1 The Pain of Abdominal PainOverview and a practical Approach to Paediatric Chronic Abdominal Pain Nir Fireman MD FRACP Paediatric Gastroenterologist MacMurray Centre

2 “I know of no symptom which can be more obscure in its causation than colicky abdominal pain in childhood”. (G. Still) Common Diseases and Disorders in Childhood (ed. Still, G. F.) 168–175 (Oxford University Press, 1909)

3 “5 symptoms of GI tract” Abdominal pain Nausea Vomiting Diarrhea Constipation But… “ potential causes”

4 TERMINOLOGY "chronic abdominal pain"intermittent or constant abdominal pain (of functional or organic aetiology) present for at least two months (rarely is. distinct in clinical practice) The term "chronic abdominal pain" encompasses "recurrent abdominal pain" classically defined by four criteria: ≥3 episodes of abdominal pain pain sufficiently severe to affect activities episodes occur over a period of ≥3 months no known organic cause "recurrent abdominal pain" is description rather than a diagnosis.

5 EPIDEMIOLOGY chronic abdominal pain occur in 10 to 19% of] children.The prevalence is increased in children age 4-6years and early adolescents. In a community-based population study, as many as 17 % of middle and high school students reported weekly episodes of abdominal pain Among the pupils who reported abdominal pain, approximately 21 % had discomfort that was sufficiently severe to affect activity. In a 2015 meta-analysis of 58 studies including 196,472 children from around the world, the pooled prevalence of functional abdominal pain disorders was 13.5%.

6 PATHOGENESIS — Pain perception is incompletely understood, but depends upon the type of stimulus and the interpretation of receptor signals in the central nervous system (CNS). Pain receptors in the gastrointestinal tract are located on serosal surfaces, within the mesentery, and within the walls of hollow viscera Pain receptors in the abdomen respond to mechanical and chemical stimuli. Mucosal receptors respond primarily to chemical stimuli (e.g., substance P, bradykinin, serotonin, histamine, prostaglandins), which are released in response to inflammation or ischemia. Different types of stimuli may act simultaneously to influence the perception of pain example, the gastric mucosa typically is insensitive to pressure or chemical stimuli, however, these stimuli may cause pain if the gastric mucosa is inflamed The processing of visceral pain signals by the CNS and psychologic factors also influence the perception of pain [20]. The threshold for perceiving pain from visceral stimuli may vary among individuals

7 Abdominal Pain Usually stimulated by one of three pathways:Visceral Somatic Referred Variability in the experience of pain Neuroanatomic, neurophysiologic, pathophysiologic, environmental, and psychosocial

8 Visceral Pain Visceral pain receptors located on serosal surfaces, within the mesentery, and within the walls of hollow viscera and mucosal receptors. Visceral receptors respond to mechanical and chemical stimuli whereas mucosal receptors respond primarily to chemical stimuli Distended viscus activates a local nerve, sending an impulse that travels through autonomic afferent fibers to the spinal tract and central nervous system Localization of pain is difficult because there are few afferent nerves traveling from the viscera, and nerve fibers overlap

9 Somatic Pain Carried by somatic nerves in the parietal peritoneum, muscle, or skin Usually well localized and sharp

10 Referred Pain Perceived at a site remote from the actual affected viscera Referred pain usually is located in the cutaneous dermatomes sharing the same spinal cord level as the visceral inputs. Sharp, localized, or diffuse Sometimes pain originating in the viscera is perceived to originate at a distant site (ie, referred pain). Referred pain usually is located in the cutaneous dermatomes sharing the same spinal cord level as the visceral inputs (figure 1). As an example, nociceptive stimuli from the gallbladder enter the spinal cord at T5 to T10. Thus, pain from an inflamed gallbladder may be perceived in the scapula. Precise localization of the pain to the right upper quadrant in patients with acute cholecystitis usually occurs once the overlying parietal peritoneum (which is somatically innervated) becomes inflame

12 ETIOLOGY- Concepts of GI disease, Motility and Functional DisordersOrganic or structural disorders Motility disorders Functional GI disorders classified in terms of organ morphology and classified in terms of organ function and specifically altered motility Classified in the terms of symptoms Relates to the patient's interpretation and reporting of an illness experience macro and micro pathology Motility studies Rome Criteria e.g. oesophagitis, IBD e.g. Gastroparesis, CIPO .e.g. Functional dyspepsia, IBS

13 ETIOLOGY Functional gastro intestinal disordersisorders of the gut-brain interaction. A group of disorders classified by GI symptoms related to any combination of the following- Motility disturbance Visceral hypersensitivity Altered mucosal and immune function Altered gut microbiota Altered CNS processing

14 Douglas A. Drossman Gastroenterology 2016;150:1262–1279

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16 DIAGNOSTIC ALGORITHM Making a Diagnosis- HISTORYOnset of pain Early life? Event/triggers (feeding, weaning, allergy, infections, illnesses, school, etc) Nature and severity Nature/ Location/ Frequency Associated symptoms (food, stool etc)/ behaviour Exacerbating/ alleviating factors Other medical history Appetite, weight loss Associated systems (genitourinary tract) Family Hx 3rd Dimension – psychosocial

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18 DIAGNOSTIC ALGORITHM Making a Diagnosis- EXAMINATIONGeneral (Well being, Hydration, Weight, Height…) Dysmorphic features CVS/Resp Skin (birth marks/ eczema) Abdomen/ anal inspection / ?Rectal examination Spine (Dimple, tuft of hair, gluteal cleft deviation..) Neurological and Neurodevelopmental Musculoskeltal 3rd Dimension (behaviour, fear, scars…)

19 ALARM SIGNS IN ABDOMINAL PAIN Historical FindingsPersistent right upper or right lower quadrant pain Persistent vomiting Gastrointestinal blood loss Chronic sever diarrhoea Dysphagia Involuntary weight loss Deceleration of linear growth Delayed puberty Unexplained fever Family Hx of IBD, CD or FMF

20 ALARM SIGNS IN ABDOMINAL PAIN Examination FindingsDeceleration of linear growth Uveitis Oral lesions Skin rashes Icterus Anaemia Hepatomegaly/ splenomegaly Arthritis Perianal Abnormalities

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22 DIAGNOSTIC ALGORITHM Laboratory investigation? Alarming signs??

23 DIAGNOSTIC ALGORITHM Laboratory investigation? Stool for occult blood Complete blood count with differential Erythrocyte sedimentation rate and/or C-reactive protein Metabolic panel (i.e., electrolytes, glucose, blood urea nitrogen, creatinine, calcium, total protein, albumin, alkaline phosphatase, ALT, AST Urinalysis with urine culture as indicated Serologic tests for celiac disease Serum amylase and lipase Enteric parasitic or protozoal infection Enteric bacterial infections – Clostridium difficile toxin and stool cultures Helicobacter BHCG?

24 DIAGNOSTIC ALGORITHM Laboratory investigation?Faecal Calprotectin?? Increased in IBD Infectious enterocolitis GI malignancies NSAID use Untreated food allergy Juvenile polyps Untreated coeliac Young age (<5)

25 DIAGNOSTIC ALGORITHM Imaging investigation?Abdominal ultrasonography - gallstones, extrahepatic bile ducts (choledochal cyst), pancreatic pseudocyst, hydronephrosis or retroperitoneal mass. Pelvic ultrasonography may be indicated to evaluate ovarian masses or pregnancy. An upper gastrointestinal series may be warranted to evaluate bowel obstruction (eg, late presentation of malrotation, surgical adhesions, etc) Magnetic resonance enterography may be warranted if inflammatory bowel disease is suspected. Computed tomography (CT) of the abdomen with contrast may be warranted to evaluate retroperitoneal or intraabdominal abscess (eg, associated with inflammatory bowel disease). CT usually is reserved for urgent evaluation (eg, abscess, mass) Endoscopy

26 DIAGNOSTIC ALGORITHM Chronic abdominal painHistory and Physical examination Yes Presence of alarming signs? Evaluate further CBC, LFTs, Amylase, ESR, CRP Coeliac screening Urinalysis Calprotectin Stool Stool H Pylori Ag Abdominal USS No Yes Fulfils criteria of constipation? Treat constipation No Working Diagnosis of functional abdominal pain disorders Diagnosis According ROME IV criteria Diagnostic tests Positive findings No findings Pain alone? Functional abdominal pain (NOS) Pain in upper abdomen Functional dyspepsia Pain + abnormal bowel habit IBS Paroxysmal episodes of pain Abdominal migraine Evaluate Further/ Refer Appropriate treatment

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28 FUNCTIONAL ABDOMINAL PAIN DISORDERS Functional DyspepsiaFunctional dyspepsia – Dyspepsia is pain or discomfort that is centered in the epigastric region. Discomfort may be characterized by fullness, early satiety, bloating, nausea, retching, or vomiting [1]. The pain or discomfort may be exacerbated by eating. Children with dyspepsia and alarm findings should be evaluated for an organic disorder (eg, acid peptic disease). The pathophysiology of functional dyspepsia is not clear. Abnormalities in gastric electrical rhythm, delayed gastric emptying, reduced gastric volume response to feeding, and antroduodenal dysmotility have been demonstrated in some children and adolescents [59-63]. Abnormal motor function, visceral sensitivity, and psychosocial factors have been studied as possible contributing factors in adults

29 FUNCTIONAL ABDOMINAL PAIN DISORDERS Irritable Bowel SyndromeIrritable bowel syndrome – Irritable bowel syndrome (IBS) is characterized by chronic abdominal pain and altered bowel habits (diarrhea or constipation) in the absence of any alarm findings. Children with chronic abdominal pain, altered bowel habits, and alarm findings should be evaluated for organic conditions. (See 'Patients with alarm findings' above.) The diagnosis of IBS can be made on the basis of symptoms (table 1); it is not a "diagnosis of exclusion" and does not require an extensive evaluation to exclude organic disease [6]. However, it may be reasonable to screen children who meet Rome IV criteria for IBS for celiac disease [64]. In a prospective cohort of 992 children referred for chronic abdominal pain, 270 met criteria for IBS [65]. Among these, 12 (4.4 percent) had positive serology for celiac disease (compared with 0.3 to 1.3 percent in the general pediatric population). (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Epidemiology'.) IBS occurs infrequently before late adolescence and may be preceded by a long history of constipation [14,23] or an episode of gastroenteritis [66-68]. Compared with healthy volunteers and children with childhood functional abdominal pain syndrome (a Rome III diagnosis, which Rome IV calls "functional abdominal pain – not otherwise specified"), children who have IBS have a lowered rectal pain threshold and disturbed rectal contractile response to meals [69,70]. Compared with control subjects and children with functional dyspepsia, children with IBS have abnormal pain referral after rectal distension (ie, they report pain at a location other than the S3 dermatome) [28]. In addition, adolescents who have IBS-type symptoms have higher anxiety and depression scores than do those without such symptoms

30 FUNCTIONAL ABDOMINAL PAIN DISORDERS Abdominal Migraine

31 FUNCTIONAL ABDOMINAL PAIN DISORDERS Functional Abdominal pain-NOS

32 Treatment of FGID Biopsychosocial model of careGenuine pain The pain is the disease Reassurance Prevalence of FGID Benign clinical course Emphasize normal growth Therapeutic approach Effective physician-family relationship Set realistic therapeutic goals Decrease stress and tension Improvement of daily symptoms and quality of life Identify and address obstacles related to school attendance How much school has been missed Working with school teachers Initial reduction of home work MDT Approach Paediatrician, Psychologist, Psychiatrist, Dietitian, Social worker, Paediatric Gastroenterologist

33 Diagnosis of AP related FGID Reassurance and education Lifestyle and food habits Discuss expectations Abdominal Pain dairy Yes Continue Evaluate after 2-3 weeks ? Intervention effective Pharmacological Antispasmodics Antireflux/ anti acid agents Antihistamin agents Antidepressants No Non Pharmacological Hypnotherapy CBT Probiotics Start therapy (Depend on subtype and patient preference) No Evaluate after 2-3 weeks ? Intervention effective No Change therapy/ Reconsider diagnosis Evaluate after 2-3 weeks ? Intervention effective Yes Yes Stop therapy and evaluate after 2 months Continue or adjust therapy Taper medication after 2-6 months Korterinket al. Nat Rev. Gastroenterol. Hepatol 2015;12:159

34 Histamine AntagonistsPredominant dyspepsia, a short course of empiric therapy with an H2- histamine receptor antagonist is acceptable Failure to respond or a recurrence of symptoms following discontinuation prompts further evaluation Study showed only subjective improved in symptoms, and placebo was equally effective when looking at objective scores M.C. See, A.H. Birnbaum, C.B. Schecter, et al.: Double-blind, placebo-controlled trial of famotidine in children with abdominal pain and dyspepsia. Dig Dis Sci. 46:

35 Cyproheptadine Periactin- not available in NZA central and peripheral H1 nonselective histamine receptor antagonist with antiserotonergic properties A double-blind, randomized, placebo-controlled trial was performed in 29 children ages 4 to 12 years with FAP (M. Sadeghianet al Pediatr. 60: ) Randomized to placebo or cyproheptadine 86% in the cyproheptadine group and 36% in the placebo group had improvement or resolution Induce appetite (Sant'Anna AM et al. JPGN Nov 2014)

36 Peppermint Oil Soothe the GI tract for hundreds of yearsRelaxes intestinal smooth muscle by decreasing calcium influx into the smooth muscle cells Meta-analysis of five randomized, double-blinded, placebo-controlled trials performed in adult patients supported the efficacy of peppermint oil in the treatment of irritable bowel syndrome Randomized, double-blind, controlled trial in pediatric patients with IBS demonstrated the efficacy of enteric-coated peppermint oil capsules in the reduction of pain during the acute phase of IBS R.M. Kline, J.J. Kline, J. Di Palma, et al.: Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children J Pediatr. 138:

37 Anticholinergics Dicyclomine and hyoscyamine (Gastro Soothe)Smooth muscle relaxants, block the muscarinic effects of acetylcholine on the GI tract, relaxing smooth muscle and reducing spasm and abdominal pain, slowing intestinal motility, and decreasing diarrhea Efficacy not clearly established in adult trials, no randomized, double- blind, placebo-controlled trials in pediatrics Potential side effects: drowsiness, blurred vision, dry mouth, tachycardia, constipation, and urinary retention PRN or episodic, up to four times daily

38 Tricyclic AntidepressantsShown to provide relief to patients with FGIDs Neuromodulatory and analgesic effects, from a combined anticholinergic effect on the gastrointestinal tract, mood elevation and central analgesia Two clinical trials to evaluate the efficacy of TCA therapy in the treatment of FAP in children A single-center study of 33 adolescents with IBS found a beneficial effect of amitriptyline in comparison to placebo in terms of quality of life and pain relief A multicenter randomized double-blinded trial on 90 children showed improvement in 59% of the children receiving amitriptyline* M. Saps, N. Youssef, A. Miranda, et al.: Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology. 137:

39 Serotonin Serotonin is found in high concentrations in the enterochromaffin 14 serotonin receptor subtypes with varying actions in the peripheral and central nervous systems exist 5-HT3 and 5-HT4 receptors appear to play a role in the pathophysiology of IBS

40 SSRIs Selective serotonin reuptake inhibitors are helpful for some patients with unremitting pain and impaired daily functioning, even if no depressive symptoms are present Citalopram has been studied in children with FGIDs 12-week open-label flexible-dose trial By week 12, 50% rated their symptoms as very much improved Also showed improvement in comorbid depression and anxiety J.V. Campo, J. Perel, A. Lucas, et al.: Citalopram treatment of pediatric recurrent abdominal pain and comorbid internalizing disorders: an exploratory study. J Am Acad Child Adolesc Psychiatry. 43:

41 5-HT3 antagonist Ondansetron (Zofran)Some chemotherapeutic and radiotherapeutic agents cause the release of 5-HT from enterochromaffin cells Serotonin activates vagal afferents via 5-HT3 receptors, triggering emesis by stimulation of the area postrema and chemoreceptor trigger zone Ondansetron and granisetron are very effective in reducing postchemotherapy nausea, but do not consistently alleviate the pain associated with FGIDs Not routinely recommended for FGIDs unless nausea is a predominant symptom

42 Probiotics Double-blind randomized controlled trial, 50 children with IBS were treated with either Lactobacillus GG or placebo for 6 weeks No significant differences between treatment and placebo groups with the exception of abdominal distention Larger, 4-week placebo-controlled study, 104 patients who fulfilled the Rome III criteria for functional dyspepsia, IBS, or FAP 25% in the treatment group and 9.6% in the placebo group responded to therapy IBS more likely to respond to probiotic, compared to placebo or FAP M. Bausserman, S. Michail: The use of Lactobacillus GG in irritable bowel syndrome in children: a double-blind randomized control trial. J Pediatr. 147: A. Gawronska, Horbath A. Dziechciarz, et al.: A randomized double-blind placebo-controlled trial of Lactobacillus GG for abdominal pain disorders in children. Aliment Pharmacol Ther. 25:

43 Cognitive Behavioral Therapy6 studies in a Cochrane review Relatively small and had some weaknesses in design and reporting Each reported a statistically significant benefit to participants in the intervention group Cochrane reviewers thought CBT is worth considering A.A. Huertas-Ceballos, S. Logan, C. Bennett, C. Macarthur: Psychosocial interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood (Review). Cochrane Library. (Issue 4)2009

44 Relaxation/Arousal ReductionA variety of techniques to teach patients to counteract the physiological sequelae of stress or anxiety The most commonly used techniques include progressive muscle relaxation training; biofeedback for striated muscle tension, skin temperature, or electrodermal activity; and transcendental or yoga meditation Most techniques incorporate a quiet environment, a relaxed and comfortable body position, and a mental image to focus attention away from distracting thoughts or body perceptions Audiotapes may be used to guide practice at home Relaxation training has been shown in adults to significantly reduce gastrointestinal symptoms as compared with controls R.D. Anbar: Self-hypnosis for the treatment of functional abdominal pain in childhood. Clin Pediatr. 40:

45 SMT- Standard Medical TherapyHT- Hypnotherapy Conclusion- This study clearly showed the efiicacy of gut-directed HT in the treatment of children with long standing IBS and FAP. The authurs advocate that HT become the treatment of choise in children with persisting complaints of either FAP or IBS in whom first-line therapies such as education and dietary advice have failed

46 Questions?