PRIMER Paediatric functional abdominal pain disorders Nikhil Thapar1,2,14 ✉ , Marc A. Benninga3, Michael D. Crowell4, Carlo Di Lorenzo5, Isabelle Mack6, Samuel Nurko7, Miguel Saps8, Robert J. Shulman9, Hania Szajewska10, Miranda A. L. van Tilburg11,12,13 and Paul Enck6 ✉ Abstract | 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. Hyperalgesia Dedication: We dedicate this manuscript to the (IBS), functional dyspepsia, abdominal migraine and An abnormally heightened memory of Paul E. Hyman, MD, who passed away functional abdominal pain not otherwise specified sensitivity to pain. on 7 August 2020. Paul was a true pioneer and (FAP-NOS)4. FAPDs are frequently characterized by the master of the field of functional gastrointestinal presence of visceral hyperalgesia as well as increased cen- disorders and dedicated much of his career to caring tral perception of visceral stimuli leading to disability, for children suffering from such conditions. A great which seems to occur as the final outcome of sensitizing family man, friend, colleague, mentor and inspiration psychosocial factors and medical factors superimposed to so many. on a background of genetic predisposition and early-life events (Fig. 1). Early life is likely to include all childhood Functional abdominal pain disorders (FAPDs) are some and adolescent stages where growth as well as the struc- of the most commonly encountered disorders in child- tural and functional development of organs occurs, hood, affecting up to 25% of all children and infants although the vulnerability of the gut–brain–microbiota worldwide1. Given their biopsychosocial aetiology axis seems to be highest during the perinatal period involving complex interactions within the gut–brain and first years of life. FAPDs are grouped according to axis, FAPDs are currently referred to as ‘disorders of gut– symptom profile, which differs based on the section brain interaction’2. Furthermore, the gut–brain axis is of gastrointestinal tract that is primarily involved (for now accurately referred to as the ‘microbiota–gut–brain example, functional dyspepsia versus IBS) or depending axis’, reflecting an explosion in our understanding of on similarities with other conditions such as headache the magnitude, complexity, role and interactions of the migraine (BOx 1). microbial populations hosted within the lumen of IBS describes a symptom profile reflecting distal gas- ✉ e- mail: nikhil.thapar@ 3,4 health.qld.gov.au; the gastrointestinal tract . trointestinal tract involvement; abdominal pain in IBS paul.enck@uni- tuebingen.de Akin to adults, paediatric FAPDs are subclassified can be associated with defaecation or a change in the https://doi.org/10.1038/ utilizing the Rome IV criteria into a number of clini- frequency or form of the stool but does not resolve with s41572-020-00222-5 cally distinct entities, namely irritable bowel syndrome resolution of any associated constipation. Paediatric IBS NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2020) 6:89 1 0123456789(); PRIMER Author addresses Abdominal migraine is characterized by the pres- ence of paroxysmal prolonged episodes of intense, acute 1 Neurogastroenterology and Motility Unit, Department of Paediatric Gastroenterology, periumbilical, midline or diffuse abdominal pain. These Great Ormond Street Hospital NHS Foundation Trust, London, UK. painful episodes are typically incapacitating and interfere 2UCL Great Ormond Street Institute of Child Health, London, UK. with normal activities and occur in a stereotypical pat- 3Emma Children’s Hospital, Amsterdam University Medical Center, Amsterdam, Netherlands. tern (that is, in a set form or pattern, for example, with 4Department of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA. regards to the presence or form of aura and the escalation 5Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Columbus, of symptoms, severity and frequency) for the individual OH, USA. patient. The episodes are often but not always associ- 6University Hospital Tübingen, Department of Internal Medicine VI: Psychosomatic ated with other symptoms (such as anorexia, nausea, Medicine and Psychotherapy, Tübingen, Germany. vomit ing, headache, photophobia and pallor), which 7Boston Children’s Hospital, Harvard medical School, Boston, MA, USA. might precede or coincide with the duration of pain, and 8 Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Miami, such symptomatic episodes may be separated by weeks Miller School of Medicine, Miami, FL, USA. to months. 9Children’s Nutrition Research Center, Baylor College of Medicine, Texas Children’s FAP- NOS accounts for those instances of episodic Hospital, Houston, TX, USA. 10Department of Pediatrics, The Medical University of Warsaw, Warsaw, Poland. pain or continuous abdominal pain that does not occur 11College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC, USA. solely during physiological events and does not meet 4 12Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, criteria for the other FAPDs . NC, USA. For paediatric cases, the Rome IV criteria heralded a 13School of Social Work, University of Washington, Seattle, WA, USA. number of key milestones with respect to defining and 14Present address: Queensland Children’s Hospital, Paediatric Gastroenterology, characterizing these disorders. First, the term ‘functional Hepatology and Liver Transplant, Brisbane, Australia. abdominal pain disorders’ superseded the previously used terminology ‘abdominal pain- related functional Postprandial fullness can be further divided into subtypes analogous to adults gastrointestinal disorders’, allowing better focus for cli- 5 Unpleasant sensation thought based on the predominant stool pattern (BOx 2). nicians on the four subclassifications. Second, in the to emanate from the stomach Functional dyspepsia describes a symptom profile Rome IV classification, the previous criterion phrase “no for a considerable period after predominantly from the proximal gastrointestinal tract evidence of an inflammatory, anatomic, metabolic, or eating a meal giving the feeling of the persistence of food. involving epigastric abdominal pain and/or bothersome neoplastic process that explains the subject’s symptoms” postprandial fullness and/or early satiation. Similar to the has been replaced with “after appropriate medical eval- criteria in adults, subtypes of paediatric functional dys- uation, the symptoms cannot be attributed to another pepsia now recognized include postprandial distress medical condition”9. This modification has allowed syndrome and epigastric pain syndrome, accepting a greater autonomy to the clinicians to use their expertise frequent overlap between them6–8. to decide whether selective testing, or, in some cases, • Dysbiosis • Inflammation • Motility Sensitizing medical 2 events and/or factors • Early use of antibiotics (infections, allergies) disorders Early-life events Vulnerability of the microbiota–gut–brain axis • Central hypervigilance • Central sensitization 1 Functional Genetic predisposition • Disordered microbiota–gut–brain axis abdominal pain disorder • Visceral hypersensitivity and dysmotility Early-life events • Early-life pain and/or trauma • Depression • Coping style Sensitizing psychosocial 3 • Family stress • Anxiety • Secondary events and/or factors • Parenting factors • Stress gains • Abuse Fig. 1 | Summary of the aetiopathogenesis and pathophysiology of adrenal axis, sex hormones, or changes in the brain structure or function. FAPDs. This figure illustrates the likely contribution of genetic These changes might explain why children in the second decade of life are predisposition as well as of sensitizing psychosocial and medical events to most vulnerable to the development of FAPDs. Bidirectional arrow (2) the disruption of the structure and/or function of the microbiota–gut–brain denotes the possibility of FAPDs and their consequences (both medical and axis and to the development of the