Refractory Gastroesophageal Reflux Disease

Educational Objectives

The goal of this program is to improve the management of refractory gastroesophageal reflux disease (GERD) ). After hearing and assimilating this program, the clinician will be better able to:

1. Ensure patients with refractory GERD take proton pump inhibitors properly for optimal effect.

2. Determine whether symptoms are due to persistent acidic or nonacidic reflux.

3. Prescribe appropriate medical therapy for residual symptoms of GERD.

Summary

Efficacy of proton pump inhibitors (PPIs) for symptoms of gastroesophageal reflux disease (GERD): survey study of >1000 patients found 38% had residual symptoms; ≈50% of patients still take over-the-counter medications; patients with erosive GERD have better response to treatment, but majority of patients evaluated for GERD have nonerosive disease

Refractory GERD: defined as continued symptoms on PPI taken twice daily (dosing not approved by Food and Drug Administration [FDA]); studies show that, with once daily use of PPI, ≤30% of patients have continued production of acid; twice daily dosing commonly recommended and used (associated with abnormal production of acid in <10% of patients); few patients have resistant secretion of acid

Mechanism of PPIs: medication reaches parietal cells of stomach from basal side through bloodstream; PPIs subsequently excreted into lumen of stomach in which proton pumps located; PPIs protonated and activated in acidic environment (medication must be taken near mealtime, when acid present in stomach); once patient reaches steady state of PPI use, majority of pumps blocked; in general, all PPIs equally effective

GERD due to motility disorder: occurs at lower esophageal sphincter (consists of tonically contracted muscular center and diaphragmatic crura); frequency and duration of transient lower esophageal sphincter relaxations (TLESRs) increased; TLESR can be due to hiatal hernia

Visceral hypersensitivity: when bolus contacts wall of gastrointestinal tract, distention triggers motor and sensory signals; serotonergic neurons send signals to interneurons; above bolus, acetylcholine signal causes contraction of esophagus to push food down; inhibitory signals (eg, nitric oxide, vasoactive intestinal peptide [VIP]) go downstream of bolus to relax esophagus; serotonergic pathway sends signals to brain (cause sensations of pain, distension, difficulty swallowing, and/or globus); nerves possibly hypersensitive in patients with GERD

Management of refractory GERD

Compliance with medications: study by El-Serag et al (2009) — only 66% to 70% of prescriptions for PPIs filled; at 1 yr, compliance <50%; directions — take PPI before breakfast (first meal activates all proton pumps) for once-daily dosing; drug should not be taken before bedtime (medication does not work well in nonacidic stomach); patients using twice-daily dosing should take PPI before breakfast and dinner; correct timing of medication may be sufficient to resolve symptoms

Indications for endoscopy: generally not required for average person with GERD; appropriate if — GERD untreated >5 yr (screen for, eg, Barrett syndrome); reflux develops at >50 yr of age (risk for malignancy increased); warning signs (eg, dysphasia, bleeding) present; eosinophilic esophagitis (EE) — feline esophagus (ie, transient transverse esophageal folds) seen on endoscopy; incidence increasing; biopsy often performed on middle portion of esophagus; patients with EE respond well to immunosuppressive therapy (first line, 6 wk of swallowed fluticasone; recurrent or long-term therapy may be needed); presents with persistent reflux on PPIs and (often) some dysphagia; most common structural inflammatory disease seen in patients with reflux

pH testing: can identify persistent acid reflux; Bravo capsule pH monitoring system — affixes device to wall of esophagus; radio controls monitor pH activity for 48 hr; study often done with patient on PPI; results may show persistent acid reflux

Nonacidic reflux: may contribute to symptoms of gas and liquid from stomach (especially in hypersensitive patients), bile acids from duodenum, and reflux into mid- and upper esophagus; impedance testing — can identify nonacidic reflux; catheter placed down esophagus through nose; small amount of air precedes bolus of liquid; when air reaches catheter, impedance increases; when fluid bolus reaches catheter, impedance decreases markedly; when esophagus contracts, impedance increases again and returns to baseline; as bolus moves down, areas of impedance normally fall in stepwise fashion; in patients with reflux, impedance moves in opposite direction (low at bottom)

Practical tips for treatment: residual acid reflux — histamine blockers taken before bedtime (in addition to PPI taken before breakfast and dinner) may be helpful; studies variable but some show improvement in nocturnal symptoms; bile acid binders — eg, cholestyramine; can be used to treat nonalkaline reflux; no data on efficacy; promotility agents — metoclopramide effective in some patients with GERD but use restricted due to side effect profile; erythromycin only effective short term (tachyphylaxis develops after ≈3 days); TLESR inhibitors — g-aminobutyric acid (GABA) receptor agonists may decrease TLESRs (eg, baclofen appears to decrease reflux of gastric contents in placebo-controlled studies) but data limited

Functional heartburn: may be due to visceral hypersensitivity (diagnostic criteria from Rome Foundation); visceral pain modulators — effective in treatment of noncardiac chest pain; not proven for treatment of refractory GERD, but small studies show some benefit; drugs used include — amitriptyline (eg, Elavil, Endep, Vanatrip) dosed at 10 mg twice daily or 25 mg at bedtime; selective serotonin reuptake inhibitors (eg, paroxetine [Paxil, Pexeva], citalopram [Celexa])

Questions and Answers

Discontinuation of PPIs after GERD effectively controlled: studies show discontinuation produces rebound effect; only 20% to 25% of patients with proven GERD can stop medication (most patients [eg, almost 100% of those with erosive disease, 60%-75% of those with nonerosive disease] have recurrence of symptoms)

Risks of long-term use of PPIs: increased risk for osteoporosis (generally in patients with preexisting osteomalacia); associated with small increases in incidence of hospital-acquired pneumonia and Clostridium difficile infection; risks not high enough to contraindicate long-term use, but use only if indicated

Recommendations for travel to developing countries: no data available; Infectious Disease Society currently does not recommend discontinuation of PPIs

Readings

Abonia JP, Rothenberg ME: Eosinophilic esophagitis: rapidly advancing insights. Annu Rev Med 2012;63:421-34; Alexander JA et al: Swallowed fluticasone improves histologic but not symptomatic response of adults with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2012 Jul;10(7):742-749; El-Serag HB et al: The extent and determinants of prescribing and adherence with acid-reducing medications: a national claims database study. Am J Gastroenterol 2009 Sep;104(9):2161-7; Fass R: Therapeutic options for refractory gastroesophageal reflux disease. J Gastroenterol Hepatol 2012 Apr;27 Suppl 3:3-7; Filik L: Montelukast and maintenance of steroid-induced remission in eosinophilic esophagitis. Dig Dis Sci 2012 Jan;57(1):258-9; Gonsalves N et al: Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointest Endosc 2006 Sep;64(3):313-9; Hershcovici T, Fass R: An algorithm for diagnosis and treatment of refractory GERD. Best Pract Res Clin Gastroenterol 2010 Dec;24(6):923-36; Karamanolis G et al: Yield of combined impedance-pH monitoring for refractory reflux symptoms in clinical practice. J Neurogastroenterol Motil 2011 Apr;17(2):158-63; Liacouras CA et al: Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011 Jul;128(1):3-20; Liu JJ, Saltzman JR: Refractory gastro-oesophageal reflux disease: diagnosis and management. Drugs 2009 Oct 1;69(14):1935-44; Redd M, Schey R: Eosinophilic Esophagitis: Current Treatment. Dig Dis Sci 2012 Sep 22 [Epub ahead of print]; Roorda AK et al: Algorithmic approach to patients presenting with heartburn and epigastric pain refractory to empiric proton pump inhibitor therapy. Dig Dis Sci 2011 Oct;56(10):2871-8; Scarpignato C: Poor effectiveness of proton pump inhibitors in non-erosive reflux disease: the truth in the end! Neurogastroenterol Motil 2012 Aug;24(8):697-704; Schoepfer AM et al: Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am J Gastroenterol 2010 May;105(5):1062-70; Sifrim D, Zerbib F: Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut 2012 Sep;61(9):1340-54; Straumann A: Treatment of eosinophilic esophagitis: diet, drugs, or dilation? Gastroenterology 2012 Jun;142(7):1409-11; Straumann A et al: Pediatric and adult eosinophilic esophagitis: similarities and differences. Allergy 2012 Apr;67(4):477-90; Yan BM, Shaffer EA: Eosinophilic esophagitis: a newly established cause of dysphagia. World J Gastroenterol 2006 Apr 21;12(15):2328-34; Zaninotto G, Attwood SE: Surgical management of refractory gastro-oesophageal reflux. Br J Surg 2010 Feb;97(2):139-40; Zerbib F et al: Functional heartburn: definition and management strategies. Curr Gastroenterol Rep 2012 Jun;14(3):181-8; Zur E: Eosinophilic esophagitis: treatment with oral viscous budesonide. Int J Pharm Compd 2012 Jul-Aug;16(4):288-93.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and the planning committee reported nothing to disclose. In his lecture, Dr. Lowe presents information that is related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Lowe was recorded at Controversies in Internal Medicine 2012, held May 7-11, 2012, in Hilton Head Island, SC, and presented by Boston University School of Medicine.  For information about Boston University School of Medicine’s Controversies in Internal Medicine 2013, scheduled for May 6-10, 2013, please visit their website at www.bu.edu. The Audio-Digest Foundation thanks the speaker and the sponsor for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM600501

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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