Clinical trial: Randomized controlled trial of linaclotide in children aged 6-17 years with functional constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 µg, B: 18 or 36 µg, or C: 36 or 72 µg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 µg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 µg] and 2.86 in 12- to 17-year-olds [72 µg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation.

Safety and efficacy of linaclotide in children aged 7-17 years with irritable bowel syndrome with constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years old with functional constipation. This study evaluated the safety and efficacy of various linaclotide doses in children 7-17 years old with irritable bowel syndrome with constipation (IBS-C). METHODS: In this 4-week, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study, children with IBS-C were randomized to once-daily placebo or linaclotide (Dose A: 18 or 36 µg, B: 36 or 72 µg, and C: 72 µg or 145 µg, or 290 µg); those aged 7-11 years in a 1:1:1:1 allocation based on weight (18 to <35 kg:18 µg, 36 µg, or 72 µg; or ≥35 kg: 36 µg, 72 µg, or 145 µg), and those aged 12-17 years in a 1:1:1:1:1 allocation (the higher option of Doses A-C or 290 µg). The primary efficacy endpoint was a change from baseline in 4-week overall spontaneous bowel movement (SBM) frequency rate over the treatment period. Adverse events and clinical laboratory measures were also assessed. RESULTS: Efficacy, safety, and tolerability were assessed in 101 patients. In the intent-to-treat population, numerical improvement was observed in overall SBM frequency rate with increasing linaclotide doses (A: 1.62, B: 1.52, and C: 2.30, 290 µg: 3.26) compared with placebo. The most reported treatment-emergent adverse events were diarrhea and pain, with most cases being mild and none being severe. CONCLUSIONS: Linaclotide was tolerated well in this pediatric population, showing numerical improvement in SBM frequency compared with placebo.

Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Linaclotide, a guanylate cyclase C agonist, has been approved in the USA for the treatment of chronic idiopathic constipation and irritable bowel syndrome with predominant constipation in adults. We aimed to assess the efficacy and safety of linaclotide in paediatric patients aged 6-17 years with functional constipation. METHODS: This randomised, double-blind, placebo-controlled, multicentre, phase 3 study was done at 64 clinic or hospital sites in seven countries (USA, Canada, Israel, Italy, the Netherlands, Ukraine, and Estonia). Patients aged 6-17 years who met modified Rome III criteria for functional constipation were randomly assigned (1:1), with a block size of four and stratified by age (6-11 years and 12-17 years), to receive either oral linaclotide 72 µg or placebo once daily for 12 weeks. Participants, investigators, and data assessors were masked to assignment. The primary efficacy endpoint was change from baseline (CFB) in the 12-week frequency rate of spontaneous bowel movements (SBMs; occurring in the absence of rescue medication on the calendar day of or before the bowel movement) per week and the secondary efficacy endpoint was CFB in stool consistency over the 12-week treatment period; efficacy and safety were analysed in all patients in the randomised population who received at least one dose of study intervention (modified intention-to-treat population and safety population, respectively). The study is registered with ClinicalTrials.gov, NCT04026113, and the functional constipation part of the study is complete. FINDINGS: Between Oct 1, 2019, and March 21, 2022, 330 patients were enrolled and randomly assigned to linaclotide (n=166) or placebo (n=164). Two patients in the linaclotide group did not receive any treatment; thus, efficacy and safety endpoints were assessed in 328 patients (164 patients in each group). 293 (89%) patients completed the 12-week treatment period (148 in the linaclotide group and 145 in the placebo group). 181 (55%) of 328 patients were female and 147 (45%) were male. At baseline, the mean frequency rate for SBMs was 1·28 SBMs per week (SD 0·87) for placebo and 1·16 SBMs per week (0·83) for linaclotide, increasing to 2·29 SBMs per week (1·99) for placebo and 3·41 SBMs per week (2·76) for linaclotide during intervention. Compared with placebo (least-squares mean [LSM] CFB 1·05 SBMs per week [SE 0·19]), patients treated with linaclotide showed significant improvement in SBM frequency (LSM CFB 2·22 SBMs per week [0·19]; LSM CFB difference 1·17 SBMs per week [95% CI 0·65-1·69]; p<0·0001). Linaclotide also significantly improved stool consistency over placebo (LSM CFB 1·11 [SE 0·08] vs 0·69 [0·08]; LSM CFB difference 0·42 [95% CI 0·21-0·64]; p=0·0001). The most reported treatment-emergent adverse event (TEAE) by patients treated with linaclotide was diarrhoea (seven [4%] of 164 vs three [2%] of 164 patients in the placebo group) and by patients treated with placebo was COVID-19 (five [3%] vs four [2%] in the linaclotide group). The most frequent treatment-related TEAE was diarrhoea (linaclotide: six [4%] patients; placebo: two [1%] patients). One serious adverse event of special interest (treatment-related severe diarrhoea resulting in dehydration and hospitalisation) occurred in a female patient aged 17 years in the linaclotide group; this case resolved without sequelae after administration of intravenous fluids. No deaths occurred during the study. INTERPRETATION: Linaclotide is an efficacious and well tolerated treatment for functional constipation in paediatric patients and has subsequently been approved by the US Food and Drug Administration for this indication. FUNDING: AbbVie and Ironwood Pharmaceuticals.

Psychological distress and coping efficacy in children with disorders of gut-brain interaction.

BACKGROUND: Multiple psychological factors influence disorders of gut-brain interaction (DGBIs). We aimed to evaluate psychological distress in Colombian schoolchildren with and without DGBIs. METHODS: We included children ages 8-18 years without organic medical conditions from largest regional public schools in Colombia. Children completed Spanish versions of Rome III diagnostic questionnaire for DGBIs, State Trait Anxiety Inventory for Children (STAIC), Children's Somatization Inventory (CSI), and a measure of coping efficacy. These data, demographic and socioeconomic characteristics, were compared between children with DGBIs and healthy peers. Exploratory analyses investigated differences between youth with symptoms of functional abdominal pain disorders (FAPDs) compared with healthy peers. KEY RESULTS: Of 1496 children, 281 (mean age 12.9 ± 2.2 years, 49.8% females) self-reported criteria for DGBIs and 125 reported (44.5%) FAPDs. Children with DGBIs had higher trait anxiety, emotional sensitivity, somatization including GI, non-GI, pain-related, and non-pain-related subscales (p < 0.001 each) and lower coping efficacy (p = 0.02) compared to healthy peers. Females had higher trait anxiety and somatization (p = 0.04 and p = 0.005, respectively). State and trait anxiety and coping efficacy differed based on location in children with DGBIs (p = 0.02, p = 0.03, and p < 0.001, respectively). Children with FAPDs had higher trait anxiety (p = 0.02) and somatization (p < 0.001) compared to healthy youth. CONCLUSIONS & INFERENCES: Children with DGBIs had higher anxiety, emotional sensitivity, and somatization, and lower coping efficacy compared with healthy youth. This highlights the importance of appraising psychological distress characteristics as well as incorporating conflict resolution, assertiveness training, and resilience building during the treatment of DGBIs.

ESPGHAN and NASPGHAN 2023 protocol for paediatric FAPD treatment guidelines (standard operating procedure).

INTRODUCTION: To date, no international guidelines have been published for the treatment of paediatric functional abdominal pain disorders (FAPDs), subcategorised into functional abdominal pain-not otherwise specified (FAP-NOS), irritable bowel syndrome (IBS), functional dyspepsia and abdominal migraine (AM). We aim for a treatment guideline, focusing on FAP-NOS, IBS and AM, that appreciates the extensive array of available therapies in this field. We present the prospective operating procedure and technical summary protocol in this manuscript. METHODS: Grading of Recommendations, Assessment, Development and Evaluation (GRADE) will be followed in the development of the guideline, following the approach as laid out in the GRADE handbook, supported by the WHO. The Guideline Development Group (GDG) is formed by paediatric gastroenterologists from both the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, as well as the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Also, one clinical psychologist with expertise in FAPDs is a voting member in the GDG. A final consensus list of treatment options is translated into 'patient, intervention, comparison, outcome' format options. Prospective agreement on the magnitude of health benefits or harms categories was reached through a Delphi process among the GDG to support grading of the literature.There will be a detailed technical evidence review with randomised controlled trial data that will be judged for risk of bias with the Cochrane tool. Recommendations are preferably based on GRADE but could also be best practice statements following the available evidence. A full Delphi process will be used to make recommendations using online response systems. This set of procedures has been approved by all members of the GDG.

Quality of life measures in children with Down syndrome with disorders of gut-brain interaction.

Down syndrome (DS) is associated with multiple medical comorbidities. Perhaps related to such, caregivers of individuals with DS report lower quality of life (QoL) compared to individuals without DS. It has been shown that disorders of gut-brain interaction (DGBI) such as functional constipation (FC) and irritable bowel syndrome (IBS) are common in individuals with DS. We measured caregiver-reported QoL in individuals with DS with a DGBI and compared them to individuals with DS without a DGBI via a cross-sectional national survey. All measures of QoL were lower in those with DS who meet criteria for a DGBI compared to those with DS without a DGBI. Males and females with DS and at least one DGBI had similar QoL scores. While FC was the most common DGBI seen in individuals with DS, there was no difference in any aspect of QoL in subjects with FC when compared to individuals with other DGBIs. However, all measures of QoL were lower in those with IBS compared to individuals with other DGBIs. These findings suggest that management of gastrointestinal symptoms from DGBIs, particularly IBS, may serve as a target for increasing QoL in a notable subset of individuals with DS.

First study to assess the reliability of commonly used pain scales in children with disorders of gut-brain interaction.

BACKGROUND: There are no validated measures to assess chronic abdominal pain (AP) in clinical trials of children with disorders of gut-brain interaction (DGBIs). Currently used AP measures are extrapolated from studies on adults or children with acute AP. The primary aim of the study was to assess the commonly used pain scales in children with DGBIs. The secondary aim of the study was to compare specific pain measures with the overall subjective assessment of AP well-being in children. METHODS: A sub-study from multicenter crossover randomized controlled trial (RCT) was conducted. Children with AP-DGBIs completed daily diaries for 7 weeks. It included three widely used AP scales: the numeric rating scale (NRS), the visual analog scale (VAS), the Faces Pain Scale Revised (FPS-R), and a global improvement question. Strength of correlations among scales and questions was assessed with the Pearson correlation coefficient (r). KEY RESULTS: Thirty subjects completed the study. Children completed 4975 of 5880 (84.6%) pain and global responses. The VAS and NRS had strongest correlation among them, r = 0.893 (p < 0.001). The FPS-R also demonstrated strong correlations with the VAS r = 0.773 (p < 0.001), NRS = 0.783 (p < 0.001). The three scales exhibited weaker but significant correlations with the global question. Strong correlations were consistent when stratified by age groups. CONCLUSION: This is the first study to assess the most used AP scales in children with DGBIs. It supports the Rome IV recommendations on using the VAS and NRS scales. It also suggests that FPS-R, that was not part of Rome IV, can also be used in RCTs. Congruent with the biopsychosocial model, there was a weaker correlation between AP measures and the global question. This suggests that the global question measures more domains than AP alone and that it should also be incorporated in DGBIs RCTs in children.

A Rare Case of Cannabinoid Hyperemesis Syndrome Secondary to Cannabidiol for Refractory Epilepsy.

Cannabinoid hyperemesis syndrome (CHS) is associated with tetrahydrocannabinol, and rarely has been reported with cannabidiol. Cannabidiol is used in treatment-refractory epilepsy. This is a case of a pediatric patient with Lennox-Gastaut syndrome on cannabidiol, who was started on the ketogenic diet with significant seizure reduction. However, within 6 months he developed monthly bouts of severe emesis unresponsive to conventional anti-emetic therapy. Based on the stereotypical nature of his vomiting episodes, CHS was suspected. Cannabidiol was discontinued and within 2 months his emesis resolved. He has had no increase in seizure frequency or hospitalizations for emesis since cannabidiol was discontinued nearly 1 year ago. This is the first case of CHS secondary to cannabidiol for refractory epilepsy reported in the literature. We review the mechanism by which cannabidiol is believed to reduce seizures and be both anti- and pro-emetic, mainly through interactions with cannabinoid receptors and transient receptor channels.

Disorders of Gut-Brain Interaction in a National Cohort of Children With Down Syndrome.

Background/Aims: Disorders of brain-gut interaction (DGBIs) are present in adults and children around the world. Down syndrome (DS) is the most common chromosomal condition in humans. While DS has associations with many organic medical conditions, the frequency of DGBIs in children and adolescents with DS has not previously been studied. We assess the rate of DGBIs in children and adolescents 4-18 years of age with DS in the United States using the Rome IV criteria by caregiver report. Methods: This is a cross-sectional national survey study in which caregivers (n = 114) of children with DS completed an online survey about their child's gastrointestinal symptoms and quality of life (QoL). Results: Using the Rome IV parent-report diagnostic questionnaire, 51.8% of children met symptom-based criteria for at least 1 DGBI. Functional constipation (36.0%) and irritable bowel syndrome (14.9%) were the most common disorders identified. QoL was lower in children with at least 1 disorder as compared to children who did not meet criteria for any disorders (mean QoL = 62.3 vs mean QoL = 72.9, P < 0.001). Almost all children with DS and concomitant autism (87.5%) had at least 1 DGBI. Conclusions: DGBIs are common in children with DS and are associated with diminished QoL.

Efficacy of transcutaneous posterior tibial nerve stimulation in functional constipation.

Most children with functional constipation (FC) improve with conventional treatments. However, a proportion of children have poor treatment outcomes. Management of intractable FC may include botulinum toxin injections, transanal irrigation, antegrade enemas, colonic resections, and in some cases sacral nerve stimulation (SNS). SNS is surgically placed, not readily available and expensive. Posterior tibial nerve stimulation (PTNS) allows transmission of electronic impulses and retrograde stimulation to the sacral nerve plexus in a portable, simple and non-invasive fashion. To assess the efficacy and safety of transcutaneous PTNS for the treatment of FC in children. Single-center, prospective interventional study. Children 4-14 years with Rome IV diagnosis of FC received ten daily PTNS (30 min/day) sessions. Electrodes placed over skin of ankle. Strength of stimulus was below pain threshold. Outcomes were assessed during treatment and 7 days after. Twenty-three subjects enrolled. Two children excluded (acute gastroenteritis, COVID-19 contact). Twenty completed the study (4-14 years), (8.4 ± 3.2 years, 71.4% female). We found significant improvement in the consistency of bowel movements (BM) (p = 0.005), fecal incontinence (FI) (p = 0.005), abdominal pain presence (p = < 0.001) and intensity (p = 0.005), and a significant for improvement in blood in stools (p = 0.037). There was 86.3% improvement in abdominal pain. 96.7% reported treatment satisfaction. Only one child required rescue therapy. CONCLUSION: We found significant improvement in stool consistency, FI, abdominal pain, and hematochezia. This suggests that transcutaneous PTNS could be a promising noninvasive treatment for FC in children. Large studies are needed. WHAT IS KNOWN: • Functional constipation is one of the most common disorders in children. • Current management of functional constipation consists of an integrative approach that includes medications, diet and behavioral strategies. WHAT IS NEW: • Posterior tibial nerve stimulation is a novel noninvasive and easy to use therapy that can improve stool consistency, fecal incontinence and blood in stools.

Gut Microbiome Remains Static in Functional Abdominal Pain Disorders Patients Compared to Controls: Potential for Diagnostic Tools.

Background: Functional Abdominal Pain disorders (FAPDs) are a group of heterogeneous gastrointestinal disorders with unclear pathophysiology. In children, FAPDs are more common in the winter months than summer months. The possible influence of school stressors has been proposed. Previously, our group showed differences in bacterial relative abundances and alpha diversity in the gut microbiome and its relationship with stressors in a cross-sectional evaluation of children suffering from FAPDs compared to a healthy control group. We present longitudinal data to assess whether the gut microbiome changes over school terms in the control and FAPDs groups. Methods: The longitudinal study included children with FAPDs (n = 28) and healthy controls (n = 54). Gastrointestinal symptoms, as well as stool microbiome, were assessed in both groups. Stool samples were serially collected from all participants during both the school term and summer vacation. The stool samples were subjected to total genomic extraction, 16S rRNA amplicon sequencing, and bioinformatics analysis. The gut microbiome was compared at school and during vacation. Other metrics, alpha diversity, and beta diversity, were also compared between the two school terms in every group. Results: In the healthy group, there were differences in microbiome composition between school terms and summer vacation. Conversely, we found no differences in the FAPDs group between the two terms. The healthy control group revealed differences (p-value < 0.05) in 55 bacterial species between the school term and vacation. Several of the differentially abundant identified bacteria were involved in short-chain fatty acids production (SCFAs), inflammation reduction, and gut homeostasis. Alpha diversity metrics, such as the Shannon index, were different in the control group and remained unchanged in the FAPDs group. Conclusion: Although preliminary, our findings suggest that the gut microbiome is static in FAPDs. This compares with a more dynamic healthy gut microbiome. Further studies are warranted to corroborate this and understand the interplay between stress, symptoms, and a less diverse and static microbiome. Future studies will also account for different variables such as diet and other patient demographic criteria that were missing in the current study.

Risk Factors for Abdominal Pain-Related Disorders of Gut-Brain Interaction in Adults and Children: A Systematic Review.

BACKGROUND & AIMS: Many studies have assessed risk factors of irritable bowel syndrome (IBS) and other abdominal pain-related disorders of gut-brain interaction (AP-DGBI); however, the role of these factors is unclear due to heterogeneous study designs. The aim of this systematic review was to extensively evaluate the literature and determine clinical risk and protective factors for the presence and persistence of AP-DGBI in children and adults. METHODS: A PubMed search identified studies investigating potential risk and protective factors for AP-DGBI in adults and children. Inclusion criteria included fully published studies with a control group; exclusion criteria included poor-quality studies (using a validated scale). For each factor, the proportion of studies that found the factor to be a risk factor, protective factor, or neither was summarized. The number of studies, diagnostic criteria, number of subjects, and average study quality rating provided further context. Whenever possible, a meta-analysis generated pooled odds ratios or mean difference. RESULTS: The systematic review included 348 studies. Female sex, gastroenteritis, abuse, stress, psychological disorders, somatic symptoms, and poor sleep were consistent risk factors for developing AP-DGBI in adults and children. In adults, additional risk factors included obesity, smoking, and increased use of medical resources. Protective AP-DGBI factors in adults included social support and optimism; no studies for protective factors were found for children. CONCLUSIONS: There are multiple risk factors for AP-DGBI in adults and children. These include female sex, gastroenteritis, abuse, stress, poor sleep, obesity, psychological disorders, and somatic symptoms. Additional studies are needed in children, on protective factors, and on factors associated with persistence of AP-DGBI.

Prevalence of joint hypermobility, postural orthostatic tachycardia syndrome (POTS), and orthostatic hypotension in school-children. / Prevalencia de la hipermovilidad articular, el síndrome de taquicardia postural (POTS) y la hipotensión ortostática en escolares.

INTRODUCTION: Children with joint hypermobility, postural orthostatic tachycardia syndrome, and orthostatic hypotension report autonomic symptoms such as dizziness, nausea, headaches, and palpitations. It is unclear if there is a pathophysiological link between connective tissue disorders and autonomic symptoms. There is no published data on the prevalence of disorder at the community level. PRIMARY OBJECTIVE: To assess the prevalence of joint hypermobility, orthostatic hypotension, and postural or thostatic tachycardia syndrome in children. SECONDARY OBJECTIVE: To determine the relationship bet ween joint hypermobility, orthostatic hypotension, and postural orthostatic tachycardia syndrome. PATIENTS AND METHOD: Participants aged 10 to 18 years were selected from public schools in three Colombian cities. The surveys included historical questions on the incidence of dizziness, nausea, headache, tremor, blurred vision, vertigo, anxiety, near syncope and syncope, sweating, palpitations triggered by standing in the two months prior to the investigation. Each of these signs and symptoms was also assessed during the recumbency (10 minutes) and standing (2, 5 and 10 minutes) phases of the investigation. HR and BP measurements were obtained at the same intervals. Joint mobility was measured with a mechanical goniometer and assessed with the Beighton score. RESULTS: Prevalence of joint hyperlaxity: 87 of 306 (28.4%). Prevalence of orthostatic hypotension: 5 of 306 (1.6%). Prevalen ce of postural orthostatic tachycardia syndrome: 6 of 306 (2.0%). Of 87 children with joint hyperlaxi ty, only 1 child had joint hyperlaxity at the same time as postural hypotension (1.2%) (p = 0.6735), and 1 child had joint hyperlaxity and postural orthostatic tachycardia syndrome simultaneously (1.2%) (p = 0.5188). CONCLUSION: Children with joint hyperlaxity did not have a higher prevalence of postural orthostatic tachycardia syndrome and orthostatic hypotension. It seems unlikely that con nective tissue disorders are responsible for most cases of postural orthostatic tachycardia syndrome and orthostatic hypotension in the community. Of note, the pathophysiology of postural orthostatic tachycardia syndrome and orthostatic hypotension requires further investigation.

A therapeutic guide on pediatric irritable bowel syndrome and functional abdominal pain-not otherwise specified.

Disorders of the gut-brain interaction negatively impact quality of life and carry a substantial socioeconomic burden. Irritable bowel syndrome (IBS) and functional abdominal pain-not otherwise specified (FAP-NOS) are common functional abdominal pain disorders in childhood. The pathophysiology is not fully understood, and high-quality intervention trials and international guidelines are missing. Therefore, the management of these disorders remains challenging. This review aims to provide an up-to-date overview of therapeutic possibilities for pediatric IBS or FAP-NOS and recommends management strategies. To prevent unnecessary referrals and extensive costs, it is fundamental to make a positive diagnosis of IBS or FAP-NOS in children with chronic abdominal pain with only minimal investigations. A tailor-made approach for each patient, based on the accompanying physical and psychological symptoms, is proposed to date. CONCLUSION: Shared decision-making including non-pharmacological and pharmacological interventions should be considered and discussed with the family. WHAT IS KNOWN: • Irritable bowel syndrome and functional abdominal pain-not otherwise specified are common in childhood. • Although the number of treatment options has grown recently, managing these disorders can be challenging and unsatisfactory, and no evidence-based international management guidelines are available. WHAT IS NEW: • We suggest using a stepwise individualized approach to management, where after first-line management, both non-pharmacological and pharmacological interventions should be discussed.

Hypnosis to Reduce Distress in Children Undergoing Anorectal Manometry: A Randomized Controlled Pilot Trial.

Background/Aims: To assess the effectiveness and feasibility of a brief session of hypnosis to reduce distress in children with functional constipation undergoing anorectal manometry (ARM). Methods: A partially-blinded randomized controlled pilot trial was conducted in children 4-18 years old scheduled for ARM. Children were randomized to receive a brief session of hypnosis prior to ARM or standard care. Non-blinded and blinded observers rated the child's level of distress using the Observation Scale of Behavioral Distress and a 4-point-Likert scale, respectively. Differences between groups were analyzed using Fisher's exact test or Mann-Whitney U test as appropriate. Results: Data from 32 children (15 hypnosis and 17 standard care) were analyzed. Prior to insertion of the catheter, the observed mean levels of distress were lower in the hypnosis group according to both the non-blinded observer (median 0.0 [interquartile range {IQR} 0.0-0.3] vs 1.4 [IQR 0.3-2.4]; P = 0.009) and the blinded observer (median 0.0 [IQR 0.0-0.0] vs 0.5 [IQR 0.0-1.0]; P = 0.044). During ARM, observed and reported levels of distress did not differ significantly. In the hypnosis group, 92.9% of parents and children reported that hypnosis helped the child to relax. There were no significant differences in resting pressure, squeeze pressure, or duration of the procedure between both groups. Conclusion: A brief session of hypnosis for children before ARM is an easily incorporable intervention that lowers distress levels prior to the procedure and is positively perceived by children and parents.

Probiotics for treatment of chronic constipation in children.

BACKGROUND: Functional constipation is defined as chronic constipation with no identifiable underlying cause. It is a significant cause of morbidity in children, accounting for up to 25% of visits to paediatric gastroenterologists. Probiotic preparations may sufficiently alter the gut microbiome and promote normal gut physiology in a way that helps relieve functional constipation. Several studies have sought to address this hypothesis, as well as the role of probiotics in other functional gut disorders. Therefore, it is important to have a focused review to assess the evidence to date. OBJECTIVES: To evaluate the efficacy and safety of probiotics for the management of chronic constipation without a physical explanation in children. SEARCH METHODS: On 28 June 2021, we searched CENTRAL, MEDLINE, Embase, CINAHL, AMED, WHO ICTR, and ClinicalTrials.gov, with no language, date, publication status, or document type limitations. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed probiotic preparations (including synbiotics) compared to placebo, no treatment or any other interventional preparation in people aged between 0 and 18 years old with a diagnosis of functional constipation according to consensus criteria (such as Rome IV). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 studies (1127 randomised participants): 12 studies assessed probiotics in the treatment of functional constipation, whilst two studies investigated synbiotic preparations. Three studies compared probiotics to placebo in relation to the frequency of defecation at study end, but we did not pool them as there was very significant unexplained heterogeneity. Four studies compared probiotics to placebo in relation to treatment success. There may be no difference in global improvement/treatment success (RR 1.29, 95% CI 0.73 to 2.26; 313 participants; low-certainty evidence). Five studies compared probiotics to placebo in relation to withdrawals due to adverse events, with the pooled effect suggesting there may be no difference (RR 0.64, 95% CI 0.21 to 1.95; 357 participants; low-certainty evidence). The pooled estimate from three studies that compared probiotics plus an osmotic laxative to osmotic laxative alone found there may be no difference in frequency of defecation (MD -0.01, 95% CI -0.57 to 0.56; 268 participants; low-certainty evidence). Two studies compared probiotics plus an osmotic laxative to osmotic laxative alone in relation to global improvement/treatment success, and found there may be no difference between the treatments (RR 0.95, 95% CI 0.79 to 1.15; 139 participants; low-certainty evidence). Three studies compared probiotics plus osmotic laxative to osmotic laxative alone in relation to withdrawals due to adverse events, but it is unclear if there is a difference between them (RR 2.86, 95% CI 0.12 to 68.35; 268 participants; very low-certainty evidence). Two studies compared probiotics versus magnesium oxide. It is unclear if there is a difference in frequency of defecation (MD 0.28, 95% CI -0.58 to 1.14; 36 participants), treatment success (RR 1.08, 95% CI 0.74 to 1.57; 36 participants) or withdrawals due to adverse events (RR 0.50, 95% CI 0.05 to 5.04; 77 participants). The certainty of the evidence is very low for these outcomes. One study assessed the role of a synbiotic preparation in comparison to placebo. There may be higher treatment success in favour of synbiotics compared to placebo (RR 2.32, 95% CI 1.54 to 3.47; 155 participants; low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. One study assessed a synbiotic plus paraffin compared to paraffin alone. It is uncertain if there is a difference in frequency of defecation (MD 0.74, 95% CI -0.96, 2.44; 66 participants; very low-certainty evidence), or treatment success (RR 0.91, 95% CI 0.71 to 1.17; 66 participants; very low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. One study compared a synbiotic preparation to paraffin. It is uncertain if there is a difference in frequency of defecation (MD -1.53, 95% CI -3.00, -0.06; 60 participants; very low-certainty evidence) or in treatment success (RR 0.86, 95% CI 0.65, 1.13; 60 participants; very low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. All secondary outcomes were either not reported or reported in a way that did not allow for analysis. AUTHORS' CONCLUSIONS: There is insufficient evidence to conclude whether probiotics are efficacious in successfully treating chronic constipation without a physical explanation in children or changing the frequency of defecation, or whether there is a difference in withdrawals due to adverse events when compared with placebo. There is limited evidence from one study to suggest a synbiotic preparation may be more likely than placebo to lead to treatment success, with no difference in withdrawals due to adverse events. There is insufficient evidence to draw efficacy or safety conclusions about the use of probiotics in combination with or in comparison to any of the other interventions reported. The majority of the studies that presented data on serious adverse events reported that no events occurred. Two studies did not report this outcome. Future studies are needed to confirm efficacy, but the research community requires guidance on the best context for probiotics in such studies, considering where they should be best considered in a potential treatment hierarchy and should align with core outcome sets to support future interpretation of findings.

Effect of Open-label Placebo on Children and Adolescents With Functional Abdominal Pain or Irritable Bowel Syndrome: A Randomized Clinical Trial.

IMPORTANCE: Although it is widely believed that concealment or deception is required to elicit a placebo response, recent studies with adults suggest that open-label placebo (OLP) (ie, honestly prescribed placebos) can yield significant benefits. No studies of OLP have been performed with children. OBJECTIVE: To evaluate the efficacy of OLP for the treatment of children and adolescents with functional abdominal pain or irritable bowel syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter crossover randomized clinical trial was conducted from July 1, 2015, to June 15, 2018, at 3 US centers among children and adolescents aged 8 to 18 years with functional abdominal pain or irritable bowel syndrome defined per Rome III criteria. Statistical analysis was performed from March 1, 2019, to September 30, 2020, on an intention-to-treat basis. INTERVENTIONS: Patients completed 1 week of observation prior to randomization to 1 of 2 counterbalanced groups: OLP for 3 weeks followed by a 3-week control period or control period for 3 weeks followed by OLP for 3 weeks. During the OLP period, participants took 1.5 mL of an inert liquid placebo twice a day. A standardized method for explaining the OLP was used, and the interaction with clinicians had the same duration and style for both time periods. Hyoscyamine was allowed as a rescue medication. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean daily pain score during each of the interventions, measured on a 0- to 100-mm visual analog scale, where higher scores indicated greater pain. The number of rescue medications taken during each intervention served as an objective secondary measure. RESULTS: Thirty patients (mean [SD] age, 14.1 [3.4] years; 24 female participants [80.0%]; 16 [53.3%] with functional abdominal pain and 14 [46.7%] with irritable bowel syndrome) completed the study. The mean (SD) pain scores were significantly lower during OLP treatment compared with the control period (39.9 [18.9] vs 45.0 [14.7]; difference, 5.2; 95% CI, 0.2-10.1; P = .03). Patients took nearly twice as many hyoscyamine pills during the control period compared with during the OLP period (mean [SD] number, 3.8 [5.1] pills vs 2.0 [3.0] pills; difference, 1.8 pills; 95% CI, 0.5-3.1 pills). CONCLUSIONS AND RELEVANCE: During OLP, patients with functional abdominal pain or irritable bowel syndrome reported significantly less pain and took significantly fewer pain medications. Open-label placebo may be an effective treatment for children and adolescents with functional abdominal pain or irritable bowel syndrome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02389998.