Ronnie Fass, MD. Professor of Medicine Case Western Reserve University The Role of Stress in Gastroesophageal Reflux Disease – What Do We Know? Ronnie Fass, MD. Professor of Medicine Case Western Reserve University Pathophysiology and Treatment of GERD, Atlanta, March 2008

MetroHealth Medical Center

Case Western Reserve University Pathophysiology and Treatment of GERD, Atlanta, March 2008

Chronic Vs. Acute

The Effect of Life Stress on Symptoms of Heartburn Sixty subjects with current heartburn symptoms were recruited by community advertisement All assessed for presence of stressful life events retrospectively over the preceding 6 months and prospectively for 4 months. Symptom severity by daily diary, quality of life, and psychological symptoms of anxiety, depression, and vital exhaustion were also measured.

The Effect of Life Stress on Symptoms of Heartburn Naliboff BD Psychosom Med 2004 May-Jun;66(3):426-34.

The Effect of Life Stress on Symptoms of Heartburn The presence of a severe, sustained life stress during the previous 6 months significantly predicted increased heartburn symptoms during the following 4 months Naliboff BD Psychosom Med 2004 May-Jun;66(3):426-34.

Acute Stress and GERD Up to 64% of GERD patients reported that stress exacerbated their reflux symptoms (Gallup survey, 1988) What is the mechanism?

Does Stress Increase Intra – Esophageal Acid Exposure? Stressful tasks in normal subjects - no change in pH measurements (Cook, 1986) Prolonged stressors in GERD patients - no change in intra-esophageal acid exposure post prandially (Bradley, 1993) No!

Stress and GERD Highly anxious patients reported increased reflux symptoms during stress despite no change in intra-esophageal pH (Bradley, 1993)

Aim To determine the effect of an established acute psychologic stress condition on perceptual and emotional responses in healthy controls and patients with established GERD, subclassified as nonerosive reflux disease (NERD) and erosive esophagitis (EE).

Study Design Fass et al. Gastroenterology 2008;134:696-706

Stress Induction Psychologic stress was achieved by using dichotic listening, which involves 2 conflicting types of music delivered simultaneously at 30 dB, via separate headphone channels. Folk music in a foreign language was heard by the subject in one ear and “heavy metal” music in the other ear. Objectively, increased autonomic function was documented during stress induction. Subjectively, by using the SRR, subjects scored higher as compared with baseline on the stress scale. During the control period, background instrumental music was delivered through both headphone channels. All patients and normal controls were exposed to the same music. Fass et al. Gastroenterology 2008;134:696-706

Dual Chamber Harvard Apparatus Fass & Eslick. Noncardiac Chest Pain–A Growing Medical Problem. Plural Publishing, San Diego, 2007.

Fass et al. Gastroenterology 2008;134:696-706

Auditory Stress and Esophageal Sensitivity † ‡ * + ** ++ * P = 0.01 ** P = 0.1 + P < 0.001 ++ P = 0.01 † P = NS ‡P = NS Fass et al. Gastroenterology 2008;134:696-706

Effect of Stress on Acute Mood Rating Fass et al. Gastroenterology 2008;134:696-706

Conclusions Auditory stress can enhance perceptual responses to intra-esophageal acid stimuli (esophageal hypersensitivity) Increased perceptual response to intraluminal acid was associated with increased emotional responses to the stressor but was not related to the presence or absence of esophageal mucosal injury Fass et al. Gastroenterology 2008;134:696-706

Anxiety Increases Acid – Induced Esophageal Hyperalgesia Sharma A et al. Psychosom Med.2010 Oct;72(8):802-9.

Esophageal Hypersensitivity The perception of non-painful esophageal stimuli as being painful and painful esophageal stimuli as being more painful Remes and Fass, Handbook of GI Motility and Functional Disorders textbook 2015

Esophageal hypersensitivity Reflux hypersensitivity Acid exposure Figure 2 (QA 1) Roles of acid exposure and esophageal hypersensitivity in overlapping GERD and functional esophageal syndromes. Acid exposure and response to proton pump inhibitors decreases from erosive esophagitis to functional heartburn while esophageal hypersensitivity increases across the same spectrum. (Adapted from Galmiche et al, UEG Journal 2013). Erosive esophagitis NERD Reflux hypersensitivity Functional heartburn 09-02 QA 1 Galmiche et al, UEG 2013

Esophageal Pain Sensation “Think Outside of the Lumen” Heartburn Central Stress Intraesophageal Stimulus Pathological Physiological Esophageal hypersensitivity Fass & Tougas Gut 2002;51(6):885-892.

Stress and Mechanisms of Heartburn Ang, Sifrim & Tack, Nat Clin Pract Gastroenterol Hepatol 2008;5(7):383-392

The Effect of Psychological Distress on Response to PPI Treatment (Rabeprazole 20mg/d for 8 weeks) Nojkov B et al. Aliment Pharmacol Ther 2008:27;473-482

Factors Associated with Partial Response to PPI Treatment of GERD Patients in Primary care -The health improvement network – UK -Partial responders – 120/6453 (18.6%) - New tx, increase dose, switching PPI Factor OR 95% CI Female 1.25 1.05 – 1.37 Anxiety or Depression 1.15 1.00 – 1.31 Prescription > 6 drugs before GERD 1.42 1.14 -1.78 Ruigomez et al. Scand J Gastroenterol. 2012 Jul;47(7):751-61

Prediction of Response to PPI Therapy and Factors Influencing Treatment Outcome in Patients with GORD -1888 GERD patients - A multicentre, multinational, prospective, open study of 8 weeks pantoprazole treatment, 40 mg daily Heading RC et al. BMC Gastroenterol. 2011 May 11;11:52

Aim To determine whether sleep deprivation by itself can exacerbate GERD by evaluating stimulus response functions to acid in GERD patients vs healthy controls, who experience sleep deprivation and sufficient sleep conditions.

Methods Ten healthy controls and 10 patients with erosive esophagitis (grades B–D) were included in the study. All subjects were randomized to either sleep deprivation (1 night with <3 hours of sleep) or sufficient sleep (3 days with >7 hours sleep/night). Patients crossed over to the other arm after a washout period of 1 week. To ensure proper sleep time, we objectively monitored subjects with an actigraph. The morning after sufficient sleep or sleep deprivation, patients underwent stimulus response functions to esophageal acid perfusion.

Acid Perfusion Sensitivity Score The Relationship Between Acid Perfusion Sensitivity Score and Sleep Deprivation During an Acid Perfusion Test 0.1 N HCl 10 cc/min Acid Sensitivity * Acid Perfusion Sensitivity Score *p < 0.05 Sleep Groups Schey R et al. Gastroenterology 2007;133:1787-1795 Sleep & GERD--An Eye-Opening Experience,Israel_Dec2011

Conclusions Sleep deprivation is hyperalgesic in patients with GERD This is a potential mechanism for increase in GERD symptom severity in sleep-deprived patients. Schey R et al. Gastroenterology 2007;133:1787-1795

The Bidirectional Relationship Between Sleep and GERD Increase Alter Esophageal physiology Sleep GERD Increase Decrease Decrease Increase Fass R. J Gastroenterol Hepatol 2010:25;S41 – S44 Sleep & GERD--An Eye-Opening Experience,Israel_Dec2011

Aims To determine if esomeprazole 40 mg daily, given over a period of 8 weeks, may attenuate the effect of acute stress on symptom perception of patients with GERD as compared with placebo To determine the clinical predictive factors for response to esomeprazole 40 mg daily in GERD patients undergoing stressful stimulus. Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e489-96. 

Study Design Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e489-96. 

Comparison of Mean Acid Perfusion Sensitivity Score Between the Esomeprazole Group and Those Who Received Placebo Once Daily Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e489-96. 

Conclusions Treatment with a PPI significantly reduced esophageal perceptual responses to acid even during a stressful stimulus. Interpersonal sensitivity was the sole predictor for response to antireflux treatment during acute stress. Poh CH et al. Neurogastroenterol Motil 2011 Nov;23(11):e489-96. 

Chernivtsi

Conclusions Chronic and acute stress exacerbate GERD symptoms Acute stress exacerbates GERD symptoms through centrally induced esophageal hypersensitivity to intra-luminal stimuli Chronic stress affects response to PPI treatment PPI treatment attenuates the effect of acute stress on esophageal hypersensitivity

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