ArticlePDF Available

Can we treat visceral hypersensitivity in functional abdominal pain?

Authors:
Miranda A L Van Tilburg at Cape Fear Valley Medical Center
Miranda A L Van Tilburg
Download full-text PDF
Read full-text
Download citation
Content uploaded by Miranda A L Van Tilburg
Author content
All content in this area was uploaded by Miranda A L Van Tilburg on Sep 28, 2017
Content may be subject to copyright.
Lancet Gastroenterol Hepatol. 2017 Oct;2(10):694-695. doi: 10.1016/S2468-1253(17)30258-3. Epub 2017 Aug 18.
Can we treat visceral hypersensitivity in Functional Abdominal Pain?
Miranda A.L. van Tilburg. PhD
Campbell University, College of Pharmacy & Health Sciences
University of North Carolina, Department of Medicine
University of Washington, School of Social Work
Almost any pediatrician who has encountered a child with chronic abdominal pain in their office has
thought “Now what?”. Functional Abdominal Pain Disorders (FAPD) are frustrating disorders for
patients, their families, and physicians alike. The frustration starts with the perceived inability to answer
two related questions: “What is the cause of the pain?” and “What can we do to treat it?”. Despite
being common and disabling conditions, FAPD are still shrouded in mystery and few effective
treatments are available. In the past decade, enormous strides that have been made in the diagnosis
and understanding the complex pathophysiology of FAPD1, but few effective treatments are available.
Recent reviews and meta-analyses found no evidence for pharmacological treatment or most dietary
treatments2-4. Although there is some evidence for the psychological therapy5,6, these are not widely
available to most patients. Hence, a clinician has little in their repertoire to confidently treat FAPD and
the development of novel treatments is a high priority.
The lack of evidence, is largely driven by the lack of funding for and conducting of randomized
controlled trials in FAPD. However, clinical practice also teaches that few treatments work in the
majority of patients. The Rome IV committee suggests to tailor treatment to the child’s underlying
pathophysiological mechanism1. The pathophysiology of FAPD is complex and can involve any number of
combinations of various factors in each patient. One of the most common pathophysiological factors in
FAPD is visceral hypersensitivity or a decreased pain threshold in the gut1. Increased pain sensitivity is an
interplay between disturbances in the periphery (e.g, disturbances in the gut microbiota and immune
system) and central nervous processes of gut sensations (e.g, brain areas involved in attention and
emotion regulation are upregulated)7. Pharmacological manipulation of visceral hypersensitivity in
adults has included antidepressants, serotonin receptor modulators, and hypnotherapy7. However, anti-
depressants have not been found efficacious for FAPD2 (plus many carry a black box warning for
adolescents), serotonin receptor modulators were removed from the market due to risk of serious side
effects, and one study could not replicate that hypnotherapy affects visceral sensitivity in children8.
Hence, new treatments are needed to ameliorate visceral hypersensitivity with a better efficacy and side
effect profile.
The study by Kovacic and colleagues in this issue of The Lancet Gastroenterology and
Hepatology offers a new direction for treating visceral hypersensitivity through central pathways.
Percutaneous electric nerve simulators (PENFS) targets the auricular branches of the vagal nerve and
there is evidence it modulates the pain matrix in the central nervous system such as the amygdala9. The
study by Kovacic and colleagues shows that a 4-week treatment of PENFS reduces pain and disability
compared to sham, and these effects were sustained 2-3 months after treatment. Its largest benefit is in
the non-invasive approach – PENFS is administered through the ear and electrical stimulation is below
sensation threshold. As a safe and efficacious treatment, PENFS could be an important addition to the
treatment arsenal for FAPD.
However, before recommending PENFS widely, the study results should be replicated. The
current study found a small placebo response (30% vs 41% on average in FAPD trials)10. Many treatment
trials of FAPD have failed to show significance due to a robust placebo response in FAPD patients.
Investigating if PENFS will remain superior to placebo/sham should be scrutinized more closely.
Secondly, the study by Kovacic did not investigate if PENFS changed visceral hypersensitivity and/or
central pain pathways. Nor did it indicate if pain reduction was more robust in patients with pre-existing
visceral hypersensitivity. Data on treatment mechanism of PENFS would strengthen the findings and
ease the worries around a possible low placebo response. In addition, it would give important
information to target PENFS treatment to the right patient.
It is the hope that in the future we can confidently explain why a child suffers from FAPD and
have access to safe and efficacious treatment options. The current study is a major step in this direction.
Although more studies are needed, the current findings suggest that PENFS is a novel treatment
targeting visceral hypersensitivity, that can safely and unobtrusively reduce pain and disability in FAPD.
1. Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Functional disorders: Children
and adolescents. Gastroenterology. 2016. doi: S0016-5085(16)00181-5 [pii].
2. Martin AE, Newlove-Delgado TV, Abbott RA, et al. Pharmacological interventions for recurrent
abdominal pain in childhood. Cochrane Database Syst Rev. 2017;3:CD010973. doi:
10.1002/14651858.CD010973.pub2 [doi].
3. Newlove-Delgado TV, Martin AE, Abbott RA, et al. Dietary interventions for recurrent abdominal pain
in childhood. Cochrane Database Syst Rev. 2017;3:CD010972. doi: 10.1002/14651858.CD010972.pub2
[doi].
4. van Tilburg MA, Felix CT. Diet and functional abdominal pain in children and adolescents. J Pediatr
Gastroenterol Nutr. 2013;57(2):141-148. doi: 10.1097/MPG.0b013e31829ae5c5 [doi].
5. Abbott RA, Martin AE, Newlove-Delgado TV, et al. Psychosocial interventions for recurrent abdominal
pain in childhood. Cochrane Database Syst Rev. 2017;1:CD010971. doi:
10.1002/14651858.CD010971.pub2 [doi].
6. Reed-Knight B, Claar RL, Schurman JV, van Tilburg MA. Implementing psychological therapies for
functional GI disorders in children and adults. Expert Rev Gastroenterol Hepatol. 2016;10(9):981-984.
doi: 10.1080/17474124.2016.1207524 [doi].
7. Farzaei MH, Bahramsoltani R, Abdollahi M, Rahimi R. The role of visceral hypersensitivity in irritable
bowel syndrome: Pharmacological targets and novel treatments. J Neurogastroenterol Motil.
2016;22(4):558-574. doi: 10.5056/jnm16001 [doi].
8. Vlieger AM, van den Berg MM, Menko-Frankenhuis C, Bongers ME, Tromp E, Benninga MA. No change
in rectal sensitivity after gut-directed hypnotherapy in children with functional abdominal pain or
irritable bowel syndrome. Am J Gastroenterol. 2010;105(1):213-218. doi: 10.1038/ajg.2009.613 [doi].
9. Babygirija R, Sood M, Kannampalli P, Sengupta JN, Miranda A. Percutaneous electrical nerve field
stimulation modulates central pain pathways and attenuates post-inflammatory visceral and somatic
hyperalgesia in rats. Neuroscience. 2017;356:11-21. doi: S0306-4522(17)30335-4 [pii].
10. Hoekman DR, Zeevenhooven J, van Etten-Jamaludin FS, et al. The placebo response in pediatric
abdominal pain-related functional gastrointestinal disorders: A systematic review and meta-analysis. J
Pediatr. 2017;182:155-163.e7. doi: S0022-3476(16)31419-6 [pii].
Modified Liu-Jun-Zi decoction alleviates visceral hypersensitivity in functional dyspepsia by regulating EC cell-5HT3r signaling in duodenum
Article
  • Dec 2019
  • J ETHNOPHARMACOL
Ethnopharmacological relevance: Modified Liu-Jun-Zi (MLJZ) is derived from one of the most famous traditional Chinese prescription Liu-Jun-Zi. It exhibits therapeutic effects in functional dyspepsia (FD), but the underlying mechanisms remain not well understood. Enterochromaffin (EC) cells contribute to the pathogeneses of visceral hypersensitivity in functional gastrointestinal disorders. But whether and how EC cells in duodenum participate in the mechanism of FD remain unsettled. Aim of the study: To detect the crucial factors related to EC, and to evaluate the therapeutic effect of MLJZ and to determine whether MLJZ relieves visceral hypersensitivity in FD by regulating EC cell-5HT3r signaling. Materials and methods: FD rats were established by iodoacetamide gavage combined with tail clamping method. The verification of FD model and the evaluation of the therapeutic effect of MLJZ was taken place by hematoxylin-eosin (HE) staining and visceral sensitivity measurement. The expression of EC cells and 5-hydroxytryptamine (5HT) in duodenum was detected by Immunohistochemistry (IHC) staining and enzyme-linked immunosorbent assay (ELISA). IHC staining and quantitative polymerase chain reaction (qPCR) were applied to measure the expression of tryptophan hydroxylase-1 (TPH1), paired box gene 4 (PAX4), transient receptor potential A1 (TRPA1), transient receptor potential C4 (TRPC4) and 5-hydroxytryptamine 3 receptor (5HT3r). Duodenum sections were stained by double immunofluorescence (IF) to study the synthesis of 5HT in EC cells. Results: The gastric sensitivity increased in FD rats while MLJZ decoction significantly attenuated visceral hypersensitivity. The duodenum of FD rats displayed increased expressions of EC cells, 5HT, TPH1, PAX4 and 5HT3r. And the overexpression was reduced in response to MLJZ decoction treatment. Conclusions: EC cell-5HT3r signaling pathway is abnormally active in FD with visceral hypersensitivity. And MLJZ decoction can alleviates visceral hypersensitivity in FD by regulating EC cell-5HT3r signaling in duodenum.
View
The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments
Article
Full-text available
  • Jul 2016
Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1-receptors, serotonin (5-hydrodytryptamine; 5-HT) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase (Trk) receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH.
View
Implementing psychological therapies for functional GI disorders in children and adults
Article
Full-text available
  • Jun 2016
Introduction: Functional GI disorders (FGIDs) are common in adults and children. Psychological factors play an important role in the onset and maintenance of FGIDs and in explaining the associated disability. Psychological treatments such as Cognitive Behavioral Therapy and Hypnotherapy have been found efficacious in FGIDs but Integrating psychological treatments into traditionally medically-oriented care can be challenging. Areas covered: This review outlines the case for integrating psychological therapies into medical care for FGIDs and examine various models of integrated care that can be adapted to fit specific practice scenarios. Expert commentary: We advise integrating a psychologist in the care and treatment planning of every patient. Clinic-specific needs dictate how integrated care for patients with FGIDs can be delivered.
View
Diet and Functional Abdominal Pain in Children and Adolescents
Article
Full-text available
  • May 2013
  • J PEDIATR GASTR NUTR
Functional abdominal pain (FAP) is a common complaint among children and adolescents. For many patients, symptoms exacerbate with eating. This review discusses findings concerning the role of diet in FAP. The foods that are discussed are divided into two major groups: (1) Food allergies or intolerances, which focus on milk, gluten, and FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides and polyols), and (2) Functional foods, which hone in on foods that reduce abdominal pain in adolescents such as fiber, peppermint oil, and probiotics. Lastly we discuss the role of eating habits in FAP and how the physics of eating may be the real culprit of symptoms associated with eating.
View
Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial
Article
  • Aug 2017
Background: Development of safe and effective therapies for paediatric abdominal pain-related functional gastrointestinal disorders is needed. A non-invasive, US Food and Drug Administration-cleared device (Neuro-Stim, Innovative Health Solutions, IN, USA) delivers percutaneous electrical nerve field stimulation (PENFS) in the external ear to modulate central pain pathways. In this study, we evaluated the efficacy of PENFS in adolescents with abdominal pain-related functional gastrointestinal disorders. Methods: In this randomised, sham-controlled trial, we enrolled adolescents (aged 11-18 years) who met Rome III criteria for abdominal pain-related functional gastrointestinal disorders from a single US outpatient gastroenterology clinic. Patients were randomly assigned (1:1) with a computer-generated randomisation scheme to active treatment or sham (no electrical charge) for 4 weeks. Patients were stratified by sex and presence or absence of nausea. Allocation was concealed from participants, caregivers, and the research team. The primary efficacy endpoint was change in abdominal pain scores. We measured improvement in worst abdominal pain and composite pain score using the Pain Frequency-Severity-Duration (PFSD) scale. Participants with less than 1 week of data and those with organic disease identified after enrolment were excluded from the modified intention-to-treat population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT02367729. Findings: Between June 18, 2015, and Nov 17, 2016, 115 children with abdominal pain-related functional gastrointestinal disorders were enrolled and assigned to either PENFS (n=60) with an active device or sham (n=55). After exclusion of patients who discontinued treatment (n=1 in the PENFS group; n=7 in the sham group) and those who were excluded after randomisation because they had organic disease (n=2 in the PENFS group; n=1 in the sham group), 57 patients in the PENFS group and 47 patients in the sham group were included in the primary analysis. Patients in the PENFS group had greater reduction in worst pain compared with sham after 3 weeks of treatment (PENFS: median score 5·0 [IQR 4·0-7·0]; sham: 7·0 [5·0-9·0]; least square means estimate of change in worse pain 2·15 [95% CI 1·37-2·93], p<0·0001). Effects were sustained for an extended period (median follow-up 9·2 weeks [IQR 6·4-13·4]) in the PENFS group: median 8·0 (IQR 7·0-9·0) at baseline to 6·0 (5·0-8·0) at follow-up versus sham: 7·5 (6·0-9·0) at baseline to 7·0 (5·0-8·0) at follow-up (p<0·0001). Median PFSD composite scores also decreased significantly in the PENFS group (from 24·5 [IQR 16·8-33.3] to 8·4 [3·2-16·2]) compared with sham (from 22·8 [IQR 8·4-38·2] to 15·2 [4·4-36·8]) with a mean decrease of 11·48 (95% CI 6·63-16·32; p<0·0001) after 3 weeks. These effects were sustained at extended follow-up in the PENFS group: median 24·5 (IQR 16·8-33·3) at baseline to 12 (3·6-22·5) at follow-up, compared with sham: 22·8 (8·4-38·2) at baseline to 16·8 (4·8-33·6) at follow-up (p=0·018). Ten patients reported side-effects (three of whom discontinued the study): ear discomfort (n=6; three in the PENFS group, three in the sham group), adhesive allergy (n=3; one in the PENFS group, two in the sham group), and syncope due to needle phobia (n=1; in the sham group). There were no serious adverse events. Interpretation: Our results show that PENFS with Neuro-Stim has sustained efficacy for abdominal pain-related functional gastrointestinal disorders in adolescents. This safe and effective approach expands treatment options and should be considered as a non-pharmacological alternative for these disorders. Funding: American Neurogastroenterology and Motility Society.
View
Percutaneous Electrical Nerve Field Stimulation Modulates Central Pain Pathways and Attenuates Post-Inflammatory Visceral and Somatic Hyperalgesia in Rats
Article
  • May 2017
A non-invasive, auricular percutaneous electrical nerve field stimulation (PENFS) has been suggested to modulate central pain pathways. We investigated the effects of BRIDGE® device on the responses of amygdala and lumbar spinal neurons and the development of post-colitis hyperalgesia. Male Sprague-Dawley rats received intracolonic trinitrobenzene sulfonic acid (TNBS) and PENFS on the same day. Control rats had sham devices. The visceromotor response (VMR) to colon distension and paw withdrawal threshold (PWT) was recorded after 7 days. A different group of rats had VMR and PWT at baseline, after TNBS and following PENFS. Extracellular recordings were made from neurons in central nucleus of the amygdala (CeA) or lumbar spinal cord. Baseline firing and responses to compression of the paw were recorded before and after PENFS. Sham treated rats exhibited a much higher VMR (>30mmHg) and lower PWT compared to PENFS treated rats (p<0.05). PENFS decreased the VMR to colon distension and increased the PWT compared to pre-stimulation (p<0.05). PENFS resulted in a 57% decrease in spontaneous firing of the CeA neurons (0.59 ±0.16 vs control: 1.71±0.32imp/sec). Similarly, the response to somatic stimulation was decreased by 56% (3.6 ± 0.52 vs control: 1.71 ± 0.32 imps/s, p<0.05). Spinal neurons showed a 47% decrease in mean spontaneous firing (4.05 ±0.65 vs control: 7.7±0.87 imp/sec) and response to somatic stimulation (7.62±1.7 vs control: 14.8± 2.28 imp/sec, p<0.05). PENFS attenuated baseline firing of CeA and spinal neurons which may account for the modulation of pain responses in this model of post-inflammatory visceral and somatic hyperalgesia.
View
Dietary interventions for recurrent abdominal pain in childhood
Article
  • Mar 2017
Background: This is an update of the original Cochrane review, last published in 2009 (Huertas-Ceballos 2009). Recurrent abdominal pain (RAP), including children with irritable bowel syndrome, is a common problem affecting between 4% and 25% of school-aged children. For the majority of such children, no organic cause for their pain can be found on physical examination or investigation. Many dietary inventions have been suggested to improve the symptoms of RAP. These may involve either excluding ingredients from the diet or adding supplements such as fibre or probiotics. Objectives: To examine the effectiveness of dietary interventions in improving pain in children of school age with RAP. Search methods: We searched CENTRAL, Ovid MEDLINE, Embase, eight other databases, and two trials registers, together with reference checking, citation searching and contact with study authors, in June 2016. Selection criteria: Randomised controlled trials (RCTs) comparing dietary interventions with placebo or no treatment in children aged five to 18 years with RAP or an abdominal pain-related, functional gastrointestinal disorder, as defined by the Rome III criteria (Rasquin 2006). Data collection and analysis: We used standard methodological procedures expected by Cochrane. We grouped dietary interventions together by category for analysis. We contacted study authors to ask for missing information and clarification, when needed. We assessed the quality of the evidence for each outcome using the GRADE approach. Main results: We included 19 RCTs, reported in 27 papers with a total of 1453 participants. Fifteen of these studies were not included in the previous review. All 19 RCTs had follow-up ranging from one to five months. Participants were aged between four and 18 years from eight different countries and were recruited largely from paediatric gastroenterology clinics. The mean age at recruitment ranged from 6.3 years to 13.1 years. Girls outnumbered boys in most trials. Fourteen trials recruited children with a diagnosis under the broad umbrella of RAP or functional gastrointestinal disorders; five trials specifically recruited only children with irritable bowel syndrome. The studies fell into four categories: trials of probiotic-based interventions (13 studies), trials of fibre-based interventions (four studies), trials of low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diets (one study), and trials of fructose-restricted diets (one study).We found that children treated with probiotics reported a greater reduction in pain frequency at zero to three months postintervention than those given placebo (standardised mean difference (SMD) -0.55, 95% confidence interval (CI) -0.98 to -0.12; 6 trials; 523 children). There was also a decrease in pain intensity in the intervention group at the same time point (SMD -0.50, 95% CI -0.85 to -0.15; 7 studies; 575 children). However, we judged the evidence for these outcomes to be of low quality using GRADE due to an unclear risk of bias from incomplete outcome data and significant heterogeneity.We found that children treated with probiotics were more likely to experience improvement in pain at zero to three months postintervention than those given placebo (odds ratio (OR) 1.63, 95% CI 1.07 to 2.47; 7 studies; 722 children). The estimated number needed to treat for an additional beneficial outcome (NNTB) was eight, meaning that eight children would need to receive probiotics for one to experience improvement in pain in this timescale. We judged the evidence for this outcome to be of moderate quality due to significant heterogeneity.Children with a symptom profile defined as irritable bowel syndrome treated with probiotics were more likely to experience improvement in pain at zero to three months postintervention than those given placebo (OR 3.01, 95% CI 1.77 to 5.13; 4 studies; 344 children). Children treated with probiotics were more likely to experience improvement in pain at three to six months postintervention compared to those receiving placebo (OR 1.94, 95% CI 1.10 to 3.43; 2 studies; 224 children). We judged the evidence for these two outcomes to be of moderate quality due to small numbers of participants included in the studies.We found that children treated with fibre-based interventions were not more likely to experience an improvement in pain at zero to three months postintervention than children given placebo (OR 1.83, 95% CI 0.92 to 3.65; 2 studies; 136 children). There was also no reduction in pain intensity compared to placebo at the same time point (SMD -1.24, 95% CI -3.41 to 0.94; 2 studies; 135 children). We judged the evidence for these outcomes to be of low quality due to an unclear risk of bias, imprecision, and significant heterogeneity.We found only one study of low FODMAP diets and only one trial of fructose-restricted diets, meaning no pooled analyses were possible.We were unable to perform any meta-analyses for the secondary outcomes of school performance, social or psychological functioning, or quality of daily life, as not enough studies included these outcomes or used comparable measures to assess them.With the exception of one study, all studies reported monitoring children for adverse events; no major adverse events were reported. Authors' conclusions: Overall, we found moderate- to low-quality evidence suggesting that probiotics may be effective in improving pain in children with RAP. Clinicians may therefore consider probiotic interventions as part of a holistic management strategy. However, further trials are needed to examine longer-term outcomes and to improve confidence in estimating the size of the effect, as well as to determine the optimal strain and dosage. Future research should also explore the effectiveness of probiotics in children with different symptom profiles, such as those with irritable bowel syndrome.We found only a small number of trials of fibre-based interventions, with overall low-quality evidence for the outcomes. There was therefore no convincing evidence that fibre-based interventions improve pain in children with RAP. Further high-quality RCTs of fibre supplements involving larger numbers of participants are required. Future trials of low FODMAP diets and other dietary interventions are also required to facilitate evidence-based recommendations.
View
Psychosocial interventions for recurrent abdominal pain in childhood
Article
  • Jan 2017
Background: This review supersedes the original Cochrane review first published in 2008 (Huertas-Ceballos 2008).Between 4% and 25% of school-aged children complain of recurrent abdominal pain (RAP) severe enough to interfere with their daily activities. No organic cause for this pain can be found on physical examination or investigation for the majority of such children. Although many children are managed by reassurance and simple measures, a large range of psychosocial interventions involving cognitive and behavioural components have been recommended. Objectives: To determine the effectiveness of psychosocial interventions for reducing pain in school-aged children with RAP. Search methods: In June 2016 we searched CENTRAL, MEDLINE, Embase, eight other databases, and two trials registers. We also searched the references of identified studies and relevant reviews. Selection criteria: Randomised controlled trials comparing psychosocial therapies with usual care, active control, or wait-list control for children and adolescents (aged 5 to 18 years) with RAP or an abdominal pain-related functional gastrointestinal disorder defined by the Rome III criteria were eligible for inclusion. Data collection and analysis: We used standard methodological procedures expected by Cochrane. Five review authors independently selected studies, assessed them for risk of bias, and extracted relevant data. We also assessed the quality of the evidence using the GRADE approach. Main results: This review includes 18 randomised controlled trials (14 new to this version), reported in 26 papers, involving 928 children and adolescents with RAP between the ages of 6 and 18 years. The interventions were classified into four types of psychosocial therapy: cognitive behavioural therapy (CBT), hypnotherapy (including guided imagery), yoga, and written self-disclosure. The studies were carried out in the USA, Australia, Canada, the Netherlands, Germany, and Brazil. The majority of the studies were small and short term; only two studies included more than 100 participants, and only five studies had follow-up assessments beyond six months. Small sample sizes and the degree of assessed risk of performance and detection bias in many studies led to the overall quality of the evidence being rated as low to very low for all outcomes.For CBT compared to control, we found evidence of treatment success postintervention (odds ratio (OR) 5.67, 95% confidence interval (CI) 1.18 to 27.32; Z = 2.16; P = 0.03; 4 studies; 175 children; very low-quality evidence), but no evidence of treatment success at medium-term follow-up (OR 3.08, 95% CI 0.93 to 10.16; Z = 1.85; P = 0.06; 3 studies; 139 children; low-quality evidence) or long-term follow-up (OR 1.29, 95% CI 0.50 to 3.33; Z = 0.53; P = 0.60; 2 studies; 120 children; low-quality evidence). We found no evidence of effects of intervention on pain intensity scores measured postintervention (standardised mean difference (SMD) -0.33, 95% CI -0.74 to 0.08; 7 studies; 405 children; low-quality evidence), or at medium-term follow-up (SMD -0.32, 95% CI -0.85 to 0.20; 4 studies; 301 children; low-quality evidence).For hypnotherapy (including studies of guided imagery) compared to control, we found evidence of greater treatment success postintervention (OR 6.78, 95% CI 2.41 to 19.07; Z = 3.63; P = 0.0003; 4 studies; 146 children; low-quality evidence) as well as reductions in pain intensity (SMD -1.01, 95% CI -1.41 to -0.61; Z = 4.97; P < 0.00001; 4 studies; 146 children; low-quality evidence) and pain frequency (SMD -1.28, 95% CI -1.84 to -0.72; Z = 4.48; P < 0.00001; 4 studies; 146 children; low-quality evidence). The only study of long-term effect reported continued benefit of hypnotherapy compared to usual care after five years, with 68% reporting treatment success compared to 20% of controls (P = 0.005).For yoga therapy compared to control, we found no evidence of effectiveness on pain intensity reduction postintervention (SMD -0.31, 95% CI -0.67 to 0.05; Z = 1.69; P = 0.09; 3 studies; 122 children; low-quality evidence).The single study of written self-disclosure therapy reported no benefit for pain.There was no evidence of effect from the pooled analyses for any type of intervention on the secondary outcomes of school performance, social or psychological functioning, and quality of daily life.There were no adverse effects for any of the interventions reported. Authors' conclusions: The data from trials to date provide some evidence for beneficial effects of CBT and hypnotherapy in reducing pain in the short term in children and adolescents presenting with RAP. There was no evidence for the effectiveness of yoga therapy or written self-disclosure therapy. There were insufficient data to explore effects of treatment by RAP subtype.Higher-quality, longer-duration trials are needed to fully investigate the effectiveness of psychosocial interventions. Identifying the active components of the interventions and establishing whether benefits are sustained in the long term are areas of priority. Future research studies would benefit from employing active control groups to help minimise potential bias from wait-list control designs and to help account for therapist and intervention time.
View
The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis
Article
  • Jan 2017
Objective: To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain-related functional gastrointestinal disorders. Study design: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo-controlled trials concerning children 4-18 years of age with an abdominal pain-related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta-regression analysis. Results: Twenty-one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%-49%; 17 studies) and with no pain was 17% (95% CI, 8%-32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was -0.73 (95% CI, -1.04 to -0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). Conclusions: Approximately 41% of children with abdominal pain-related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies.
View
View
View