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Functional abdominal pain disorders in children: therapeutic strategies focusing
on hypnotherapy
Rutten, J.M.T.M.
Publication date
2015
Document Version
Final published version
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Citation for published version (APA):
Rutten, J. M. T. M. (2015). Functional abdominal pain disorders in children: therapeutic
strategies focusing on hypnotherapy.
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FUNCTIONAL
ABDOMINAL PAIN
DISORDERS IN
CHILDREN
THERAPEUTIC STRATEGIES FOCUSING ON HYPNOTHERAPY
Juliette M.T.M. Rutten
FUNCTIONAL ABDOMINAL P
AIN DISORDERS IN CHILDREN
JULIETTE M.T
FUNCTIONAL ABDOMINAL PAIN
DISORDERS IN CHILDREN
- Therapeutic strategies focusing on hypnotherapy -
Functional abdominal pain disorders in children - Therapeutic strategies focusing on hypnotherapy - Thesis, University of Amsterdam, the Netherlands
ISBN: 978-94-91602-37-5
Lay-out by: Aniek van de Kuilen (Sinds 1961 Grafisch Ontwerp) Printed by: Print Service Ede, the Netherlands
Part of the research in this thesis was granted by the Netherlands Organization for Health Research and Development, ZonMW.
The financial support for printing of this thesis by the following foundations and companies is gratefully acknowledged:
Universiteit van Amsterdam, Nederlandse Beroepsvereniging van Hypnotherapeuten,
Nederlandse Vereniging voor Gastroenterologie, Nederlandse Vereniging voor Hypnose, Alpro Nederland B.V., Danone Nutricia Research, Hero Benelux, Olympus Nederland B.V., Shire International Licensing B.V., Solgar Vitamins Holland, Will Pharma and Winclove Probiotics B.V. © Juliette Rutten, the Netherlands 2015
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording or otherwise, without the written permission of the author.
FUNCTIONAL ABDOMINAL PAIN
DISORDERS IN CHILDREN
- Therapeutic strategies focusing on hypnotherapy -
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof. dr. D.C. van den Boom
ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel
op vrijdag 11 september 2015, te 12.00 uur door
Juliette Mathilde Theodora Maria Rutten geboren te Beuningen
PROMOTIECOMMISSIE
Promotor: Prof. dr. M.A. Benninga Universiteit van Amsterdam
Copromotor: Dr. A.M. Vlieger St. Antonius Ziekenhuis, Nieuwegein
Overige leden: Dr. D.K. Bosman Universiteit van Amsterdam
Prof. dr. P.M.M. Bossuyt Universiteit van Amsterdam
Prof. dr. M.A. Grootenhuis Universiteit van Amsterdam
Prof. dr. E.E.S. Nieuwenhuis Universiteit Utrecht
Prof. dr. F.A. Wijburg Universiteit van Amsterdam
Prof. dr. N.J. de Wit Universiteit Utrecht
Faculteit der Geneeskunde
TABLE OF CONTENTS
General introduction and outline of the thesis 9
PART I – CHARACTERISTICS OF CHILDREN AND THEIR PARENTS
Chapter 1 IBS and FAP(S) in children: a comparison of psychological and clinical 29
features
Chapter 2 Parental physical health status, psychological distress, personality and 45
child-rearing style in children with irritable bowel syndrome or functional abdominal pain (syndrome)
PART II – MANAGEMENT
Chapter 3 Annual costs of care for pediatric irritable bowel syndrome and functional 63
abdominal pain (syndrome)
Chapter 4 Pharmacologic treatment in pediatric functional abdominal pain disorders: 79
a systematic review
Chapter 5 Nonpharmacologic treatment of functional abdominal pain disorders: 107
a systematic review
PART III – GUT-DIRECTED HYPNOTHERAPY
Chapter 6 Gut-directed hypnotherapy for functional abdominal pain or 149
irritable bowel syndrome in children: a systematic review
Chapter 7 Long-term follow-up of gut-directed hypnotherapy versus standard care 165
in children with functional abdominal pain or irritable bowel syndrome
Chapter 8 Gut-directed hypnotherapy in children with irritable bowel syndrome or 177
functional abdominal pain (syndrome): a randomized controlled trial on self-exercises at home using CD versus individual therapy by qualified therapists
Chapter 9 Efficacy of gut-directed hypnotherapy for children with irritable bowel 193
syndrome or functional abdominal pain (syndrome): a non-inferiority randomized controlled trial on self-exercises at home using CD versus individual therapy by qualified therapists
Chapter 10 Cost-effectiveness and cost-utility of home-based hypnotherapy using CD 219 versus individual hypnotherapy by a therapist in pediatric irritable bowel
syndrome and functional abdominal pain (syndrome)
Summary and discussion 239
Samenvatting en discussie 253 Contributing authors 267 List of publications 271 PhD Portfolio 275 Dankwoord 279 Curriculum Vitae 285
GENERAL
INTRODUCTION &
OUTLINE OF THE
THESIS
PARTS OF THIS INTRODUCTION HAvE BEEN PUBLISHED AS: Chapter 23.3: Chronic abdominal pain, including functional abdominal pain, irritable bowel
syndrome and abdominal migraine Juliette M.T.M. Rutten, Arine M. Vlieger, Marc A. Benninga
Kleinman R. (ed), Walker’s Pediatric Gastrointestinal Disease, 6th ed. 2015. BC Decker Inc. Hamilton, IL. [in press]
Chronische buikpijn bij kinderen Juliette M.T.M. Rutten, Arine M. Vlieger, Marc A. Benninga
INTRODUCTION
Chronic abdominal pain is one of the most commonly encountered symptoms in childhood and
adolescence and accounts for 2 to 4% of pediatric office visits.1 It is characterized by chronic,
recurrent or continuous abdominal pain which is not well localized. The pain may wax and wane, with asymptomatic episodes interposed with painful periods and can profoundly affect daily activities. Children often have symptoms of depression and/or anxiety and distress leading
to significant school absence.2 Studies of these children revealed self-reported quality of life
(QoL) scores comparable to children with inflammatory bowel diseases, highlighting the clinical
significance of this problem.3
Many pathologic conditions can cause chronic or recurrent abdominal pain, but in the vast majority
of children, no objective evidence for an underlying organic disease can be found.4 These children
are diagnosed as having one of the abdominal-pain related functional gastrointestinal disorders
(AP-FGIDs) according to the Rome III criteria.5 Five AP-FGIDs can be distinguished: functional
dyspepsia (FD), irritable bowel syndrome (IBS), abdominal migraine (AM), functional abdominal pain (FAP) and functional abdominal pain syndrome (FAPS). The pediatric Rome III criteria for these functional abdominal pain disorders are shown in Table 1. According to adult Rome III criteria, IBS can be classified into subtypes based on the predominant bowel habit, which are constipation predominant (IBS-C), diarrhea predominant (IBS-D), and mixed type with alternating episodes of both constipation and diarrhea (IBS-M). If abnormality of stool consistency is not sufficient to
meet criteria for IBS-C, -D, or -M, IBS is classified as unsubtyped (IBS-U).6 These criteria for IBS
subtyping are not available for children and therefore adult criteria are commonly used.5
EPIDEMIOLOGY
AP-FGIDs are common worldwide, with prevalence rates of 0.3 to 19% (median 8.4%) in
western countries.7 This very wide range in prevalence rates is likely to be caused by differences
in methodologies used to assess the diagnosis. AP-FGIDs are also prevalent in developing countries, with prevalence rates up to 22.6% in recent studies conducted in Sri Lanka, China
and Turkey.8–10 IBS is most frequently diagnosed in up to 45% of pediatric AP-FGIDs.11–13
There is evidence to suggest a bimodal age peak in which the symptoms of abdominal pain are
more prevalent in children below 5 years of age and between 8 and 10 years of age.4,7 Females
seem to have a higher prevalence of AP-FGIDs compared to males (ratio 1.4:1), but this difference
manifests not earlier than around puberty.7,14 Other factors associated with a higher prevalence
of AP-FGIDs are familial factors, such as a single parent household (odds ratio 2.9) and having a
parent with gastrointestinal complaints (odds ratio 5.3).15 A lower socioeconomic environment
has also been associated with AP-FGIDs and children of immigrants reported recurrent abdominal
pain in a significantly higher proportion compared to the indigenous population.7
PATHOPHYSIOLOGY
general introduction of evidence that the pain is resulting from a dysfunction of the brain-gut axis, involving both
efferent and afferent pathways by which the enteric and central nervous systems communicate.16
Table 1. Rome III criteria for functional abdominal pain disorders5
Functional dyspepsia (FD)
- Persistent or recurrent pain or discomfort centered in the upper abdomen (above the umbilicus) - Not relieved by defecation or associated with the onset of a change in stool frequency or stool
form (i.e. not IBS)
Criteria fulfilled at least once per week for at least 2 months before diagnosis Irritable bowel syndrome (IBS)
- Abdominal discomfort (an uncomfortable sensation not described as pain) or pain associated with 2 or more of the following at least 25% of the time:
1) Improved with defecation
2) Onset associated with a change in frequency of stool 3) Onset associated with a change in form (appearance) of stool Criteria fulfilled at least once per week for at least 2 months before diagnosis Symptoms that cumulatively support the diagnosis of IBS are:
a) abnormal stool frequency (4 or more stools per day and 2 or less stools per week) b) abnormal stool form (lumpy/hard or loose/watery stool)
c) abnormal stool passage (straining, urgency, or feeling of incomplete evacuation) d) passage of mucus
e) bloating or feeling of abdominal distension Abdominal migraine (AM)
- Paroxysmal episodes of intense, acute periumbilical pain that lasts for 1 hour or more - Intervening periods of usual health lasting weeks to months
- The pain interferes with normal activities
- The pain is associated with 2 or more of the following: a) Anorexia b) Nausea c) Vomiting d) Headache e) Photophobia f) Pallor
All above criteria must be included and fulfilled > 2 times in the preceding 12 months Functional Abdominal Pain (FAP)
- Episodic or continuous abdominal pain - Insufficient criteria for other AP-FGIDs
Criteria fulfilled at least once per week for at least 2 months before diagnosis Childhood Functional Abdominal Pain Syndrome (FAPS)
- Must include functional abdominal pain at least 25% of the time and 1 or more of the following: 1) Some loss of daily functioning
2) Additional somatic symptoms such as headache, limb pain, or difficulty sleeping Criteria fulfilled at least once per week for at least 2 months before diagnosis
In all subgroups, no evidence is found of an inflammatory, anatomic, metabolic, or neoplastic process that explains the subject’s symptoms
Biopsychosocial model
The cornerstone for understanding of the etiology of AP-FGIDs is the biopsychosocial model (Figure 1). This model is based on a complex interplay of genetic, environmental, physiological
and psychosocial factors and their influence on symptoms and illness.16,17 Genetic influences
and early social learning may result in a predisposition that is influenced by later psychological experiences and physiological factors. The relative contribution of each of these factors may vary among patients.
Early life -‐ Genetics -‐ Environmental factors Psychosocial factors -‐ Stress
-‐ Psychological or psychiatric comorbidity
-‐ Coping strategies -‐ Social support
Physiological factors
-‐ Abnormal gut motility -‐ Visceral hypersensitivity Central nervous system Enteric nervous system AP-‐FGIDs -‐ Symptom experience -‐ Behavior Outcomes
-‐ Use of medication -‐ Healthcare visits -‐ Daily functioning -‐ Quality of life
Figure 1. Biopsychosocial model16
Genetics
Familial clustering of AP-FGIDs has been described and suggests a genetic transmittance of these disorders. Adult studies have demonstrated that IBS is more common in first-degree
relatives of individuals with IBS.18,19 Furthermore, children with chronic abdominal pain are more
likely to have a parent, especially a mother, with functional gastrointestinal complaints.15 A twin
study showed a 17% concordance for IBS in monozygotic patients with only 8% concordance
in dizygotic twins, supporting a genetic contribution to IBS.18
Drawing any conclusions on genetic factors associated with AP-FGIDs however is not yet possible, since it has also been shown that parental history of IBS was a stronger predictor of IBS
than having a twin with IBS.18,20 This finding suggests that the contribution of social learning,
that is a tendency to report more symptoms, to consult doctors more often and to have more school or work absenteeism, is more important than genetic factors and that familial clustering of AP-FGIDs is a reflection of a shared exposure to environmental factors.
general introduction
Visceral hypersensitivity
The pathogenesis of AP-FGIDs may involve the interrelationship between altered gastrointestinal motility and changes in visceral sensation, called visceral hyperalgesia or hypersensitivity. Symptoms of altered motility can include diarrhea, constipation, bloating and distension, whereas symptoms of hypersensitivity are pain and discomfort. Studies on hypersensitivity however, are inconclusive and it has been shown that a large proportion of IBS patients have
perception thresholds within the normal range, despite similarities in symptomatology.21
Three pediatric studies showed lower pain thresholds for rectal sensation in IBS children
compared to healthy controls.22–24 Studies in children with FAP on the other hand show
conflicting results. Two studies showed that FAP children were hypersensitive in both the upper
and lower gastrointestinal tract compared to healthy controls,23,24 while another study did not
find hypersensitivity.22 Another study reported visceral hypersensitivity to be present in only 23%
of children with IBS or FAP and showed that rectal sensitivity scores were not correlated with symptom severity. Furthermore, response to treatment was not associated with improvement
in rectal sensitivity.25 Increased colonic sensitivity in adult IBS patients was shown to be strongly
influenced by psychological tendency to report pain and urge rather than increased neurosensory
sensitivity.26 A pediatric IBS study reported that emotional instability seems to modulate the
perception response to visceral stimulations.27 These findings question the central role of visceral
hypersensitivity in the etiology of AP-FGIDs.
Altered central modulation of sensation
Central processing of pain is complex and occurs through different pathways. Pain is thought to have two dimensions: a sensory-discriminative component and an affective-motivational component. The discriminative component of gastrointestinal pain encodes location, intensity and nature of pain and follows a route from the gut, through the dorsal horn of the spinal cord, the ventral posterior portions of the thalamus to the insula. The affective-motivational component is thought to encode pain affect and suffering and runs through the spinal cord, the reticular formation of the brainstem, via the medial portions of the thalamus to the limbic system, particularly the anterior cingulated cortex (ACC), which is a critical center involved in the ‘unpleasantness’ of pain. Information from both the insula and ACC reach the frontal cortex,
where cognitive processing occurs.28
Several studies demonstrated an increased activation of the ACC in IBS patients compared to healthy controls. This activation occurred both during actual painful stimuli applied to the colon
and anticipation of such painful stimuli.29,30 It is hypothesized that emotional processes like
anxiety and depression and cortical factors like previous experience of pain, coping mechanisms
and psychosocial stressors can interact with limbic circuits to amplify the pain experience.31,32
Serotonin (5-HT) is a neurotransmitter found both in the enteric and central nervous system. It has emerged as a key mediator in modulating the brain-gut axis and it has been shown that various elements of serotonin signaling differ in patients with IBS. Studies on the role of serotonin, however are inconsistent and it is not yet understood whether changes in serotonin
signaling contribute to altered motility and sensitivity or are in fact a response to altered gut
functioning.33
Inflammation
Low-grade mucosal inflammatory processes may also play a role in AP-FGIDs, since experiencing of a bacterial gastroenteritis has been shown to be associated with the development of IBS in
children.34,35 Post-infectious IBS seems to occur particularly after Campylobacter and Shigella
enteritis and it has been suggested that the severity of tissue damage and ulceration in these infections is a key factor in developing post-infectious IBS. Increased numbers of inflammatory cells have also been detected in the gastrointestinal tract of IBS patients and mediators released by activated inflammatory cells can affect the brain-gut axis, thereby causing gastrointestinal
symptoms, such as abdominal pain.36
Gastrointestinal microbiota
Recent insights indicate that the composition of intestinal microbiota may be of importance in the pathogenesis of AP-FGIDs, especially IBS. The human body is inhabited by a complex community of approximately 10^14 microbes of which the vast majority is found in the gastrointestinal tract. Firmicutes, Bacteriodetes and Actinobacteria predominate in the colon. The occurrence of post-infectious IBS in a subset of patients supports the hypothesis that gut
microbiota play a role in the pathogenesis.37 Qualitative and quantitative differences in bacterial
components of the gut microbiome of IBS children compared to healthy controls were shown, with greater proportions of Proteobacteria in IBS, while Bacterioides were enriched in healthy
children. Moreover, IBS-C and IBS-D could be distinguished by global microbiome analyses.38
It is hypothesized that changes in the microbiome may contribute to IBS symptoms through
alterations in the brain-gut axis.37
Gas-related symptoms, such as flatulence, bloating and distension are common among patients with AP-FGIDs. It has been suggested that increased gas production could be due to colonization of the proximal small bowel by fermenting bacteria, as occurs in small intestinal bacterial
overgrowth (SIBO).37 There is however, conflicting evidence regarding the role of SIBO in
AP-FGIDs. A recent Dutch study reported abnormal glucose breath tests, suggesting SIBO, in 14.3%
of children with AP-FGIDs39 and an Italian study reported a significantly higher proportion of
abnormal lactulose breath tests, suggesting SIBO, among children with IBS compared to healthy
controls.40 A double-blind, placebo-controlled study showed an abnormal lactulose breath test
in 65% of children with chronic abdominal pain, suggesting SIBO, but there were no significant
differences in symptom improvement after antibiotic treatment.41 Furthermore, breath tests
used to establish the role of SIBO in IBS have not been validated for utility in this group of
patients and therefore the role of SIBO in IBS remains unclear.37
Stressful events
general introduction
and subsequently cause visceral hypersensitivity, which may have life-long consequences.42
Prevalence rates of physical and sexual abuse are significantly higher among adults with IBS
compared to the general population.43 Prevalence rates of 2.1% and 8.0% were found in two
low quality studies on sexual abuse in children with chronic abdominal pain, but real prevalence
rates may be higher.44 Indeed, it was recently shown that two-thirds of children with a history
of sexual abuse suffered from unexplained abdominal pain, but screening for AP-FGIDs was not
performed.45 A recent Sri Lankan study showed that AP-FGIDs were significantly more prevalent
in children exposed to sexual (34.0%), emotional (25.0%) and physical (20.2%) abuse, compared to children who were not abused. Additionally, symptom scores were significantly
higher in abused AP-FGID children compared to children with AP-FGIDs not exposed to abuse.46
Stressful life-events are important predictors of AP-FGIDs in children and children who are regularly being bullied have a higher risk of developing a variety of health-related symptoms,
including abdominal pain.47,48
Stressful events later in life also play a role in AP-FGIDs. Both adult and pediatric patients often
describe a correlation between stress and the onset or exacerbation of their symptoms.49 Studies
have shown that stress results in both acute and chronic changes in the activity and regulation of the hypothalamo-pituitary-adrenal (HPA) axis, but literature is conflicting. Most studies report increased basal cortisol levels and enhanced responses to physical and psychological stressors in adult IBS patients, but others show a blunted HPA axis response or no difference between IBS
patients and controls.50 Pediatric studies are lacking.
Another possible mechanism in which stress plays a pathophysiological role is through the activation of mast-cells in the gut. It has been shown that IBS patients show higher numbers and increased activation of mast cells and it has also been shown that presence of activated mast cells in proximity to colonic mucosal innervations, is correlated to both frequency and severity
of abdominal pain.51,52
Psychiatric factors
An anxiety disorder is found in approximately 80% of children with AP-FGIDs and almost
40% meet criteria for a depressive disorder.2,53,54 Evidence exists for a bidirectional causal links
between (abdominal) pain and mood,55,56 and it is also possible that pain and mood are both the
result of a biological factor, such as altered functioning of the HPA axis.50 Ineffective mechanisms
of coping with stress may contribute, since successful coping mechanisms like problem solving, acceptance and positive thinking are associated with less pain, anxiety and depression in children with AP-FGIDs. Less successful coping mechanisms like involuntary engagement (rumination and catastrophizing) or disengagement (escape and inaction) on the other hand are associated
with more somatic symptoms and higher levels of anxiety and depression.57
DIAGNOSIS
Since the exact pathophysiological mechanisms underlying AP-FGIDs are unknown and no diagnostic markers are available, a thorough history and physical examination are key in the
diagnosis of AP-FGIDs. Frequency, severity, location, and timing (postprandial, waking during the night) of abdominal pain do not help distinguishing between organic and functional abdominal
pain.58 In addition, children with AP-FGIDs are very likely to have associated symptoms, such
as anorexia, nausea, episodic vomiting, headache, back pain or arthralgia, but none of these associated symptoms have been reported to help in distinguishing between organic abdominal
pain and AP-FGIDs.59 There is also no evidence that psychosocial history helps to distinguish
between AP-FGIDs and organic disease, but psychosocial history taking is especially important with respect to treatment options.
Only the presence of so-called alarm symptoms or red flags suggests a higher prevalence of
organic disease and indicate the performance of diagnostic tests (Table 2).58 Joint pain and
waking from sleep occur similarly between AP-FGID patients and patients with Crohn’s disease
and should therefore not be considered red flags.60
Table 2. Alarm symptoms / red flags for organic disease58
- involuntary weight loss - growth retardation - significant vomiting - chronic, significant
diarrhea
- gastrointestinal blood loss
- persistent, localized tenderness in the right upper or lower quadrant
- unexplained fever
- family history of inflammatory bowel disease
Additional diagnostic testing
Since common laboratory blood, urine and feces (parasitical) tests are neither very invasive nor expensive, clinicians are likely to perform these tests, even in the absence of alarm signals. However, there are no studies that have evaluated the usefulness of these tests to distinguish
between organic disease and AP-FGIDs.58 The common diagnostic workup of children with
chronic abdominal pain was found to include numerous tests, but none of these tests resulted in any meaningful abnormality. Instead, exposure to radiation, inconvenience for patients and costs were significant and these results were likely to cause confusion and lead to more
(unnecessary) invasive testing and procedures.61 Additional diagnostic testing in the absence
of alarm symptoms, also does not influence the prognosis of AP-FGIDs.62 A recent study in a
cohort of 220 children with RAP, however, showed that 88% of these children had at least one abnormal test that could be the cause of the abdominal pain. These results, however, should be interpreted carefully and clinical relevance of these findings remains to be established, because
an abnormal test result does not necessarily indicates a causal relationship.63 In the last years,
fecal calprotectin levels of school-aged children with AP-FGIDs were shown to be within normal limits and therefore calprotectin may be a useful and non-invasive test to distinguishing
AP-FGIDs and inflammatory bowel diseases in these children.11
In children without alarm symptoms, ultrasonography and endoscopy might be done as a reassurance to parents and patient. Abdominal ultrasonography and endoscopy, however,
general introduction
Furthermore, negative outcome of endoscopy did not improve clinical outcome67 and quality of
life and did not result in reassurance of parents.66
MANAGEMENT
Education is an important part of the treatment of children with AP-FGIDs. It needs to be emphasized that although the pain is real, there is no underlying serious or chronic disease and that a positive diagnosis of an AP-FGID is not a failure to identify underlying organic illness. The primary goal of therapy is resumption of a normal lifestyle with regular school attendance, school performance to the child’s ability, participation in desired extracurricular activities and a
normal sleep pattern.68
An important factor in management of pediatric AP-FGIDs is the parental response to the abdominal pain of the child. Parents often believe that attention to somatic complaints is beneficial and distraction is potentially harmful. The opposite however, seems true, when looking at a randomized controlled trial on the effects of parental attention versus distraction or no instruction following induction of visceral discomfort in the child. Compared to the “no instruction” group, symptom complaints nearly doubled in the attention group and were
reduced by half in the distraction group.69 Parental over-involvement in pain behavior and
reinforcement of sick role behavior are thought to be associated with ineffective coping with chronic pain and a perseverance of symptoms. However, negative attention to pain in children with low self-esteem has also been associated with increased pain behavior, possibly by creating
affective distress that may further contribute to somatic symptoms. 70
Another important therapeutic goal is to identify, clarify and possibly reverse physical and psychological stressors that may play an important role in the onset, exacerbation or maintenance of abdominal pain. Acceptance of a biopsychosocial model of illness by parents has been shown
to be important for the resolution of symptoms in children with AP-FGIDs.71,72
Pharmacologic and nonpharmacologic treatment
Management of children with AP-FGIDs can be very challenging, due to the incomplete pathophysiological understanding and treatment therefore remains mainly symptomatic. A wide variety of treatments are available in treating pediatric AP-FGIDs. Dietary interventions are frequently used in AP-FGIDs, since many patients and some physicians consider symptoms
being meal related.73 Pharmacologic therapy for AP-FGIDs has generally been directed at
symptom alleviation, rather than at precise pathophysiological abnormalities. However, due to increased understanding of the pathophysiological role of the brain-gut axis, potential targets for pharmacologic treatment were identified including smooth muscle cells throughout the gastrointestinal tract, peripheral receptors, central interneurons and cortical regions involved in
conscious perception of pain.74 Due to the strong association with stress, psychological factors
and psychiatric comorbidity, psychological interventions aiming to teach alternative responses to stress, such as cognitive behavioral therapy and hypnotherapy, are frequently used in pediatric
Efficacy and safety of all available pharmacologic and nonpharmacologic treatments for pediatric AP-FGIDs are described in detail in chapter 4 and 5.
Placebo effect
In interpreting therapeutic AP-FGID-trials, the placebo effect must be taken into account.
Placebo responses in adult IBS trials vary from 16.0%-71.4%76 and high placebo rates up
to 53% have been reported in RCTs in children and adolescents with IBS.77–79 High placebo
responses may also display the natural course of functional gastrointestinal disorders with
fluctuating symptoms.16 Treatment and placebo effects are often additive, so enhancing the
placebo component increases response to treatment. Patient-practitioner relationship and active listening approach are known to be important in mediating the placebo response, which
may be especially important in nonpharmacologic therapies for AP-FGIDs.80,81
PROGNOSIS
A significant proportion of 25 to 66% of children with AP-FGIDs were shown to have either continued abdominal pain symptoms throughout adolescence and adulthood or develop other symptoms, such as chronic headache, back pain, fibromyalgia, anxiety and sleep
disturbances.62,82–85
Adverse prognostic factors that play a role include a family history of IBS, parental refusal to acknowledge the role of psychological factors in the genesis and maintenance of symptoms
and increased healthcare consumerism.71,72 High baseline levels of anxiety or depression, more
negative life-events, lower self-worth, obesity and a ‘high pain dysfunctional profile’ with low perceived pain coping efficacy, high levels of negative affect, pain catastrophizing and functional
general introduction
OUTLINE OF THE THESIS
Pediatric abdominal pain related functional gastrointestinal disorders (AP-FGIDs) comprise five common, heterogenic disorders, in which understanding of underlying pathophysiological mechanisms is incomplete. This incomplete pathophysiological understanding hampers management. Irritable bowel syndrome (IBS) and functional abdominal pain (syndrome) (FAP(S)) are most commonly diagnosed and can have significant impact on the child and their family.
Part I of this thesis discusses clinical characteristics of children with IBS or FAP(S) and their
parents and in Part II management strategies for pediatric IBS and FAP(S) pass in review. Part
III of this thesis focusses on gut-directed hypnotherapy as treatment for children with IBS and
FAP(S).
PART I – CHARACTERISTICS OF CHILDREN AND THEIR PARENTS
It has been suggested that different subcategories of childhood AP-FGIDs are not separate clinical entities, but instead represent variable expressions of the same functional gastrointestinal
disorder.89 In chapter 1, clinical and psychological characteristics of children with IBS and FAP(S)
are compared to shed some more light on the issue whether IBS and FAP(S) must be considered different entities.
Parental factors are suggested to play a role in causing, maintaining or exacerbating symptoms
in children with AP-FGIDs, since familial clustering of these disorders is common.18–20 Chapter
2 therefore describes physical health status, psychological distress, personality and child-rearing style of mothers and fathers of children with IBS or FAP(S), since this may improve insight in the etiology of these disorders and may lead to more systemic treatment approaches.
PART II – MANAGEMENT
Chronic abdominal pain is one of the most important reasons for parents to consult a doctor and
accounts for 25 to 50% of referrals to a (tertiary) pediatric gastroenterology clinic.1 Additionally,
children with IBS or FAP(S) report increased usage of health care services.90 These disorders are
therefore thought to have significant impact on health care costs and in chapter 3 annual costs of care for children are assessed, since data on costs of care for children with IBS or FAP(S) are not available to this date.
Management of children with IBS or FAP(S) can be challenging and a wide variety of both pharmacologic and nonpharmacologic treatments are available. Different kinds of treatments are mostly prescribed by health care professionals based on their own clinical experiences and results of adults studies, since pediatric data are often scarce. Chapter 4 systematically reviews available evidence on safety and efficacy of pharmacologic treatments for children with AP-FGIDs, whereas chapter 5 describes a systematic review on the quantity and quality of evidence for the efficacy and safety of different kinds of nonpharmacologic treatments available for pediatric AP-FGIDs.
PART III – GUT-DIRECTED HYPNOTHERAPY
Spontaneous remission of symptoms occurs in a lot of children with IBS or FAP(S), but a significant proportion of children continues to experience symptoms of abdominal pain, even
into adulthood.16,62,85 In the last 30 years, multiple trials have demonstrated that gut-directed
hypnotherapy (HT) is an effective therapy in adult patients with IBS.91 The systematic review
described in chapter 6 summarizes available evidence for efficacy and safety of gut-directed HT in children with IBS and FAP(S). Gut-directed HT was shown to have long-lasting beneficial
effects in adult IBS patients.92,93 Between 2002 and 2005, a randomized controlled trial (RCT)
was conducted in the Netherlands to compare the effects of standard medical care plus
supportive therapy and gut-directed HT in 52 pediatric patients with long-lasting IBS or FAP.94
To assess whether effects of HT are also long-lasting in children with IBS or FAP, we performed a follow-up study of this RCT and results of this study are described in chapter 7.
Gut-directed HT performed by a therapist has been shown to be effective in children with IBS or FAP(S), but it is still unavailable to many children due to costs, a lack of qualified child-hypnotherapists and because it requires a significant investment of time by child and
parent(s).94,95 Home-based HT by means of exercises on CD has been shown effective as well,
and has potential benefits, such as lower costs and less time investment.96 We therefore
performed a non-inferiority RCT to compare the (cost-)effectiveness of individual HT performed by a qualified therapist with HT by means of CD recorded self-exercises at home in children with IBS or FAP(S). Chapter 8 describes the protocol of this non-inferiority RCT. Chapter 9 focusses on the results of this trial with respect to efficacy, while chapter 10 discusses the results of the cost-effectiveness and -utility analyses.
general introduction
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ABSTRACT
Objectives: It has been suggested that different subcategories of childhood abdominal pain related functional gastrointestinal disorders (AP-FGIDs) are not separate clinical entities, but represent variable expressions of the same FGID. The aim of the present study was to compare clinical and psychological characteristics of children with irritable bowel syndrome (IBS), functional abdominal pain (FAP) and functional abdominal pain syndrome (FAPS).
Methods: A total of 259 children, aged 8-18 years, fulfilling Rome III criteria for IBS or FAP(S) were included in a randomized controlled trial evaluating the effect of hypnotherapy. At inclusion, questionnaires assessed demographics, clinical features, abdominal pain frequency and intensity, depression and anxiety, somatization, health-related quality of life, pain beliefs and coping strategies.
Results: No differences were found between children with IBS and those with FAP(S) with respect to the main outcomes: frequency and intensity of abdominal pain, symptoms of depression and anxiety, somatization, health-related quality of life, pain beliefs and coping strategies. A significantly higher percentage of patients with IBS had a positive family history for AP-FGIDs (56.8% vs 37.8%; P=0.00). Characteristics of patients with IBS subtypes did not differ. Patients with FAP or FAPS differed only with respect to problem-focused coping strategy (2.21 ±0.61 vs 2.52 ±0.49; P=0.00).
Conclusions: Pediatric patients with IBS and those with FAP(S) have similar psychosocial profiles. These results may explain why treatment response of psychological therapies in these AP-FGIDs is similar. These results may indicate that pediatric IBS and FAP(S) are different expressions of 1 underlying functional disorder, but similarities in psychosocial characteristics do not exclude the possibility that these disorders are different entities, because these similarities can exist between disorders of various causes. Therefore, future research is required on the role of other (physiological) factors in pediatric IBS and FAP(S).
PART
I
CHAPTER 1
IBS AND FAP(S) IN CHILDREN: A COMPARISON OF
PSYCHOLOGICAL AND CLINICAL FEATURES
Juliette M.T.M. Rutten, Marc A. Benninga, Arine M. Vlieger
ABSTRACT
Objectives: It has been suggested that different subcategories of childhood abdominal pain related functional gastrointestinal disorders (AP-FGIDs) are not separate clinical entities, but represent variable expressions of the same FGID. The aim of the present study was to compare clinical and psychological characteristics of children with irritable bowel syndrome (IBS), functional abdominal pain (FAP) and functional abdominal pain syndrome (FAPS).
Methods: A total of 259 children, aged 8-18 years, fulfilling Rome III criteria for IBS or FAP(S) were included in a randomized controlled trial evaluating the effect of hypnotherapy. At inclusion, questionnaires assessed demographics, clinical features, abdominal pain frequency and intensity, depression and anxiety, somatization, health-related quality of life, pain beliefs and coping strategies.
Results: No differences were found between children with IBS and those with FAP(S) with respect to the main outcomes: frequency and intensity of abdominal pain, symptoms of depression and anxiety, somatization, health-related quality of life, pain beliefs and coping strategies. A significantly higher percentage of patients with IBS had a positive family history for AP-FGIDs (56.8% vs 37.8%; P=0.00). Characteristics of patients with IBS subtypes did not differ. Patients with FAP or FAPS differed only with respect to problem-focused coping strategy (2.21 ±0.61 vs 2.52 ±0.49; P=0.00).
Conclusions: Pediatric patients with IBS and those with FAP(S) have similar psychosocial profiles. These results may explain why treatment response of psychological therapies in these AP-FGIDs is similar. These results may indicate that pediatric IBS and FAP(S) are different expressions of 1 underlying functional disorder, but similarities in psychosocial characteristics do not exclude the possibility that these disorders are different entities, because these similarities can exist between disorders of various causes. Therefore, future research is required on the role of other (physiological) factors in pediatric IBS and FAP(S).
IBS vs F AP(S)
1
INTRODUCTION
Chronic abdominal pain in childhood is one of the most important reasons for parents to visit a general pediatrician, with prevalence rates ranging from 0.3 to 19% and accounting for 25
to 50% of referrals to a (tertiary) pediatric gastroenterology clinic.1,2 In the vast majority of
these children no objective evidence for an underlying organic disease can be found, and these children are diagnosed as having one of the abdominal-pain related functional gastrointestinal
disorders (AP-FGIDs) according to the Rome III criteria.3 Two of the most common AP-FGIDs in
children are irritable bowel syndrome (IBS) and functional abdominal pain (FAP), both of which are characterized by chronic or recurrent abdominal pain. The defecation pattern in children with FAP is usually normal, whereas children with IBS have a change in their bowel movements
at the onset of abdominal pain and/or relief of abdominal pain after defecation.3 According
to adult Rome III criteria, IBS is classified into 3 subtypes based on the predominant bowel habit, which are constipation predominant (IBS-C), diarrhea predominant (IBS-D), and mixed type with alternating episodes of both constipation and diarrhea (IBS-M). If abnormality of stool consistency is not sufficient to meet criteria for IBS-C, -D, or -M, IBS is classified as unsubtyped
(IBS-U).4 These criteria for IBS subtyping however are not available for children.3 If loss of daily
functioning and/or accompanying somatic symptoms form an important part of their symptoms,
children with FAP are classified as having functional abdominal pain syndrome (FAPS).3
Underlying pathophysiological mechanisms of AP-FGIDs are not completely understood, but they are believed to be a result of a complex interplay of genetic, psychosocial, and physiological factors. In this biopsychosocial model, psychosocial factors such as a child’s psychological state, coping, and social support and physiological factors such as altered motility, differences in the
microbiome and visceral hypersensitivity may play a role.5 Among clinicians, controversy exists
whether or not it is important to discern the different types of AP-FGIDs in children, as defined by the Rome III criteria. It has been suggested that the different subcategories of AP-FGIDs, such as IBS, FAP(S) and functional dyspepsia, are no separate clinical entities with different underlying pathological mechanisms, but are more likely to represent variable expressions of
the same functional disorder.6 For example, the frequent occurrence of functional dyspeptic
complaints and lower abdominal symptoms because of IBS in the same patient, and the fact that it is common that children change from FAP(S) to IBS or vice versa over time, supports this
suggestion.7,8
The aim of the present study is to compare clinical and psychological characteristics of children with IBS, FAP, and FAPS, because this may shed some more light on the issue whether IBS and FAP(S) must be considered different entities.
METHODS
Study design and participants
All of the patients participating in the present study were included in an on-going nationwide multicentre, randomized controlled trial (RCT) evaluating the effect of gut-directed hypnotherapy in children and adolescents with IBS or FAP(S). All patients and/or parents gave written informed consent to participate in the present study, and medical ethics committees of all participating hospitals approved the trial. Children were recruited from the outpatient clinic of the department of pediatric gastroenterology of 2 academic medical centers and from the outpatient clinic of the departments of pediatrics of seven teaching hospitals.
Children aged 8 to 18 years diagnosed as having IBS, FAP or FAPS according to the Rome III
criteria were included.3 Subtyping of IBS was executed using adult Rome III criteria.4 To exclude
underlying organic diseases, all children underwent routine laboratory testing before inclusion, including complete blood cell count, C-reactive protein, alanine transaminase, aspartate aminotransferase, glutamyltransferase, creatinine, total bilirubin, amylase, celiac screening (anti-transglutaminase antibodies and IgA), urinalysis, stool parasite analysis, and H pylori antigens in stool. The need for further diagnostic testing was left to the discretion of the treating pediatrician or pediatric gastroenterologist. Exclusion criteria were a concomitant organic gastrointestinal (GI) disease, treatment by another health care professional for abdominal pain symptoms, previous hypnotherapy, mental retardation, and insufficient knowledge of the Dutch language.
Questionnaires
Treating pediatricians filled out a questionnaire on demographics and clinical features prior to inclusion in the RCT. Questionnaires were used to assess other patient characteristics at the time of inclusion in the RCT. Children were instructed to fill out the questionnaires themselves, but, if needed, younger children were allowed to be assisted by their parent(s).
Abdominal pain
Abdominal pain was assessed by means of a diary card, on which the intensity and frequency of abdominal pain episodes was recorded daily by the children themselves on 7 consecutive
days.9–11 “Pain frequency” was recorded in minutes of abdominal pain per day and was scored
as 0 when there was no pain, 1 if children experienced 1 to 30 minutes of pain, 2 if children had pain for 31 to 120 minutes and 3 if abdominal pain lasted for more than 120 minutes. Pain frequency scores (PFS) were then calculated by summing the scores of the 7 days, giving
a maximum PFS of 21.11 “Pain intensity” was scored using an affective facial scale with faces
ranging from showing no pain at all (face A) to the most severe pain (face I).10,11 Scores on the
facial scale were transported to a daily score ranging from 0 to 3. No abdominal pain was scored as 0, faces A to C were scored as 1, faces D to F were scored as 2 and faces G to I were scored as 3. Again, scores of 7 days were totalled giving a pain intensity score (PIS), with a maximum
IBS
vs
F
AP(S)
1
Depression and anxiety
Depression and anxiety were measured using the Revised Anxiety and Depression Scale-short
version (RCADS-25).12 The RCADS-25 has been shown to be a valid and reliable instrument
to assess symptoms of depression and anxiety in the Dutch population. It consists of 5 scales assessing symptoms of generalized anxiety disorder, separation anxiety disorder, social phobia, panic disorder and major depressive disorder. Each of these 5 scales consists of 5 items that are scored on a 4-point scale ranging from 0 (never) to 3 (always). A total score on anxiety is calculated by summing the scores on the 4 individual anxiety scales. Cut-off scores for the top 10% of children validated in the Dutch population are available to identify greatly anxious or
depressed children.12
Somatization
Somatic complaints were scored using the Children’s Somatization Inventory (CSI).13 The CSI
contains 35 items, reflecting the extent to which somatic symptoms were experienced in the last 2 weeks. Items are scored on a 5-point scale ranging from 0 (not at all) to 4 (a whole lot). The Dutch CSI was shown to be a reliable and valid self-report instrument for assessing somatization in children and adolescents. Higher scores reflect a higher intensity of somatic complaints. A total score was calculated by summing scores on all individual items. Because we were also interested in the amount of non-GI symptoms that patients experience, a separate CSI score was calculated for non-GI symptoms by leaving out all items concerning GI symptoms, namely nausea, constipation, diarrhea, epigastric pain, vomiting, and bloating. To assess GI symptoms other than abdominal pain, we summed scores on all items concerning GI symptoms and left out the item on abdominal pain.
Health-related quality of life (QoL)
Health-related QoL was measured using the KIDSCREEN-52 questionnaire, which is a frequently used, reliable and validated instrument for the assessment of health-related QoL in children
and adolescents. The KIDSCREEN-52 has been validated in Dutch pediatric patient groups.14,15
The KIDSCREEN-52 contains questions on 10 dimensions of health-related QoL: physical well-being, psychological well-well-being, moods and emotions, self-perception, autonomy, relations with parents and home life, social support and peers, school environment, social acceptance (bullying), and financial resources. Items are scored using a 5-point Likert-type scale, and the recall period is 1 week. Rasch scores for each dimension are computed, and these are transformed into T-values, with higher scores indicating a better health-related QoL and well-being. Norm data validated in Dutch children are available to identify patients scoring lower
than the tenth percentile.15
Pain beliefs
The Pain Beliefs Questionnaire (PBQ) was used to assess both negative and positive beliefs children have about their abdominal pain. We used a Dutch translation of the PBQ, which is a
