Anti-tuberculosis treatment (ATT) leads to adverse gastrointestinal disturbances (vomiting, nausea, postprandial distress) due to its prolonged duration in TB patients. This study assessed the prokinetic effects of ginger, caraway, and peppermint nutraceuticals in alleviating these symptoms in pulmonary TB patients on ATT. The selected nutraceuticals were procured, cleaned, dried, and crushed to perform proximate analysis, TPC, TFC, DPPH, ABTS, and FRAP. Further, a randomized clinical trial (Registered No. NCT06157034) involved 200 participants divided into four groups (placebo = 48, ginger = 47, caraway = 48, peppermint = 46), with 11 dropouts. Participants received varied dosages of selected nutraceuticals (Ginger: 1 g, Caraway: 2 g, and Peppermint: 3 mL daily), and data were collected at baseline, intervention (after 3 months), and washout (after 1 month) phases. Ginger and peppermint showed the highest moisture content (81.67%, 81.74%), while caraway had the highest protein (29.72%) and crude fiber (45.11%). Peppermint had the highest crude fat (54.47%) and crude fiber (4.81%). Moreover, ginger had the highest TPC (1035.51 mgGAE/g) and TFC (465.34 mgQE/g), with notable DPPH, FRAP, and ABTS values. Participants had a mean age (39.03 years), family income (17,385 ± 528.72Rs), and BMI (19.43 ± 5.67). Sputum testing and other biochemical analyses were also done. Energy and macronutrient consumption did not differ significantly across all phases (p > 0.05). The hierarchical heatmap graph depicted the intensity/severity of relieving gastrointestinal disturbances with the consumption of nutraceuticals. Thus, the results concluded that both ginger and peppermint groups, particularly during the washout phase, showed a promising reduction in GI disturbances, suggesting their potential as adjunctive therapy for TB patients on ATT.

There is a paucity of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of menthol, the active ingredient in peppermint oil (PMO). We studied the PK of menthol (540 and 900 mg) in children and measured their effects on gut transit/contractility.

Children 7-12 years of age with functional abdominal pain underwent wireless motility capsule (WMC) testing. One week later, they were randomized to 540 mg or 900 mg of oral enteric-coated PMO. Blood was sampled over 24 h to determine menthol PK. The WMC test was repeated while they took their respective dose (180 mg thrice or 180 mg five times daily) for a week.

Twenty-five children received 540 mg, and 15 received 900 mg (mean age 10.4 ± 1.1 years, 60% female). Peak plasma concentrations (Cmax) were observed at approximately 2.5 h post-dose. There was no evident dose effect for the apparent elimination rate constant, time of peak plasma concentration (Tmax), Cmax, total plasma clearance, nor the apparent volume of distribution. Mean area under the plasma concentration vs. time curve (AUC) for the 900 mg PMO dose cohort was approximately 1.5-fold higher compared with the 540 mg dose; the difference disappeared correcting for dose. Colonic and whole bowel transit time were significantly positively correlated with menthol AUC. The 900 mg (vs. 540 mg) dose decreased colonic (P = 0.002) and whole gut (P = 0.02) contraction frequency.

The PK of menthol derived from PMO demonstrates apparent dose-proportionality, and gut transit and contractility are associated with the systemic concentration of menthol.

Background/Objectives: Gastrointestinal disorders include a broad spectrum of clinical conditions due to various symptoms. Abdominal pain claims attention as it can be associated with multiple diseases, and some of them can lead to chronic abdominal pain, such as chronic gastritis and irritable bowel syndrome. Moreover, dyspepsia is also a prevalent condition, and its symptoms are postprandial fullness, epigastric pain or burn, and early satiety. Conventional therapeutic approaches for gastrointestinal disorders exist, but the Mentha plant has a millenary tradition. Mentha aerial parts and leaves hold therapeutic and pharmacological value, and its components are characterized as non-essential oil with superabundant phenolic compounds, and essential oil classified as volatile secondary metabolites like menthol and menthone. Studies have shown that Mentha species can exert benefits by modulating the inflammatory process and scavenging free radicals, which can benefit gastrointestinal tract disorders. The aim of this review was to systematically investigate the effects of Mentha species on gastrointestinal disorders. Methods: Sixteen clinical trials included patients diagnosed with irritable bowel syndrome, functional dyspepsia, and functional abdominal pain, as well as some healthy volunteers. The COCHRANE tool was utilized to assess the bias of the included studies. Results: Most studies reported significant outcomes for Mentha oil-treated groups, such as better control of abdominal pain and discomfort, even though two trials did not report superior outcomes. Conclusions: Due to the increasing interest in natural compounds, further clinical trials are necessary to confirm the status of Mentha for improvement in gastrointestinal disorders.

In many cultures, "food as medicine" has existed for centuries as the foundation of health. It is a practice built on the knowledge that food and diet play important roles in disease prevention and management. Foods possessing therapeutic properties are often referred to as functional foods. Many herbs and spices contain numerous nutritional and non-nutritional components that can interact with pharmacologically relevant receptors, either directly or indirectly via their metabolites, to regulate cellular biochemical processes. Although opinions are changing, the concept of food as a therapeutic intervention goes against conventional Western medicine. To provide guidance to clinicians interested in using these products, members of the Food as Medicine working group of the Nutrition Committee NASPGHAN, as part of a two-part review series, have identified frequently used foods, supplements, herbs, and spices that are utilized for therapeutic intent and have created summaries of commonly used indications, doses, and caveats. In this review, the focus is the use of select herbs and spices for medicinal purposes. Gaps in our knowledge in how to effectively use these agents in pediatric patients are discussed. Evidence supporting their use for management of gastrointestinal conditions, especially in the pediatric population, is provided when available. Circumstances in clinical settings and patient indications may require actions different from those recommended in this review and professional judgment should prevail.

While research on complementary and alternative medicine (CAM) for the general population is expanding, there remains a scarcity of studies investigating the efficacy and utilisation of CAM practices, specifically in the paediatric population. In accordance with the World Health Organization (WHO), the prevalence of the parental utilisation of CAM in their dependents is estimated to reach up to 80%. This literature review identified broad, heterogeneous, and inconclusive evidence regarding CAM's applications and effectiveness, primarily attributed to variance in sociodemographic factors and differences in national healthcare systems. Additionally, the review identified a lack of consensus and polarised positions among mainstream professionals regarding the mechanisms of action, applications, and effectiveness of CAM. This narrative review presents varied results concerning the efficacy of most CAM therapies and their applications; however, some evidence suggests potential benefits for acupuncture, yoga, tai chi, and massage in improving physical and mental health. Moreover, the available evidence indicates that meditation may enhance mental health, while reiki may only influence patients' perceptions of comfort. In light of the intricate and multifaceted nature of herbal medicine, it is imperative to assess its efficacy on a case-by-case basis, taking into account the specific compounds and procedures involved. This comprehensive review serves as a valuable resource for health professionals, offering guidance for personalised healthcare approaches that consider the values and beliefs of patients, thereby facilitating integrated, evidence-based practices aimed at enhancing the quality of healthcare services and patient satisfaction.

There is a limited number of studies focusing on ethnomedical practices in children, particularly in Eastern Europe. Romania has a rich history of using medicinal plants in ethnopediatric care, and our objective was to identify the medicinal plants currently employed in treating childhood illnesses in the southern region of the country. Material and methods Our investigation used structured interviews, focusing on respondent demographics, local names of therapeutically employed herbs, the specific plant part(s) utilized, methods of preparation and administration, and local folk indications of taxa. A total of 326 mothers with children aged 0 to 18, hospitalized in the "Grigore Alexandrescu" Children Emergency Hospital Bucharest and residing in Southern Romania, were enrolled in the study. Use Value Citation Index (UVc), Informant Consensus Factor (Fic), and Fidelity Level (FL) were calculated. Results Twenty-five plants were identified for treating children's diseases in Southern Romania. The majority of informants resided in urban areas, and mothers primarily acquired knowledge from family members and healthcare professionals. The herbs most frequently employed were Mentha spp. (UV = 0.509) for diarrhea, Matricaria spp. (UV = 0.301) for skin infections (Fic = 0.99) and digestive diseases (Fic = 0.98), and Calendula officinalis L. (UV = 0.365) for skin diseases (Fic = 0.99). Less utilized were Raphanus raphanistrum subsp. sativus (L.) Domin in respiratory diseases, Prunus avium (L.) L. stalks in urinary tract ailments, Helianthus annuus L. in ear infections, Allium sativum L. in intestinal parasitosis, Viola tricolor L. in hives, Triticum aestivum L. in dermatitis and Allium ursinum L. as a tonic. In 184 cases herbal treatment was used in conjunction with conventional medications. Education level correlated with the number of employed plants and the variety of treated ailments, while residency (rural vs. urban) did not. Both residency and education influenced plant procurement methods: rural background and, surprisingly, higher education were linked to a preference for harvesting rather than purchasing plants. Conclusion Botanical remedies are still commonly used in the treatment of pediatric diseases in Southern Romania, although the variety of taxa seems reduced compared to the past. Further exploration is essential to unlock the maximum benefits of ethnopediatric practices.

Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome.

A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement.

Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect.

The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect.

This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID), whose prevalence has widely increased in pediatric population during the past two decades. The exact pathophysiological mechanism underlying IBS is still uncertain, thus resulting in challenging diagnosis and management. Experts from 4 Italian Societies participated in a Delphi consensus, searching medical literature and voting process on 22 statements on both diagnosis and management of IBS in children. Recommendations and levels of evidence were evaluated according to the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was reached for all statements. These guidelines suggest a positive diagnostic strategy within a symptom-based approach, comprehensive of psychological comorbidities assessment, alarm signs and symptoms' exclusion, testing for celiac disease and, under specific circumstances, fecal calprotectin and C-reactive protein. Consensus also suggests to rule out constipation in case of therapeutic failure. Conversely, routine stool testing for enteric pathogens, testing for food allergy/intolerance or small intestinal bacterial overgrowth are not recommended. Colonoscopy is recommended only in patients with alarm features. Regarding treatment, the consensus strongly suggests a dietary approach, psychologically directed therapies and, in specific conditions, gut-brain neuromodulators, under specialist supervision. Conditional recommendation was provided for both probiotics and specific fibers supplementation. Polyethylene glycol achieved consensus recommendation for specific subtypes of IBS. Secretagogues and 5-HT4 agonists are not recommended in children with IBS-C. Certain complementary alternative therapies, antispasmodics and, in specific IBS subtypes, loperamide and rifaximin could be considered.

In recent years there has been growing interest in the use of nutraceuticals and biotics in both pediatric and adult clinical practice. The overlapping and often ambiguous symptoms of both functional and organic gastrointestinal disorders have led to a search for alternative therapeutic approaches that avoid the use of synthetic or chemical treatments. However, while nutraceuticals and natural supplements are widely used, their health benefits are often not supported by adequate scientific evidence, and an unregulated use of nutraceuticals can be potentially harmful. The correct use of nutraceuticals, prebiotics, and probiotics can optimize the results of drug therapy in some cases and reduce the risk of side effects. This review aims to provide clinicians with guidance on the use of complementary therapies for pediatric gastrointestinal symptoms and disorders, highlighting the scarcity of studies on the kinetics and dynamics of nutraceuticals and biotics. While it is generally difficult to associate their intakes with adverse events due to the often-coexisting pharmacological treatments, it is essential to avoid the abandonment of traditional drugs with proven efficacy in the treatment of single diseases. Overall, the use of nutraceuticals, prebiotics, and probiotics in pediatric gastroenterological practice requires caution and medical supervision. Further research is needed to determine the effects of alternative therapies on pediatric gastrointestinal symptoms and disorders, and to ensure their safe and effective use in the clinical practice.

Different nutraceuticals are often considered by parents of infants and children with abdominal pain and disorders of the gut-brain interaction. Herb extracts and natural compounds have long been used in traditional medicine, but clinical pediatric trials are very limited. This narrative review based on relevant studies identified through a search of the literature in Pubmed and Medline updated to October 2023 focused on the effect of nutraceuticals in infantile colic, functional abdominal pain, and irritable bowel syndrome in children and adolescents. Significant reductions in colic episodes and crying time were reported in two studies on fennel (seeds oil or tea), in three studies on different multiple herbal extracts (all including fennel), in one study on Mentha piperita, and in at least two double-blind randomized controlled studies on Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12 (108 CFU/day for at least 21 days) in breast-fed infants. Compared to a placebo, in children with functional abdominal pain or irritable bowel syndrome, a significant reduction in pain was reported in two studies supplementing peppermint oil capsules or psyllium fibers, and in one study on corn fiber cookies, partial hydrolyzed guar gum, a specific multiple herbal extract (STW-5), or vitamin D supplementation. To date, there is moderate-certainty evidence with a weak grade of recommendation on Lactobacillus reuteri DSM 17938 (108 CFU/day) in reducing pain intensity in children with functional abdominal pain and for Lactobacillus rhamnosus GG (1-3 × 109 CFU twice daily) in reducing pain frequency and intensity in children with IBS. Further large and well-designed pediatric studies are needed to prove the efficacy and safety of different herbal extracts and prolonged use of studied products in infants and children with pain disorders of the gut-brain interaction.

Irritable bowel syndrome (IBS) is a prolonged bowel illness that is generally stress-related and is characterized by a variety of gastrointestinal problems, the most prominent of which is chronic visceral abdominal discomfort. As a result, IBS typically impacts sufferers' standard of living, and it is typically associated with depression and anxiety symptoms. IBS medication is based mostly on symptom alleviation. However, no effective medicines have been discovered too far. As a result, it is essential to discover novel anti-IBS medications.

The purpose of this brief review is to describe the existing research on nutraceutical supplements in irritable bowel syndrome management, including probiotics, prebiotics, symbiotics, herbal products, and dietary fibers.

This review covered the relevant papers from the previous twenty years that were available in different journals such as Science Direct, Elsevier, NCBI, and Web of Science that were related to the role and function of nutraceuticals in Irritable Bowel Syndrome.

Nutraceutical substances have a variety of modes of action, including restoring the healthy microbiome, improving the function of the gastrointestinal barrier, immunomodulatory, antiinflammatory, and antinociceptive properties. According to the literature, these substances not only can improve irritable bowel syndrome symptomatology but also have an excellent long-term safety profile.

Irritable bowel syndrome is a prolonged bowel illness with a lot of gastrointestinal problems. The nutraceuticals treatment works as an anti-IBS intervention and enhances patient compliance with minimum side effects since patients take it better than pharmaceutical treatments.

The pathophysiology of irritable bowel syndrome in children involves multiple factors. Thus, treatment options are variable, targeting both diet and the child's and parents' behavior via pharmacological and psychological interventions or neuromodulation. Parents are increasingly interested in complementary and alternative therapies for children with irritable bowel syndrome, especially when other treatments have been tried without relieving the child's symptoms. This paper examines current evidence for the benefits and side effects of herbal remedies and spices in pediatric patients with IBS. The benefits of peppermint oil, STW5, psyllium fiber, Curcuma, ginger, and other herbal medicines are discussed based on findings in the current literature.

Menthol exerts relaxing, antibacterial, and anti-inflammatory activities, and is marketed as a functional food and therapeutic drug.

In the present study, the effects of menthol on the expression of multidrug resistance associated protein 2 (MRP2) and its association with the cytotoxicity of epirubicin (EPI) and cisplatin (CIS) were examined using HepG2 cells.

The expression levels of target genes were examined by real-time PCR. The intracellular concentration of incorporated EPI was measured by high-performance liquid chromatography. Cell viability was evaluated by MTT analysis.

The expression of MRP2 mRNA was increased by exposing HepG2 cells to menthol for 24 hr. Consistent with a previous report suggesting an inverse correlation between MRP2 and Akt behavior, increased expression of MRP2 was also observed on suppression of the Akt function. Intracellular accumulation of EPI was significantly decreased by exposure of HepG2 cells to menthol, and a significant decrease in the intracellular concentration of EPI remaining was observed in HepG2 cells exposed to menthol. The decreased intracellular accumulation of EPI was significantly suppressed by treatment with MK-571, but not verapamil. Both EPI and CIS exerted cytocidal effects on HepG2 cells, but the decrease in cell viability was significantly attenuated by 24-hr menthol pre-exposure.

These results demonstrate that menthol causes hepatocellular carcinoma to acquire resistance to anticancer drugs such as EPI and CIS by MRP2 induction.

Functional abdominal pain disorders (FAPDs) affect up to 25% of children in the United States. These disorders are more recently known as disorders of "brain-gut" interaction. The diagnosis is based on the ROME IV criteria, and requires the absence of an organic condition to explain the symptoms. Although these disorders are not completely understood, several factors have been involved in the pathophysiology including disordered gut motility, visceral hypersensitivity, allergies, anxiety/stress, gastrointestinal infection/inflammation, as well dysbiosis of the gut microbiome. The pharmacologic and non-pharmacologic treatments for FAPDs are directed to modifying these pathophysiologic mechanisms. This review aims to summarize the non-pharmacologic interventions used in the treatment of FAPDs including dietary modifications, manipulation of the gut microbiome (neutraceuticals, prebiotics, probiotics, synbiotics and fecal microbiota transplant) and psychological interventions that addresses the "brain" component of the brain-gut axis (cognitive behavioral therapy, hypnotherapy, breathing and relaxation techniques). In a survey conducted at a large academic pediatric gastroenterology center, 96% of patients with functional pain disorders reported using at least 1 complementary and alternative medicine treatment to ameliorate symptoms. The paucity of data supporting most of the therapies discussed in this review underscores the need for large randomized controlled trials to assess their efficacy and superiority compared to other treatments.

Infants, children, and adolescents are at risk of experiencing a multitude of gastrointestinal disorders (GID). These disorders can adversely affect the quality of life or be life-threatening. Various interventions that span the conventional and complementary therapeutic categories have been developed. Nowadays, parents increasingly seek complementary options for their children to use concurrently with conventional therapies. Due to the high prevalence and morbidity of diarrhea, constipation, and irritable bowel syndrome (IBS) in children, in this review, we decided to focus on the current state of the evidence for conventional and complementary therapies used for the treatment of these diseases in children. Diarrhea treatment focuses on the identification of the cause and fluid management. Oral rehydration with supplementation of deficient micronutrients, especially zinc, is well established and recommended. Some probiotic strains have shown promise in reducing the duration of diarrhea. For the management of constipation, available clinical trials are insufficient for conclusive recommendations of dietary modifications, including increased use of fruit juice, fiber, and fluid. However, the role of laxatives as conventional treatment is becoming more established. Polyethylene glycol is the most studied, with lactulose, milk of magnesia, mineral oil, bisacodyl, and senna presenting as viable alternatives. Conventional treatments of the abdominal pain associated with IBS are poorly studied in children. Available studies investigating the effectiveness of antidepressants on abdominal pain in children with IBS were inconclusive. At the same time, probiotics and peppermint oil have a fair record of benefits and safety. The overall body of evidence indicates that a careful balance of conventional and complementary treatment strategies may be required to manage gastrointestinal conditions in children.

Chronic abdominal pain is one of the most common problems seen by both pediatricians and pediatric gastroenterologists. Abdominal-pain-related functional gastrointestinal disorders (AP-FGIDs) are diagnosed in children with chronic and recurrent abdominal pain meeting clinical criteria set forth in the Rome IV criteria. AP-FGIDs affect approximately 20% of children worldwide and include functional dyspepsia (FD), irritable bowel syndrome (IBS), functional abdominal pain (FAP), and abdominal migraine. IBS accounts for 45% of pediatric AP-FGIDs. The pathophysiology of functional abdominal pain involves an interplay of factors including early life events, genetics, psychosocial influences, and physiologic factors of visceral sensitivity, motility disturbance, altered mucosal immune function, and altered central nervous system processing. Treatment approaches are varied and can include dietary, pharmacologic, and complementary medicine interventions, as well as psychosocial support, depending on the many aspects of the disorder and the needs of the individual patient. There is a strong interest in complementary and integrative medicine approaches to pediatric pain from both patients, providers, and families. In this article, we discuss popular herbal treatments typically used in the field of complementary medicine to treat pediatric AP-FGIDs: peppermint oil, Iberogast®, cannabis, fennel, and licorice. While high-quality data are rather limited, studies generally show that these remedies are at least as effective as placebo, and are well tolerated with minimal side effects. We will need more placebo-controlled, double-blind, and unbiased prospective studies to document and quantify efficacy.

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.

Shared decision-making including non-pharmacological and pharmacological interventions should be considered and discussed with the family.

• 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.

• We suggest using a stepwise individualized approach to management, where after first-line management, both non-pharmacological and pharmacological interventions should be discussed.

Functional abdominal pain disorders (FAPDs) are common among children and are associated with decreased quality of life and school attendance. Several dietary interventions have been suggested to improve symptoms of FAPDs. This systematic review assessed the efficacy and safety of dietary interventions for pediatric FAPDs.

Electronic databases were searched (inception-October 2021). Systematic reviews or RCTs were included if children (4-18 years) with FAPDs were treated with dietary interventions and compared to placebo, no diet or any other diet. Data extraction and assessment of quality of evidence based on GRADE system was independently performed by two review authors. Outcomes were treatment success, pain intensity and frequency, and withdrawal due to adverse events.

Twelve articles were included, representing data of 819 pediatric FAPD patients. Trials investigating fibers, FODMAP diet, fructans, fructose-restricted diet, prebiotic (inulin), serum-derived bovine immunoglobulin, and vitamin D supplementation were included. We found very low-certainty evidence that the use of fibers leads to higher treatment success (NNT = 5).

Based on current evidence, the use of fibers can be discussed in daily practice. High-quality intervention trials are highly needed to investigate if other dietary interventions are effective in the treatment of pediatric FAPD.

Functional abdominal pain disorders (FAPDs) are an important and prevalent cause of functional gastrointestinal disorders among children, encompassing the diagnoses of functional dyspepsia, irritable bowel syndrome, abdominal migraine, and the one not previously present in Rome III, functional abdominal pain not otherwise specified. In the absence of sufficiently effective and safe pharmacological treatments for this public problem, non-pharmacological therapies emerge as a viable means of treating these patients, avoiding not only possible side effects, but also unnecessary prescription, since many of the pharmacological treatments prescribed do not have good efficacy when compared to placebo. Thus, the present study provides a review of current and relevant evidence on non-pharmacological management of FAPDs, covering the most commonly indicated treatments, from cognitive behavioral therapy to meditation, acupuncture, yoga, massage, spinal manipulation, moxibustion, and physical activities. In addition, this article also analyzes the quality of publications in the area, assessing whether it is possible to state if non-pharmacological therapies are viable, safe, and sufficiently well-based for an appropriate and effective prescription of these treatments. Finally, it is possible to observe an increase not only in the number of publications on the non-pharmacological treatments for FAPDs in recent years, but also an increase in the quality of these publications. Finally, the sample selection of satisfactory age groups in these studies enables the formulation of specific guidelines for this age group, thus avoiding the need for adaptation of prescriptions initially made for adults, but for children use.

Little is known regarding the pharmacokinetics and pharmacodynamics of menthol, the active ingredient in peppermint oil (PMO). Our aim was to investigate the pharmacokinetics of menthol at 3 dose levels in children and determine their effects on gut motility and transit.

Thirty children ages 7-12 years with functional abdominal pain underwent wireless motility capsule (WMC) testing. Approximately 1 week later they were randomized to 180, 360 or 540 mg of enteric coated PMO (10 participants per dose). Menthol pharmacokinetics were determined via blood sampling over 24 hours. They then took their respective dose of PMO (180 mg once, 180 mg twice or 180 mg thrice daily) for 1 week during which time the WMC test was repeated.

Evaluable area under the plasma concentration vs. time curve (AUC_last ) data were available in 29 of 30 participants. A direct linear relationship (apparent dose-proportionality for systemic menthol exposure) was observed between PMO dose and menthol systemic exposure with mean elimination half-life 2.1, 3.5 and 4.6 hours for the 180, 360 and 540 mg doses, respectively. WMC technical issues precluded complete motility data in all participants. Colonic transit time was inversely related to AUC_last (P = .003); transit time in other regions was not affected. In contrast, stomach, small bowel and whole gut (but not colonic) contractility positively correlated with menthol AUC_last (P < .05).

Pharmacokinetics and pharmacodynamics of menthol derived from PMO demonstrated apparent dose-proportionality. A higher dose of PMO may be needed to achieve maximal gut response. www.clinicaltrials.gov NCT03295747.

This paper discusses the risk factors and management of paediatric irritable bowel syndrome (IBS), with a focus on the role of the gastrointestinal microbiome.

English articles of interest published in PubMed and Google Scholar were searched using subject heading and keywords of interest.

Only few randomised controlled trials on the management of IBS in children have been published. The vast majority of these intervention trials target to change the composition of the gastrointestinal microbiome. Most studies are underpowered. Major heterogeneities in study designs such as differences in inclusion criteria, including patients with different pain-related functional gastrointestinal disorders and differences in primary outcomes, make it impossible to formulate recommendations. Overall, few adverse events are reported what could indicate safety or point to suboptimal conduction of clinical trials and safety reporting. However, it can also not be excluded that some interventions such as the administration of selected probiotic products may result in benefit.

There is insufficient evidence to recommend any therapeutic intervention in paediatric IBS, including manipulation of the gastrointestinal tract microbiome, despite the evidence that dysbiosis seems an associated pathophysiologic factor. More designed prospective trials are needed since IBS is not a rare condition during childhood.

Symptomatic celiac artery compression syndrome (CACS) or median arcuate ligament syndrome (MALS) is a controversial diagnosis that should be considered in patients with chronic abdominal pain of unknown etiology despite an extensive medical evaluation. Once suspected, patients should undergo mesenteric duplex ultrasound. Diagnosis is confirmed with elevated celiac artery velocities which normalize with deep inspiration followed by CT angiogram showing the typical "J-hook" conformation of the celiac artery. Patients should then undergo evaluation by a multi-disciplinary team to appropriately select and prepare patients for potential surgical treatment. Surgical options include release of the median arcuate ligament, with or without neurolysis of the celiac nerve plexus, and with or without concomitant revascularization procedures. Approaches can be open, laparoscopic, or robotic. Surgical treatment has an overall success rate of 70-80% with patients reporting improved abdominal pain and quality of life. Post-operatively, patients can have persistent or recurrent abdominal pain and should undergo re-evaluation for possible need for a revascularization procedure for stenosis of the celiac artery or celiac plexus block if the celiac artery flow is normalized. Additionally, some patients will have persistent pain consistent with functional gastrointestinal disorder (FGID) that will then require medical management. Psychiatric comorbidities have been identified as a predisposing factor that may predict poorer outcomes, and there are preliminary findings suggesting that patients with dysautonomia diagnoses may have worse outcomes as well.

Irritable bowel syndrome is a common functional gastrointestinal disorder in children, characterized by recurrent abdominal pain associated with altered bowel habits in terms of both frequency and consistency. According to change in stool consistency it is categorized into 4 subtypes. From the etiological perspective, it is a combination of factors takes part in symptoms' generation, the overall treatment response rate is often unsatisfactory if a multidisciplinary is not pursued.

The aim of this manuscript is to summarize the current pharmacotherapy in pediatric irritable bowel syndrome in order to aid clinicians in treating this challenging disorder.

Most evidence involving pediatric populations rely on open label or retrospective studies and/or are not specifically designed for irritable bowel syndrome but tend to generalize their results to mixed populations of children with functional gastrointestinal disorders. A high placebo response rate combined with poor patients' selection could account for the overall weak evidence supporting the use of pharmacological agents in pediatric irritable bowel syndrome. Given the multifaceted nature of the disorder, multidisciplinary approaches combining pharmacotherapy with alternative treatments is highly recommendable.

Functional abdominal pain disorders (FAPDs) are common in childhood, impacting quality of life and school attendance. There are several compounds available for the treatment of pediatric FAPDs, but their efficacy and safety are unclear because of a lack of head-to-head randomized controlled trials (RCTs).

To systematically review the efficacy and safety of the pharmacologic treatments available for pediatric FAPDs.

Electronic databases were searched from inception to February 2021.

RCTs or systematic reviews were included if the researchers investigated a study population of children (4-18 years) in whom FAPDs were treated with pharmacologic interventions and compared with placebo, no treatment, or any other agent.

Two reviewers independently performed data extraction and assessed their quality. Any interresearcher disagreements in the assessments were resolved by a third investigator.

Seventeen articles representing 1197 children with an FAPD were included. Trials investigating antispasmodics, antidepressants, antibiotics, antihistaminic, antiemetic, histamine-2-receptor antagonist, 5-HT4-receptor agonist, melatonin, and buspirone were included. No studies were found on treatment with laxatives, antidiarrheals, analgesics, antimigraines, and serotonergics.

The overall quality of evidence on the basis of the Grading of Recommendations, Assessment, Development and Evaluations system was very low to low.

On the basis of current evidence, it is not possible to recommend any specific pharmacologic agent for the treatment of pediatric FAPDs. However, agents such as antispasmodics or antidepressants can be discussed in daily practice because of their favorable treatment outcomes and the lack of important side effects. High-quality RCTs are necessary to provide adequate pharmacologic treatment. For future intervention trials, we recommend using homogenous outcome measures and instruments, a large sample size, and long-term follow-up.

Irritable bowel syndrome (IBS) is one of the most common functional gastro-intestinal disorders which significantly impacts the quality of life of affected children. Abdominal pain improved by defecation, associated with a change in stool form and frequency, represents its specific clinical marker. Even if a number of potential patho-physiological mechanisms have been described, the exact underlying etiology of IBS is so far unclear. Likewise, no optimal treatment has ever been found neither for adult nor for pediatric patients. Current therapeutic options include drugs, dietary interventions and biopsychosocial therapies. The present review aims at evaluating the scientific evidence supporting the efficacy of these treatments for children with IBS.

To describe the use of complementary and alternative medicine (CAM) in pediatric functional abdominal pain disorders at a large Midwestern pediatric gastroenterology center.

A survey of patients attending a follow-up visit for functional abdominal pain disorders was completed. Data were collected on demographics, quality of life, use of conventional therapies, patient's opinions, and perception of provider's knowledge of CAM.

Of 100 respondents (mean age, 13.3 ± 3.5 years), 47 (60% female) had irritable bowel syndrome, 29 (83% female) had functional dyspepsia, 18 (67% female) had functional abdominal pain, and 6 (83% female) had abdominal migraine (Rome III criteria). Ninety-six percent reported using at least 1 CAM modality. Dietary changes were undertaken by 69%. Multivitamins and probiotics were the most common supplements used by 48% and 33% of respondents, respectively. One-quarter had seen a psychologist. Children with self-reported severe disease were more likely to use exercise (P < .05); those with active symptoms (P < .01) or in a high-income group (P < .05) were more likely to make dietary changes; and those without private insurance (P < .05), or who felt poorly informed regarding CAM (P < .05), were more likely to use vitamins and supplements. Seventy-seven percent of patients described their quality of life as very good or excellent.

The use of CAM in children with functional abdominal pain disorders is common, with a majority reporting a high quality of life. Our study underscores the importance of asking about CAM use and patient/family knowledge of these treatments.

Paediatric functional abdominal pain disorders, currently referred to as disorders of gut-brain interaction, comprise irritable bowel syndrome, functional dyspepsia, abdominal migraine and functional abdominal pain not otherwise specified, as defined by the Rome IV diagnostic criteria. Functional abdominal pain disorders are common disorders with a prevalence of 3-16% depending on country, age and sex. A greater understanding of aetiopathogenesis and pathophysiology is emerging and includes intestinal components (inflammation, motility and the microbiota), central factors (psychological aspects, sensitization and/or differences in connectivity or activity of certain brain regions) as well as extrinsic factors (infections). In particular, the timing of disruption of the microbiota-gut-brain axis seems to be important. Diagnosis is challenging but is primarily based on clinical symptoms and exclusion of other organic causes, with an emphasis on avoiding unnecessary invasive diagnostic procedures. The available pharmacological interventions are limited in children and, therefore, management has focused on combined approaches, including mind-targeted interventions (hypnotherapy and cognitive behavioural therapy), diet (probiotics) and percutaneous electrical nerve field stimulation. The evidence for their clinical efficacy, although limited, is favourable, with positive impacts on symptoms and overall quality of life. The coming decades hold promise for improved understanding and management of these enigmatic disorders.

Abdominal pain-predominant functional gastrointestinal disorders encompass a group of chronic conditions featuring abdominal pain where no serious gastrointestinal or intra-abdominal pathology is present. The Rome IV classification system defines and categorises this group based on symptomatology as: functional dyspepsia, irritable bowel syndrome, functional abdominal pain - not otherwise specified and abdominal migraine. These conditions can impact the functioning of the child and family significantly and are challenging to manage. Although the causes of these conditions are not clear, recent years have seen an improved understanding of underlying pathophysiology and identification of effective management options for these conditions.

Abdominal pain in childhood is extremely common and presents frequently to both primary and secondary care, with many children having recurrent pain which impacts on daily functioning. Despite this most children have no discernible underlying pathology. We discuss the underlying mechanism for functional abdominal pain (visceral hypersensitivity), the evidence base linking parental anxiety and patient symptoms, and how parents can be supported in managing their children's symptoms by addressing questions commonly asked by children and families. We look at the evidence for a one-stop rational approach to investigation including a coeliac screen, inflammatory markers and consideration of stool faecal calprotectin, in the absence of red flags. We evaluate commonly used treatments for functional abdominal pain, within a context of managing family expectations. Given the limitations in pharmacological treatment options, trials of probiotics, peppermint oil, mebeverine and (for short-term use only) hyoscine butylbromide may be appropriate. Psychological interventions including cognitive-behavioural therapy, distraction techniques and hypnotherapy have a better evidence base. There is also some evidence for other complementary therapies in children, including yoga and neurostimulation. Outcome is generally good providing there is child and family acceptance of the multiple factors implicated in the aetiology of the pain.

Nearly 20,000 pediatric patients undergo cholecystectomy annually, and abnormal gallbladder emptying ("biliary dyskinesia") has replaced cholelithiasis as the leading indication for this operation in the USA. Nonetheless, patients with abnormal gallbladder emptying nuclear medicine scans do not uniformly benefit from cholecystectomy. This article reviews the available data on presentation, workup and treatment of patients with abnormally low and high rates of gallbladder emptying.

The pathophysiology of functional gastrointestinal disorders (FGIDs) is still unclear and various complex mechanisms have been suggested to be involved. In many cases, improvement of symptoms and quality of life (QoL) in patients with FGIDs is difficult to achieve with the single-targeted treatments alone and clinical application of these treatments can be challenging owing to the side effects. Herbal preparations as complementary and alternative medicine can control multiple treatment targets of FGIDs simultaneously and relatively safely. To date, many herbal ingredients and combination preparations have been proposed across different countries and together with a variety of traditional medicine. Among the herbal therapies that are comparatively considered to have an evidence base are iberogast (STW-5) and peppermint oil, which have been mainly studied and used in Europe, and rikkunshito and motilitone (DA-9701), which are extracted from natural substances in traditional medicine, are the focus of this review. These herbal medications have multi-target pharmacology similar to the etiology of FGIDs, such as altered intestinal sensory and motor function, inflammation, neurohormonal abnormality, and have displayed comparable efficacy and safety in controlled trials. To achieve the treatment goal of refractory FGIDs, extensive and high quality studies on the pharmacological mechanisms and clinical effects of these herbal medications as well as efforts to develop new promising herbal compounds are required.

This Review summarises recent pharmacological and upcoming alternative interventions for children with functional abdominal pain disorders (FAPDs). Pharmacological targets include prokinetics and drugs affecting gastric accommodation to treat postprandial distress and nausea. Similarly, anti-inflammatory agents, junctional protein regulators, analgesics, secretagogues, and serotonin antagonists have a therapeutic role for irritable bowel syndrome. Non-pharmacological treatments include peripheral electrical nerve field stimulation to the external ear, gastric electrical stimulation, dietary interventions such as low fructose and fibre based diets, and nutraceuticals, which include probiotics, prebiotics, and synbiotics. Newer psychological advances such as exposure-based cognitive behavioural therapy, acceptance and commitment therapy, and mindfulness meditation are being investigated for paediatric functional pain. Lastly, alternative therapies such as acupuncture, moxibustion, yoga, and spinal manipulation are also gaining popularity in the treatment of FAPDs.

Irritable bowel syndrome (IBS) is a well diagnosed disease, thoroughly attributed to series of symptoms criteria that embrace a broad range of abdominal complainers. Such criteria help to diagnosis the disease and can guide controlled clinical trials to seek new therapeutic agents. Accordingly, a verity of mechanisms and pathophysiological conditions including inflammation, oxidative stress, lipid peroxidation and different life styles are involved in IBS. Predictably, diverse therapeutic approaches are available and prescribed by clinicians due to major manifestations (i.e., diarrhea-predominance, constipation-predominance, abdominal pain and visceral hypersensitivity), psychological disturbances, and patient preferences between herbal treatments versus pharmacological therapies, dietary or microbiological approaches. Herein, we gathered the latest scientific data between 1973 and 2019 from databases such as PubMed, Google Scholar, Scopus and Cochrane library on relevant studies concerning beneficial effects of herbal treatments for IBS, in particular polyphenols. This is concluded that polyphenols might be applicable for preventing IBS and improving the IBS symptoms, mainly through suppressing the inflammatory signaling pathways, which nowadays are known as novel platform for the IBS management. Graphical abstract.

To evaluate the efficacy of Western herbal medicines in the treatment of irritable bowel syndrome (IBS).

A computer-based search of MEDLINE, EMBASE, CINAHL, AMED, GreenFILE, Health Source: Nursing/Academic Edition, and the Cochrane Library was conducted. A hand-search of the bibliographies of relevant papers and previous meta-analyses and reviews was also undertaken. Trials were included in the review if they were double-blind and placebo-controlled investigating the effects of Western herbal medicines on IBS-related symptoms or quality of life. There were no language restrictions. Eligibility assessment and data extraction were performed by two independent researchers. For herbal medicines where there was more than 1 trial of similar design, data were synthesised using relative risk of symptoms improving using the random effects model.

Thirty-three trials were identified that met all eligibility criteria. Seventeen of these evaluated peppermint essential oil, fifteen other Western herbal medicines, and one trial evaluated peppermint oil in one arm and aniseed essential oil in the other arm. Eighteen different herbal preparations were evaluated in these trials. Data suggests that a number of Western herbal medicines may provide relief of IBS symptoms. Meta-analyses suggest that peppermint essential oil is both efficacious and well-tolerated in the short-term management of IBS. Aloe vera and asafoetida also demonstrated efficacy in reducing global IBS symptoms in meta-analyses. The herbal formulas STW 5, STW 5-II and Carmint, along with Ferula assa-foetida, Pimpenella anisum oil, the combination of Curcumin and Foeniculum vulgare oil, and the blend of Schinopsis lorentzii, Aesculus hippocastanum, and peppermint essential oil also demonstrated efficacy in rigorously-designed clinical trials.

A number of Western herbal medicines show promise in the treatment of IBS. With the exception of peppermint essential oil, Aloe vera, and asafoetida, however, none of the positive trials have been replicated. This lack of replication limits the capacity to make definitive statements of efficacy for these herbal medicines.

To investigate paediatricians' understanding of, and approaches to, the diagnosis and treatment of functional abdominal pain (FAP) and irritable bowel syndrome (IBS) in children.

This study used an electronic survey of doctors subscribing to a popular Australian-based paediatrics email forum. Responses about investigation and management in two clinical vignettes were correlated with respondent demographic data, practice setting, attitudes and knowledge.

The 327 respondents were mostly female (60.3%), aged <45 years (54.5%), general paediatricians (53.5%), working in public outpatient clinics (50.5%). Awareness of Rome III diagnostic criteria was low (37.2%) but associated with confidence in diagnosing FAP/IBS in the vignettes. Respondents who lacked confidence in diagnosing FAP/IBS requested more investigations (P < 0.05), although most acknowledged they would not be helpful. Most (70.5%) believed that families are unlikely to accept an FAP diagnosis without investigations requested. Fewer than 1 of 3 were aware of clear evidence for the effective therapy of FAP or IBS, although awareness did not influence management options selected. Two-thirds of respondents believe that FAP is a psychological rather than a medical problem, while few (8.8%) believe the same about IBS (P < 0.001). Parental pressure to find an immediate cure was cited as the most frequent challenge to successful management in both FAP (86.6%) and IBS (75.9%).

Awareness of the Rome criteria was associated with greater confidence in diagnosing FAP and IBS. Attitudes to FAP and IBS being diagnoses of exclusion are prevalent among paediatricians and associated with more investigations requested. There is a lack of awareness of evidence-based therapies for FAP and IBS.

To systematically review definitions of functional abdominal pain orders (FAPDs) and outcome measures used in therapeutic randomized controlled trials in pediatric FAPDs adhering to the Outcome Measures in Rheumatology recommendations.

Cochrane, MEDLINE, Embase, and Cinahl databases were systematically searched from inception to April 2018. English-written therapeutic randomized controlled trials concerning FAPDs in children aged 4-18 years were included. Definitions of FAPDs, interventions, outcome measures, measurement instruments, and outcome assessors of each study were tabulated descriptively. Quality was assessed using the Delphi List.

A total of 4771 articles were found, of which 64 articles were included (n = 25, 39% of high methodologic quality). The Rome III (50%), Rome II (17%), Apley (16%), and author-defined (17%) criteria were used to define FAPDs. Fourteen studies (22%) assessed a pharmacologic, 25 (39%) a dietary, and 25 (39%) a psychosocial intervention. Forty-four studies (69%) predefined their primary outcomes. In total, 211 reported predefined outcome measures were grouped into 23 different outcome domains; the majority being patient-reported (n = 27, 61%). Of the 14 studies that evaluated a pharmacologic intervention, 12 (86%) reported on adverse events.

Studies on pediatric FAPDs are of limited methodologic quality and show large heterogeneity and inconsistency in defining FAPDs and outcome measures used. Development of a core outcome set is needed to make comparison between intervention studies possible.

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.