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Original Articles: Gastroenterology

Recurrent Abdominal Pain in Children: Summary Evidence From 3 Systematic Reviews of Treatment Effectiveness

Abbott, Rebecca A.; Martin, Alice E.∗,†; Newlove-Delgado, Tamsin V.; Bethel, Alison; Whear, Rebecca S.; Thompson Coon, Jo; Logan, Stuart

Author Information
Journal of Pediatric Gastroenterology and Nutrition: July 2018 - Volume 67 - Issue 1 - p 23-33
doi: 10.1097/MPG.0000000000001922

Abstract

What Is Known/What Is New

What Is Known

  • Between 4% and 25% of school-aged children experience recurrent abdominal pain sufficient to interfere with activities of daily living; often causing significant anxiety for parents and carers.
  • The lack of guidelines or consensus on management of patients with recurrent abdominal pain means that treatment is inconsistent.
  • What Is New
  • There is some evidence to suggest that probiotics, cognitive-behavioural therapy, and hypnotherapy may be effective in the treatment of recurrent abdominal pain.
  • The lack of evidence of effectiveness for any drug suggests that they should be used with caution outside of well-conducted clinical trials.

Recurrent abdominal pain (RAP) is a common problem in paediatric practice, with prevalence estimates ranging from 2% to 41% (1). Between 4% and 25% of school-aged children intermittently experience RAP, sufficient to interfere with their activities of daily living (2,3). RAP is associated with school absences, hospital admissions and on occasions, unnecessary surgical intervention (4–6). The abdominal pain is commonly associated with other symptoms, including headaches, recurrent limb pains, pallor, and vomiting (7–9) and can continue into adulthood (6,10). RAP can cause significant anxiety in parents and carers, who may become overwhelmed by fear of serious disease or feel helpless because they are unable to relieve their child's symptoms (11).

RAP in children represents a group of functional gastrointestinal disorders that have an unclear aetiology. The latest consensus from the Rome Foundation suggest these disorders are related to motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota and altered central nervous system processing. They suggest RAP is “the product of ... interactions of psychosocial factors and altered gut physiology via the brain–gut axis” (12). For the purpose of this review, RAP has been used as an umbrella term to describe what are now referred to as “functional abdominal pain disorders” under the new Rome IV classification: functional dyspepsia, irritable bowel syndrome, abdominal migraine, and functional abdominal pain (with the caveat that most of the studies were carried out prior to this, commonly using the Rome III classification) (12,13).

There is no consensus or guidelines on which treatments to offer patients, hence treatment of RAP remains inconsistent. We have systematically reviewed the effectiveness of dietary, pharmacological, and psychological interventions for children of school age presenting with RAP, published as 3 companion Cochrane reviews (14–16). Summarising these reviews, this article brings together the current evidence to underpin treatment decisions in young people with RAP.

METHODS

A full protocol for each review was published in the Cochrane Library (17–19). The systematic review was conducted following the general principles published by Cochrane (20) and has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (21).

Inclusion/exclusion Criteria

Children aged 5 to 18 years old with RAP or an abdominal pain-related functional gastrointestinal disorder, as defined by the Rome III criteria (13), were included. Any dietary, pharmacological, or psychosocial intervention compared to placebo, waiting list, no treatment, active control (psychosocial interventions only), or standard care were included. Included studies were restricted to randomised controlled trials (RCTs) and randomised cross-over studies. The primary outcome was pain: intensity, frequency, duration, or the proportion of participants with significant improvement in pain (as defined by the trial authors). Studies were grouped according to duration of follow-up: short-term follow-up (0–3 months), medium-term follow-up (3–6 months postintervention), and long-term follow-up (6 months or longer). Secondary outcomes were school performance, social or psychological functioning, quality of daily life, and adverse events. Findings related to secondary outcomes are not reported here, but are reported in the published Cochrane reviews (14–16).

Search Strategy

The search strategy was developed by an information specialist (A.B.) in consultation with topic and methods experts (A.M., T.N.D., S.L., R.A., J.T.C., R.W.), an example of which for MEDLINE is shown in Supplementary Digital Content, Appendix File 1, http://links.lww.com/MPG/B392. Eleven databases were searched from inception to June 2016: AMED, ASSIA, British Education Index, CENTRAL, CINAHL, Embase, ERIC, Lilacs, MEDLINE, OpenGrey, and PsycINFO. No date or language restrictions were used. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry for recently completed and ongoing studies. Forward and backward citation chasing of included articles was conducted. Two reviewers (R.A., T.N.D., A.M., B.W., J.T.C., A.B.) independently screened titles, abstracts, and full texts using the eligibility criteria. Discrepancies were discussed and resolved by a third reviewer where necessary. An update search was undertaken in MEDLINE (November 21, 2017).

Data Collection

We extracted data on study characteristics (number of participating children, type of intervention and comparison, intervention characteristics, number of withdrawals, study design), participant characteristics (gender, age, diagnosis, for example, RAP or syndrome defined by the Rome III criteria) and outcome measures (measurement of pain and any secondary outcome measured). Data were extracted by 1 reviewer and checked by a second.

Risk of Bias

Risk of bias within studies was assessed using the Cochrane risk of bias tool (22). We also assessed whether the data collection tools were valid, whether there was sufficient power in terms of appropriate sample size, whether baseline parameters were similar, and whether data analyses were appropriate. Two review authors (R.A., A.M., T.N.D., A.B., J.T.C., or R.W.) independently assessed each study. We resolved any disagreements by discussion until consensus was reached. Risk of bias across studies was assessed using the approach outlined by the “Grading of Recommendations Assessment Development and Evaluation” (GRADE) working group (23). The GRADE assessment assigned a measure of the quality of evidence; high, moderate, low, or very low.

Data Analysis and Synthesis

We used Review Manager 5 for statistical analysis (Review Manager 2014). We analysed dichotomous data using odds ratios (ORs). We calculated numbers needed to treat (NNTB) for an additional beneficial outcome using the risk in the control arm as an estimate of baseline population risk. For continuous data we analysed mean differences and standard deviations, if these were available or could be calculated, and there was no clear evidence of skewness in the distribution (24). When different scales were used to measure the same clinical outcome, we combined standardised mean differences across the studies. We conducted meta-analyses where possible for studies within the same intervention type, assessing equivocal outcomes at similar time points. We used a random-effects model because we anticipated significant statistical and clinical heterogeneity. We provided a narrative description of the results when, due to the heterogeneity of the intervention or the variety of methods used to measure pain, meta-analysis was not appropriate.

Role of the Funding Source

This research was funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

RESULTS

The electronic searches and hand searching retrieved a total of 14,700 results. Excluding duplicates, 9649 titles and abstracts were screened and after full-text screening a total of 52 studies, reported across 68 articles, were included. Reasons for exclusion at the full text stage can be seen in Figure 1. The update search identified 3 further RCTs.

FIGURE 1
FIGURE 1:
PRISMA flow chart of study identification and selection. PRISMA = preferred reporting items for systematic reviews and meta-analyses.

Characteristics of Included Studies

Twenty-one studies assessed a dietary intervention, 15 assessed pharmacological intervention and 19 investigated some form of psychosocial intervention. One study had both a dietary and pharmacological arm. The studies were conducted in 15 countries, recruiting children from secondary/tertiary paediatric gastroenterology or pain clinics (n = 37), primary care (n = 1), the community (n = 1), or from a combination of these (n = 10), or not described (n = 3). A summary of the populations and interventions is shown in Table 1.

TABLE 1
TABLE 1:
Characteristics of studies

Study Quality

The majority of dietary studies were rated as low risk of bias for most of the domains. The pharmacological studies which reported effective treatments were either small, single studies, or had key methodological weaknesses with a substantial risk of bias. None of these “positive” results have been reproduced in subsequent studies. We judged the evidence of effectiveness to be of low quality. For the psychosocial studies, most (16 out of the 18) were considered to be at high risk of bias for blinding of outcome assessment as the majority of outcomes were self-reported, and children were aware of their treatment group. The other domains were mainly considered low risk or were unclear. Detailed reports on the risk of bias for each study are available in the 3 reviews (14–16).

Dietary Intervention

Effects of Probiotics: 15 Studies, 1123 Children

The trials ranged in duration from 4 to 12 weeks, and used a range of probiotic preparations (25–39). The precise dose, frequency, and strains used are shown in Supplemental Digital Content 2, http://links.lww.com/MPG/B284, but in summary: 5 trials used Lactobacillus rhamnosus GG; 5 used Lactobacillus reuteri DSM 17938; 2 used Bacillus coagulans with fructo-oligosaccharides; 1 used a patented mixture called VSL#3 containing 8 different strains (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus bulgaris, Streptococcus thermophiles); 1 used a combination of 3 Bifidobacterium species (B longum BB536, B infantis M-63, and B breve M-16 V; and 1 used L plantarum LP299 V). Probiotics were assessed as one intervention type and not assessed according to strain in line with our protocol. The majority of studies measured short-term outcomes at 0 to 3 months’ postintervention only. We found that probiotic intervention improved pain in the meta-analysis of 9 probiotic trials at this time point (OR 1.61, 95% CI 1.15 to 2.27; P = 0.006) (Fig. 2), with an estimated NNTB of 8, meaning that 8 children would need to receive probiotics for 1 to experience improvement in pain in this timescale (26–31,35,38,39). Longer-term data for this outcome was limited. The pooled analysis from 2 studies at 3 to 6 months’ postintervention for improvement in pain was 1.94 (95% CI 1.10 to 3.43; P = 0.023), with an NNTB of 7 (28,35). For all children, we also found a reduction in pain frequency (SMD −0.48, 95% CI −0.87 to −0.09; P = 0.02) (25,27–29,33,36,39) and pain intensity (SMD −0.62, 95% CI −1.04 to −0.21; P = 0.003) (25,27–29,32,33,36,38,39), in those treated with probiotics compared to placebo at 0 to 3 months’ postintervention (see Supplemental Digital Content 3, http://links.lww.com/MPG/B285). Post-hoc subgroup analyses of outcomes according to probiotic strain are shown in Figures 3–5.

FIGURE 2
FIGURE 2:
Forest plot showing odds ratio for improvement in pain post-intervention for probiotics compared to placebo.
FIGURE 3
FIGURE 3:
Forest plot of pain improvement post-intervention for probiotics compared to placebo, by strain of probiotics.
FIGURE 4
FIGURE 4:
Forest plot of change in pain intensity post-intervention for probiotics compared to placebo, by strain of probiotics.
FIGURE 5
FIGURE 5:
Forest plot of change in pain frequency post-intervention for probiotics compared to placebo, by strain of probiotics.

Effects of Fibre-based Interventions: 4 Studies, 299 Children

Four trials used fibre-based interventions: a fibre biscuit containing 5 g of corn fibre (38), a preparation of glucomannan (39), a preparation of partially hydrolysed guar gum (40), and psyllium fibre (41). Two studies were included in the meta-analysis for the outcome of improvement of pain, with a pooled OR of 1.83 (95% CI 0.92 to 3.65; P = 0.09) (40,41). Two different studies were pooled for the outcome of change in pain intensity: the SMD of effect across the studies was −1.24 (95% CI −3.41 to 0.94; P = 0.27); both studies included only children with irritable bowel syndrome (42,43). No long-term data were reported.

Effects of a FODMAP diet (1 Study, 34 Children) and Fructose Restricted Diet (1 Study, 103 Children)

Only 1 small, short duration study each examined the effects of a low fermentable, oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) diet (44) and a fructose-restricted diet (45) on pain in children with RAP. Both studies reported reductions in pain frequency and Wirth et al (45) also reported a reduction in pain intensity.

Pharmacological Interventions

Meta-analyses were not possible due to the heterogeneity of the interventions and variation in outcome measures.

Effects of Antispasmodics: 4 Studies, 377 Children

Two studies investigating peppermint oil found discordant results: significant reductions in pain intensity, duration, and frequency compared to placebo in 1 study (25) and no significant changes in the above compared to placebo in another (46). The studies had key methodological weaknesses. Therefore, these studies provide insufficient evidence to support the use of peppermint oil in the treatment of RAP. Narang et al (47) reported significant differences in pain episodes over 4 weeks (MD 11.3 (95% CI 2.1 to 20.1)) but not in the number of pain-free days over the same period (MD 1.8, −1.2 to 4.8) in children given drotaverine compared to placebo. Pourmoghaddas et al (48) found no difference in self-reported or physician rated pain in children treated with mebeverine compared to placebo.

Effects of Tricyclic Antidepressants: 2 Studies, 213 Children

Both studies (49,50) reported no significant differences in self-reported pain in children receiving amitriptyline compared to placebo.

Effects of Antibiotics: 2 Studies, 112 Children

The studies assessing the effect of rifaximin (51) or co-trimoxazole (52) found no difference in reported pain outcomes in children receiving either drug compared to placebo.

Effects of Other Pharmacological Interventions: 8 Single Studies, 412 Children

Single studies assessed the effectiveness of 8 different pharmacological agents compared to usual care or placebo: the anti-muscarinic drug trimebutine (53), the 5-HT4 (5-hydroxytryptamine) agonist tegaserod (54), the antihistamine cyproheptadine (55), the serotonin agonist pizotifen (56), the selective serotonin reuptake inhibitor citalopram (57), the hormone melatonin (58), the dopamine receptor agonist domperidone (59), and the H2 receptor agonist famotidine (60). Four studies reported significant reductions in pain (53–56), 2 reported mixed findings (59,60), and 3 no effect on pain outcomes (57,58). Small sample sizes, poor reporting, and a lack of recognised pain outcome measures meant there was insufficient evidence of effectiveness for these single studies of pharmacological intervention.

Psychosocial Interventions

Effects of Cognitive-behavioural Therapy: 11 Studies, 687 Children

CBT improved pain immediately post intervention, in the meta-analysis of 4 trials (OR 5.67, 95% CI 1.18 to 27.32, P = 0.03, see Fig. 6) with an estimated NNTB of 4. This means that 4 children would need to receive CBT for one to experience improvement in pain at this time point (61,63,66,67). Three of the 4 studies provided medium term 3 to 6 month follow-up data on pain improvement (63,66,67). The pooled OR for medium-term pain improvement was 3.08 (95% CI 0.93 to 10.16; P = 0.06) with a NNTB of 5. Two of the 4 studies provided long-term (12 months or more) follow-up data on pain improvement (63,67). The pooled OR for long-term pain improvement was 1.29 (95% CI 0.50 to 3.33; P = 0.60).

FIGURE 6
FIGURE 6:
Forest plot showing the odd ratio of pain improvement post-intervention for those receiving cognitive-behavioural therapy (CBT) compared to control (shown according to “control” group type).

Data from 7 studies was available to estimate the effects of CBT intervention compared to control groups on pain intensity postintervention (61,63,65,67–70). The pooled SMD of pain intensity across the studies was −0.33 (95% CI −0.74 to 0.08; P = 0.12) (77–79). Three additional studies reported postintervention pain intensity outcome data (62,64,66,71), which could not be pooled with the studies above due to insufficient data, such as missing standard deviations (SDs). Two studies reported significant benefits of decreased pain intensity with CBT compared to control (62,66,71), and one found no difference (64). Three studies provided long-term follow-up data (63,65,67) for these the pooled SMD of pain intensity was −0.04 (95% CI −0.39 to 0.31; P value = 0.82).

Effects of Hypnotherapy (4 Studies, 152 Children)

Data from all 4 studies (72–75) were entered into a meta-analysis to estimate the effect of hypnotherapy compared to control groups on pain improvement immediately postintervention. The pooled OR for pain improvement was 6.78 (95% CI 2.41 to 19.07; P < 0.0003) with an estimated NNTB of 3 (Fig. 7). Long-term data from Vlieger et al (76) in their 5-year follow-up, which included 45 of the original 49 children, found 68% of the intervention group were symptom free compared to 20% in the control arm (P = 0.005).

FIGURE 7
FIGURE 7:
Forest plot showing the odd ratio of pain improvement post-intervention for those receiving hypnotherapy compared to control (shown according to “control” group type).

The same studies provided data on pain intensity and pain frequency postintervention. The pooled SMDs of pain intensity and pain frequency across the 4 studies postintervention were −1.01 (95% CI −1.41 to −0.61; P < 0.00001) and −1.28 (95% CI −1.84 to −0.72; P < 0.00001), respectively. Long-term data from Vlieger et al (76) reported that pain both intensity and frequency remained significantly lower at 5 years (P < 0.001 for both) in the group that had received 3 months of hypnotherapy.

Effects of Yoga (3 Studies, 127 Children) and Written Self-disclosure (1 Study, 63 Children)

The pooled SMD of pain intensity immediately post-intervention across 3 yoga studies was −0.31 (95% CI −0.67 to 0.05; P = 0.09). One study (78) provided long-term data (12 months), and found no significant effect for the yoga intervention compared to usual care (P = 0.09). The single study on written self-disclosure, found no evidence of effect on pain immediately post-intervention, but did report a significant effect at 6 months follow-up (80).

Quality of the Evidence

As evaluated using the GRADE approach (22), we found the overall certainty of evidence across the reviews ranged from very low to moderate, due to the high or unclear risk of bias across the studies. There was significant heterogeneity (>70%), wide confidence intervals, and low number of participants in many of the studies. Future research in this area is therefore likely to impact on our confidence in the estimate of the majority of effects observed in this review.

DISCUSSION

RAP is common, causes considerable distress to families and consumes substantial health service resources but we found relatively little high-quality evidence to guide treatment decisions. Many of the trials had a significant risk of bias, few assessed outcome in the medium or long term, and for many interventions, particularly drugs, we found no high-quality studies.

These data provide some moderate-quality evidence suggesting that probiotics may be effective in the management of children with RAP. Probiotics were reported to result in reduced pain intensity and frequency in the short term, but there was limited evidence to suggest that this was sustained up to 3 to 6 months after treatment. The evidence regarding relative effectiveness of different strains of probiotics is currently insufficient to guide clinical practice. The review also found low-quality evidence to suggest that CBT and hypnotherapy may be effective in treating RAP, with both reported to be effective in reducing pain in the short term. Sustained effects of CBT and hypnotherapy were also reported but the evidence is limited. We found insufficient evidence to support the use of fibre-based diets, FODMAP diets or fructose-restricted diets, yoga therapy, or written self-disclosure. We found no evidence that pharmacological approaches were effective in treating RAP.

The findings are in keeping with other systematic reviews of dietary, pharmacological, and psychosocial interventions for children with RAP and pain more widely. Horvath et al (81), and more recently Rutten et al (82), reported that L rhamnosus GG and VSL#3 were associated with significantly more treatment responders than placebo in their systematic review of nonpharmacological treatments; the same authors found inconclusive data regarding the effects of fibre-based supplements. Rutten et al (82) also concluded there was some evidence for CBT and hypnotherapy, but a lack of evidence for yoga. In a review of face-to-face interventions for children with pain (dichotomised as headache and nonheadache pain), Eccleston et al (83) produced pooled estimates of effect comparable with those reported here for CBT and hypnotherapy. A Cochrane review evaluating the effectiveness of antidepressants in pain-related functional abdominal disorders in children reported no evidence of effectiveness (84).

We found few trials conducted in specific subgroups of RAP as defined by the Rome III criteria (13), most including children within the broad diagnosis of RAP, which encompasses children with a variety of RAP classifications such as IBS, functional abdominal pain, or functional dyspepsia. Therefore, we were unable to conclude of the effectiveness of interventions on particular subgroups of RAP (12).

Strengths and Limitations

We used robust methods, published in protocol form before the review was started (17–19). We contacted authors of included studies for additional data when the presented data were insufficient or missing to maximise our ability to pool data. We did not include studies that had a mix of ages or reported only mean age of participants greater than 20 where it was not possible to separate the data for those less than 18 years of age. We did not contact these authors asking whether they collected data for children less than 18 years of age which raises the possibility that we may have missed important data.

Implications for Practice

Overall there is some evidence to suggest that probiotics, CBT, and hypnotherapy may be effective in improving pain in the short term, supporting the advice given in the “Practical Management” review of functional abdominal pain, published in this journal in July 2016 (85). It is unclear from existing evidence whether there are differences in the relative effectiveness of different strains of probiotics. Indeed, the small number of studies investigating each particular strain means we need to exert considerable caution in making recommendations. Clinicians may want to consider and discuss these treatments as part of a holistic management strategy for children with RAP and their families. We are, however, unable to recommend the optimum strain and dosage of probiotics or the format of CBT or hypnotherapy.

There is extremely weak evidence for the efficacy of any pharmacological agents in children with RAP and limited evidence of any effect for fibre-based diets, FODMAP diets, and yoga therapy. While clinicians may choose to prescribe a “therapeutic trial” of drugs to children whose symptoms are severe and who have not responded to simple management they need to be aware that RAP is a fluctuating condition and any “response” may reflect the natural history of the condition or a placebo effect, rather than drug efficacy.

Implications for Research

The evidence for the effectiveness of probiotics and cognitive-behavioural therapy (CBT) is based largely on shorter-term outcomes. Further trials are required to assess whether improvements in pain are maintained over the longer term. Future research on probiotics should address the question of the optimal strain and dosage schedule, as well as consider the effectiveness of probiotics in different settings. For CBT interventions, the mode (face-to-face vs remote delivered) and dose of delivery warrants further exploration. The pathogenesis of RAP in children remains unclear (86) and there is a need for further studies to elucidate this aetiology. It may be that the complaint of abdominal pain is a unifying manifestation for a wide variety of causal pathways and triggers relating to psychological and physical processes rather than a single entity. It has been suggested that there are distinct clinical subtypes of RAP and that these should guide treatment choice (12) but this is not currently based on high-quality evidence. Further large trials, stratified by postulated subtypes are therefore needed not only to guide the management of children with RAP, but also to validate the usefulness of suggested classifications (13).

Funding

This study presents independent research funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health in England.

REFERENCES

1. Korterink JJ, Diederen K, Benninga MA, et al. Epidemiology of pediatric functional abdominal pain disorders: a meta-analysis. PLoS One 2015; 10:e0126982.
2. Konijnenberg AY, Uiterwaal CS, Kimpen JL, et al. Children with unexplained chronic pain: substantial impairment in everyday life. Arch Dis Child 2005; 90:680–686.
3. Youssef NN, Murphy TG, Langseder AL, et al. Quality of life for children with functional abdominal pain: a comparison study of patients’ and parents’ perceptions. Pediatrics 2006; 117:54–59.
4. Scharff L. Recurrent abdominal pain in children: a review of psychological factors and treatment. Clin Psychol Rev 1997; 17:145–166.
5. Stordal K, Nygaard EA, Bentsen BS. Recurrent abdominal pain: a five-year follow-up study. Acta Paediatr 2005; 94:234–236.
6. Walker LS, Guite JW, Duke M, et al. Recurrent abdominal pain: a potential precursor of irritable bowel syndrome in adolescents and young adults. J Pediatr 1998; 132:1010–1015.
7. Abu-Arafeh I, Russell G. Prevalence and clinical features of abdominal migraine compared with those of migraine headache. Arch Dis Child 1995; 72:413–417.
8. Devanarayana NM, Mettananda S, Liyanarachchi C, et al. Abdominal pain-predominant functional gastrointestinal diseases in children and adolescents: prevalence, symptomatology, and association with emotional stress. J Pediatr Gastroenterol Nutr 2011; 53:659–665.
9. Hyams JS, Treem WR, Justinich CJ, et al. Characterization of symptoms in children with recurrent abdominal pain: resemblance to irritable bowel syndrome. J Pediatr Gastroenterol Nutr 1995; 20:209–214.
10. Youssef NN, Atienza K, Langseder AL, et al. Chronic abdominal pain and depressive symptoms: analysis of the national longitudinal study of adolescent health. Clin Gastroenterol Hepatol 2008; 6:329–332.
11. Paul SP, Candy DC. Clinical update: recurrent abdominal pain in children. Community Pract 2013; 86:48–51.
12. Drossman DA, Chey WD, Kellow J, et al. Rome IV Functional Gastrointestinal Disorders: Disorders of Gut-Brain Interaction. Raleigh, NC: Rome Foundation; 2016.
13. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 2006; 130:1527–1537.
14. Abbott RA, Martin AE, Newlove-Delgado TV, et al. Psychosocial interventions for recurrent abdominal pain in childhood. Cochrane Database Syst Rev 2017; 1: CD010971.
15. Martin AE, Newlove-Delgado TV, Abbott RA, et al. Pharmacological interventions for recurrent abdominal pain in childhood. Cochrane Database Syst Rev 2017; 3:CD010973.
16. Newlove-Delgado TV, Martin AE, Abbott RA, et al. Dietary interventions for recurrent abdominal pain in childhood. Cochrane Database Syst Rev 2017; 3:CD010972.
17. Martin AE, Newlove-Delgado TV, Abbott RA, et al. Psychosocial interventions for recurrent abdominal pain in childhood (Protocol). Cochrane Database Syst Rev 2014; 2: Art. No.: CD010971. DOI: 10.1002/14651858.CD010971.
18. Martin AE, Newlove-Delgado TV, Abbott RA, et al. Pharmacological interventions for recurrent abdominal pain in childhood (Protocol). Cochrane Database Syste Rev 2014; 2: Art. No.: CD010973. DOI: 10.1002/14651858.CD010973.
19. Martin AE, Newlove-Delgado TV, Abbott RA, et al. Dietary interventions for recurrent abdominal pain in childhood (Protocol). Cochrane Database Syst Rev 2014; 2: Art. No.: CD010972. DOI: 10.1002/14651858.CD010972.
20. Centre for Reviews and Dissemination Systematic Reviews: CRD's Guidance for Undertaking Reviews in Healthcare. York: CRD, University of York; 2009.
21. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339:b2535.
22. Higgins JPT, Altman D, Sterne JAC. Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2011.
23. Guyatt GH, Oxman AD, Santesso N, et al. GRADE guidelines: 12. Preparing summary of findings tables – binary outcomes. J Clin Epidemiol 2013; 66:158–172.
24. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:177–188.
25. Asgarshirazi M, Shariat M, Dalili H. Comparison of the effects of pH-dependent peppermint oil and synbiotic lactol (Bacillus coagulans + fructooligosaccharides) on childhood functional abdominal pain: a randomized placebo-controlled study. Iran Red Crescent Med J 2015; 17:e23844.
26. Bausserman M, Michail S. The use of Lactobacillus GG in irritable bowel syndrome in children: a double-blind randomized control trial. J Pediatr 2005; 147:197–201.
27. Eftekhari K, Vahedi Z, Kamali Aghdam M, et al. A randomized double-blind placebo-controlled trial of Lactobacillus reuteri for chronic functional abdominal pain in children. Iran J Pediatr 2015; 25:e2616.
28. Francavilla R, Miniello V, Magista AM, et al. A randomized controlled trial of Lactobacillus GG in children with functional abdominal pain. Pediatrics 2010; 126:e1445–e1452.
29. Gawronska A, Dziechciarz P, Horvath A, et al. A randomized double-blind placebo-controlled trial of Lactobacillus GG for abdominal pain disorders in children. Aliment Pharmacol Ther 2007; 25:177–184.
30. Giannetti E, Maglione M, Alessandrella A, et al. A mixture of 3 bifidobacteria decreases abdominal pain and improves the quality of life in children with irritable bowel syndrome: a multicenter, randomized, double-blind, placebo-controlled, crossover trial. J Clin Gastroenterol 2017; 51:e5–e10.
31. Guandalini S, Magazzu G, Chiaro A, et al. VSL#3 improves symptoms in children with irritable bowel syndrome: a multicenter, randomized, placebo-controlled, double-blind, crossover study. J Pediatr Gasterol Nutr 2010; 51:24–30.
32. Kianifar H, Jafari SA, Kiani M, et al. Probiotic for irritable bowel syndrome in pediatric patients: a randomized controlled clinical trial. Electron Physician 2015; 7:1255–1260.
33. Romano C, Ferrau V, Cavataio F, et al. Lactobacillus reuteri in children with functional abdominal pain (FAP). J Paediatr Child Health 2014; 50:E68–E71.
34. Sabbi T. The use of lactobacillus GG in children with functional abdominal pain: a double-blind randomized control trial. Clinical Nutrition Supplements 2011; 6:198.
35. Saneian H, Pourmoghaddas Z, Roohafza H, et al. Synbiotic containing Bacillus coagulans and fructo-oligosaccharides for functional abdominal pain in children. Gastroenterol Hepatol Bed Bench 2015; 8:56–65.
36. Weizman Z, Abu-Abed J, Binsztok M. Lactobacillus reuteri DSM 17938 for the management of functional abdominal pain in childhood: a randomized, double-blind, placebo-controlled trial. J Pediatr 2016; 4:160.e1–164.e1.
37. Young RJ. Successful probiotic therapy of chronic recurrent abdominal pain in children. AGA Abstracts Gastroenterol 1997; 112:A856.
38. Jadresin O, Hojsak I, Misak Z, et al. Lactobacillus reuteri DSM 17938 in the treatment of functional abdominal pain in children: RCT study. J Pediatr Gastroenterol Nutr 2017; 64:925–929.
39. Maragkoudaki M, Chouliaras G, Orel R, et al. Lactobacillus reuteri DSM 17938 and a placebo both significantly reduced symptoms in children with functional abdominal pain. Acta Paediatr 2017; 106:1857–1862.
40. Feldman W, McGrath P, Hodgson C, et al. The use of dietary fiber in the management of simple, childhood, idiopathic, recurrent, abdominal pain. Results in a prospective, double-blind, randomized, controlled trial. Am J Dis Child 1985; 139:1216–1218.
41. Horvath A, Dziechciarz P, Szajewska H. Glucomannan for abdominal pain-related functional gastrointestinal disorders in children: a randomized trial. World J Gastroenterol 2013; 19:3062–3068.
42. Romano C, Comito D, Famiani A, et al. Partially hydrolyzed guar gum in pediatric functional abdominal pain. World J Gastroenterol 2013; 19:235–240.
43. Shulman RJ, Hollister EB, Cain K, et al. Psyllium fiber reduces abdominal pain in children with irritable bowel syndrome in a randomized, double-blind trial. Clin Gastroenterol Hepatol 2017; 15:712.e4–719.e4.
44. Chumpitazi BP, Cope JL, Hollister EB, et al. Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome. Aliment Pharmacol Ther 2015; 42:418–427.
45. Wirth S, Klodt C, Wintermeyer P, et al. Positive or negative fructose breath test results do not predict response to fructose restricted diet in children with recurrent abdominal pain: results from a prospective randomized trial. Klin Padiatr 2014; 226:268–273.
46. Kline RM, Kline JJ, Di Palma J, et al. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J Pediatr 2001; 138:125–128.
47. Narang M, Shah D, Akhtar H. Efficacy and safety of drotaverine hydrochloride in children with recurrent abdominal pain: a randomized placebo controlled trial. Indian Pediatr 2015; 52:847–851.
48. Pourmoghaddas Z, Saneian H, Roohafza H, et al. Mebeverine for pediatric functional abdominal pain: a randomized, placebo-controlled trial. BioMed Res Int 2014; 2014:191026.
49. Bahar RJ, Collins BS, Steinmetz B, et al. Double-blind placebo-controlled trial of amitriptyline for the treatment of irritable bowel syndrome in adolescents. J Pediatr 2008; 152:685–689.
50. Saps M, Youssef N, Miranda A, et al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology 2009; 137:1261–1269.
51. Collins BS, Lin HC. Double-blind, placebo-controlled antibiotic treatment study of small intestinal bacterial overgrowth in children with chronic abdominal pain. J Pediatr Gasterol Nutr 2011; 52:382–386.
52. Heyland K, Friedt M, Buehr P, et al. No advantage for antibiotic treatment over placebo in Blastocystis hominis-positive children with recurrent abdominal pain. J Pediatr Gasterol Nutr 2012; 54:677–679.
53. Karabulut GS, Beser OF, Erginoz E, et al. The incidence of irritable bowel syndrome in children using the Rome III criteria and the effect of trimebutine treatment. J Neurogastroenterol Motil 2013; 19:90–93.
54. Khoshoo V, Armstead C, Landry L. Effect of a laxative with and without tegaserod in adolescents with constipation predominant irritable bowel syndrome. Aliment Pharmacol Ther 2006; 23:191–196.
55. Sadeghian M, Farahmand F, Fallahi GH, et al. Cyproheptadine for the treatment of functional abdominal pain in childhood: a double-blinded randomized placebo-controlled trial. Minerva Pediatr 2008; 60:1367–1374.
56. Symon DN, Russell G. Double blind placebo controlled trial of pizotifen syrup in the treatment of abdominal migraine. Arch Dis Child 1995; 72:48–50.
57. Roohafza H, Pourmoghaddas Z, Saneian H, et al. Citalopram for pediatric functional abdominal pain: a randomized, placebo-controlled trial. Neurogastroenterol Motil 2014; 26:1642–1650.
58. Zybach K, Friesen CA, Schurman JV. Therapeutic effect of melatonin on pediatric functional dyspepsia: a pilot study. World J Gastrointest Pharmacol Ther 2016; 7:156–161.
59. Karunanayake A, Devanarayana NM, Rajindrajith S, et al. Op-7 therapeutic effects of domperidone on abdominal pain-predominant functional gastrointestinal disorders: randomized, double-blind, placebo- controlled trial. J Pediatr Gastroenterol Nutr 2015; 61:511–512.
60. See MC, Birnbaum AH, Schechter CB, et al. Double-blind, placebo-controlled trial of famotidine in children with abdominal pain and dyspepsia: global and quantitative assessment. Dig Dis Sci 2001; 46:985–992.
61. Gros M, Warschburger P. Evaluation of a cognitive-behavioral pain management program for children with chronic abdominal pain: a randomized controlled study. Int J Behav Med 2013; 20:434–443.
62. Robins PM, Smith SM, Glutting JJ, et al. A randomized controlled trial of a cognitive-behavioral family intervention for pediatric recurrent abdominal pain. J Pediatr Psychol 2005; 30:397–408.
63. van der Veek SMC, Derkx BHF, Benninga MA, et al. Cognitive behavior therapy for pediatric functional abdominal pain: a randomized controlled trial. Pediatrics 2013; 132:e1163–e1172.
64. Duarte MA, Penna FJ, Andrade EMG, et al. Treatment of nonorganic recurrent abdominal pain: cognitive-behavioral family intervention. J Pediatr Gasterol Nutr 2006; 43:59–64.
65. Levy RL, Langer SL, Walker LS, et al. Cognitive-behavioral therapy for children with functional abdominal pain and their parents decreases pain and other symptoms. Am J Gastroenterol 2010; 105:946–956.
66. Sanders MR, Morrison M, Rebgetz M, et al. Behavioural treatment of childhood recurrent abdominal pain, children's psychological characteristics and family functioning. Behaviour Change 1990. 16–24.
67. Sanders MR, Shepherd RW, Cleghorn G, et al. The treatment of recurrent abdominal pain in children: a controlled comparison of cognitive-behavioral family intervention and standard pediatric care. J Neurol Neurosurg Psychiatry 1994; 62:306–314.
68. Palermo TM, Law EF, Fales J, et al. Internet-delivered cognitive-behavioral treatment for adolescents with chronic pain and their parents: A randomized controlled multicenter trial. Pain 2015; 157:174–185.
69. Palermo TM, Wilson AC, Peters M, et al. Randomized controlled trial of an Internet-delivered family cognitive-behavioral therapy intervention for children and adolescents with chronic pain. Pain 2009; 146:205–213.
70. Wassom MC. A minimal contact cognitive-behavioral intervention for abdominal pain-related functional gastrointestinal disorders: pilot study of “Gutstrong”. University of Kansas; 2009:131p.
71. Bonnert M, Olen O, Lalouni M, et al. Internet-delivered cognitive behavior therapy for adolescents with irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol 2017; 112:152–162.
72. Gulewitsch MD, Muller J, Hautzinger M, et al. Brief hypnotherapeutic-behavioral intervention for functional abdominal pain and irritable bowel syndrome in childhood: a randomized controlled trial. Eur J Pediatr 2013; 172:1043–1051.
73. Vlieger AM, Menko-Frankenhuis C, Wolfkamp SCS, et al. Hypnotherapy for children with functional abdominal pain or irritable bowel syndrome: a randomized controlled trial. Gastroenterology 2007; 133:1430–1436.
74. van Tilburg MA, Chitkara DK, Palsson OS, et al. Audio-recorded guided imagery treatment reduces functional abdominal pain in children: a pilot study. Pediatrics 2009; 124:e890–e897.
75. Weydert JA, Shapiro DE, Acra SA, et al. Evaluation of guided imagery as treatment for recurrent abdominal pain in children: a randomized controlled trial. BMC Pediatr 2006; 6:29.
76. Vlieger AM, Rutten JMTM, Govers AMAP, et al. Long-term follow-up of gut-directed hypnotherapy vs. standard care in children with functional abdominal pain or irritable bowel syndrome. Am J Gastroenterol 2012; 107:627–631.
77. Evans S, Lung KC, Seidman LC, et al. Iyengar yoga for adolescents and young adults with irritable bowel syndrome. J Pediatr Gasterol Nutr 2014; 59:244–253.
78. Korterink JJ, Ockeloen LE, Hilbink M, et al. Yoga therapy for abdominal pain related-functional gastrointestinal disorders in children. A randomized controlled trial. J Pediatr Gasterol Nutr 2016; 63:481–487.
79. Kuttner L, Chambers CT, Hardial J, et al. A randomized trial of yoga for adolescents with irritable bowel syndrome. Pain Res Manag 2006; 11:217–223.
80. Wallander JL, Madan-Swain A, Klapow J, et al. A randomised controlled trial of written self-disclosure for functional recurrent abdominal pain in youth. Psychol Health 2011; 26:433–447.
81. Horvath A, Dziechciarz P, Szajewska H. Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood. Aliment Pharmacol Ther 2011; 33:1302–1310.
82. Rutten JM, Korterink JJ, Venmans LM, et al. Nonpharmacologic treatment of functional abdominal pain disorders: a systematic review. Pediatrics 2015; 135:522–535.
83. Eccleston C, Palermo TM, Williams AC, et al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev 2014; 5: Art. No.: CD003968. DOI: 10.1002/14651858.CD003968.pub4.
84. Kaminski A, Kamper A, Thaler K, et al. Antidepressants for the treatment of abdominal pain-related functional gastrointestinal disorders in children and adolescents. Cochrane Database Syst Rev 2011;(7):CD008013.
85. Brown LK, Beattie RM, Tighe MP. Practical management of functional abdominal pain in children. Arch Dis Child 2016; 101:677–683.
86. Hyams JS, Hyman PE. Recurrent abdominal pain and the biopsychosocial model of medical practice. J Pediatr 1998; 133:473–478.
Keywords:

children; chronic pain; functional abdominal pain; recurrent abdominal pain; systematic review

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