Functional Dyspepsia and Gastroparesis

David J. Levinthal, MD, PhD Director, Neurogastroenterology and Motility Center Assistant Professor, Department of Medicine Division of Gastroenterology, Hepatology, and Nutrition University of Pittsburgh Medical Center Disclosures

Takeda Pharmaceuticals InControl Medical, LLC Overview

• Functional dyspepsia (FD) and gastroparesis (GP) • Epidemiology and Definitions

• Pathophysiological Mechanisms in Dyspepsia • FD/GP overlap – spectrum of gastric sensorimotor dysfunction

• Treatment options • Diet • Medications • Cognitive / Mind-Body interventions • Devices / Surgical Interventions (last resort) “Dyspepsia” – what do patients say?

• Early satiety and/or post-prandial fullness (often several hours)

• Bloating

• Abdominal pain / burning / intense discomfort (upper abdomen)

• Nausea +/- vomiting

• Loss of Appetite FD vs GP: Epidemiology

Functional Dyspepsia Gastroparesis

Prevalence (general population) 10-20% 0.2 - 1%

Gender F ≥ M 3:1 F>M

Age All adults All adults

Delayed Gastric Emptying ~33% 100%

Associated Conditions Anxiety / Depression Diabetes Early-life adversity Parkinson’s Other chronic pain disorders Scleroderma (>50% idiopathic) Functional Dyspepsia: Rome IV Criteria

1 or more: post-prandial fullness, early satiation, epigastric pain or burning AND No evidence of structural disease (i.e. normal EGD; negative H. pylori)

Symptom persistence – last 3 months, onset at least 6 months prior Symptom frequency – must meet either EPS or PDS criteria

Comment: Nausea +/- vomiting “warrants consideration of another disorder” Functional Dyspepsia: EPS vs. PDS

• Epigastric Pain Syndrome (EPS) • At least 1 day / week: epigastric pain and/or burning • Severe enough to impact “usual activities”

• Post-prandial Distress Syndrome (PDS) • At least 3 days / week: postprandial fullness and/or early satiation • Severe enough to prevent finishing a “regular-size meal”

• Imprecise distinctions (significant symptom overlaps in FD) • 61% PDS, 18% EPS, 21% both1

1 Lancet Gastroenterol Hepatol. 2018 Apr;3(4):252-262. 2 Dtsch Arztebl Int 2018; 115: 222-232. Defining Gastroparesis

• Symptoms: Dyspepsia (PDS>EPS-like), often with some nausea/vomiting

• Presence of significantly delayed gastric emptying • Typically via a solid-phase, 4 hour gastric emptying test

• Absence of mechanical obstruction (often via normal EGD) Blurred Lines in FD and GP: Are they really distinct disorders?

Normal Gastric Motor Physiology Potential Pathophysiological Mechanisms

Gastroenterology 2009;136:1526–1543 Gastroenterology 2016;150:1380–1392 Measuring Visceral (gastric) Hypersensitivity

Gastric “balloon” inflated (fundus)

Shaded region = “normal range” (+/- 2 SD)

“Left shift” of the distention pressure- sensation curve in FD patients = “Hypersensitivity”

~35% of FD patients show “allodynia” (presumably mostly EPS subtype)

Clinical Phenotype: “Within 30 seconds, I have pain after I eat anything”

Gastroenterology 2001;121:526–535. Measuring Fundic Accommodation

Gastric barostat (research tool)

FD patients have impaired meal- induced fundic accommodation

Impaired fundic accommodation is independent of gastric sensitivity (pathophysiologic dissociation)

Clinical Phenotype: “I feel full after swallowing just a few bites of a sandwich.”

Gastroenterology 2001;121:526–535. Mind Influences the Stomach: normal physiology

Neutral Face (Visual) Neutral Story (Audio)

Fearful Face (Visual) Scary Story (Audio)

Geeraerts et al. (2005) Gastroenterology 129:1437-1444. Measuring Gastric Emptying 4 hour solid-phase GES: Lag Phase 99mTc-infused egg sandwich

NORMAL: <10% retention @ 4 hrs Emptying Phase ~1/3 FD pts have mild GE delay GP w/ severe GE delay “FD” w/ mild GE delay Poor correlation of GE delay with symptom severity

Clinical Phenotype: “I just feel like a boulder is sitting in my stomach for hours after a meal”

Gastroenterology 2009;136:1526 –1543 FD vs. GP – Can one make the distinction?

1,287 pts with “functional upper GI symptoms”

Mixed FD/GP population, partially investigated (only ~40% had an EGD)

Limitation: No precise measure of sensitivity (likely present in those w/ “normal GE and GA”)

GE = gastric emptying GA = gastric accommodation

Am J Gastroenterol 2017; 112:1689-1699 Personalized Medicine for FD/GP?

CBT / Mind-Body Therapies

Gastric Electrical Simulation Pyloric Botox Injection

Current Opinion in Pharmacology 2018, 43:111–117 Personalized Medicine for FD/GP? Symptom-Directed Therapy

• “PDS-dominant”: likely impaired accommodation, possibly delayed gastric emptying

• “EPS-dominant”: likely visceral hypersensitivity

• “N/V-dominant”: consider gastric emptying, but likely central mechanisms + visceral hypersensitivity Dietary Approaches for Dyspepsia

• Smaller, more frequent meals (snacking/grazing, rather than 3 meals/day)

• Decrease fat content (avoid fried, greasy foods)

• Avoid highly fibrous foods (raw vegetables) • Cooked vegetables may be tolerated

• Nutritive soft/liquid diet for severe dyspeptic symptoms (with weight loss) Tailored Pharmacotherapy for Dyspepsia

• Visceral Hypersensitivity • PPI • TCAs • Neuromodulators (SNRIs, gabapentanoids)

• Impaired Fundic Accommodation • •

• Impaired Gastric Emptying • Prokinetics

• Nausea Dominance • Anti-emetics PPI for Dyspepsia

Meta-analysis

15 RCTs; n=5,853 FD pts

RR = 0.87 [0.82-0.94] w/ PPI

ACG and CAG Clinical Guideline: Management of Dyspepsia. Am J Gastroenterol. 2017 Jul;112(7):988-1013. Neuromodulators for Dyspepsia

“EPS” 292 FD Patients

12-week RCT: 1:1:1

Placebo (50 mg) (20 mg)

~12% withdrawal in all arms “PDS” ITT Analysis

Talley et al. Gastroenterology 2015;149:340–349 Neuromodulators for Gastroparesis

NORIG ( for Idiopathic GP)

15 week double-blind RCT: n=130 1:1 – Placebo: 75 mg Nortriptyline (dose-escalation)

NO EVIDENCE OF EFFICACY

Talley et al. Gastroenterology 2015;149:340–349 JAMA. 2013 Dec 25;310(24):2640-9. Neuromodulators for Dyspepsia

Gabapentin (low dose, 50 to 300 mg PO TID)

Open Label, Retrospective Cohort Study (Pain) N=62 “Treatment Refractory” FD Pts

2/3 with anxiety and or depression 1/2 of cohort on TCA/SSRI/SNRI prior to tx

50% responder rate (Using minimal clinical significant cutoff of 0.3 on total symptom score)

J Clin Gastroenterol. 2019 May/Jun;53(5):379-384. “Fundus Relaxants” for Dyspepsia

5-HT1a Receptor : Buspirone (5-15 mg PO TID)

Clin Gastroenterol Hepatol 2012;10:1243 Mirtazapine for Dyspepsia

34 patients with FD and >10% wt loss from baseline (15% delayed GE; 50% impaired accommodation; 44% hypersensitivity)

RCT: 8 weeks placebo vs. mirtazapine 15 mg qhs

Clinical Gastroenterology and Hepatology 2016;14:385–392 Prokinetics for Dyspepsia

Risk Ratio [95% CI]

Meta-Analysis: Cisapride for FD

567 FD pts (mixed population)

Random-effects model

Conclusion: Improvement in ~25% of patients

Am J Gastroenterol. 2017 Jul;112(7):988-1013. Prokinetics for Gastroparesis

Improvements in Gastric Emptying Do NOT clearly correlate with symptom improvement!!

Am J Gastroenterol 2013; 108:1382 – 1391 Anti-Emetics for Nausea-Dominant Dyspepsia

Standard Medications: • , , (the “big 3”) • Anti-histamines () • Anti-cholinergics ( patch)

Emerging use: • Mirtazapine • • Aprepitant

CAM therapies: • Aromatherapy • Accupuncture / Accupressure Psychological Interventions for Dyspepsia

“Psychotherapy” 2 trials; n=250 RR 0.56 [0.48-0.67] Psychological therapies – NNT ~2

High placebo rates in FD and GP trials CBT 2 trials; n=144 CAM / Mind-Body Medicine RR 0.44 [0.26-0.75] - Need for high quality trials!

RR 0.53 [0.44-0.65] Total psych therapy 4 trials; n=394

Favors Treatment Favors Control Am J Gastroenterol. 2017 Jul;112(7):988-1013. Devices/Surgery for Gastroparesis

Meta-Analysis of GES for Gastroparesis Often considered when nutritional status is impaired

Nutrition-support: 1) Nasojejunal tube 2) Venting gastrostomy + jejunostomy (or combined G-J tube) 3) TPN (rare)

Non-pharmacological treatments 1) Pyloric Botox injection (failed placebo-RCTs) 2) Gastric electrical stimulation (GES) (failed placebo-RCTs) 3) Pyloroplasty (surgical vs. G-POEM) (no sham-RCTs) 4) Partial gastrectomy / Roux-en-Y (no formal studies)

Favors treatment Favors control Autonomic Neuroscience: Basic and Clinical 202 (2017) 45–55 Questions?