Update on GI Medication Management Megan Butler, M.D

Update on GI medication management Megan Butler, M.D. Pediatric Gastroenterology Duke University Objectives

• Discuss common GI diseases in children • Reflux • EoE • Constipation • Functional GI disorders • Review pharmacologic and non-pharmacologic treatment for GI disorders in children • Understand adverse events associated with GI medications Reflux

“Name’s Reflux. Medical condition or super power, you decide.” -Reflux ©Disney-Pixar Reflux

• Gastroesophageal Reflux • Reflux ≠ Reflux • Kids are NOT just little adults • Reflux in kids can be physiologic or pathologic • 80% of babies regurgitate in the first month of life • ~10% at 1yo • Need to distinguish • Important to rule out other reasons for symptoms Reflux

• Definitions • GER • Passage of gastric contents into the esophagus with or without regurgitation and vomiting • GERD • When GER leads to symptoms that affect daily functioning and/or complications • Refractory GERD • GERD not responding to optimal treatment after 8 weeks • Look for “alarm signs” Reflux - DDxs • Gastrointestinal Obstruction • Cardiac • Pyloric stenosis, Malrotation with • Heart failure, vascular ring, autonomic volvulus, Intussusception, Hirschsprung dysfunction disease, Antral/duodenal web, Incarcerated hernia, Superior mesenteric • Other GI disorders artery syndrome • Achalasia, gastroparesis, gastroenteritis, peptic ulcers, eosinophilic esophagitis, • Neurologic food allergy/intolerance, inflammatory • Hydrocephalus, Subdural hematoma, bowel disease, pancreatitis, appendicitis Intracranial hemorrhage, Intracranial mass • Infectious • Sepsis/meningitis, UTI, upper/lower • Metabolic airway infection, otitis media, hepatitis • Galactosemia, hereditary fructose intolerance, urea cycle defects, amino • Other and organic acidemias, fatty acid • Pediatric condition falsification/factitious oxidation disorders, metabolic acidosis, disorder by proxy, child neglect or abuse, congenital adrenal hyperplasia/adrenal self-induced vomiting, cyclic vomiting crisis syndrome, rumination syndrome • Toxic • Lead poisoning, other toxins Alarm signs

• Weight loss • Macro/microcephaly • Lethargy • Persistent forceful vomiting • Fever • Nocturnal vomiting • Excessive irritability/pain • Bilious vomiting • Dysuria • Hematemesis • Onset >6 months or increasing >12- • Chronic diarrhea 18 months of age • Rectal bleeding • Bulging fontanel/rapidly increasing • Abdominal distention head size • Seizures Clinical management algorithms

• Etiologies can differ by age • Treatment algorithms differ by age • 2018 NASPGHAN clinical guidelines • Infants < 6 months • Infants and children ≥6 months Reflux - DDxs • Gastrointestinal Obstruction • Cardiac • Pyloric stenosis, Malrotation with • Heart failure, vascular ring, autonomic volvulus, Intussusception, Hirschsprung dysfunction disease, Antral/duodenal web, Incarcerated hernia, Superior mesenteric • Other GI disorders artery syndrome • Achalasia, gastroparesis, gastroenteritis, peptic ulcers, eosinophilic esophagitis, • Neurologic food allergy/intolerance, inflammatory • Hydrocephalus, Subdural hematoma, bowel disease, pancreatitis, appendicitis Intracranial hemorrhage, Intracranial mass • Infectious • Sepsis/meningitis, UTI, upper/lower • Metabolic airway infection, otitis media, hepatitis • Galactosemia, hereditary fructose intolerance, urea cycle defects, amino • Other and organic acidemias, fatty acid • Pediatric condition falsification/factitious oxidation disorders, metabolic acidosis, disorder by proxy, child neglect or abuse, congenital adrenal hyperplasia/adrenal self-induced vomiting, cyclic vomiting crisis syndrome, rumination syndrome • Toxic • Lead poisoning, other toxins Infant with H&P Yes Alarm sign? Appropriate testing suspected GERD No Avoid overfeeding Thicken feeds Education 1st Not improved? 2-4 week trial protein hydrolysate or AA Improved? Discuss protein formula, or cow’s milk reintroduction at follow up elimination (EBF) Formula/elimination trial 2nd Not improved Medications 3rd line

Consider 4-8 week trial of Pediatric GI referral acid suppression, wean if sxs improve Adapted from Rosen et al, 2018 Child with suspected H&P Yes Alarm sign? Appropriate testing GERD No Lifestyle and dietary Improved? st Continue management 1 line education Not improved

Acid suppression x 4-8 Improved? nd Attempt wean 2 line weeks

Not improved

Symptoms recur with weaning

Pediatric GI referral

Adapted from Rosen et al, 2018 GERD management

• Non pharmacologic • Thickened feedings • Modification of feeding volumes/intervals • Discuss overfeeding! • Infants: Milk elimination, extensively hydrolyzed formula, AA formulas • Children: discuss excessive body weight, foods that may exacerbate reflux (tomato, spicy, chocolate, citrus, peppermint) • No evidence: • Massage therapy, hypnotherapy, homeopathy, acupuncture, herbal medicine, dietary supplementation, pre- and pro-biotics Medications for GERD

• Histamine-2 Receptor Antagonist • Proton pump inhibitor • Prokinetics • Antacids Histamine-2 Receptor Antagonist

• Ranitidine • Tachyphylaxis • 5-10 mg/kg/day (max 300mg) • Many drug interactions • Cimetidine • cytochrome P450 • 30-40 mg/kg/day (max 800mg) • Interfere with absorption • Nizatidine • Inhibit Renal excretion • 10-20 mg/kg/day (max 300mg) • CNS • Famotidine • Confusion • 1 mg/kg/day (max 40mg) • Headache • depression • Hematologic • thrombocytopenia • CV • Related to IV administration Proton Pump Inhibitors

• Omeprazole • Changes in gastric mucosa • 1-4 mg/kg/day (max 40 mg) • ↑risk of GI and respiratory infxns • Lansoprazole • Vit B12 def • 2 mg/kg/day infants (max 30 mg) • ↓Mg • Esomeprazole • 10 mg/day (< 20kg) • ↑risk of fractures • 20 mg/day (>20 kg) • Rebound hyperacidity • Pantoprazole • ↑gastric microbiota • 1-2 mg/kg/day (max 40 mg) • headache • ?CV • ?renal • ?neuro Prokinetics

• Metoclopramide • AE: Neurologic • Extrapyramidal, dyskinesia, dystonia, seizures, hypertonia, tremor • AE: Cardiac • Shock, hypotension, cardiac arrest, tachycardia, bradycardia, hypertension, cardiorespiratory arrest, circulatory collapse • tachyphylaxis • Domperidone • NOT FDA approved in US • AE: Cardiac toxicity • Baclofen • AE: Muscle weakness, somnolence, muscle weakness, nausea, paresthesia Miscellaneous medications

• Antacids and aglinates • Neutralize acid • Sodium/potassium bicarbonate, or Al, Mg or Ca salts • Mg alginate, sodium alginate, Ca carbonate, Al hydroxide • Unclear benefit • AE: milk alkali syndrome (↑Ca, alkalosis, renal failure), ↑serum Al • Sucralfate • Site protective agent • AE: Al toxicity, intraluminal drug binding, drug interactions • Bethanechol • Cholinergic used for urinary retention • AE: flushing, hypotension, tachycardia, colic, bronchoconstriction… When to use medicines for GERD?

• Erosive esophagitis  PPI 1st line • Crying/distress in infants • Regurgitation in infants  • Children with symptomatic GERD (heartburn, etc) 4-8 wks H2RAs or PPI • Extraesophageal sxs (cough, asthma, wheezing) • Other medications?

Rosen et al. 2018 Eosinophilic Esophagitis

• Chronic condition • Immune mediated • 1 in 10,000 people • Clinically can be very similar to GERD Eosinophilic Esophagitis

• Often mistaken for GERD • Vomiting, regurgitation, chest pain, dysphagia, food impactions • Needs EGD to differentiate • > 15 eos/HPF in ≥ 1 biopsy specimen • Management • Non-pharmacologic • Elimination diet • Pharmacologic • Steroids (topical and systemic) • Response to therapy • EGD!! Eosinophilic esophagitis

Uptodategastro.wordpress.com University of Chicago EoE non-pharmacologic management

• Multi-disciplinary approach • GI • A/I • RD • PCP • Elimination diet • 4 food/6 food • Milk, wheat, egg, soy • +/- nuts and seafood • Intact protein elimination • AA formula • May need feeding tube (NG/GT) EoE medications

• Swallowed, topical corticosteroids • OVB • Budesonide slurry Nothing to eat/drink x 20 mins • Fluticasone • PPI? • AE: thrush, incorrect administration, steroid SE • Systemic steroids • Rarely required • AE: many Constipation

• Common in children • 3% PCP visits • 25% Pediatric GI visits

©2019 the Awkward Store Constipation

• Infrequent and/or painful bowel movements • fecal incontinence • abdominal pain • Can significantly impact quality of life and health care costs • Vast majority of children no underlying medical disease found Rome III diagnostic criteria

• Need ≥ 2 in absence of organic pathology: • ≤ 2 bowel movements in the toilet per week • 1 episode fecal incontinence per week • History of excessive stool retention or retentive posturing • History of painful or hard bowel movements • Presence of large fecal mass in rectum • History or large diameter stools that may obstruct the toilet • Developmental age <4y sxs present at least 1 month • DA ≥4y, sxs present at least 2 months

Hymen et al 2006 and Rasquin et al 2006 Constipation DDxs

• Celiac • Anal achalasia • Hypothyroid • Colonic inertia • Electrolyte abnormalities • Anorectal malformations • Dietary protein allergy • Pelvic mass • Medications/toxins • Spinal cord anomalies • Vitamin D intoxication • Abnormal abdominal musculature • Botulism • Pseudoobstruction • Cystic fibrosis • Multiple endocrine neoplasia type • Hirschsprung disease 2B • Behavioral/anxiety Alarm signs

• Onset <1 mo • Perianal fistula • Passage of meconium >48 hours • Abnormal position of anus • Family h/o HD • Absent anal or cremasteric reflex • Ribbon stools • Decreased LE strength/tone/reflex • Blood in stools (absence of anal • Tuft of hair on spine fissure) • Sacral dimple • FTT • Gluteal cleft deviation • Bilious emesis • Extreme fear during anal • Abnormal thyroid gland inspection • Severe abdominal distension • Anal scars Management

• Non-pharmacologic • Pharmacologic • Fiber • Osmotic laxatives • Fluids • Fecal softeners • Physical activity • Stimulant laxatives • Pre-/pro-biotics • Rectal laxatives/enemas • Behavior therapy • Miscellaneous medications • Alternative therapies • Acupuncture, homeopathy, mind- body therapy, musculoskeletal • 2014 NASPGHAN guidelines manipulations • <6 months • ≥6 months H&P Constipation alarm signs? yes Refer < 6 mo accordingly Oral Rx PRN suppository no

Breastfed >2 no Re-assessment Effective? yes wko? re-education no no Likely normal yes Functional constipation Maintenance Effective? Effective? therapy f/u 2-4 yes weeks Education Attempt no Verify to wean formula Pediatric GI Relapse? preparation Referral

Adapted from Tabbers et al, 2013 H&P Constipation alarm signs? yes Refer ≥ 6 mo accordingly Oral Rx no PRN suppository Functional constipation Re-assessment no re-education Effective? Medication Disimpact yes Fecal no adjustment with Rx impaction? yes no yes Education Effective? Maintenance yes Diary Effective Effective? therapy Toilet after 2 yes weeks? no training Attempt no Oral Rx to wean Pediatric GI Pediatric GI Referral Relapse? Referral

Adapted from Tabbers et al, 2013 Management summary

• PEG 1st line • Lactulose alternative • 2nd line: magnesium hydroxide, mineral oil, stimulant laxatives • Continue at least 2 months • All sxs resolved for at least 1 month before gradual discontinuation of treatment • Patient education important • “The Poo In You” “The poo in you” gikids.org Fiber, Fluids and Physical Activity

• Fiber • Studies did NOT show improvement with use of fiber supplements • Normal fiber intake is recommended • ~ Age (years) + 5 = grams per day • AE: bloating, diarrhea • Fluids • No evidence to support additional fluid intake • Recommend normal fluid intake • Physical activity • Not studied Pre- and Pro-biotics

• Very few studies • Some positive results in up to 8 week follow up • No long term data • Not enough data to recommend Other non-pharmacologic treatments

• Behavioral therapy • Biofeedback • Multidisciplinary ??? • Acupuncture • Homeopathy Not studied • Mind-body therapy • Musculoskeletal manipulations • yoga Osmotic laxatives

• Lactulose • 1-2 g/kg daily-BID • AE: dehydration, electrolyte abnormalities, abd cramping, abd distention, N/V/D • PEG 3350 • 0.2-0.8 g/kg/day • AE: abd distention, pain, diarrhea, N/V, interacts with digoxin • Magnesium hydroxide • 2-5y: 0.4-1.2 g/kg/day • 6-11y: 1.2-2.4 g/kg/day • 12-18y: 2.4-4.8 g/kg/day • 1-2 cc/kg/day • AE: caution in renal impairment, dehydration, diarrhea, drug interactions Fecal softeners

• Mineral oil • 1-3 ml/kg/day • Max 90 ml/day • AE: • Aspiration risk • Mix with yogurt? • Anal leakage Stimulant laxatives

• Bisacodyl • 2-10y: 5 mg daily • >10y: 5-10 mg daily • AE: cramps, electrolyte disturbance, vertigo, N/V • Senna • 2-6y: 2.5-5 mg daily-BID • 6-12y: 7.5-10 mg/day • >12y: 15-20 mg/day • AE: cramps, N/V/D Rectal laxatives/enemas

• Bisacodyl • 2-10y: 5 mg daily • >10y: 5-10 mg daily • Sodium docusate enema • <6y: 60 ml • >6y: 120 ml • Sodium phosphate • 1-18y: 2.5 ml/kg (max 133ml) • NaCl • Neonate: <1kg, 5ml; >1 kg, 10ml • >1y: 6 ml/kg once or twice/day • Mineral Oil • 2-11y: 30-60 ml daily • >11y: 60-150 ml daily Misc. medications

• Lubiprostone (Amitiza) • Chloride channel-2 activator • Studies in pediatrics positive? • Linaclotide (Linzess®) • Guanylate cyclase C agonist • Black box warning for pediatric use • Contraindicated < 6y • Recommended to avoid use 6y – 18y • Death due to dehydration in mice studies • Prucalopride (Motegrity™) • Selective serotonin (5-HT4) receptor agonist • Pilot study? (open label) favorable • Multicenter RCT not efficacious Functional Abdominal Pain Disorders Functional abdominal pain disorders

• Most common cause of chronic abdominal pain in pediatrics • 10-19% children • Peak ages: 4-6y and early adolescents • Can cause significant disruptions and healthcare costs

Uptodate.com, 2019 Functional abdominal pain disorders

• Variable combination of symptoms without identifiable organic condition • Not diagnosis of exclusion • Interplay between GI and CNS • Thought to be due to visceral hyperalgesia, reduced threshold for pain, abnormal pain referral, impaired gastric relaxation response to meals • So, how do we know if it is functional?? Alarm findings

• Involuntary weight loss • Deceleration in linear growth • Dysphagia • Odynophagia • Oral aphthous ulcerations • Significant vomiting • RUQ tenderness • Chronic severe diarrhea • RLQ pain • Unexplained fevers • Urinary symptoms • Suprapubic tenderness • Back pain • Hepatomegaly • Family history IBD, Celiac, PUD • Splenomegaly • Bloody diarrhea • Melena • CVA tenderness • Skin changes • Perianal abnormalities • guaiac-positive stool Approach to child with chronic abdominal pain • History & PE • Careful search for alarm findings • Consider stool hemoccult • Low yield for additional studies • 2005 AAP/NASPGHAN additional testing may be performed to “reassure the patient, parent, and physician of the absence of organic disease, particularly if the pain significantly diminishes the quality of life of the patient” • ????But does it really • 2008 review showed additional testing in children without alarm findings did not influence prognosis of chronic abdominal pain (Gieteling, 2008) Functional abdominal pain disorders

• Functional dyspepsia • Irritable Bowel Syndrome • Abdominal migraine • Functional abdominal pain NOS Functional Dyspepsia

• Epigastric pain or discomfort • Sxs at least 2 months, ≥ 4 day/month • May be exacerbated by eating • ?abnormal gastric electrical rhythm, delayed GE, reduced gastric response to eating, antroduodenal dysmotility • 2 subtypes • Postprandial distress syndrome • Postprandial fullness, early satiety, bloating, nausea, excessive belching • Epigastric pain syndrome • Pain or burning not relieved by defecation Irritable Bowel Syndrome

• Chronic abdominal pain and altered bowel habits • Sxs at least 2 months, ≥4 day/month • Can be diarrhea or constipation predominant or mixed Abdominal migraine

• Paroxysmal intense, acute, periumbilical, midline or diffuse abdominal pain lasting ≥1 hour at least twice in 6 month period • Episodes separated by weeks or months • Pain is incapacitating and interferes with activities • Stereotypical pattern and symptoms • Family history of migraine headache is common • Plus at least 2: • Anorexia • Nausea • Vomiting • Headache • Photophobia • Pallor Functional abdominal pain NOS

• Episodic or continuous pain that does not occur solely during physiologic events (eating, menses) Non-pharmacologic Management of functional abdominal pain • Therapeutic relationship • Patient education • Behavior modification • Strategies to improve pain tolerance and coping • Avoidance of triggers • Pharmacologic symptom management Biopsychosocial model of abdominal pain

©2019 UpToDate, Inc Therapeutic relationship

• Patient and family must believe their complaints are being taken seriously • Acknowledge pain is real and has impacted their life • Reassure that clinician will initiate treatment plan and follow up on a regular basis • Focus on shared goal of return to normal function • Prescribe a return to structured activities of daily living Patient education

• Education should include • Functional abdominal pain disorders are common (10-20% children) • Pain is real • Heightened sensitivity to normal function of bowel • Pain can be triggered by many psychosocial factors • Pain is not life-threatening, does not require activity restrictions • Treatment focuses on return to normal activity • Chronic pain (regardless of etiology) can be associated with depression and anxiety • Define realistic expectations early Patient education

• Plan for return to school • Plan ahead for pain episodes at school • May need part time schedule to facilitate return • Provide guidelines to help parent decide when child is too sick to go to school • Activity restrictions when child remains home • Identify school related sources of stress • May need letters for school • Bathroom privileges • Letter to document evaluation for symptoms Behavior modification

• Reinforcement of well behaviors • Praise/reward for attending school • Identify and support interests outside of sick role • Model healthy responses to pain • Avoid reinforcing pain behavior • Avoid providing attention to pain • Do not allow pain to disrupt normal function • Do not allow child who stays home from school to watch TV or other entertainment Improve coping skills

• Relaxation techniques • Distraction • Guided imagery/hypnotherapy • Cognitive behavioral therapy • Biofeedback • Yoga therapy? • Written self-disclosure? Management of triggers

• Anxiety • Dietary • Lactose • ?gluten/wheat • Limited data • FODMAPs FODMAPs

• Fermentable oligosaccharides, disaccharides, monosaccharides and polyols • Fructose • Fruits, honey, HFCS • Lactose • Fructans • Wheat, onion, garlic • Galactans • Beans, lentils, legumes, soy • Polyol • Sorbitol, mannitol, xylitol, maltitol, stone fruits (avocado, apricot, cherries, nectarines, peaches, plums) Stanford University, 2012 FODMAPs

• FODMAPs are ostmotic and may not be absorbed or digested well • Can become fermented • Low FODMAP diet trial • 6 weeks low FODMAP • Slowly add back in foods to diet • Often need RD Pharmacologic symptom management

• Symptoms • Abdominal pain • Dyspepsia • Diarrhea • Constipation • Medication/supplements • Probiotics • Fiber • Peppermint oil • Antispasmodics • others Probiotics in functional GI disorders

• Mechanism unclear • ?restore microbial balance • Most effective strain/dose/duration unknown • ?4-8 week trial • Can be expensive • ?benefit • Studies results variable • Generally try to stick with well studied, commercially available strains • Culturelle® • VSL#3® • Florastor® • AE: diarrhea, bacteremia (CVL) Fiber

• Mechanism unknown • Modify intestinal microbiota? • Accelerates GI transit time? • Alters composition of stool and gas? • AE: bloating and increased pain • Dose: age in years + 5 • ?trial at least 4 weeks • ?benefit • Systematic review did not show benefit Peppermint Oil

• Decreases smooth muscle spasms • Enteric coated tablet • <45kg: 187 mg TID • >45kg: 374 mg TID • Heather’s tummy care® • 181 mg peppermint oil, fennel oil and ginger oil • AE: GER, intersterstitial nephritis, acute renal failure Antispasmodics

• ?efficacy in pediatrics • Hyoscyamine • Dicyclomine • AE: anticholinergics (dry mouth, blurred vision, dizziness), drug interactions (TCAs) Other medications

• Cyproheptadine • Antihistaminic, anticholinergic, antiserotonergic, ?Ca channel blockade • ↑appetite • ↓pain and vomiting in CVS • Studies have shown some benefit in Functional GI disorders • AE: many • Amitriptyline • Limited studies in children • Low dose • AE: many • Rifaximin • Lubiprostone • Iberogast • herbal How to treat functional abdominal pain disorders? • Education  • Setting realistic expectations  • More testing ? • Therapeutic relationship • Dietary changes ? • Supplements ? • Medications ? References

• R Rosen, Y Vandenplas, M Singendonk, M Cabana, C DiLorenzo, F Gottrand, S Gupta, M Langendam, A Staiano,N Thapar, N Tipnis, M Tabbers. Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. JPGN 2018;66: 516- 554. • Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2006; 130:1519–26. • Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 2006; 130:1527–37. • MM Tabbers, C DiLorenzo, MY Berger, C Faure, MW Langendam, S Nurko, A Staiano, Y Vandenplas, MA Benninga. Evaluation and Treatment of Functional Contsipation in Infants and Children: Evidence-Based Recommendations from ESPGHAN and NASPGHAN. JPGN 2014;58: 258-274. • MJ Gieteling, SM Bierma-Zeinstra, J Passchier, MY Berger. Prognosis of chronic or recurrent abdominal pain in children. J Pediatr Gastroenterol Nutr. 2008 Sep;47(3):316-26. • MJ Gieteling, SM Bierma-Zeinstra, J Passchier, MY Berger. Prognosis of chronic or recurrent abdominal pain in children. J Pediatr Gastroenterol Nutr. 2008 Sep;47(3):316-26. • MR Chacko, E Chiou. Functional Abdominal pain in children and adolescents: management in primary care. UpToDate, Inc. 2019.