagnosis and
treatment for recurrent abdominal pain in Infant. Sapparo
Medical Journal 1991;60(6):5613.
ster 1972
ster J. Recurrent abdominal pain, headache and limb
pains in children and adolescents. Pediatrics 1972;50(3):
42936.
References to other published versions of this review
Huertas-Ceballos 2008a
Huertas-Ceballos AA, Logan S, Bennett C, Macarthur C.
Pharmacological interventions for recurrent abdominal pain
(RAP) and irritable bowel syndrome (IBS) in childhood.
Cochrane Database of Systematic Reviews 2008, Issue 1.
[DOI: 10.1002/14651858.CD003017.pub2]
Indicates the major publication for the study
10
ADDITIONAL TABLES
Table 1. Assessment of risk of bias in included studies

Domain Risk of bias judgement

Low High Unclear

Selection bias

Random sequence generation If the study details any of the
following methods: (1) simple
randomisation (such as coin-
tossing, throwing dice or deal-
ing previously shuffled cards,
a list of random numbers,
or computer generated random
numbers) or (2) restricted ran-
domisation such as blocked,
ideally with varying block sizes
or stratified groups, provided
that within groups randomisa-
tion is not affected
If the study details no ran- If there is not sufficient detail to
domisation or an inadequate judge the risk of bias.
method such as alternation, as-
signment based on date of birth,
case record number, and date
of presentation. These may be
referred to as quasi-random
methods

Allocation concealment
If the study details concealed al- If the study details a method If there is not sufficient detail to
location sequence in sufficient where the allocation is known judge the risk of bias.
detail to determine that alloca- prior to assignment
tions could not have been fore-
seen in advance of or during en-
rolment

Performance bias

Blinding of participants and If the study details a method If the methods detail that the If there is not sufficienIt detail
personnel of blinding the participants and participants or study personnel to judge the risk of bias
personnel. This requires suffi- were not blinded to the study
cient detail to show they were medication or placebo.
unable to identify the therapeu-
tic intervention from control
intervention.

Detection bias

Blinding of outcome assess- If the study details a blinded
ment outcome assessment. This may
only be possible for outcomes
that are externally assessed
If the outcome assessment is not If there is not sufficient detail to
blinded. We expect this may be judge the risk of bias.
unavoidable for self-rated out-
comes of unblinded interven-
tions

Attrition bias

Pharmacological interventions for recurrent abdominal pain in childhood (Protocol) 11

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Assessment of risk of bias in included studies (Continued)

Incomplete outcome data
If the study reports attrition We may judge the risk of at- If there is not sufficient detail
and exclusions, including the trition bias to be high due to to judge the risk of bias. For ex-
numbers in each intervention the amount, nature or handling ample, if the number of people
group (compared with total (such as per-protocol analysis) randomised to each treatment is
randomised participants), rea- of incomplete outcome data not reported
sons for attrition or exclusions
and any re-inclusions. And the
impact of missing data is not
felt to alter the conclusions and
there are acceptable reasons for
the missing data

Reporting bias

Selective reporting If there is complete reporting, If the reporting is selective, so If there is not sufficient detail to
this will be found on compar- some outcome data is not re- judge the risk of bias. For exam-
ison of the protocol and pub- ported ple, protocols are unavailable
lished study, if available

WHATS NEW

Date Event Description

31 January 2014 New citation required and major changes Update of review with revised protocol

CONTRIBUTIONS OF AUTHORS
Review design: AM, SL
Review co-ordination: AM
Data collection:

Search strategy design: AM, AB

Searches undertaken: AM, AB
Search results screened: AM, AB, RA, TN, JTC
Retrieval of papers: AM, AB
Paper screening and appraisal, and extraction of data: AM, AB, RA, TN, JTC
Writing to authors for additional information: AM, AB
Entering the data into RevMan: AM, AB, RA, TN, JTC

Analysis of the data: AM, AB, RA, TN, JTC, SL

Pharmacological interventions for recurrent abdominal pain in childhood (Protocol) 12
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Interpretation of the data:

Methodological perspective: AM, AB, RA, TN, JTC

Clinical perspective: AM, TN, SL

DECLARATIONS OF INTEREST
Alice E Martin (AM) - none known.
Tamsin V Newlove-Delgado (TN) - none known.
Rebecca A Abbott (RA) - none known.
Alison Bethel (AB) - none known.
Jo Thompson-Coon (JTC) - none known.
Stuart Logan (SL) - none known.
Vasilis Nikolaou (VN) - none known.
The authors who practice clinical paediatrics are AM and SL. AM is a paediatric trainee and works under the guidance of various
Consultant Paediatricians. SL is a Consultant Paediatrician and treats children according to current best evidence, in light of their
preference. Therefore, there are no conflicts of interest with this review.

SOURCES OF SUPPORT

Internal sources
None, Not specified.

External sources
None, Not specified.

NOTES
This is a new protocol for an update of a previously published review (Huertas-Ceballos 2008a).

Pharmacological interventions for recurrent abdominal pain in childhood (Protocol) 13

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.