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

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

  • 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

    10-20%

    F ≥ M

    All adults

    ~33%

    Anxiety / Depression Early-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 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.

    https://www.ncbi.nlm.nih.gov/pubmed/?term=Epidemiology,+clinical+characteristics,+and+associations+for+symptom-based+Rome+IV+functional+dyspepsia+in+adults+in+the+USA,+Canada,+and+the+UK:+a+cross-sectional+population-based+study

  • 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;136:1526–1543 Gastroenterology 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) 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.”

  • 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:

  • 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 emptying GA = 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.

    https://www.ncbi.nlm.nih.gov/pubmed/28631728

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

    Neuromodulators for Dyspepsia “EPS”

    “PDS”

    292 FD Patients

    12-week RCT: 1:1:1

    Placebo Amitriptyline (50 mg) Escitalopram (20 mg)

    ~12% withdrawal in all arms ITT 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

    https://www.ncbi.nlm.nih.gov/pubmed/?term=NORIG+gastroparesis

  • Neuromodulators for Dyspepsia

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

    Open Label, Retrospective Cohort Study 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)

    (Pain)

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

    https://www.ncbi.nlm.nih.gov/pubmed/29668559

  • Clin Gastroenterol Hepatol 2012;10:1243

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

  • Clinical Gastroenterology and Hepatology 2016;14:385–392

    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

  • 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.

    https://www.ncbi.nlm.nih.gov/pubmed/28631728

  • 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

    CBT 2 trials; n=144

    Total psych therapy 4 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!

    https://www.ncbi.nlm.nih.gov/