European Journal of Pediatrics (2022) 181:2603–2617

https://doi.org/10.1007/s00431-022-04459-y

REVIEW

A therapeutic guide on pediatric irritable bowel syndrome and functional

abdominal pain‑not otherwise specified
Robyn Rexwinkel1 · Arine M. Vlieger2 · Miguel Saps3 · Merit M. Tabbers1 · Marc A. Benninga1

Received: 14 December 2021 / Revised: 27 March 2022 / Accepted: 29 March 2022 / Published online: 23 April 2022
© The Author(s) 2022

Abstract
Disorders of the gut-brain interaction negatively impact quality of life and carry a substantial socioeconomic burden. Irritable
bowel syndrome (IBS) and functional abdominal pain-not otherwise specified (FAP-NOS) are common functional abdominal
pain disorders in childhood. The pathophysiology is not fully understood, and high-quality intervention trials and international
guidelines are missing. Therefore, the management of these disorders remains challenging. This review aims to provide an
up-to-date overview of therapeutic possibilities for pediatric IBS or FAP-NOS and recommends management strategies.
To prevent unnecessary referrals and extensive costs, it is fundamental to make a positive diagnosis of IBS or FAP-NOS in
children with chronic abdominal pain with only minimal investigations. A tailor-made approach for each patient, based on
the accompanying physical and psychological symptoms, is proposed to date.
Conclusion: Shared decision-making including non-pharmacological and pharmacological interventions should be con-
sidered and discussed with the family.

What is Known:
• Irritable bowel syndrome and functional abdominal pain-not otherwise specified are common in childhood.
• Although the number of treatment options has grown recently, managing these disorders can be challenging and unsatisfactory, and no
evidence-based international management guidelines are available.
What is New:
• We suggest using a stepwise individualized approach to management, where after first-line management, both non-pharmacological and
pharmacological interventions should be discussed.

Keywords  Children · Management · Therapy · Treatment · Chronic abdominal pain

Abbreviations FGID Functional gastrointestinal disorder

CBT Cognitive behavior therapy FODMAP Fermentable oligosaccharides, disaccharides,
FAP Functional abdominal pain monosaccharides, and polyols
FAPD Functional abdominal pain disorders HT Hypnotherapy
FAP-NOS Functional abdominal pain-not otherwise IBS Irritable bowel syndrome
specified IBS-C Irritable bowel syndrome, predominant
constipation
Communicated by Peter de Winter IBS-D Irritable bowel syndrome,
predominant-diarrhea
* Robyn Rexwinkel
r.rexwinkel@amsterdamumc.nl
IBS-M Irritable bowel syndrome mixed or alternat-
ing stool forms
1
Emma Children’s Hospital, Amsterdam UMC, Pediatric IBS-U Irritable bowel syndrome unclassified
Gastroenterology, University of Amsterdam, Room C2‑312, GI Gastrointestinal
PO Box 22700, 1100 DD Amsterdam, Netherlands
PEG Polyethylene glycol
2
Department of Pediatrics, St. Antonius Hospital, Nieuwegein, PENFS Percutaneous electrical nerve field
Netherlands
stimulation
3
Department of Pediatric Gastroenterology, University TCA​ Tricyclic antidepressant
of Miami, Miami, FL, USA

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2604 European Journal of Pediatrics (2022) 181:2603–2617

Introduction 1. First-line management

  The cornerstone of helping a child with IBS or FAP-
Functional abdominal pain disorders (FAPDs) are disorders NOS is first to validate the symptoms followed by a
of the gut-brain axis characterized by chronic abdominal proper explanation of the diagnosis according to the
pain and altered bowel movements in the case of irritable biopsychosocial model [7]. An evidence-based, multi-
bowel syndrome (IBS). FAPDs comprise four disorders: disciplinary treatment plan is essential to improve recov-
functional dyspepsia, IBS, abdominal migraine, and func- ery and long-term prognosis [13].
tional abdominal pain-not otherwise specified (FAP-NOS) • Validation, explanation, and a positive diagnosis. One
(Supplemental Table 1) [1, 2]. In IBS, four types can be of the first steps is to acknowledge that the pain is
distinguished: predominant-diarrhea (IBS-D), predominant- real even though no severe organ damage is present.
constipation (IBS-C), mixed or alternating stool forms (IBS- It can be helpful to explain that the pain is caused
A), and unclassified (IBS-U) [3]. by hypersensitive nerves, using metaphors like a fire
FAPDs are common, with an estimated prevalence ranging alarm that keeps on alarming although there is no
from 1.6 to 41.2% in the pediatric population. These disor- fire [13]. Enough time must be allocated to make a
ders have a profoundly negative impact on quality of life and positive diagnosis by discussing all the evidence that
carry a substantial socioeconomic burden [4–6]. Despite their supports your diagnosis of IBS or FAP-NOS. Edu-
high prevalence and impact, the pathophysiology underlying cation on the interplay of different biopsychosocial
FAPDs is not well understood. FAPDs are presumably mul- factors that generate and maintain chronic abdominal
tifactorial and include genetic factors; psychological factors complaints is also helpful. Finally, one needs to elicit
such as child abuse, stress, or depression; hypersensitivity to expectations and elucidate that the long-term progno-
food products; and gut microbiota alterations [7]. Although sis is favorable. The primary treatment goal should not
the number of treatment options has grown recently, man- be the complete eradication of pain but optimization
aging these disorders can be challenging and unsatisfactory. of daily functioning, including school participation,
In this review, we aim to provide an up-to-date overview of a normal sleep pattern, and participation in extracur-
therapeutic approaches, and we recommend management ricular activities [14, 15]. The practitioner should
strategies focusing on pediatric IBS and FAP-NOS. remain connected with patients and parents through
email and/or phone contact and follow-up visits tai-
lored to each case every 4–12 weeks to increase treat-
Methods ment adherence and reduce the feeling that patients
and families are discharged and left without support.
We searched for relevant articles in English up to August • The parental response to their child’s abdominal
2021 in PubMed, MEDLINE, EMBASE, PsycINFO, and pain. A multidisciplinary family approach is an
Cochrane Library. To identify unpublished or ongoing studies, essential part of the treatment strategy. An RCT stud-
the ClinicalTrials.gov register, the Current Controlled Trials ied the effects of parental attention versus distraction
meta-Register of Controlled Trials–active registers, and the versus no instruction in children with chronic FAP
WHO International Clinical Trials Registry Platform Search [16]. Abdominal complaints were reduced by half in
Portal were searched. To identify relevant articles and reviews the distraction group and nearly doubled in the atten-
missed by the search strategies, the reference lists from tion group. The study suggests that parental distrac-
reviewed articles were searched by hand. Only randomized tion is a powerful coping strategy. Moreover, Lindley
controlled trials and systematic reviews were included. The et al. showed that healthcare consumerism in fami-
full search strategies are available upon request. Inclusion and lies lacking insight into their child’s problem can be
exclusion criteria are presented in Supplementary File 1. We harmful to the child with FAP [17]. Prognostic indi-
assessed the risk of bias of all included studies in earlier stud- cators of “healthcare consumerism” were refusal to
ies, using the Cochrane risk of bias tool [8–12]. engage with psychological services, involvement of
more than three consultants, lodging of a manipu-
lative complaint with hospital management by the
Management of IBS and FAP‑NOS child’s family, and lack of development of insight
into psychosocial influences on symptoms [17].
Treatment often includes one or more of these strategies: (1) • Identify psychological and physical stressors that
first-line management consisting of validation, explanation, may play a crucial role in a child’s abdominal
and a positive diagnosis, (2) non-pharmacological treatment, pain experience and, possibly, help reverse them.
and (3) pharmacological treatment. Parental acceptance of the biopsychosocial model

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European Journal of Pediatrics (2022) 181:2603–2617 2605

of illness has shown to be an important factor for food is associated with deterioration of their GI symptoms.
symptom relief in children with FAPDs [18]. As a result, children frequently avoid foods and implement
• Additional analgesic therapysuchas non-steroidal diet strategies [22, 23]. However, it is likely that these food-
anti-inflammatory drugs, acetaminophen, and aspi- associated symptoms are more the result of the gastrocolic
rin is sometimes used by generalpractitioners to treat reflex than that they are caused by food intolerances [24–26].
pain. However,the efficacy of these drugs in treating Indeed, research has shown little evidence that dietary inter-
pediatric chronic abdominal pain is notsupported in ventions are helpful for this population [15, 27, 28]. There is
any clinical trial and should be used with caution in some evidence regarding probiotics and dietary fibers, such
clinicalpractice [19–21]. as psyllium fibers [9, 12]. A detrimental effect of gluten is
frequently self-reported [29]. Non-celiac gluten sensitivity
2. Non-pharmacological treatment is a clinical condition that has been insufficiently studied in
children but may contribute to trigger or worsen GI symp-
toms (Table 1) [30].
Dietary interventions
Dietary fiber
In the last decade, there has been a great interest in the role
of diet in the pathogenesis and management of FAPDs. More A normal fiber intake is recommended for every child [31,
than 90% of children with a FAPD report that at least one 32]. Inadequate fiber intake has been proposed as a risk

Table 1  Non-pharmacological interventions
Intervention Participants Results

Fibers
Psyllium [35]a Children 7–18 years (N = 103) Improvement in reduction of mean number of pain episodes (8.2 ± 1.2
IBS (Rome II criteria) vs 4.1 ± 1.3; P = 0.03); no difference in pain intensity
Soluble fiber [25]a Children 4–18 years (N = 385) Difference in treatment success in favor of soluble fiber group (RR
FAPD (Rome II, III, IV criteria) 2.40, 95% CI 1.10–5.25; NNT = 3, 4 studies, 268 participants); no
difference in pain intensity after soluble fiber treatment (SMD—0.63,
95% CI − 1.61 to 0.35; 2 studies, 135 participants)
Low FODMAP diet
Low FODMAP diet [46]b Children 5 to 12 years (N = 29) No significant differences apparent in pain frequency and intensity
FAP (Rome III) FAP-NOS (Rome IV) between the two diets
Low FODMAP diet [47]c Children 7 to 17 years (N = 33) Treatment success defined as ≥ 50% decrease in frequency of abdomi-
IBS (Rome III criteria) nal pain episodes (50% vs 59%; P > 0.05); significant improvement in
abdominal pain episodes/day (1.1 ± 0.2 vs 1.7 ± 0.4; P < 0.05)
Probiotics
Lactobacillus reuteri DSM [24]a Children 4–18 years (N = 360) Difference in treatment success in favor of Lactobacillus reuteri group
IBS/FAP (RR 1.33, 95% CI 0.86 to 2.4; 5 studies, 178 participants); difference
(Rome III criteria) in complete resolution of pain in favor of Lactobacillus reuteri group
(RR 1.35, 95% CI 0.76 to 2.41; 4 studies, 151 participants);
difference in frequency of pain (episodes/week) in favor of Lactobacil-
lus reuteri group (RR − 0.14, 95% CI − 1.18 to 0.90; 3 studies, 116
participants)
Lactobacillus Rhamnosus CG [24]a Children 5–16 years (N = 245) Difference in treatment success in favor of Lactobacillus rhamnosus
IBS/FAP CG group (RR 1.57, 95% CI 0.73 to 3.34; 2 studies, 123 partici-
(Rome II criteria) pants); difference in complete resolution of pain in favor of Lactoba-
cillus rhamnosus CG group (RR 2.60, 95% CI 1.00 to 6.77; 1 study,
52 participants); difference in frequency of pain (episodes/week)
in favor of Lactobacillus rhamnosus CG group (RR − 0.57, 95%
CI −0.81 to −0.33; 2 studies, 122 participants)
AP-FGIDs abdominal pain predominant functional gastrointestinal disorders, CAP chronic abdominal pain, FAP functional abdominal pain, FD
functional dyspepsia, FGID functional gastrointestinal disorder, FODMAP fermentable oligosaccharides, disaccharides, monosaccharides, and
polyols, IBS irritable bowel syndrome, IBS-C irritable bowel syndrome, predominant constipation, NICE National Institute for health and Care
Excellence, RAP recurrent abdominal pain
a
 Compared with placebo
b
 compared with diet based on the NICE guidelines
c
 compared with American diet

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2606 European Journal of Pediatrics (2022) 181:2603–2617

factor for developing FAPDs in children [33, 34]. Increas- gluten sensitivity. IBS patients frequently report gluten sen-
ing dietary fiber intake was recommended as first-line treat- sitivity in the absence of a celiac disease diagnosis [30].
ment for IBS since fibers potentially decrease intracolonic Future research is required to investigate the role of non-
pressure, accelerate gut transit time, and reduce abdominal celiac gluten sensitivity in children with IBS. Currently, two
pain [35, 36]. Soluble fibers may be particularly useful in the pediatric IBS trials are underway, one being a double-blind
management of IBS-C, since they attract water into stools placebo-controlled crossover trial evaluating the prevalence
and therefore may relieve symptoms of constipation [37, of gluten sensitivity (NCT02431585) and the other evalu-
38]. However, increased gas production may also occur due ating a gluten-free diet compared to a low FODMAP diet
to fiber fermentation [39]. A meta-analysis of adult studies (NCT03694223).
has shown the benefit of soluble fibers, such as psyllium, as
opposed to insoluble fiber, such as bran [40, 41]. Therefore, Probiotics
adult IBS clinical guidelines support soluble fiber in IBS
treatment [39, 42]. A recent meta-analyses in children with Probiotics are defined as “live microorganisms that, when
FAPDs, including five RCTs, found some beneficial effects administered in adequate amounts, confer a health benefit
for the use of soluble fibers, in particular psyllium, with a on the host” [56]. Probiotics are used to restore the altered
number needed to treat of 3. Certainty of the evidence is microbiome composition, hamper the overgrowth of poten-
very low, but given the low cost, absence of serious side tially pathogenic bacteria, and alter intestinal inflammation
effects, and easy availability, soluble fiber may be considered and permeability [57–59]. Since there is growing evidence
in daily practice [9]. for the role of the microbiome in the pathogenesis of FAPDs,
probiotics may be a promising treatment option [60, 61].
Low FODMAP diet A recently published Cochrane review evaluated the effi-
cacy and safety of probiotics in children with FAPDs [12].
Studies in adults have shown the beneficial effect of a diet Meta-analyses showed moderate to high-quality evidence
low in fermentable oligosaccharides, disaccharides, mono- for the effectiveness of Lactobacillus rhamnosus GG and
saccharides, and polyols (FODMAP) for the treatment of Lactobacillus reuteri DSM in successfully treating IBS and
IBS [43]. It is hypothesized that one of the mechanisms of FAP in children [12]. There is limited evidence for the use
action involves a reduction in gas production and subse- of VSL#3.
quently in luminal distention, resulting in a decrease in pain
[43, 44]. A meta-analysis of adult studies on the efficacy of Psychological interventions
the low FODMAP diet showed a reduction in GI symptoms
and an improved quality of life [45]. However, adherence to Psychosocial interventions, such as cognitive behavioral
the low FODMAP diet is difficult, it involves high cost, and therapy (CBT) and hypnotherapy (HT), have proven to be
the involvement of a dietician is essential to achieve nutri- successful in the management of pediatric FAPDs (Table 2)
tional adequacy and successful treatment outcomes [46–48]. [15].
It is unknown when and how eliminated foods should be
reintroduced, but continuing a low FODMAP diet for longer Cognitive behavior therapy
than 6 weeks is accompanied with the risk of malnutrition
[49, 50]. To date, evidence-based recommendations to sup- Cognitive behavioral therapy (CBT) aims to alter the behav-
port the use of the low FODMAP diet in the pediatric popu- iors, cognitions, and emotions, that may contribute to IBS
lation are lacking. Only two low-quality RCTs have been symptom escalation or maintenance [62–64]. Children and
conducted, showing no efficacy, but more data from well- parents are taught to implement different coping and dis-
designed studies are needed before definitive conclusions traction strategies, and often also relaxation techniques, to
can be drawn [51, 52]. To make the low FODMAP diet more decrease symptoms. CBT can be provided in various set-
available, new methods need to be implemented in clinical tings, such as face-to-face therapy [65–67], to parents via
practice. The use of online apps and the widespread use the telephone, [68] or targeted to children via the Internet
of dietician-led groups may play an important role in near [69–71]. A systematic review and meta-analysis in children
future [53, 54]. aged 4–18 years with FAPDs included 17 studies (N = 1760)
of CBT [10]. This SR found moderate certainty evidence
Gluten‑free diet that CBT leads to significant reduction in pain intensity
and frequency scores compared with no intervention with
In the last decade, adult studies have highlighted the poten- a number needed to treat of 5. There was low certainty evi-
tial role of gluten sensitivity as a trigger of GI symptoms dence that found that there is no difference between CBT
in IBS [29, 30, 55]. This condition is known as non-celiac and educational support in reducing pain intensity and

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Table 2  Psychological interventions
Intervention Participants Results

Cognitive Behavioral Therapy

CBT vs no intervention [65] Children 6–18 years (N = 785) Difference in treatment success in favor of CBT
FAPDs (Rome II,III, IV criteria) and RAP group (38% vs 15%) (RR 2.37, 95% CI 1.30 to
(Apley criteria) 4.34; NNT = 5, 6 studies, 324 participants)
CBT leads to lower pain frequency (RR − 0.36,
95% CI 0.63 to − 0.09; 7 studies, 446
participants)
CBT leads to lower pain intensity (RR − 0.58,
95% CI 0.83 to − 0.32; 6 studies, 332
participants)
CBT vs educational support [65] Children 5–18 years (N = 975) No difference in pain intensity between
FAPDs (Rome III, IV criteria) and RAP CBT group and educational support group
(Apley criteria) (MD − 0.36, 95% CI 0.87 to − 0.15; 1 study,
127 participants)
No difference in composite pain scores
(MD − 0.07, 95% CI − 0.29 to 0.15; 1 study,
300 participants)
Hypnotherapy and guided imagery
HT vs no intervention [65] Children 6 to 18 years (N = 91) Difference in treatment success in favor of HT
IBS/FAP (Rome II, III) group (56% vs 19%) (RR 2.86, 95% CI 1.19 to
6.83; NNT = 5, 2 studies, 91 participants)
Gut-directed HT vs HT [65] Children 6 to 17 years (N = 73) In both groups, results suggest a high efficacy of
IBS/FAP (Rome III criteria) standardized home-based HT
Audio-recorded guided imagery vs no Children 6 to 15 years (N = 34) ITT-analysis, significant difference in treatment
intervention [72] FAP (Rome II) responders (63% vs 27%; P = 0.03; NNT = 3);
Home-based HT vs iHT [71] Children 12 to 18 years (N = 260) Home-based HT by using a CD was non-inferior
IBS/FAP (Rome III criteria) to individual
HT group (62.1% vs 71%; P = 0.002) at 1-year
follow-up
Yoga
Yoga vs no intervention [65] Children 8 to 18 years (N = 127) No difference in treatment success between both
IBS/FAP (Rome I, III criteria) groups (28% vs 24%; P = 0.78) (RR 1.09, 95%
CI 0.58 to 2.08, 2 studies, 99 participants)
Neurostimulation
Electrical neurostimulation (PENFS) [84]a Children 11 to 18 years (N = 115) Significant difference in lower median PFSD
AP-FGIDs (Rome III criteria) composite scores with a mean decrease of
11.48 (95% CI 6.63 to 16.32; P < 0·0001);
lower worst pain scores (p < 0·0001); improved
global well-being
(p = 0·0003) after 3 weeks; greater reduction in
median PFSD composite scores (p = 0·018),
and worst pain (p < 0·0001) compared with
sham at long-term follow-up

AP-FGID abdominal pain-related functional gastrointestinal disorder, CBT cognitive behavioral therapy, FAP functional abdominal pain, FAPD
functional abdominal pain disorder, FGID functional gastrointestinal disorder, HT hypnotherapy, IBS irritable bowel syndrome, NNT number
needed to treat, RAP recurrent abdominal pain, PENFS percutaneous electrical nerve field stimulation
a
 Compared with sham

frequency scores. Limitations of CBT are that there may Hypnotherapy

be limited access to mental health professionals and that
insurance may not cover treatment. To overcome the low In HT, a patient is induced into a hypnotic state. During this
availability of mental health professions, Internet-delivered state, a therapist guides the patient to respond to suggestions
and telephone-delivered CBT have shown to be effective to alter its subjective experiences, perception, emotion, sensa-
alternatives, potentially reduce healthcare costs, and increase tion, and thoughts or behavior [73, 74]. HT can be provided
the availability of treatment [69–72]. individually by a therapist [75, 76], or home-based by the

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use of HT-exercises on CD [77, 78]. Eight RCTs of children system. By stimulating auricular branches of nerves that
with IBS or FAP-NOS (6–18 years of age; N = 496) found allow accessing the central nervous system, also visceral
low certainty results indicating that HT (both individually by hypersensitivity can be modulated [90]. A large randomized,
a therapist or as self-exercise using a CD) may be an effective sham-controlled study assessed the efficacy of PENFS in the
treatment option (number needed to treat = 5) [10]. Even in external ear in 115 children with FAPDs. Compared with the
the long-term, there is a continued benefit of HT at 5-years sham control group, PENFS treatment improved well-being
follow-up [79, 80]. One of the disadvantages of HT is the lack with a significant reduction in pain and disability. Further-
of enough well-trained hypnotherapists, its time investment, more, beneficial effects were sustained at follow-up [90].
and the lack of coverage by healthcare insurances. Home- Although more evidence is needed, these data suggest that
based HT using standardized scripts is an attractive alterna- PENFS may be a good and safe non-pharmacological treat-
tive treatment option and was originally developed to make ment option for pediatric FAPDs.
hypnosis for children with IBS and FAP-NOS more widely
available, especially in countries or areas with a low number Fecal microbiota transplantation
of licensed hypnotherapists or with high costs for therapist. It
has proven to be non-inferior to individual HT by a therapist Fecal microbiota transplantation targets the microbiome and
at 1-year and 5-year follow-up [77, 80]. To date, online pack- may be a potential future therapeutic strategy in IBS patients.
ages with ready-to-use HT exercises for at home use, together However, results in adult IBS studies have shown conflicting
with an instruction manual and additional video material, are results and data in the pediatric population is lacking. There-
available for children in English, Spanish, and Dutch [81–83]. fore, no valid conclusions on the efficacy of this treatment
for pediatric IBS can be drawn [91, 92]. Currently, an RCT
is assessing the use of fecal microbiota transplantation for
Yoga
refractory IBS in adolescents (NCT03074227).
Yoga practice using meditation techniques and breathing prac-
tices in combination with physical poses has been shown to
Pharmacological treatment
improve body tone, reduce anxiety, and heighten feelings of
well-being [84]. Three RCTs, including 127 children with IBS
Based on the current evidence, it is not possible to recom-
or FAP, have been performed to evaluate the effect of yoga
mend any specific pharmacological treatment for the treat-
[85–87]. After meta-analysis, no differences in treatment suc-
ment of pediatric FAPDs [11]. The efficacy of several agents
cess were found between the yoga intervention and the control
has been assessed for the treatment of pediatric FAPDs.
group [10]. Studies were of low quality since only small groups
Information on these studies is shown in Table 3.
of children were included and methodological shortcomings.
Therefore, there is no evidence to recommend yoga as a routine
Antispasmodics
intervention in the management of pediatric FAPDs.
Antispasmodic agents act directly on the intestinal smooth
Other forms of complementary and alternative medicine muscles to ensure relaxation, or indirectly on the nerves of the
intestinal smooth muscles via receptor blockade, decreasing
To date, the efficacy of complementary therapies such as gastrointestinal contractions, and, consequently, alleviating
acupuncture, herbal therapy, homeopathy, chiropractic abdominal pain complaints [93–95]. Only five RCTs have
therapy, or osteopathy have not been evaluated in pediat- been conducted on the use of antispasmodics in children. Two
ric clinical FAPD trials [10]. However, these alternative studies investigated the effect of peppermint oil [96, 97], and
therapies are used by about 40% of children diagnosed with three investigated drotaverine [98], mebeverine [99], or tri-
FAPDs [88, 89]. Potential reasons for using complementary mebutine [100]. A recent meta-analysis found a significant
and alternative medicine are the lack of perceived benefit difference in treatment success between the antispasmodic
of conventional therapy and its associated side effects [89]. and placebo groups. No difference was found in withdrawals
More research in this field is clearly needed. due to adverse events [11]. However, the overall quality of the
studies was very low, and results should therefore be inter-
Other treatments preted with caution. Furthermore, these RCTs comprise small
sample sizes, short-duration of therapy, and limited follow-up.
Neurostimulation More data are needed before definitive conclusions can be
drawn. Currently, an RCT is investigating the effectiveness
Percutaneous electrical nerve field stimulation (PENFS) to of mebeverine on abdominal pain reduction in children with
the outer ear targets specific pain areas in the central nervous IBS or FAP-NOS (Trial NL7508).

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Table 3  Pharmacological interventions
Intervention Participants Results

Antispasmodics
Peppermint oil [91]a Children 4–13 years Compared with placebo a decrease in pain severity (P = 0.001), pain duration
(N = 120) (P = 0.0001) and pain frequency (P = 0.0001)
FGIDs (Rome III criteria)
Trimebutine [95]a Children 4–18 years Overall clinical recovery (in pain or discomfort) (95% vs 21%; P < 0.0001)
(N = 78)
IBS (Rome III criteria)
Peppermint oil [92]a Children 8–17 years Treatment success (pain severity) defined as “better” or “much better” (71%
(N = 42) vs 43%; P < 0.001); significantly decrease in pain intensity in peppermint oil
IBS (Rome I/Manning criteria) group (P < 0.03)
Drotaverine [93]a Children 4–12 years Significant reduction of pain episodes (P = 0.01); decrease in school
(N = 132) absenteeism (P = 0.05)
RAP (Apley criteria)
Mebeverine [94]a Children 6–18 years Response rate defined as reduction in pain (41% vs 30%; P = 0.117)
(N = 115)
FAP (Rome III criteria)
Antidepressants
Citalopram [99]a Children 6–18 years (N = 115) Responded (pain) to treatment at 4 weeks (41% vs 30%; P = 0.17); responded
FAP (Rome III criteria) (pain) to treatment at 8 weeks (53% vs 41%; P = 0.15)
Amitriptyline [100]a Children 8–17 years (N = 90) Satisfactory relief (59% vs 52%; P = 0.81); no significant difference in pain
FAP, FD, IBS (Rome II criteria) intensity scores; large placebo response reported
Amitriptyline [101]a Children 12 to 18 years (N = 33) Improvement in overall quality of life (39% vs 0%; P = 0.013); improvement
IBS (Rome II criteria) in periumbilical pain at week 10 (P = 0.018);
no significant differences in pain frequency and intensity
Antibiotics
Rifaximin [111]a Children 8–18 years No significant differences apparent in pain frequency and intensity between
(N = 75) both groups
CAP (Rome II criteria)
Rifaximim [110]c Children 3–15 years Benefit in improving abdominal pain, bloating, and flatulence (P < 0.005)
(N = 50)
IBS (Rome II criteria)
Prokinetics
Domperidone [123]a Children 5–12 years Improved cure rate (44% vs 28%; P = 0.028), decreased severity of abdominal
(N = 100) pain (54% vs 30%; P = 0.008)
AP-FGIDs (Rome III criteria)
Laxatives
PEG 3350 + Tegaserod [113]d Children 13 – 18 years Significant improvement as a reduction in pain (67% vs 19%; P < .05);
(N = 48) statistically significant different in pain intensity between the two groups in
IBS-C (Rome II criteria) favor of the tegaserod group (P < .05)

AP-FGIDs abdominal pain predominant functional gastrointestinal disorders, CAP chronic abdominal pain, FAP functional abdominal pain, FD
functional dyspepsia, FGID functional gastrointestinal disorder, IBS irritable bowel syndrome, IBS-C irritable bowel syndrome, predominant
constipation, RAP recurrent abdominal pain
a
 Compared with placebo
b
 compared with usual care
c
 open-trial
d
 compared with PEG350

Antidepressants found insufficient evidence to support the use of antidepres-

sants (amitriptyline and citalopram) in children with FAPDs
Antidepressants, such as amitriptyline and citalopram, are [103–106]. Currently, antidepressants are commonly used
central neuromodulators affecting the brain-gut axis. They in clinical practice for children who do not respond to first-
have anticholinergic effects, decrease visceral sensitivity line treatments [107]. However, some safety issues regard-
and GI motility, and improve mood and sleep patterns [101, ing these agents should be considered. In 2004, the Food
102]. A recent Cochrane review, including three RCTs, and Drug Administration (FDA) issued boxed warnings

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2610 European Journal of Pediatrics (2022) 181:2603–2617

on antidepressant drugs due to a potential increased risk been studied only in children with functional constipation
of suicidality in the pediatric population [108]. In addition, and showed conflicting results [123–125]. Recently, the
the practitioner should be cautioned of the potential risk efficacy and safety of different dosages of linaclotide were
of cardiac-related side effects of tricyclic antidepressants evaluated in a phase 2 trial for IBS-C in children, with lim-
(TCAs). Current practice advises performing an electro- ited but promising results (NCT02559817). Thus, there is
cardiogram to screen for prolonged QT intervals or bun- a clear need for large placebo-controlled RCTs evaluating
dle branch block before the administration of TCAs and the efficacy of this new compound in children with IBS-C
advising families about the risks [109]. However, studies before making any recommendations for its use.
found no correlation between serious adverse cardiac events
and the use of low-dose TCA in pediatric FGIDs, and side Prokinetics
effect risks are usually reduced over time [110, 111]. More
research is needed to draw firm conclusions. Dopamine antagonists, such as domperidone, have ben-
eficial effects in adults with functional dyspepsia and IBS
Antibiotics [126–129]. Only a single placebo-controlled trial assessed
the efficacy of domperidone in children with FAPDs
Rifaximin is a nonabsorbed antibiotic, which is thought (n = 100) [130]. There was no significant difference in
to eliminate small-intestinal bacterial overgrowth. Since treatment success after 8 weeks of treatment. However,
it is hypothesized that IBS-D patients have an abnormal there was a significant decrease in abdominal pain inten-
microbiome, rifaximin may be a potential treatment for sity in the domperidone group compared with placebo.
GI disorders [112–114]. In adult IBS, the use of rifaximin No side effects were reported. Children with FAPDs often
to treat global IBS-D symptoms has shown to be effective report other symptoms, such as nausea, which is experi-
and safe [42, 115]. In the pediatric population, two tri- enced by about half of the children at least twice a week
als were conducted on the efficacy of rifaximin. The first [131, 132]. Therefore, domperidone treatment can be used
trial showed that, in 50 children with IBS and an abnor- as symptomatic treatment in children with comorbid nau-
mal lactulose breath hydrogen test, rifaximin significantly sea. However, caution is warranted since the use of dom-
improved abdominal pain, bloating, and flatulence [116], peridone has been associated with prolonged QT intervals
while the other RCT, evaluating rifaximin in 75 children and is therefore not licensed in children under the age of
with FAP, found no significant difference in pain scores 12 [133, 134].
[117]. To date, rifaximin in pediatric IBS is not recom-
mended. There is a long-term safety concern of rifaximin Antidiarrheal agents
use as it may produce cross-resistant bacterial strains and
interfere with the healthy microbiome in children [118]. Loperamide is an over-the-counter opioid receptor ago-
nist commonly used in clinical practice to treat diarrhea
Laxatives [135–137]. However, guidelines do not recommend it as
first-line treatment for adults with IBS-D since it is not
A small study investigated polyethylene glycol 3350 (PEG) effective for the most bothersome IBS symptoms, abdomi-
and tegaserod in children with IBS-C. The study found sig- nal pain, and bloating [121, 135]. Although no RCTs have
nificant improvements in pain scores in the PEG + tegas- evaluated the efficacy of loperamide in children with IBS-
erod treatment group compared with the PEG-alone group D, it may still be considered for the symptomatic treatment
[119]. No evidence exists that PEG reduces abdominal in children with IBS-D [136].
pain in patients with IBS-C. However, PEG is commonly
used as a first-line treatment for constipation since it is Bile acid sequestrants
effective and safe. Therefore, it could be recommended to
treat symptomatic constipation in IBS-C. In adult and pediatric patients with IBS-D, there is some
The relatively new therapeutic agents prucalopride (a evidence that a subset of these patients has bile acid mal-
5-HT4 receptor agonist), and lubiprostone (prostaglandin absorption [138–140]. This suggests that bile acid seques-
­E1 derivative) and linaclotide and plecanatide (both a gua- trants could play a role in treating diarrheal symptoms in
nylyl cyclase agonist) (both licensed for the management of IBS. Several agents have indeed been shown to improve
IBS-C in adults) have shown benefits in adults with IBS-C stool consistency in adults with IBS-D, such as cholesty-
[120–122]. Neither of these agents have proven efficacy ramine, colestipol, and colesevelam [138, 141, 142]. To
in the pediatric population and are currently not approved date, no well-designed studies have evaluated their efficacy
for the treatment of IBS-C in children. Lubiprostone has in children with IBS.

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European Journal of Pediatrics (2022) 181:2603–2617 2611

Placebo Putting it all together

In pediatric FAPDs, the placebo response is substantial, The heterogeneity of pediatric IBS and FAP-NOS, even
with on average 41% of children improving on placebo within individual subtypes, makes it challenging to design
[143]. Different factors are significant contributors to the a treatment algorithm to fit all children. It is known that
placebo effect, such as the natural course of the disease, up to 40% of children remain symptomatic despite treat-
methodological bias, regression to the mean, and contex- ment [162–164]. A stepwise approach, including a positive
tual factors. Contextual factors, including expectations diagnostic strategy with minimal investigations, involving
and conditioning are known as the “true placebo-effect” patients and families in shared decision-making, and an indi-
[144–146]. Healthcare professionals should be mindful of vidualized approach to management, is the fundaments of
the “true placebo-effect,” since this can be influenced by IBS and FAP-NOS management. We propose a tailor-made
an active listening approach and a warm physician–patient approach for each patient, based on the family’s beliefs, pub-
relationship, potentially leading to positive patient expec- lished evidence when available, and the treatment of comor-
tations and thus improved treatment responses [147, 148]. bid symptoms such as nausea, bloating, diarrhea, or con-
It is interesting to better understand whether the placebo- stipation. Both non-pharmacological and pharmacological
effect is still present when the patient is aware of tak- interventions should be discussed (Fig. 1). The first recom-
ing a placebo. A study in children has shown a beneficial mended step in the management of both IBS and FAP-NOS
effect of non-deceptive placebo in children with FAPDs is validation, education, providing a positive diagnosis, and
[149]. A large open-label study is currently assessing the identifying stress factors. Initial treatment should include
efficacy of open-label placebo in children with FGIDs parental distraction, and simple dietary changes. When
(NCT02389998). Similar trials in adults with IBS have symptoms persist, especially in patients with functional
shown promising results [150, 151]. disability, (online) psychological treatments could be pro-
posed since those have proven to be successful therapies.
Novel treatments in adults with IBS However, while CBT or HT might be accepted by some,
others might prefer pharmacological therapies or a com-
In the adult population, management is mostly based on bination of interventions. It is important to emphasize that
the predominant symptom of the bowel dysfunction: con- although there is limited data to substantiate the efficacy of
stipation/bloating (IBS-C) or diarrhea (IBS-D) [152]. the combination of different interventions, those could be
In adults with constipation-predominant IBS several treat- combined. If patients have IBS with constipation, we recom-
ment are in development [153]. Mizagliflozin (a SGLT1 inhibi- mend increasing soluble fibers or laxatives, such as PEG.
tor) reduces the uptake of sodium ions from the lumen, result- Diarrhea may be ameliorated with loperamide. For children
ing in water retention in the lumen and loose stools. A phase 2 with troublesome and persistent IBS-D symptoms, rifaximin
placebo-controlled trial in adults with IBS-C showed that miz- and bile acid sequestrants may help. Special attention should
agliflozin had significantly higher response rates than placebo be paid to non-abdominal pain symptoms, such as headache
and also appeared to be safe [154]. Furthermore, tenapanor and chest-, back-, joint-, and extremity (arms and legs) pain
(a sodium-hydrogen exchanger inhibitor) have proven to be [165]. These comorbid somatic symptoms are present in
effective and safe in phase 2 trials in adults with IBS-C [155]. almost 75% of children and are associated with increased
Novel approaches for adults with IBS-D include opioid abdominal pain frequency and severity, functional disability,
mediators, such as eluxadoline (a mixed opioid receptor ago- poor sleep, psychosocial distress, and lower health-related
nist and antagonist), which has shown to be effective and quality of life, potentially influencing long-term progno-
safe [115, 156, 157]. However, eluxadoline has limitations sis [165–168]. Additional therapy with analgesics, such as
in its use, since patients with a previous cholecystectomy non-steroidal anti-inflammatory drugs or paracetamol, could
report sphincter of Oddi spasms and pancreatitis [157]. The be considered to treat these complaints. It is important to
efficacy of eluxadoline is currently assessed in adolescents emphasize that the majority of patients can be treated with
with IBS-D (NCT03339128). first-line management. However, various highly effective
Serum bovine-derive immunoglobulin (SBI) modulates therapies (dietary and psychological interventions) are not
junctional regulatory proteins in the gut and may therefore easily available as a result of a lack of insurance coverage
be a potential effective treatment [158]. Two pilot RCTs in and also because of a lack of allied healthcare professionals.
adolescents with IBS-D have examined the effect of this New developments include the delivery of online psycho-
drug, but have shown conflicting results [159, 160]. logical therapies, through audiotapes, by phone, or via the
Ibodutant is a selective neurokinin-2 receptor antagonist Internet. Referral to a pediatric gastroenterologist experi-
and has proven to be effective and safe in phase 2 trials in enced in pain disorders is required if first-line management
adults with IBS-D [161]. fails, or if therapy to TCAs, such as amitriptyline, and PENF

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2612 European Journal of Pediatrics (2022) 181:2603–2617

Management of pediatric
IBS/FAP-NOS

start first-line
management Add for other
Domperidone
(non) GI-symptoms
Reassurance/explanation/positive diagnosis Acid supression
Parental distraction Analgesics
Identify psychosocial stressors
Simple dietary changes

persisting symptoms

Diagnosis?

IBS FAP-NOS

Choose or mix ≥1 Choose or mix ≥1

intervention(s) intervention(s)

Cognitive behavioral therapy Cognitive behavioral therapy

Antispasmodics
Hypnotherapy Hypnotherapy
Amitriptyline**
Peppermint oil Peppermint oil
add or change PENFS**
Probiotics Probiotics

choose
IBS-type add or change

Constipation- Diarrhea-
Predominant IBS Predominant IBS
(IBS-C) (IBS-D) Antispasmodics
Amitriptyline**
PENFS**
add add

Soluble fibers
Loperamide
Osmotic laxatives

add or change add or change

Linaclotide*
Rifaximin*
Lubiprostone
Bile acid sequestrant
Prucalopride
* only evidence in adults
** may be considered by pediatricians with significant experience in the treatment of IBS and FAP-NOS

Fig. 1  Flow diagram of treatment

is considered, since these treatments are not commonly used approved the final manuscript as submitted. Dr. Vlieger, Prof. Dr. Saps
in daily clinical practice. and Dr. Tabbers reviewed and revised the manuscript, and approved the
final manuscript as submitted. Prof. Dr. Benninga critically reviewed
A multidisciplinary approach to provide patient support and revised the manuscript for important intellectual content, and
is ideal, however, not always possible. approved the final manuscript as submitted.

Declarations 
Conclusion
Ethics approval  All authors approved the final manuscript as submitted
In conclusion, IBS and FAP-NOS are common in childhood, and agree to be accountable for all aspects of the work.
though no evidence-based international management guide- Consent to participate  Not applicable.
lines are available. We suggest using a stepwise individual-
ized approach to management, where after first-line man- Consent for publication  Not applicable.
agement, both non-pharmacological and pharmacological
interventions should be discussed. More high-quality inter- Conflict of interest  The authors declare no competing interests.
vention studies in these patient groups are necessary to guide
adequate clinical management in the future. Open Access  This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
Supplementary information  The online version contains supplemen- as you give appropriate credit to the original author(s) and the source,
tary material available at https://​doi.o​ rg/1​ 0.​1007/s​ 00431-​022-0​ 4459-y. provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
Authors’ contributions  Ms. Rexwinkel conceptualized and designed included in the article's Creative Commons licence, unless indicated
the study, reviewed the literature, drafted the initial manuscript, and otherwise in a credit line to the material. If material is not included in

13
European Journal of Pediatrics (2022) 181:2603–2617 2613

the article's Creative Commons licence and your intended use is not 19. Cooper TE et al (2017a) Opioids for chronic non-cancer pain
permitted by statutory regulation or exceeds the permitted use, you will in children and adolescents. Cochrane Database Syst Rev
need to obtain permission directly from the copyright holder. To view a 7:CD012538
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. 20. Cooper TE et  al (2017b) Paracetamol (acetaminophen) for
chronic non-cancer pain in children and adolescents. Cochrane
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