Functional Dyspepsia and GastroparesisFunctional Dyspepsia and Gastroparesis David J. Levinthal, MD,...

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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

Transcript of Functional Dyspepsia and GastroparesisFunctional Dyspepsia and Gastroparesis David J. Levinthal, MD,...

Functional Dyspepsia and Gastroparesis

David J. Levinthal, MD, PhDDirector, Neurogastroenterology and Motility Center

Assistant Professor, Department of MedicineDivision of Gastroenterology, Hepatology, and Nutrition

University of Pittsburgh Medical Center

Disclosures

Takeda PharmaceuticalsInControl 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

10-20%

F ≥ M

All adults

~33%

Anxiety / DepressionEarly-life adversity

Other chronic pain disorders

Prevalence (general population)

Gender

Age

Delayed Gastric Emptying

Associated Conditions

Gastroparesis

0.2 - 1%

3:1 F>M

All adults

100%

Diabetes Parkinson’s

Scleroderma (>50% idiopathic)

Functional Dyspepsia: Rome IV Criteria

1 or more: post-prandial fullness, early satiation, epigastric pain or burning ANDNo evidence of structural disease (i.e. normal EGD; negative H. pylori)

Symptom persistence – last 3 months, onset at least 6 months priorSymptom 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)

Gastroenterology 2009;136:1526–1543Gastroenterology 2016;150:1380–1392

Blurred Lines in FD and GP: Are they really distinct disorders?

Normal Gastric Motor Physiology Potential Pathophysiological Mechanisms

Gastroenterology 2001;121:526–535.

Measuring Visceral (gastric) HypersensitivityGastric “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.”

Mind Influences the Stomach: normal physiology

Geeraerts et al. (2005) Gastroenterology 129:1437-1444.

Neutral Face (Visual)Neutral Story (Audio)

Fearful Face (Visual)Scary Story (Audio)

Gastroenterology 2009;136:1526 –1543

4 hour solid-phase GES: 99mTc-infused egg sandwich

NORMAL: <10% retention @ 4 hrs

~1/3 FD pts have 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”

Lag Phase

Emptying Phase

Measuring Gastric Emptying

“FD” w/ mild GE delay

GP w/ severe GE delay

Am J Gastroenterol 2017; 112:1689-1699

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”)

FD vs. GP – Can one make the distinction?

GE = gastric emptyingGA = gastric accommodation

Current Opinion in Pharmacology 2018, 43:111–117

CBT / Mind-Body Therapies

Pyloric Botox Injection

Personalized Medicine for FD/GP?

Gastric Electrical Simulation

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

• 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)

Dietary Approaches for Dyspepsia

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

• Impaired Fundic Accommodation • Buspirone• Mirtazapine

• Impaired Gastric Emptying • Prokinetics

• Nausea Dominance• Anti-emetics

Tailored Pharmacotherapy for Dyspepsia

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.

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

Neuromodulators for Dyspepsia“EPS”

“PDS”

292 FD Patients

12-week RCT: 1:1:1

PlaceboAmitriptyline (50 mg)Escitalopram (20 mg)

~12% withdrawal in all armsITT Analysis

NORIG (Nortriptyline for Idiopathic GP)

15 week double-blind RCT: n=130

1:1 – Placebo: 75 mg Nortriptyline (dose-escalation)

NO EVIDENCE OF EFFICACY

JAMA. 2013 Dec 25;310(24):2640-9.

Neuromodulators for Gastroparesis

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

Neuromodulators for Dyspepsia

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

Open Label, Retrospective Cohort StudyN=62 “Treatment Refractory” FD Pts

2/3 with anxiety and or depression1/2 of cohort on TCA/SSRI/SNRI prior to tx

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

(Pain)

J Clin Gastroenterol. 2019 May/Jun;53(5):379-384.

Clin Gastroenterol Hepatol 2012;10:1243

“Fundus Relaxants” for Dyspepsia5-HT1a Receptor Agonists: Buspirone (5-15 mg PO TID)

Clinical Gastroenterology and Hepatology 2016;14:385–392

Mirtazapine for Dyspepsia34 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

Prokinetics for Dyspepsia

Meta-Analysis: Cisapride for FD

567 FD pts (mixed population)

Random-effects model

Conclusion: Improvement in ~25% of patients

Risk Ratio [95% CI]

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

Prokinetics for Gastroparesis

Am J Gastroenterol 2013; 108:1382 – 1391

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

Anti-Emetics for Nausea-Dominant Dyspepsia

Standard Medications:• Promethazine, prochlorperazine, ondansetron (the “big 3”)• Anti-histamines (meclizine)• Anti-cholinergics (scopolamine patch)

Emerging use:• Mirtazapine • Dronabinol• Aprepitant

CAM therapies:• Aromatherapy• Accupuncture / Accupressure

Psychological Interventions for Dyspepsia

Favors Treatment Favors Control

RR 0.56 [0.48-0.67]

RR 0.44 [0.26-0.75]

RR 0.53 [0.44-0.65]

“Psychotherapy”2 trials; n=250

CBT2 trials; n=144

Total psych therapy4 trials; n=394

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

Psychological therapies – NNT ~2

High placebo rates in FD and GP trials

CAM / Mind-Body Medicine- Need for high quality trials!

Devices/Surgery 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

Meta-Analysis of GES for Gastroparesis

Autonomic Neuroscience: Basic and Clinical 202 (2017) 45–55

Questions?