rajindrajith2018

Prévia do material em texto

Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ierh20
Expert Review of Gastroenterology & Hepatology
ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20
Functional abdominal pain disorders in children
Shaman Rajindrajith, Judith Zeevenhooven, Niranga Manjuri Devanarayana,
Bonaventure Jayasiri Crispus Perera & Marc A. Benninga
To cite this article: Shaman Rajindrajith, Judith Zeevenhooven, Niranga Manjuri Devanarayana,
Bonaventure Jayasiri Crispus Perera & Marc A. Benninga (2018): Functional abdominal
pain disorders in children, Expert Review of Gastroenterology & Hepatology, DOI:
10.1080/17474124.2018.1438188
To link to this article: https://doi.org/10.1080/17474124.2018.1438188
Accepted author version posted online: 06
Feb 2018.
Submit your article to this journal 
View related articles 
View Crossmark data
Ac
ce
pte
d M
an
us
cri
pt
 
1 
 
Publisher: Taylor & Francis 
Journal: Expert Review of Gastroenterology & Hepatology 
DOI: 10.1080/17474124.2018.1438188 
Review 
Functional abdominal pain disorders in children 
 
Shaman Rajindrajith1, Judith Zeevenhooven2, Niranga Manjuri Devanarayana3, Bonaventure 
Jayasiri Crispus Perera4, Marc A. Benninga2 
 
1Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Sri Lanka 
2Department of Pediatric Gastroenterology and Nutrition, Emma Children, Hospital, Academic 
Medical Centre, Amsterdam, The Netherlands 
3Department of Physiology, Faculty of Medicine, University of Kelaniya, Sri Lanka 
4Asiri Hospital, Narahenpita, Sri Lanka 
 
Correspondence: 
Shaman Rajindrajith 
Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, 
Ragama, Sri Lanka. 11010 
Email: shamanrajindrajith4@gmail.com 
Telephone: +94-112-958031 
Fax: +94-112-958337 
 
 
Ac
ce
pte
d M
an
us
cri
pt
 
2 
 
Abstract 
Introduction: Chronic abdominal pain is a common problem in pediatric practice. The majority 
of cases fulfill the Rome IV criteria for functional abdominal pain disorders (FAPDs). At times, 
these disorders may lead to rather serious repercussions. 
Area covered: We have attempted to cover current knowledge on epidemiology, 
pathophysiology, risk factors related to pathophysiology, clinical evaluation and management of 
children with FAPDs. 
Expert commentary: FAPDs are a worldwide problem with a pooled prevalence of 13.5%. 
There are a number of predisposing factors and pathophysiological mechanisms including 
stressful events, child maltreatment, visceral hypersensitivity, altered gastrointestinal motility 
and change in intestinal microbiota. It is possible that the environmental risk factors intricately 
interact with genes through epigenetic mechanisms to contribute to the pathophysiology. The 
diagnosis mainly depends on clinical evaluation. Commonly used pharmacological 
interventions do not play a major role in relieving symptoms. Centrally directed, 
nonpharmacological interventions such as hypnotherapy, and cognitive behavioral therapy have 
shown both short and long term efficacy in relieving pain in children with FAPDs. However, 
these interventions are time consuming and need specially trained staff and therefore, not 
currently available at grass root level. Clinicians and researchers should join hands in searching 
for more pragmatic and effective therapeutic modalities to improve overall care of children with 
FAPDs. 
 
Keywords: Abdominal pain, Irritable bowel syndrome, functional dyspepsia, Rome criteria, child 
maltreatment, hypnotherapy, behavioral therapy, antidepressants, prokinetics 
 
 
Ac
ce
pte
d M
an
us
cri
pt
 
3 
 
1. Introduction 
Chronic abdominal pain is a common and sometimes disabling clinical condition in children. The 
spectrum of this disorder ranges from serious organic disease to functional gastrointestinal 
disorders. In day to day clinical practice, the majority of children who seek healthcare advices 
for their chronic abdominal pain are suffering from functional abdominal pain disorders (FAPDs). 
This group consists of 4 main diagnostic entities namely: irritable bowel syndrome (IBS), 
functional dyspepsia (FD), abdominal migraine (AM) and functional abdominal pain (FAP) – not 
otherwise specified. Although the majority of clinicians consider these disorders to be benign, 
these disorders have serious ramifications on health related quality of life of affected children, 
interfere with school performance, affect their education and other aspects of their lives [1]. 
Furthermore, FAPDs incur a large healthcare costs in both inpatient and outpatient settings [2]. 
In addition, the pathophysiological mechanisms underlying FAPDs are not clearly understood. 
As a result, the management strategies for FAPDs are also not very robust and evidence based. 
 
In this review, we summarize the current cutting edge knowledge on epidemiology, risk factors, 
pathophysiology, clinical evaluation and management of FAPDs in children. Furthermore, we 
also challenge the current research paradigm and have outlined a road map on possible 
directions for future research which would of benefit to children with FAPDs. 
 
2. Classification 
2.1. Recurrent abdominal pain (RAP) and Rome Criteria 
In 1958, John Apley was the first person to classify children suffering from chronic abdominal 
pain without an apparent organic disorder as having “recurrent abdominal pain”. He defined it as 
at least three episodes of abdominal pain, severe enough to affect their activities over a period 
longer than three months [3]. This broad definition served as a corner stone for both clinical 
practice and research for over four decades. The introduction of the Rome criteria in 1989 
provided a new diagnostic classification system for chronic abdominal pain in adults. Using 
these criteria, it was demonstrated that a large proportion of children with chronic abdominal 
pain fulfill adult criteria for IBS [4]. Arrival of Rome II criteria in 1999, and Rome III criteria in 
2006 revolutionized the way that clinicians and researchers define this clinical entity [5, 6]. 
Hospital based studies have shown, 72-89% of children with chronic abdominal pain could be 
classified into four FAPDs using Rome II criteria [7, 8]. Most of the children who were unable to 
fulfill the Rome II criteria for the diagnosis of FAPDs did so due to insufficient duration of pain 
(duration of 12 weeks) [8]. Moreover, 87% of children with recurrent abdominal pain (RAP) 
Ac
ce
pte
d M
an
us
cri
pt
 
4 
 
investigated in a tertiary care center fulfilled the Rome III criteria for FAPDs [9]. The authors also 
noted that the majority of the 13% who did not fulfill Rome III criteria for FAPDs did so simply 
due to insufficient pain frequency (at least once a week for 2 months). The diverse nature of 
these findings were further strengthened by another hospital based cohort study from the 
developing world which illustrated that the majority of children (71%) with abdominal pain could 
be classified to have FGIDs according to the Rome III criteria [10]. These observations led to 
replace of the term RAP to abdominal pain predominant functional gastrointestinal disorders 
(AP-FGIDs). 
 
Both Rome II and Rome III criteria did not improve diagnostic utility. Schurman et al, comparing 
child reports, parental reports and the physician diagnosis, showed a diagnostic disagreement 
between 3 groups when they used the Rome II criteria. Most of the time the reasons for the 
discrepant diagnoses were dueto the disagreement on symptoms related to defecation [8]. The 
diagnostic agreement (both Rome II and Rome III) was also poor when pediatric 
gastroenterologists were compared to gastroenterology fellows [11, 12]. Even with all these 
problems, the arrival of Rome II and Rome III criteria boosted pediatric research into this 
important area leading to a sharp rise in the number of publications together with expansion of 
knowledge during the last decade. However, the deficiencies mentioned above and the 
expansion of the knowledge and better understanding of childhood FAPDs paved the way to 
develop the Rome IV criteria [13]. 
 
2.2. Rome IV criteria 
The new Rome criteria (Rome IV) were released in 2016 after summarizing a decade of 
research in this [13]. In this iteration, the label of abdominal pain related functional 
gastrointestinal disorders was replaced by the term functional abdominal pain disorders 
(FAPDs). Although the terminology was slightly altered the basic categories (FD, IBS, AM and 
FAP) remained the same. The subcategories in FD (post prandial distress syndrome and 
epigastric pain syndrome) and IBS (diarrhea predominant, constipation predominant, mixed and 
un-sub-typed) were included in parallel with adult criteria and sub-classifications. In addition, the 
frequency of pain symptoms was differently worded from once a week for at least 2 moths in 
Rome III to at least 4 days per month for at least 2 months [13]. The new Rome IV criteria 
related to functional abdominal pain disorders are summarized in table 1. 
 
 
Ac
ce
pte
d M
an
us
cri
pt
 
5 
 
3. Epidemiology 
The first epidemiological study on RAP was conducted by Apley and Nash in 1958. Using the 
earlier definition of RAP, they found that 10.5% of British school children were suffering from 
RAP [3]. However, the changing nature of criteria has led to a significant change in the 
epidemiological picture of abdominal pain related FGIDs . The Rome II criteria were restrictive 
and the prevalence of FGIDs in the same population when using them was significantly lower 
than when using the more inclusive Rome III criteria [14]. In addition, the different methods of 
data collection (interviewing children, self-administered questionnaires, parental 
questionnaires), and inclusion of children of different age groups have led to some difficulty in 
interpretation of the ever expanding epidemiological data. 
 
A recent meta-analysis of epidemiologic studies on abdominal pain conducted from 1957 to 
2014, including 196,472 children from 58 studies, noted a global pooled prevalence of 13.5% 
[15]. In this meta-analysis, the prevalence of IBS, FD and FAP were 8.8%, 4.5% and 3.5% 
respectively. Another systematic review and meta- analysis of IBS in Asian children showed a 
much higher prevalence of 12.4% [16]. In contrast to the data from the meta-analysis, novel 
data (after 2014), from the USA has also showed a higher prevalence rate of AM (9.2%), and 
lower prevalence rates of IBS (2.8%), FAP (0.3%) and FD (0.2%) in American children and 
adolescents [17]. A more recent study from Greece found that the prevalence of IBS, FD and 
FAP were 2.9%, 0.4% and 0.8% respectively [18]. Emerging new data from the African 
subcontinent found that 9.9% of Nigerian children are suffering from AP-FGIDs and prevalence 
of IBS, FD, and FAP are 5.6%, 0.4% and 2.5% respectively [19]. Several studies from South 
America found that AP-FGIDs are a common problem in these countries as well (FD, 0.8-1.8%, 
IBS, 3.8-6.4%, FAP, 1.7-3.7% and AM 0.7-5.2%) [20, 21, 22] 
 
Recognizing subtypes of IBS is important in day to day clinical management of children as they 
present with different disabling bowel habits. Using adult Rome III criteria, some studies have 
identified the presence of subtypes of IBS in children as well. A prospective, hospital based 
study which enrolled 100 children with IBS from Italy, found that IBS with predominant 
constipation (IBS-C) has the highest prevalence of 45% followed by IBS with mixed bowel habit 
and IBS untypable (IBS-M/U) (29%) and IBS with predominant diarrhea (IBS-D) 26% [23]. A 
more recent epidemiological study estimated the distribution of IBS subtypes in Greece and 
reported higher prevalence of IBS-M (47.9%). IBS-U, IBS-D and IBS-C, which were noted in 
29%, 16.7% and 6.3% respectively [18]. On the contrary, an Asian study noted an almost similar 
Ac
ce
pte
d M
an
us
cri
pt
 
6 
 
prevalence of IBS-C, IBS-D and IBS-M (29-30%) [24]. The changing nature of IBS subtypes are 
well known and it has been shown that after 1 year of follow up a significant number of children 
change their subtype or outgrow of their symptoms [23, 25]. Data on subtypes of FD are yet to 
emerge. 
 
4. Predisposing Factors 
There are several recognized groups of predisposing factors that are associated with FAPDs 
(Table 2). Most of them intricately blend with other identified pathophysiological mechanisms to 
potentiate their effects at both central and peripheral levels and significantly contribute to the 
development of FAPDs and perpetuation of their symptoms. 
 
4.1. Age and sex 
A systematic review and a meta-analysis of children with abdominal pain revealed that FAPDs 
are more common in girls [15]. Two studies found reduction of prevalence of FAPDs in 10-16-
year-old children as they grow older. [24, 26] . However, a meta-analysis of epidemiology of AP-
FGIDs including chronic abdominal pain showed no difference in prevalence between children 
younger and older than 12 years of age [15]. 
 
4.2. Psychological stress including abuse 
Several studies have shown the association between psychological stress and the development 
of a FAPD and considered it as a cornerstone in the pathogenesis of FGIDs in children [26, 27, 
28, 29]. Recognized stressful life events in a study conducted by Devanarayana et al. included 
separation from the best friend, frequent punishments at school, failure in academic 
examination and admitted to a hospital for another illness [26]. Two studies from East Asia have 
shown higher stress scores in children with IBS [27, 28]. Excess worry is another known 
precipitating factor for IBS [28]. 
 
Exposure to traumatic life events such as physical, sexual and emotional abuse predispose 
children to develop FAPDs [29]. Children with FAPDs, who were exposed to abuse had more 
severe pain and bowel symptoms indicating the effects of abuse and trauma on the 
development and perpetuation of symptoms [29]. Furthermore, the adult literature also clearly 
shows that these exposures lead to persistence of symptoms of FAPDs such as IBS into 
adulthood [30]. 
 
Ac
ce
pte
d M
an
us
cri
pt
 
7 
 
4.3. Early life events 
Gastric suction is a common event in neonatal units in the management of sick neonates. 
Anand et al. noted that gastric suction during infancy predisposes to the development of ill-
defined gastrointestinal symptoms without obvious pathology [31]. However, the evidence is not 
strong enough to consider that this procedure clearly leads to the development of FAPDs. 
Studies using animal models have thrown some light upon this area [32, 33, 34]. Transient 
colonic irritation during very early life and maternal separation during neonatal period, lead to 
the development of visceral hypersensitivity which is considered to be the corner stone in the 
pathogenesis of FAPDs [32, 33]. Another study using a rat model reported that neonatal gastric 
suction indeed leads to visceral hypersensitivity and this could be prevented by blocking the 
corticotrophin releasing pathway [34]. Children born to mothers with gestational diabetesand 
pregnancy induced hypertension were shown to have a higher tendency to develop FAPDs in 
later life [35]. The same study showed that admission to a special care baby unit as a 
predisposing factor and Caesarian section for the delivery and introduction of cows milk formula 
and shorter duration of breast feeding were not associated with the development of FAPDs 
[35]. 
 
Having had umbilical hernia, pyloric stenosis, Henoch-Schonlein purpura, and a history of cow’s 
milk allergy are other early life events know to influence the development of FAPDs [36, 37, 
38]. However, further studies are needed to confirm these associations with FAPD directly with 
more robust studies as most of the research are based on animal models. 
 
4.5. Genetic, epigenetic and environmental factors 
Studies in adults have noted that patients with IBS are more likely to have a family history of 
similar illness or other bowel symptoms than controls [39]. Similarly, twin studies suggested that 
there is a higher concordance of occurrence of IBS in monozygotic twins than in dizygotic twins 
[40]. A study including 6060 twin pairs found that the concordance rate of IBS in monozygotic 
twins was 17.2% and 8.4% in dizygotic twins [40]. Although the finding was significant, one 
would expect a higher concordance rate in monozygotic twins if genetic factors play a major 
role. Therefore, it is possible that in the background of genetic susceptibility, social and 
environmental factors play an important role in developing IBS [40]. This finding is further 
strengthened when other studies reported that parents of children with FAPDs have higher 
tendency to develop similar illnesses [17, 41]. 
 
Ac
ce
pte
d M
an
us
cri
pt
 
8 
 
Studies among adults have revealed a large number of genes associated with FAPDs specially 
with IBS. They include genes regulating corticotrophin releasing hormone receptor 1 (CRHR1, 
single nucleotide polymorphisms [SNPs] rs7209436, rs110402 and rs242924); glucocorticoid 
receptor (NR3C1, SNPs rs2963155 and rs33389); female sex hormones (progesterone receptor 
or PGR, SNPs rs1042838 and rs10895068); 5-HT signaling system (HTR3A c.–42C>T SNP 
rs1062613), inflammation (IL1B, SNP rs16944); and catecholaminergic signaling (ADRA1D, 
SNP rs1556832; ADRA2B, SNP rs1042717; COMT, SNP rs174697) [42, 43]. Another important 
genetic factor includes TNFSF 15 polymorphism which is associated with diarrhea predominant 
IBS, constipation predominant IBS and post infectious IBS [44, 45, 46]. The protein which 
resulted from this polymorphism regulates immune modulation which in turn leads to the 
development of IBS. 
 
Although these studies are well conducted on carefully identified phenotypes, it would be an 
oversimplification if one would try to reduce the complex pathogenic nature of FAPDs with 
heritability or genetic polymorphism alone. It is possible that there could be more complex 
interactions between environments, gender, and genetic polymorphism with epigenetic DNA 
which is known to modify activity of a given gene or a group of genes to develop a particular 
phenotype of FAPD. DNA methylation and histone modification are the 2 common mechanisms 
of epigenetic modification. DNA methylation usually inhibits gene expression whereas histone 
modification increases the access of transcription factors to DNA and initiate transcription. 
Micro RNAs (miRNAs) induce translational repression and exonucleolytic mRNA decay, there 
by inhibiting production of the targeted protein [47]. 
 
One of the best examples of epigenetic effects altering the genetic function predisposing to 
FAPDs was illustrated by McGowen and colleagues. They studied postmortem hippocampal 
specimen of suicidal victims who had a history of child abuse, and compared them with suicidal 
victims with no such history. They clearly illustrated epigenetic alteration (cytosine methylation) 
of an NR3C1 promotor of neuron-specific glucocorticoid receptor leading to reduction in its 
expression. This leads to ineffective negative feedback mechanism and increase HPA axis 
activity which could predispose abused individuals to develop FAPDs [48]. All prenatal 
stresses, postnatal complications, other environmental factors, adverse life events, and 
exposure to abuse can work through these epigenetic mechanisms to alter gene expression and 
protein production which could potentially alter gut motility, pain perception and expression of 
microbiota to generate symptoms and expression of the specific type of FAPD in children. 
Ac
ce
pte
d M
an
us
cri
pt
 
9 
 
5. Effects of Functional Abdominal Pain Disorders 
5.1. Health Related Quality of Life and family impact 
Health related quality of life (HRQoL) measures the overall impact of a disease on several 
planes including physical, emotional, social and school domains. It is very valuable in assessing 
children with FAPDs as there are no precise biomarkers to assess the severity and response to 
therapy. Children with FAPDs have overall poor HRQoL [1, 17, 49, 50]. Maternal reports on 
their children have convincingly proved that children with FAPDs have poor HRQoL in all 4 
domains [17]. In addition HRQoL has negative correlation with frequency and severity of 
abdominal pain and overall severity of bowel symptoms [1]. Moreover, children with a FAPDs 
have low HRQoL which is very similar to those with severe organic gastrointestinal disorders 
like inflammatory bowel disease [49, 50]. Children with IBS had lower scores for education, 
social activity, friendships with peers, irritation, and leisure activity [51]. All these studies show 
the distressing effects of FAPDs on HRQoL in children. 
 
5.2. Impact on the health care system 
The epidemiological burden also reflects at the level of healthcare delivery. Pediatric 
gastroenterology clinics are overburdened with FGIDs. The majority of children attending to 
these clinics are suffering from IBS and FAP [52] . Data from the North America noted low 
yield from basic investigations (blood counts, ESR, and inflammatory markers), invasive 
investigations (gastrointestinal endoscopy) and rising costs in assessing children with FAPDs 
[53]. 
 
Analysis of Kids Inpatients Sample database (1997-2009), in the USA, has given some 
insightful information about the burden of FGIDs on the healthcare system. According to the 
analysis chronic abdominal pain is the commonest diagnosis on discharge from the hospital. 
Although the overall number of cases of IBS and FD are less, the frequencies are on the rise 
from 1997 to 2009. Patients discharged with a primary diagnosis of chronic abdominal pain yet 
again had the greatest increase in average cost per hospital stay (from $3558 to 13331) 
followed by IBS ($5278 to 18853). FD had always been the most expensive FAPD to treat and 
the percentage of the rise in cost was 183% from $12 674 to 35 898 [2]. Another study from The 
Netherlands noted similarly high expenditure on children with FAPDs (total annual cost of 2512 
Euros per patient). The major portion of this cost was driven by inpatient and outpatient care. 
However, contrary to the previous study, they did not find a difference in healthcare expenditure 
Ac
ce
pte
d M
an
us
cri
pt
 
10 
 
in different types of AP-FGDs [54]. These data clearly illustrate the healthcare burden and rising 
costs of FAPDs on the health budgets of countries indicating indirectly the societal cost. 
 
6. Pathophysiological mechanisms for functional abdominal pain 
Pathophysiology of childhood FAPDs is not very clearly understood even after nearly 2 decades 
of introductionof paediatric Rome criteria. Although FAPDs are classically described as disease 
entities with no underlying organic diseases, evidence is emerging that most of the FAPDs have 
a number of potential pathological mechanisms. However, the number of research conducted in 
search of the pathophysiology of each of the FAPDs in children is very limited. The available 
studies most of the time have small samples and sometimes do not included a control group 
[55]. A large number of studies included an umbrella term of recurrent abdominal pain rather 
than validated samples with a specific diagnosis such as IBS and FD. Most of the time the 
reported mean differences are small between cases and controls and do not provide a statistical 
power to identify the proposed mechanism as a meaningful pathophysiological entity. Finally, 
most of the proposed mechanisms do not correlate with the clinical symptoms. 
 
Even in adult literature, controversies exist in the pathophysiology of well researched disease 
entities such as IBS [56]. There are two main models that describe the pathophysiology of IBS 
in adults [57]. Several authorities in the field think the “bottom-up model” as the most likely 
mechanism that could explain the pathophysiology of IBS. This model proposes that peripheral 
factors in the gut such as low grade inflammation, post-infectious changes, altered gut 
microbiota, immune activation, altered serotonin and bile salt metabolism and increased 
intestinal permeability in combination or isolation play the key role and the alteration in cerebral 
functions are secondary to brain-gut interactions [58]. The proponents of the “top-bottom model” 
suggest that the main pathophysiological mechanisms initially evolved in the brain. In this 
model, the primary disease processes in the brain interact with the peripheral organs through 
the brain-gut axis to generate alterations in the gut microbiome, immune function, motility and 
secretion and intestinal epithelium which ultimately lead to clinical expression of IBS [42].. 
 
Therefore, precise underlying mechanisms remain largely undetermined in children. 
Furthermore, it is imperative to understand that most of the time a single pathophysiological 
model may not be able to explain the symptoms of FAPDs. It is possible that several proposed 
pathophysiological processes blend and interact intricately with each other to generate a 
particular phenotype such as IBS. 
Ac
ce
pte
d M
an
us
cri
pt
 
11 
 
Therefore, it is extremely difficult to prioritize the exact final common pathway of developing 
FAPDs in children. In the following section we describe all proposed pathophysiological 
mechanisms in childhood FAPDs. 
 
6.1. Brain-gut-axis 
The brain-gut-axis refers to the bidirectional exchange of information between the 
gastrointestinal tract and the brain. There is a complex, integrated network of communication 
between cognitive and emotional centers of the brain and vice versa. These, include the central 
and autonomic nervous systems, enteric nervous system and neuroendocrine system and the 
neuro-immune system [59, 60]. 
 
Altered functioning of the brain-gut axis has been suggested as one of the main underlying 
mechanism for the development of symptoms in patients with FAPDs [61]. There is a clear 
association between exposure to adverse life events (such as stress and exposure to abuse) 
and development of FAPDs [26, 27, 28, 29, 62]. This observation leads to the hypothesis that 
psychological factors cause alterations in pain processing giving rise to visceral hypersensitivity 
and other physiological changes in the gut such as alteration in motility, permeability, secretion, 
immune reactions and the microbiome [56]. Patients with FGIDs who were exposed to trauma 
are reported to have greater temporal summation than FGIDs patients not exposed to trauma 
and healthy controls [63]. The same study also demonstrated that the , patients with FGIDs 
exposed to trauma had more severe gastrointestinal and non-gastrointestinal symptoms, 
number of chronic pain sites, and disability [63]. Evidence is emerging that there are several 
networks of the brain that interact with each other in a very complicated manner to generate 
symptoms of FGIDs. Adults with IBS have interactions between central executive network 
(involving attention, working memory planning and response selection), salient network 
(responding to external and internal stimuli that reach to the brain), sensory motor network and 
autonomic networks (central control of autonomic function) [42, 56, 61]. Furthermore, these 
interactions alter the activity of enteric nervous system through the brain-gut axis and 
hypothalamo-pituitary-adrenal axis (HPA axis), and increase the permeability of the gut, alter its 
motility and even change the composition of the gut microbiota in individuals with FGIDs [42, 
61]. 
 
 
 
Ac
ce
pte
d M
an
us
cri
pt
 
12 
 
6.2. Visceral hypersensitivity 
Visceral hypersensitivity is considered to be one of the main pathophysiological mechanisms in 
patients with FAPDs [56]. A study in children with IBS has demonstrated that abdominal pain is 
associated with abnormal perception of visceral sensations and hypersensitivity [64]. Similar 
results have been reported in several previous studies [65, 66, 67]. Heightened auditory startle 
reflex is also noted in children with functional abdominal pain [68] which probably indicates that 
these children have a hyper-responsiveness to non-gastrointestinal stimuli as well. In addition, 
some FAPDs such as IBS and FD, are associated with abnormal synthesis, transport and 
inactivation of peptides and amines in the intestinal mucosa [69, 70]. These may be associated 
with abnormal sensation, motility, secretion, permeability and immune functions observed in 
these patients. 
 
6.3. Modulation of pain at the enteric nervous system 
The enteric nervous system is an intricate network of neurons which can self-regulate gut 
functions without peripheral or central nervous system input [71]. This network is primarily 
housed in two nerve pelxi, the myenteric plexus (Auerbach) and the submucous plexus 
(Meissner). Gastrointestinal afferent sensory fibers terminating within the gut wall express an 
array of membrane receptors and ion channels that obtain information about distortion of the 
mucosal epithelium and the luminal contents. These neurons activate local responses as well as 
transmit sensory information to central nervous system for processing and integration [72]. 
However, most of the afferent information received from the gut are unperceived and used in 
reflexes that control motility, secretion and blood flow [73]. There is hardly any data on this 
important area of e enteric nervous system functions in children with FAPDs. One study 
assessing mast cell-induced excitation of visceral nociceptive sensory neurons in adults with 
IBS has suggested a possibility of initiation and perpetuation of symptoms through modulation 
of sensory neurons in enteric nervous system [74]. 
 
6.4. Modulation of pain at the central nervous system 
Increased pain perception in FAP is considered to be at least partly related to altered 
descending inhibition and pain affecting at the peripheral level and catastrophizing of pain at the 
central level [75]. This implies that increased pain perception in IBS patients does not simply 
depends on a tendency to report more pain but reflects increased spinal nociceptive 
transmission [75]. Studies using functional magnetic resonance imaging (fMRI) have 
demonstrated that insular cortex and pre-frontal cortex are the main areas of the central 
Acce
pte
d M
an
us
cri
pt
 
13 
 
nervous system which are involved in the processing of visceral pain perception in patients with 
IBS [76]. It is also possible that alterations in pain appraisal, hypervigilance to interoceptive 
signals from the gut and engagement of emotional arousal could also contribute to the 
pathophysiology of FAPDs [77]. 
 
6.5. Neurotransmitters and receptors 
In addition, neurotransmitters such as serotonin have been implicated in the pathogenesis of 
FAPDs [78]. Up-regulation of the serotonin transporter (SERT) level in the midbrain and 
thalamus is considered to be related to the production of abdominal and psychological 
symptoms via a brain–gut interaction in patients with FD [70]. 
 
Furthermore, dopamine D2 receptor (D2R) binding capacity in patients with FD is reported to be 
significantly correlated with drinking capacity and evoked nausea [69]. This suggests the 
involvement of altered, probably increased, dopaminergic transmission in the striatum in FD 
[69]. However, to what extent this may be secondary to abnormalities in serotonergic pathways 
remains to be investigated. 
 
6.6. Autonomic nervous system 
Autonomic nervous system has been considered to be the main communicator between the 
brain and the gut [79]. It is possible that alterations in the autonomic nervous system can 
influence both the brain and the gut. However, the scientific evidence available so far is 
contradictory and does not indicate an exact relationship between abnormalities in autonomic 
nervous system and FAPDs. 
 
Previous studies conducted in adolescents with FAP have shown an increase in 
parasympathetic activation during both consecutive phases of cyber ball game while healthy 
children remained stable [80]. Elsenbruch and coworkers observed a correlation between vagal 
response and post prandial abdominal symptoms observed in adults with IBS-D and IBS-C [81]. 
Abnormal gastric motility and underlying vagal defects are demonstrated in adult IBS patients 
[81, 82]. In contrast to this, another study conducted in children with FAP has shown a negative 
correlation between vagal activity and psychological distress [83]. Another study has reported 
abnormal fingertip blood flow responses suggesting the presence of excess sympathetic activity 
[84]. Findings of the above studies suggest that a shifting of sympathetic-parasympathetic 
balance may contributes to the pathogenesis of FAPDs. 
Ac
ce
pte
d M
an
us
cri
pt
 
14 
 
6.7. Hypothalamo-pituitary-adrenal axis and other endocrine mediators 
The hypothalamic-pituitary-adrenal axis (HPA axis) is considered to be an important mediator of 
reactions to psychological and physiological stress. Activation of the HPA axis by stress and 
other centrally mediated mechanisms ultimately results in increased release of corticotrophin 
releasing hormone (CRH), adrenocorticotrophic hormone (ACTH) and cortisol. Increased 
release of CRH is believed to promote central sensitization while ACTH and cortisol tend to 
activate resident immune cells and extrinsic primary afferents in the gastrointestinal tract 
causing peripheral sensitization [60]. 
 
It has been shown that neonatal stress causes long-lasting epigenetic changes in the 
corticotrophin releasing factor (CRF) expression, which resulted in the transcriptional 
responses to stress in adulthood [85]. Similarly, a study conducted in rats has shown CRF 
receptor type-I upregulation, reversible mitochondrial damage and IBS like gut dysfunction after 
exposure to psychological stress. Increased CRF receptor expression, reversible mucosal 
inflammation and increased epithelial permeability and conductance after exposure to stress 
lasted for 7 days after stress cessation. Visceral hypersensitivity observed after administration 
of exogenous CRF persisted for 30 days after exposure while abnormal colonic response 
persisted for 7 days [86]. In agreement, others have reported that CRF and its receptors play 
an important role in stress related alterations of visceral sensitivity and gastrointestinal motility 
[87, 88, 89] . An upregulation of CRF-R1 has been observed in patients with IBS [90]. However, 
another study assessing diurnal rhythm of cortisol and stress reactivity has concluded that 
cortisol as a marker of stress does not have a major role in abdominal pain in infants [91]. 
 
In addition to HPA axis, acylated ghrelin is also suggested to have a possible pathophysiological 
role in FAPDs [92]. 
 
6.8. Gastrointestinal motility 
Previous studies have repeatedly demonstrated abnormal gastrointestinal motility in children 
and adults with FAPDs. The main motility abnormalities reported are abnormal gastric 
myoelectric activity [93, 94, 95, 96], decreased gastric emptying and antral motility [95, 96, 97, 
98, 99, 100, 101, 102], impaired gastric accommodation [103, 104] and abnormal small 
intestinal and colonic motility [97, 105]. Some studies have shown a correlation between motility 
abnormalities and symptoms [98, 99, 101, 106, 107] and a few have reported a relationship 
between motility abnormalities and exposure to psychological factors such as stress [100]. As 
Ac
ce
pte
d M
an
us
cri
pt
 
15 
 
mentioned earlier, stress plays a role in the onset of FAPDs. Stress can lead to alterations in 
central aminergic network involving serotonin and noradrenalin [108].This may result in changes 
in functions of autonomic nervous system and hence may have an impact on gastrointestinal 
motility. 
 
6.9. Immune mediated mechanisms 
Allergies and atopic disorders have been shown to be associated with FAPDs [109, 110, 111]. 
However, the exact link between immunoglobulin E (IgE )and FAPDs is not fully recognized 
due to the small number of research ventures conducted and small sample size [112, 113]. 
Numerous studies conducted in patients with IBS have reported increased numbers of mast 
cells throughout the gastrointestinal tract [114, 115, 116]. Degranulation of these cells release 5 
hydoxy-tryptamine which can stimulate peripheral nerves in the submucosa and increase 
visceral sensitivity which is one of the suggested pathogenic mechanism in FAPDs. 
 
6.10. Inflammation and intestinal barrier functions 
It is suggested that visceral hypersensitivity observed in patient with IBS can be secondary to 
the activation of immune cells and to the development of low-grade inflammation. Accumulation 
of inflammatory cells in the intestinal mucosa has also been shown to be associated with IBS 
and FD in children [117, 118] A previous study conducted in children with FAP or IBS has 
reported an increased gut permeability and low grade inflammation. The observed low grade 
inflammation was related to the degree to which pain interfered with the activities of affected 
children [119]. This increased permeability could be due to enlarged spaces between epithelial 
cells, cytoskeletal condensation, abnormal gene and protein expression in tight junction proteins 
of intestinal epithelial cells and reduction in the expression of occluding and zonula occludens 
protein 1 [120, 121]. It is also possible that bacterial mediated and proteasome mediated 
alterations triggered by low grade inflammation also play a role in increase intestinal 
permeability leading to a “leaky gut” [122]. 
 
6.11. Post infectious immune response 
IBS is repeatedly associated with a previous history of gastrointestinal infections [123, 124]. The 
gastrointestinal infections commonly associated with post-infectious IBS are Compylobacter 
species, Escherichia coli and Salmonella species [123, 124]. Post-infectious IBS is associated 
with hyperplasiaof EC cells, increased counts of neutrophils, mast cells and T cells in the 
Ac
ce
pte
d M
an
us
cri
pt
 
16 
 
colonic mucosa. It is believed that gastrointestinal infections stimulate the immune system 
causing low-grade inflammation leading to post-infectious IBS [125]. 
 
6.12. Microbiota 
Human gut microbiota is a decisive factor in health and disease. A fairly consistent microbial 
patterns has been described in patients with IBS including increased ratio of 
Firmicutes/Bacterods ratio, increased relative abundance of faecal Ruminoccus torque like 
phehotypes and reduced bacterial diversity [126]. Further studies have shown an increase in 
certain bacterial species (Enterobacteriaceae, Veillonella, Dorea) and reduction of other species 
(Bifidobacterium, Collinsella, Clostridiales) [77] . Children with IBS were reported to have 
significantly higher percentage of Haemophilus parainfluenzae in their gut microbial flora [127, 
128, 129]. Experimental studies using germ free animals receiving gut microbiota of patients 
with IBS found increasing visceral sensitivity, altered gastrointestinal transit and increase 
permeability of the intestine indicating potential pathogenic mechanisms [130]. Some other 
studies have reported an association between differences in short chain fatty acid production by 
colonic bacterial and the development of symptoms in diarrhea predominant IBS [131]. 
Interactions between the gut microbiota and food (fermented protein products, generation of 
gases) are potential sources for cell damage, altered barrier function and symptoms such as 
bloating and distension [132]. In addition, it is possible that gut microbiota may influence other 
pathophysiological factors such as intestinal permeability, brain function, enteric nervous 
system, gastrointestinal motility and visceral pain and largely contribute to the pathophysiology 
of FAPDs [126]. Although it is likely that altered microbiota significantly contribute to the 
pathophysiology of FAPDs, further studies are needed, especially in children to confirm the role 
of gut microbiota in FAPDs. 
 
6.13. Food 
In previous studies, children have identified a large number of food items which exacerbates 
their gastrointestinal symptoms. Most commonly identified food items are spicy foods, cow’s 
milk and pizza [133]. In addition, irritable bowel syndrome has been attributed to indigestible 
and poorly absorbed short-chain carbohydrates (FODMAPs) [134]. The exact relationship 
between intolerance to lactose and sucrose and FAPDs, is not clear [135]. The relationship with 
fiber is controversial [136, 137]. 
 
Ac
ce
pte
d M
an
us
cri
pt
 
17 
 
7. Diagnostic work-up 
7.1. Clinical evaluation 
As a first step, it is important that physicians develop a positive therapeutic alliance with the 
patient and the family during the initial visit. This endeavor should be used to educate patients 
and parents on the brain-gut axis and reasonable expectations on treatment outcome [138]. 
Furthermore, it is essential to devote adequate time for the history and physical examination as 
pathophysiological mechanisms underlying FAPDs remain unclear and currently no diagnostic 
biomarkers exist [139]. History taking should include details of abdominal pain, infectious 
episodes or stressful events associated with the onset of symptoms, psychosocial history of the 
child and parents, dietary triggers, history of previous treatments for FAPDs and family 
incidence of gastrointestinal diseases or disorders [139, 140]. In this process detailed 
description of abdominal pain (site, severity, nature, and relationship to bowel motion) often 
helps the clinician to classify the type of FAPD. In addition, a comprehensive history of bowel 
habits is also invaluable. Nature of the stools (as assessed by using the Bristol stool scale) 
provide a substantial platform to classify subtypes of IBS according to the Rome criteria [141]. 
Furthermore, these details help to identify functional constipation from constipation predominant 
IBS. However, the frequency, severity, location and timing (post-prandial or waking during the 
night) of abdominal pain do not distinguish a functional disorder from an organic disorder [142]. 
Associated symptoms, such as anorexia, nausea, episodic vomiting and headache, that occur 
often in patients with FAPDs, fail to differentiate organic disease from functional disease [143]. 
Only when alarm symptoms or so-called red flags (Box 1) are present, this might indicate the 
presence of an organic disease and subsequent diagnostic testing should then be performed 
[142]. Physical examination should include thorough general examination to identify evidence of 
an organic disease. Careful attention needs to be paid to growth parameters as well. Detailed 
abdominal examination, perianal and rectal examination are also crucial in confirming the 
diagnosis of FAPDs (Box 2). 
 
7.2. Laboratory investigations 
Most clinicians perform blood, urine and stool analysis to differentiate between organic and 
functional disorders, even when red flags are absent. However, no studies are available that 
have evaluated the predictive value of these laboratory tests [142]. It has been demonstrated 
that numerous laboratory investigations are performed during common diagnostic work-up of 
children with FAPDs, without detecting clinically meaningful abnormalities, but with additional 
inconvenience and cost [53]. When clinicians or families require further reassurance, a limited 
Ac
ce
pte
d M
an
us
cri
pt
 
18 
 
and reasonable screening protocol would include complete blood cell count, C-reactive protein 
levels, celiac disease screening and fecal calprotectin [140, 144, 145]. When a child presents 
with abdominal pain and diarrhea, fecal testing for Giardia lamblia might be considered [140]. 
 
7.3. Radiological and endoscopic investigations 
Ultrasonography should only be used in children with functional abdominal pain and atypical 
clinical features, such as jaundice, vomiting, back or flank pain, urinary symptoms or abnormal 
findings on physical examination [146]. When no atypical clinical features are present, 
abdominal ultrasonography does not have significant diagnostic value [146]. Endoscopy might 
be considered in the diagnostic work-up of pediatric chronic abdominal pain when alarm 
symptoms are present, as it has been demonstrated that esophagogastroduodenoscopy 
yielded a valuable diagnostic return in 38% of 290 children with chronic abdominal pain [147]. 
However, it was also shown that a negative outcome of endoscopy did not improve clinical 
outcome of children with FAPDs [148]. 
 
8. Management 
Current therapeutic armamentarium of FAPDs is limited to pharmacological agents, 
nonpharmacological agents and psychological interventions. Most of the pharmacological 
agents are aimed to minimize the visceral pain or alter one of the predetermined 
pathophysiological mechanisms. However, the number of studies that have assessed each of 
these pharmacological interventions are often limited to one or 2 research. Often the number of 
children included in the studies were small and sometimes the statistical differences are also 
minimal [149]. The methodological quality of the studies was also found to be poor when 
assessed against standard criteria [150]. Because of these reasons, there is no evidence to 
support routine use of one drug over the other. 
 
Similarly, nonpharmacological interventions such as dietary modifications showed no major 
benefit in FAPDs [151]. A number of psychological interventions have also been used in the 
treatment of FAPDs. They include,hypnotherapy, and cognitive behavior therapy, yoga therapy 
and written self-disclosure. Although, some of the psychological interventions such as cognitive 
behavior therapy and hypnotherapy (including guided imagery) seem to be promising in 
reducing pain intensity and duration, the evidence is still low in quality and the follow up was 
only for a short period [152]. In addition, most of the psychological interventions are yet to be 
Ac
ce
pte
d M
an
us
cri
pt
 
19 
 
available at the grass rood level. In the following section, we have discussed all available 
management approaches for children with FAPDs. 
 
Education, demystification and reassurance play key roles in the management of FAPDs, 
starting with explanation of the diagnosis to the child and caregivers. Clinicians are encouraged 
to make a positive diagnosis of FAPD instead of seeing it as a failure to identify an underlying 
disease [13, 138]. A recently published follow-up study of 83 pediatric IBS patients 
demonstrated that almost 60% of these patients reported spontaneous resolution of symptoms 
24 months after diagnosis [25]. Interestingly, 63% of these patients only received reassurance 
and education as treatment, underlining the natural symptom evolution of IBS and the role of 
education and reassurance as a management strategy in contrast to medical treatment [25]. 
However, those findings should be interpreted with great caution as this study was of 
observational and non-interventional nature. Furthermore, it was demonstrated in adults that an 
enhanced relationship with a practitioner in combination with placebo treatment yielded a 
significantly greater global improvement compared to wait-list and limited patient-practitioner 
relationships, indicating an important role for this relationship in the treatment of IBS [153]. 
 
Another important aspect in the therapeutic strategy of childhood FAPDs is the parental 
response to abdominal pain of their child. Solicitous responses by parents might have a 
negative influence on treatment outcomes in children [154]. A randomized controlled trial that 
compared parental attention versus distraction or no instruction following induced visceral 
discomfort in children with abdominal pain, demonstrated twice as much symptom complaints 
by children who received attention instead of distraction compared to the no instruction group 
[155]. Therefore, this is considered to be an important focus while managing children with 
FAPDs. In addition, multidisciplinary care might be needed when social or psychological 
comorbidities are present. The primary goal of management of pediatric FAPDs might not 
always be to completely eliminate abdominal pain, but rather to regain normal lifestyle with 
regular school attendance and school performance according to a child’s abilities, normal sleep 
pattern and participation in desired extracurricular activities [140]. When symptoms persist and 
disrupt a child’s well-being, pharmacological or non-pharmacological treatment should be 
considered. Overall, the treatment strategy should be individualized allowing for management of 
patient specific symptoms and his or her preferences. 
 
 
Ac
ce
pte
d M
an
us
cri
pt
 
20 
 
8.1. Pharmacological management 
Overall evidence for pharmacological management of FAPDs is low because of the small 
number of high-quality placebo-controlled randomized trials (RCTs) [150, 156]. The 
pharmacological agents that have been assessed for their efficacy in pediatric FAPDs comprise 
antispasmodics, antihistamines, antidepressants, antireflux agents, and hormone treatment 
(Figure 1). Before results of various therapeutic trials will be discussed, specific attention will be 
drawn to the placebo phenomenon in pediatric FAPDs. 
 
8.1.1. Placebo 
The placebo response in children with FAPDs is substantial. A recent meta-analysis including 
21 studies found a pooled placebo response of 41% in these patients [157]. The role of placebo 
is important to bear in mind when assessing efficacy of different drugs in children with FAPDs. 
This was exemplified by a trial comparing amitriptyline to placebo. The authors failed to 
demonstrate a statistically significant benefit of amitriptyline despite an absolute improvement 
after treatment with this agent [158]. This was probably due to the high proportion of children 
that responded to the placebo treatment (58%) [158]. A placebo response comprises factors 
such as the natural course of the disease, regression to the mean and methodological bias, 
together with the ‘true placebo-effect’ which includes expectations and conditioning [159, 160]. 
The ‘true placebo-effect’ can be influenced by a warm physician-patient relationship and active 
listening approach, which in turn leads to enhanced patient responses to both therapeutic and 
placebo treatments [153, 161]. Clinicians should be aware of this when prescribing any kind of 
medication. 
 
8.1.2. Antispasmodics 
The mechanism of action of antispasmodic agents is through decreasing smooth muscle 
spasms in the gastrointestinal tract. This may alleviate abdominal pain complaints [162, 163]. 
Four randomized controlled trials investigated the effect of antispasmodics in children. 
Peppermint oil (Colpermin®), an antispasmodic agent that blocks calcium channels [164, 165], 
was compared to placebo in a randomized, double-blind controlled trial of children with FAPDS 
according to Rome III criteria. The 34 children in the Colpermin group demonstrated significantly 
improved abdominal pain duration (p<0.01), frequency (p<0.01) and severity (p<0.01) compared 
to children in the placebo group. However, results have to be interpreted with caution as the 
study was at risk of attrition bias because of incomplete outcome data and a per-protocol 
analysis despite a substantial amount of drop-outs, which were unequally distributed between 
Ac
ce
pte
d M
an
us
cri
pt
 
21 
 
the placebo group (38%) and the intervention group (15%) [166]. Another randomized, double-
blind controlled trial in 42 children with IBS according to the Manning or Rome criteria also 
assessed the effect of peppermint oil capsules compared to placebo [167]. A significantly 
greater proportion of children in the peppermint oil group had clinician-judged pain improvement 
compared to the placebo group (71% vs. 43%, respectively, p<0.02). Scores on the 
Gastrointestinal Symptom Rating Scale (GSRS) reflecting abdominal pain frequency, duration, 
and impact on daily life, showed no differences between the groups. Furthermore, the results 
section reported a scarce amount of data and the sample size was only 30. None of the studies 
reported side effects. Combining the results of the two trials, evidence to recommend 
peppermint oil in the treatment of FAPDs is perhaps inadequate [156]. 
 
The efficacy of mebeverine, an antispasmodic agent acting by a direct relaxant effect on 
smooth muscles [163], was assessed in a double-blind randomized placebo-controlled trial of 
115 children with FAP according to Rome III criteria [168]. No significant differences were found 
in the self-reported treatment response rates between the mebeverine and placebo group after 
4 weeks and after 12 weeks of intervention. No adverse reactions were reported during the 
study period. [168]. 
 
One randomized placebo-controlled study evaluated the effect of drotaverine hydrochloride, 
another direct smooth muscle relaxant, in 132 children with recurrent abdominal pain as defined 
by Apley [169]. Patients in the drotaverine group reported significantly less abdominal pain 
episodes and less missed school days compared to the placebogroup. However, the number of 
pain free days after treatment did not differ significantly between both groups and the authors 
did not provide any data on pain severity [169]. The frequency of adverse events in the 
drotaverine group was comparable to the placebo group. Based on this one study, it is not 
possible to support benefit of drotaverine in the treatment of FAPDs. 
 
8.1.3. Antihistamines 
Antihistaminic agents are thought to be beneficial in the treatment of FAPDs because of their 
antiserotonin effect or calcium-channel blocking effect [170, 171, 172]. Cyproheptadine, an 
antihistaminic agent, was investigated in a double-blind placebo-controlled trial in 29 children 
with FAP [173]. A significant positive effect of cyproheptadine compared to placebo on 
abdominal pain intensity and frequency was found. However, these results should be carefully 
interpreted, as the study has several methodological shortfalls such as small sample size, non-
Ac
ce
pte
d M
an
us
cri
pt
 
22 
 
validated measurement tools, and no reproduction of the findings in other studies. The study 
reported no significant adverse effects. 
 
8.1.4. Antidepressants 
Several antidepressants, such as tricyclic antidepressants (TCA’s) and selective serotonin 
reuptake inhibitors (SSRI’s), are used in the treatment of FAPDs because of their potential 
influence on the brain-gut axis through central and peripheral mechanisms such as modulation 
of pain perception, anticholinergic effects and normalization of GI transit [174]. Amitriptyline, a 
TCA, is thought to partially increment pain thresholds through peripheral or central analgesic 
properties and anticholinergic effects when administered in low doses [175, 176]. One study 
assessed the efficacy and safety of amitriptyline in 90 children with FAP, FD or IBS according 
to Rome II criteria [158]. No significant differences in overall response to treatment (child’s 
assessment of pain relief and sense of improvement) were found between the amitriptyline and 
placebo groups (59% vs. 53%, p=0.54) [158]. A smaller study also evaluated the effect of 
amitriptyline in a randomized placebo-controlled setting [177]. The authors only found 
differences in quality of life scores and abdominal pain in favor of the intervention compared to 
the placebo group and, no differences were found for the other outcomes. The latter study had 
several methodological shortcomings with respect to selection bias and reporting bias. Thus it is 
necessary to interpret the results with some caution [156, 177]. No adverse effects were seen in 
this trial. 
 
Citalopram, a SSRI which is suggested to reduce visceral hyperalgesia through modulation of 
serotonin reuptake [178], was compared to placebo in a randomized trial of 115 children with 
FAP according to the Rome III criteria [179]. No differences were found in treatment response 
rate, self-assessed change in severity of depression or anxiety between the citalopram and the 
placebo group. Several side effects such as drowsiness and dry mouth were reported in the 
citalopram group. 
 
8.1.5. Acid suppressing agents 
It is suggested that H2 receptor antagonists, such as famotidine, inhibit gastric acid secretion 
which might be beneficial for patients with dyspeptic symptoms. One double-blind, placebo-
controlled crossover RCT of 25 children assessed famotidine as a potential treatment for 
recurrent abdominal pain in combination with dyspeptic symptoms [180]. Famotidine appeared 
to be superior over placebo in global symptom improvement (65% vs. 15%, respectively, 
Ac
ce
pte
d M
an
us
cri
pt
 
23 
 
p=0.015), but could not induce a substantial decrease in abdominal pain. Because of a lack of 
primary data to confirm findings, lack of washout period between cross-over of interventions, the 
use of a non-validated tool and no reproduction of results, firm conclusions on the use of 
famotidine in the treatment of functional abdominal pain cannot be drawn. 
 
8.1.6. Hormone treatment 
Melatonin, a commonly used agent for sleep disturbances, is suggested to be relevant in the 
treatment of FAPDs because of its motility regulatory effects, and its anxiolytic, antidepressant 
and anti-inflammatory effects [181, 182]. Especially for FD, it might delay gastric emptying 
through partial inhibition of serotonin [182]. A double-blind, placebo-controlled RCT in 12 
patients with FAP as defined by Rome III criteria demonstrated no benefit on pain response of 
melatonin compared to placebo. However, several methodological weaknesses in this trial 
hinder definitive conclusions to be drawn about the efficacy of this hormone in the treatment of 
FAPDs and further research is needed [156, 183]. 
 
8.1.7. Prokinetic agents 
Gastroprokinetic agents are a valuable therapeutic modality to augment gastric motility and 
intestinal transit. Several studies among adults have shown some therapeutic value of 
gastroprokinetic domperidone in treating FD [184, 185, 186, 187]. Only one study so far have 
looked at the beneficial effect of domperidone on functional abdominal pain in paediatric age 
group. Using intention to treat analysis, this study has reported a significantly higher cure rate, 
improvement of the condition, reduction in pain severity and improvement in gastric motility in 
domperidone group compared to placebo group [188]. However, the observed clinical 
improvement had no relationship with the baseline gastric motility status of the recruited 
participants implying that symptom improvement may not be related to the prokinetic effects of 
the drug. The subgroup analysis showed the highest therapeutic value of domperidone for FAP 
(FAP-NOS) but its effect on FD and IBS was not clear [188]. 
 
8.2. Non-pharmacological treatment 
8.2.1. Dietary fiber 
Fiber supplements are hypothesized as possible treatment option for pediatric FAPDs by 
accelerating gut transit time, modifying bowel patterns, decreasing intracolonic pressure and 
thereby reducing abdominal pain [189, 190]. On the contrary, fibers might lead to unwanted 
increased gas production, which is an end-product of fiber fermentation [191]. Formerly, 
Ac
ce
pte
d M
an
us
cri
pt
 
24 
 
increased dietary fiber intake was recommended as standard treatment for IBS. However, in the 
past few years this has been contradicted [140]. A recent systematic review [192] pooled the 
results of four studies that investigated the efficacy of fiber supplementation in children with 
chronic abdominal pain [182, 193, 194, 195].After meta-analysis, no clear evidence of 
improvement of pain following treatment with fiber supplements was found [192]. The included 
studies were of low quality [192, 196]. However, no harmful side effects were reported [192]. 
 
8.2.2. FODMAP diet 
Some fermentable short-chain carbohydrates, such as fructose and sorbitol, are suggested to 
be difficult to absorb and might induce gastrointestinal symptoms by increasing small intestinal 
water volume and colonic gas production [197, 198]. Therefore, interest is growing in treating 
FAPDs with a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and 
polyols (FODMAP) [198, 199]. One recently conducted RCT evaluated the efficacy of a low 
FODMAP diet in 33 children with IBS and demonstrated a decrease in daily episodes of 
abdominal pain after 48h of a low FODMAP diet compared with a typical American childhood 
diet (TACD) [200]. However, more studies on the (long-term) efficacy and safety of low 
FODMAP diets need to be conducted before evidence-based recommendations on this 
treatment modality can be made. 
 
8.2.3. Probiotics 
Probioticsare defined as ‘live microorganisms which when administered in adequate amounts 
confer a health benefit on the host’ [201]. As evidence for a role of the microbiome in the 
pathogenesis of FAPDs emerges [127, 129], probiotics are suggested as a promising treatment 
for pediatric FAPDs by restoring the altered microbiota, impeding the overgrowth of potential 
pathogenic bacteria , maintaining integrity of gut mucosa, and/or altering intestinal inflammatory 
responses [202]. The most commonly used probiotic species are Lactobacillus rhamnosus GG 
and Lactobacillus reuteri [192]. A recent meta-analytic review pooled the findings of 13 RCTs on 
the efficacy of probiotics and demonstrated moderate- to low-quality evidence for the benefit of 
probiotics in children with FAPDs [192]. In particular, LGG and VSL#3 were associated with 
significantly more treatment responders compared to placebo [151]. 
 
 
 
 
Ac
ce
pte
d M
an
us
cri
pt
 
25 
 
8.3. Psychological interventions 
8.3.1. Hypnotherapy 
Hypnotherapy is hypothesized to be a potential treatment for pediatric FAPDs because of its 
possible influence on gastrointestinal motility [203], visceral sensitivity [204, 205], psychologic 
factors [206, 207], and/or effects within the central nervous system [208]. During hypnosis, the 
therapist tries to guide the child to respond to suggestions for changes in subjective 
experiences, alterations in perception, sensation, emotions, thoughts, or behavior [209]. Two 
RCTs compared the efficacy of hypnotherapy to usual care and wait-list control, respectively, in 
children with FAP or IBS. The children who received hypnotherapy did so from a qualified 
therapist in individual or group sessions, supported by daily practices at home with self-
exercises on CD [210, 211]. In both studies, hypnotherapy was significantly more effective than 
the control treatment in reducing abdominal pain intensity and in enhancing treatment success 
[210, 212]. One of these studies with a long-term follow-up demonstrated continuously greater 
treatment success of hypnotherapy compared to usual care after 5 years (68% vs 20%, 
respectively, p=0.005) [213]. One recently published noninferiority RCT compared home-based 
hypnotherapy with a compact disc (CD) to individual hypnotherapy performed by a qualified 
therapist and found that hypnosis by CD was noninferior to hypnotherapy by therapist after 1 
year of follow-up [214]. Two other RCTs evaluated the efficacy of guided imagery, which is a 
form of self-regulation therapy by physical relaxation and behavior modification through imagery 
[215, 216]. A significant benefit was demonstrated of the guided imagery compared to the 
control treatment in reducing abdominal pain intensity and frequency [215, 216]. A recent meta-
analytic review provided some evidence for the short-term effectiveness of hypnotherapy and 
guided imagery [152], after including four RCTs in their analysis [210, 211, 215, 216]. 
 
8.3.2. Cognitive behavioral therapy 
In line with the biopsychosocial model as a possible explanation for the etiology of FAPDs, it is 
suggested that these disorders might be treated with psychological treatments [217]. Cognitive 
behavioral therapy (CBT) aims to modulate behavior from children and parents by teaching 
coping and distraction strategies, and relaxation techniques. Furthermore, it attempts to identify 
and reinforce the child’s and family’s pain-related thoughts [152]. CBT may be family-based or 
child specific. Ten trials examined the effect of cognitive behavioral therapy against either usual 
care, wait-list control or some form of education involving both the child and a parent [218, 219, 
220, 221, 222, 223, 224, 225, 226]. Some evidence has been produced for greater treatment 
success of CBT compared to control after less than 3- month follow-up (OR 5.67, 95%CI 1.18-
Ac
ce
pte
d M
an
us
cri
pt
 
26 
 
27.32, p=0.03) when results of those studies are pooled [152]. However, evidence for this effect 
disappeared at medium-term (3 to 12 months) and long-term (≥12 months) follow-up (p=0.06 
and p=0.6, respectively). When CBT intervention results on pain intensity scores were 
compared to controls, no robust evidence was found for significant differences at short-term and 
medium-term follow-up [152]. A recently published RCT on the overall effect of internet-
delivered CBT compared to wait-list for adolescents with IBS and their parents demonstrated a 
statistically significant effect of CBT on gastrointestinal symptoms and pain intensity [226]. 
However, the wait-list group does not control for attention and treatment expectation, and 
therefore results must be interpreted cautiously [226]. Two studies assessed the efficacy of 
individual CBT [227, 228]. Both studies used active comparators in the form of physiotherapy 
[227], or dietary fiber supplementation, biofeedback or parental support [228]. The study that 
used physiotherapy as a control treatment did not find a significant superior effect of CBT over 
physiotherapy [227]. The 4-armed study only demonstrated a significant difference when they 
compared the active treatments (CBT, biofeedback and parental support) with the fiber-only 
comparison group [228]. These imply that, some low-quality evidence exists for beneficial 
effects of CBT in the short-term in reducing abdominal pain in children and adolescents with 
FAPDs. 
 
8.4. Alternative therapy 
8.4.1. Neuromodulator 
A novel approach in the management of FAP-NOS, is the attempt at modulating central pain 
pathways and thus visceral hypersensitivity by using a percutaneous electrical nerve field 
stimulation (PENFS). A recently published study assessed the effect of PENFS in the external 
ear in 115 adolescents with an AP-FGID diagnosed on Rome III criteria on change in abdominal 
pain scores. Results demonstrated a significantly greater improvement in worst pain after 3 
weeks of PENFS compared to the sham control group. This improvement was sustained at 
follow-up 2 months later [229]. Although safe and seems to be promising, conclusions must be 
drawn carefully, as this was the first randomized, sham-controlled study of PENFS in 
adolescents with AP-FGIDs. 
 
8.4.2. Yoga and self- disclosure 
Yoga therapy aims to reduce anxiety, improve body tone and enhance feelings of well-being by 
learning physical poses in combination with daily breathing practices and meditation techniques 
Ac
ce
pte
d M
an
us
cri
pt
 
27 
 
[230]. Three randomized trials involving 122 children with IBS or FAPDs evaluated the effect of 
yoga compared to wait-list control or usual medical care [231, 232, 233]. After pooling results on 
pain intensity, pain frequency and functional disability, no differences were found between yoga 
therapy and control groups [152]. Therefore, no robust evidence exists for the effectiveness of 
this treatment. Another alternative management strategy for FAPDs is written self-disclosure 
therapy, in which a patient gets the opportunity to write down thoughts and feelings about 
something deeply distressing during three 20-minute sessions in a quiet place [234]. The only 
one RCT on written self-disclosure therapy in children with recurrent abdominal pain reported 
beneficial effects of this therapy compared to usual care on abdominal pain frequency at six 
months follow-up, but not post-intervention [234]. Further trials are needed before any 
recommendations on this treatment can be made. 
 
8.4.3. Fecal microbiota transplantation 
A body of evidence is growing for the role of altered microbiota in the pathogenesis of FAPDs 
[127, 129, 235]. In line with this, the possibilities offecal microbiota transplantation (FMT) as a 
therapeutic strategy for patients with IBS are being carefully explored. Some patients with IBS 
continue to have symptoms, decreased quality of life, and repeated consultations despite 
medical and psychological therapy. These patients are then considered to have refractory IBS 
[236]. For these patients, a fecal microbial transfer might be explored. One recently published 
open-label study in 12 IBS patients found adequate relief in 9 (75%) of them 12 weeks after 
FMT [237]. The authors also found that positive effects on IBS-related symptoms seemed to be 
linked to changes in intestinal microbiota due to FMT [237]. However, results of randomized, 
double-blind, placebo-controlled trials are needed to draw any valid conclusions on the efficacy 
of this treatment for IBS. 
 
9. Expert commentary 
Chronic abdominal pain of functional origin is a common cosmopolitan problem with a pooled 
prevalence rate of 13.5% [15]. The diagnosis of FAPDs in children is based on new Rome IV 
criteria which were released in 2016 [13]. Compared to the Rome III criteria, several minor 
changes with respect to the FAPDs have been made in the Rome IV criteria. Abdominal pain 
related functional gastrointestinal disorders has been changed to “functional abdominal pain 
disorders” and a new term, functional abdominal pain not otherwise specified was introduced to 
describe children who do not fit a specific disorder such as IBS or FD. Furthermore, within FD, 
different subtypes are now recognized; i.e. postprandial distress syndrome ad epigastric pain 
Ac
ce
pte
d M
an
us
cri
pt
 
28 
 
syndrome. This differentiation is important because the two subtypes need different therapeutic 
approach. A large number of predisposing factors have also been identified in epidemiological 
studies. Similarly, the pathophysiological studies have also come out with an almost equal 
number of potential mechanisms to explain symptoms of FAPDs. It is possible that most of the 
environmental risk factors intricately interact with genes through epigenetic mechanisms to 
contribute to the pathophysiology of this group of disorders. 
 
Clinicians need to emphasize the value of clinical evaluation of children with FAPDs with a 
thorough clinical history and a meticulous physical examination. These, almost always, unravel 
the diagnosis of functional gastrointestinal disorders. As pointed out in this review the routine 
investigations that had been used for decades have no real diagnostic value and the 
sophisticated investigations, although helpful towards understanding the pathophysiology, do 
not help in the day to day clinical management of children with FAPDs. 
 
It is also evident that commonly used pharmacological agents do not play a major role in the 
relief of symptoms of these children in the modern evidence based era. Since the gut 
microbiome is thought to play a crucial role in the pathogenesis, and there are some promising 
results from early studies on that aspect, the role of probiotics in treating FAPDs needs to be 
explored further. Although considered as a healthy habit, dietary fibers have no place in the 
management of FAPDs in children. Centrally directed, nonpharmacological interventions such 
as hypnotherapy, and cognitive behavioral therapy have shown both short and long term 
efficacy in relieving pain in children with FAPDs. 
 
10. Five-year view 
It is imperative that clinicians and researchers working in the field of FAPDs should take a more 
energetic approach to solving this conundrum. Firstly, it is necessary to appreciate that FAPDs 
leads to a significant societal burden and drain a large amount of public funds through the 
healthcare systems. To minimize that and ensure a brighter future for these children we suggest 
the following approach to childhood FAPDs in the next 5 years. 
 
A collective effort should be made to identify the burden of FAPDs through a series of world 
wide, cross-cultural research to delineate the prevalence of individual FAPDs and their risk 
factors. This will clearly document the societal and healthcare burden of FAPDs in the world. In 
addition, genetic and specially, epigenetic factors in the development of FAPDs and propagation 
Ac
ce
pte
d M
an
us
cri
pt
 
29 
 
of symptoms are waiting to be explored. Epigenetic mechanisms bridge the risk factors and 
pathophysiological mechanisms operating both centrally and peripherally in symptom 
generation. Identification of these factors would help us to modify them and provide a 
therapeutic window of opportunity for FAPDs where conventional approaches with 
pharmacological interventions have failed. There are modifiable potential predisposing factors in 
FAPDs. Therefore, rather than spending large sums of public funds on treatment, it is vital to 
take more steps in preventing FAPDs through controlling these modifiable risk factors. 
Controlling prenatal maternal conditions, minimizing neonatal invasive interventions, educating 
about the adverse long term repercussions of child maltreatment and reducing stresses at 
homes and schools need to be explored in preventing FAPDs. This approach would help to 
prevent FAPD not only in children but also in adults where early life events have been identified 
as an important risk factor. 
 
Most of the pediatric researchers’ approach FAPDs as a single group of conditions. Now, it is 
time to separate the four FAPDs and study the pathophysiological mechanisms deliberately and 
separately. Studies in adults have shown that pathophysiological mechanisms of FD are 
different from IBS. This would give us an opportunity to explore the pathophysiology of each of 
the 4 disorders. Based on that knowledge, it may be feasible to develop more robust therapeutic 
models for interventions. It is also important to shift the future therapeutic focus from total 
elimination of pain to more realistic measures such as improve the pain scores and frequency 
and improvement of daily function. This approach will allow to develop more evidence based 
therapeutic options. 
 
Functional gastrointestinal disorders related to abdominal pain such as IBS and FD are common 
in adults as well. Development of drugs in this area in adults is a very active area of research in 
FGDs. Perhaps pediatric gastroenterologists and researchers can learn from their adult 
counterparts and expand research into more therapeutic agents. This step, which is essential to 
increase our therapeutic armory to reduce pain and suffering would improve overall quality of 
life of children with FAPDs. 
 
 
 
 
 
Ac
ce
pte
d M
an
us
cri
pt
 
30 
 
Key points 
• FAPDs are a common problem in pediatric practice and it is noted that as a group, 
FAPDs have a pooled prevalence of 13.5%. As a group, these disorders affects HRQoL 
of children, reduce the quality of their school work and incur a large sum of healthcare 
expenditure. 
• Stressful life events in the neonatal period, and childhood together with exposure to child 
maltreatment are important predisposing factors. In addition, there are a number of 
pathophysiological mechanisms such as altered motility, visceral hypersensitivity and 
altered gut microbiota which contribute to symptom generation. It is possible that 
predisposing factors blend with the pathophysiological mechanisms through genetic and 
epigenetic mechanisms in the pathogenesis of FAPDs. 
• The diagnosis of FAPDs depend on the Rome IV criteria. Therefore, clinical evaluation 
plays a crucial role in the diagnosis. All routine and sophisticated investigations including 
endoscopies have a very low yield