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Review

Pharmacological Management of Gastro-Esophageal Reflux Disease: An Update of the State-of-the-Art

ORCID Icon, , ORCID Icon, , & ORCID Icon
Pages 1609-1621 | Published online: 19 Apr 2021

References

  • VakilN, van ZantenSV, KahrilasP, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–1920. doi:10.1111/j.1572-0241.2006.00630.x16928254
  • DentJ, El-SeragHB, WallanderMA, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2005;54:710–717. doi:10.1136/gut.2004.05182115831922
  • PandolfinoJE, El-SeragHB, ZhangQ, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology. 2006;130:639–649. doi:10.1053/j.gastro.2005.12.01616530504
  • SavarinoE, ZentilinP, MarabottoE, et al. Overweight is a risk factor for both erosive and non-erosive reflux disease. Dig Liver Dis. 2011;43:940–945. doi:10.1016/j.dld.2011.07.01421944835
  • HerregodsTV, BredenoordAJ, SmoutAJ. Pathophysiology of gastroesophageal reflux disease: new understanding in a new era. Neurogastroenterol Motil. 2015;27:1202–1213. doi:10.1111/nmo.1261126053301
  • SavarinoE, de BortoliN, De CassanC, et al. The natural history of gastro-esophageal reflux disease: a comprehensive review. Dis Esophagus. 2017;30:1–9. . doi:10.1111/dote.12511
  • SavarinoV, MarabottoE, ZentilinP, et al. Pathophysiology, diagnosis, and pharmacological treatment of gastro-esophageal reflux disease. Expert Rev Clin Pharmacol. 2020;13:437–449. doi:10.1080/17512433.2020.175266432253948
  • PouderouxP, VerdierE, KahrilasPJ. Patterns of esophageal inhibition during swallowing, pharyngeal stimulation, and transient LES relaxation. Lower esophageal sphincter. Am J Physiol Gastrointest Liver Physiol. 2003;284:G242–G247. doi:10.1152/ajpgi.00301.200212388187
  • SavarinoE, MeiF, ParodiA, et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology. 2013;52:1095–1100. doi:10.1093/rheumatology/kes42923382360
  • ToloneS, SavarinoE, ZaninottoG, et al. High-resolution manometry is superior to endoscopy and radiology in assessing and grading sliding hiatal hernia: a comparison with surgical in vivo evaluation. United European Gastroenterol J. 2018;6:981–989. doi:10.1177/2050640618769160
  • SavarinoE, BredenoordAJ, FoxM, et al. International working group for disorders of gastrointestinal motility and function. Expert consensus document: advances in the physiological assessment and diagnosis of GERD. Nat Rev Gastroenterol Hepatol. 2017;14:665–676. . doi:10.1038/nrgastro.2017.13028951582
  • FrazzoniM, de BortoliN, FrazzoniL, et al. Impedance-pH monitoring for diagnosis of reflux disease: new perspectives. Dig Dis Sci. 2017;62:1881–1889. doi:10.1007/s10620-017-4625-828550489
  • NobileS, MeneghinF, MarchionniP, et al. Response to therapy among neonates with gastro-esophageal reflux is associated with esophageal clearance. Early Hum Dev. 2021;152:105248. doi:10.1016/j.earlhumdev.2020.10524833188979
  • McCallumRW, BerkowitzDM, LernerE. Gastric emptying in patients with gastroesophageal reflux. Gastroenterology. 1981;80:285–291. doi:10.1016/0016-5085(81)90716-27450419
  • ZentilinP, DulbeccoP, BilardiC, et al. Circadian pattern of intragastric acidity in patients with non-erosive reflux disease (NERD). Aliment Pharmacol Ther. 2003;17:353–359. doi:10.1046/j.1365-2036.2003.01422.x12562447
  • ScarpignatoC, HongoM, WuJCY, et al. Pharmacologic treatment of GERD: where we are now, and where are we going? Ann N Y Acad Sci. 2020.
  • FarréR. Pathophysiology of gastro-esophageal reflux disease: a role for mucosa integrity? Neurogastroenterol Motil. 2013;25:783–799. doi:10.1111/nmo.1220123937353
  • ZentilinP, SavarinoV, MastracciL, et al. Reassessment of the diagnostic value of histology in patients with GERD, using multiple biopsy sites and an appropriate control group. Am J Gastroenterol. 2005;100:2299–2306. doi:10.1111/j.1572-0241.2005.50209.x16181384
  • SavarinoE, ZentilinP, MastracciL, et al. Microscopic esophagitis distinguishes patients with non-erosive reflux disease from those with functional heartburn. J Gastroenterol. 2013;48:473–482. . doi:10.1007/s00535-012-0672-223001252
  • SavarinoE, ZentilinP, SavarinoV. NERD: an umbrella term including heterogeneous subpopulations. Nat Rev Gastroenterol Hepatol. 2013;10:371–380. doi:10.1038/nrgastro.2013.5023528345
  • RonkainenJ, AroP, StorskrubbT, et al. High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report. Scand J Gastroenterol. 2005;40:275–285. doi:10.1080/0036552051001157915932168
  • ZagariRM, FuccioL, WallanderMA, et al. Gastro-oesophageal reflux symptoms, oesophagitis and Barrett’s oesophagus in the general population: the Loiano-Monghidoro study. Gut. 2008;57:1354–1359. doi:10.1136/gut.2007.14517718424568
  • SavarinoE, ZentilinP, MarabottoE, et al. A review of pharmacotherapy for treating gastroesophageal reflux disease (GERD). Expert Opin Pharmacother. 2017;18:1333–1343. doi:10.1080/14656566.2017.136140728754071
  • AzizQ, FassR, GyawaliCP, et al. Functional esophageal disorders. Gastroenterology. 2016;150(6):1368–1379. . doi:10.1053/j.gastro.2016.02.012
  • FrazzoniL, FrazzoniM, de BortoliN, et al. Critical appraisal of Rome IV criteria: hypersensitive esophagus does belong to gastroesophageal reflux disease spectrum. Ann Gastroenterol. 2018;31:1–7. doi:10.20524/aog.2017.019929333061
  • SavarinoV, MarabottoE, ZentilinP, et al. Esophageal reflux hypersensitivity: non-GERD or still GERD? Dig Liver Dis. 2020;52:1413–1420. . doi:10.1016/j.dld.2020.10.00333097427
  • SavarinoV, MarabottoE, ZentilinP, et al. Proton pump inhibitors: use and misuse in the clinical setting. Expert Rev Clin Pharmacol. 2018;11:1123–1134. doi:10.1080/17512433.2018.153170330295105
  • SavarinoV, Di MarioF, ScarpignatoC. Proton pump inhibitors in GORD. An overview of their pharmacology, efficacy and safety. Pharmacol Res. 2009;59:135–153. doi:10.1016/j.phrs.2008.09.01618977444
  • LundellLR, DentJ, BennettJR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–180. doi:10.1136/gut.45.2.17210403727
  • KhanM, SantanaJ, DonnellanC, et al. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev. 2007;CD003244.17443524
  • van PinxterenB, SigtermanKE, BonisP, et al. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev. 2010:CD002095. doi:10.1002/14651858.CD002095.pub421069670
  • KahrilasPJ, HowdenCW, HughesN. Response of regurgitation to proton pump inhibitor therapy in clinical trials of gastroesophageal reflux disease. Am J Gastroenterol. 2011;106:1419–1425. doi:10.1038/ajg.2011.14621537361
  • KahrilasPJ, HughesN, HowdenCW. Response of unexplained chest pain to proton pump inhibitor treatment in patients with and without objective evidence of gastro-oesophageal reflux disease. Gut. 2011;60:1473–1478. doi:10.1136/gut.2011.24130721508423
  • VakilNB, TraxlerB, LevineD. Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment. Clin Gastroenterol Hepatol. 2004;2:665–668. doi:10.1016/S1542-3565(04)00289-715290658
  • DeanBB, GanoAD, KnightK, et al. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol. 2004;2:656–664. doi:10.1016/S1542-3565(04)00288-515290657
  • ScarpignatoC. Poor effectiveness of proton pump inhibitors in non-erosive reflux disease: the truth in the end! Neurogastroenterol Motil. 2012;24:697–704. doi:10.1111/j.1365-2982.2012.01977.x22783985
  • WeijenborgPW, CremoniniF, SmoutAJ, et al. PPI therapy is equally effective in well-defined non-erosive reflux disease and in reflux esophagitis: a meta-analysis. Neurogastroenterol Motil. 2012;24:747–757. doi:10.1111/j.1365-2982.2012.01888.x22309489
  • VigneriS, TerminiR, LeandroG, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med. 1995;333:1106–1110. doi:10.1056/NEJM1995102633317037565948
  • ThjodleifssonB, RindiG, FioccaR, et al. European Rabeprazole Study Group. A randomized, double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther. 2003;17:343–351. doi:10.1046/j.1365-2036.2003.01446.x12562446
  • GhisaM, Della ColettaM, BarbuscioI, et al. Updates in the field of non-esophageal gastroesophageal reflux disorder. Expert Rev Gastroenterol Hepatol. 2019;13:827–838. doi:10.1080/17474124.2019.164559331322443
  • SavarinoV, DulbeccoP, SavarinoE. Are proton pump inhibitors really so dangerous? Dig Liver Dis. 2016;48:851–859.27321544
  • FreedbergDE, KimLS, YangYX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152:706–715. . doi:10.1053/j.gastro.2017.01.03128257716
  • SavarinoV, MarabottoE, FurnariM, et al. Latest insights into the hot question of proton pump inhibitor safety - a narrative review. Dig Liver Dis. 2020;52:842–852. doi:10.1016/j.dld.2020.04.02032513631
  • El-SeragH, BecherA, JonesR. Systematic review: persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Aliment Pharmacol Ther. 2010;32:720–737. doi:10.1111/j.1365-2036.2010.04406.x20662774
  • KatzPO. The proton pump inhibitor is not working: assess don’t guess. Gastroenterology. 2021;160(1):19–20. doi:10.1053/j.gastro.2020.10.04333157096
  • SavarinoE, PohlD, ZentilinP, et al. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease. Gut. 2009;58:1185–1191. doi:10.1136/gut.2008.17581019460766
  • SifrimD, ZerbibF. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;61:1340–1354. doi:10.1136/gutjnl-2011-30189722684483
  • PenaginiR, SweisR, MauroA, et al. Inconsistency in the diagnosis of functional heartburn: usefulness of prolonged wireless pH monitoring in patients with proton pump inhibitor refractory gastroesophageal reflux disease. J Neurogastroenterol Motil. 2015;21:265–272. doi:10.5056/jnm1407525843078
  • FrazzoniM, de BortoliN, FrazzoniL, et al. The added diagnostic value of postreflux swallow-induced peristaltic wave index and nocturnal baseline impedance in refractory reflux disease studied with on-therapy impedance-pH monitoring. Neurogastroenterol Motil. 2017;29(3):e12947. doi:10.1111/nmo.12947
  • de BortoliN, FrazzoniL, SavarinoEV, et al. Functional heartburn overlaps with irritable bowel syndrome more often than GERD. Am J Gastroenterol. 2016;111:1711–1717. doi:10.1038/ajg.2016.43227644732
  • WatsonRG, ThamTC, JohnstonBT, et al. Double-blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux–the “sensitive oesophagus”. Gut. 1997;40:587–590. doi:10.1136/gut.40.5.5879203934
  • PauwelsA, BoeckxstaensV, AndrewsCN, et al. How to select patients for antireflux surgery? The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery). Gut. 2019;68:1928–1941. . doi:10.1136/gutjnl-2019-31826031375601
  • HoshinoS, KawamiN, TakenouchiN, et al. Efficacy of vonoprazan for proton pump inhibitor-resistant reflux esophagitis. Digestion. 2017;95:156–161. doi:10.1159/00045607228190016
  • AkiyamaJ, HosakaH, KuribayashiS, et al. Efficacy of vonoprazan, a novel potassium-competitive acid blocker, in patients with proton pump inhibitor-refractory acid reflux. Digestion. 2020;101(2):174–183. doi:10.1159/00049777530897577
  • TackJ, KoekG, DemedtsI, et al. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett’s esophagus: acid reflux, bile reflux, or both? Am J Gastroenterol. 2004;99:981–988. doi:10.1111/j.1572-0241.2004.04171.x15180713
  • de BortoliN, GyawaliCP, FrazzoniM, et al. Bile reflux in patients with NERD is associated with more severe heartburn and lower values of mean nocturnal baseline impedance and chemical clearance. Neurogastroenterol Motil. 2020;32:e13919. doi:10.1111/nmo.1391932573065
  • VaeziMF, FassR, VakilN, et al. IW-3718 reduces heartburn severity in patients with refractory gastroesophageal reflux disease in a randomized trial. Gastroenterology. 2020;158:2093–2103. doi:10.1053/j.gastro.2020.02.03132092310
  • BurgerhartJS, van de MeebergPC, SiersemaPD, et al. Nocturnal and daytime esophageal acid exposure in normal-weight, overweight, and obese patients with reflux symptoms. Eur J Gastroenterol Hepatol. 2014;26:6–10. doi:10.1097/MEG.0b013e328365c3cb24025979
  • KahrilasPJ, McCollK, FoxM, et al. The acid pocket: a target for treatment in reflux disease? Am J Gastroenterol. 2013;108:1058–1064. doi:10.1038/ajg.2013.13223629599
  • FletcherJ, WirzA, YoungJ, et al. Unbuffered highly acidic gastric juice exists at the gastroesophageal junction after a meal. Gastroenterology. 2001;121:775–783. . doi:10.1053/gast.2001.2799711606490
  • BeaumontH, BenninkRJ, de JongJ, et al. The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD. Gut. 2010;59:441–451. doi:10.1136/gut.2009.17806119651625
  • KwiatekMA, RomanS, FareeduddinA, et al. An alginate-antacid formulation (Gaviscon Double Action Liquid) can eliminate or displace the postprandial ‘acid pocket’ in symptomatic GERD patients. Aliment Pharmacol Ther. 2011;34:59–66. doi:10.1111/j.1365-2036.2011.04678.x21535446
  • MartinucciI, BlandizziC, BodiniG, et al. Vonoprazan fumarate for the management of acid-related diseases. Expert Opin Pharmacother. 2017;18:1145–1152. doi:10.1080/14656566.2017.134608728657473
  • SavarinoE, MartinucciI, FurnariM, et al. Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations. Expert Opin Drug Metab Toxicol. 2016;12:1333–1341. doi:10.1080/17425255.2016.121471427428571
  • SakuraiY, NishimuraA, KennedyG, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising TAK-438 (Vonoprazan) doses in healthy male Japanese/non-Japanese subjects. Clin Transl Gastroenterol. 2015;6:e94. doi:10.1038/ctg.2015.1826111126
  • SavarinoV, MelaGS, ZentilinP, et al. Comparison of 24-h control of gastric acidity by three different dosages of pantoprazole in patients with duodenal ulcer. Aliment Pharmacol Ther. 1998;12:1241–1247. doi:10.1046/j.1365-2036.1998.00416.x9882033
  • SuganoK. Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the management of gastroesophageal reflux disease: safety and clinical evidence to date. Therap Adv Gastroenterol. 2018;11:1756283X17745776. doi:10.1177/1756283X17745776
  • AshidaK, SakuraiY, NishimuraA, et al. Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis. Aliment Pharmacol Ther. 2015;42:685–695. doi:10.1111/apt.1333126201312
  • AshidaK, SakuraiY, HoriT, et al. Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis. Aliment Pharmacol Ther. 2016;43:240–251. doi:10.1111/apt.1346126559637
  • AshidaK, IwakiriK, HiramatsuN, et al. Maintenance for healed erosive esophagitis: phase III comparison of vonoprazan with lansoprazole. World J Gastroenterol. 2018;24:1550–1561. doi:10.3748/wjg.v24.i14.155029662293
  • SakuraiK, SudaH, FujieS, et al. Short-term symptomatic relief in gastroesophageal reflux disease: a comparative study of esomeprazole and vonoprazan. Dig Dis Sci. 2019;64:815–822. doi:10.1007/s10620-018-5365-030415407
  • OshimaT, AraiE, TakiM, et al. Randomised clinical trial: vonoprazan versus lansoprazole for the initial relief of heartburn in patients with erosive oesophagitis. Aliment Pharmacol Ther. 2019;49:140–146. doi:10.1111/apt.1506230589965
  • ChengY, LiuJ, TanX, et al. Direct comparison of the efficacy and safety of vonoprazan versus proton-pump inhibitors for gastroesophageal reflux disease: a systematic review and meta-analysis. Dig Dis Sci. 2020. . doi:10.1007/s10620-020-06141-5
  • VelaMF, TutuianR, KatzPO, et al. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther. 2003;17:243–251. doi:10.1046/j.1365-2036.2003.01394.x12534409
  • LiS, ShiS, ChenF, et al. The effects of baclofen for the treatment of gastroesophageal reflux disease: a meta-analysis of randomized controlled trials. Gastroenterol Res Pract. 2014;307805.25389436
  • WiseJ, ConklinJL. Gastroesophageal reflux disease and baclofen: is there a light at the end of the tunnel? Curr Gastroenterol Rep. 2004;6:213–219. doi:10.1007/s11894-004-0010-915128488
  • BoeckxstaensGE, DenisonH, JensenJM, et al. Translational gastrointestinal pharmacology in the 21st century: ‘the lesogaberan story’. Curr Opin Pharmacol. 2011;11:630–633. doi:10.1016/j.coph.2011.10.01122036168
  • RenLH, ChenWX, QianLJ, et al. Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: a meta-analysis. World J Gastroenterol. 2014;20:2412–2419. doi:10.3748/wjg.v20.i9.241224605040
  • YadlapatiR, VaeziMF, VelaMF, et al. Management options for patients with GERD and persistent symptoms on proton pump inhibitors: recommendations from an expert panel. Am J Gastroenterol. 2018;113:980–986. doi:10.1038/s41395-018-0045-429686276
  • GiudicessiJR, AckermanMJ, CamilleriM. Cardiovascular safety of prokinetic agents: a focus on drug-induced arrhythmias. Neurogastroenterol Motil. 2018;30:e13302. doi:10.1111/nmo.1330229441683
  • TackJ, CorsettiM. Prucalopride: evaluation of the pharmacokinetics, pharmacodynamics, efficacy and safety in the treatment of chronic constipation. Expert Opin Drug Metab Toxicol. 2012;8:1327–1335. doi:10.1517/17425255.2012.71949722985444
  • RomanS, GyawaliCP, SavarinoE, et al. GERD consensus group. Ambulatory reflux monitoring for diagnosis of gastro-esophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil. 2017;29:1–15. . doi:10.1111/nmo.13067
  • FrazzoniM, SavarinoE, de BortoliN, et al. Analyses of the post-reflux swallow-induced peristaltic wave index and nocturnal baseline impedance parameters increase the diagnostic yield of impedance-pH monitoring of patients with reflux disease. Clin Gastroenterol Hepatol. 2016;14:40–46. doi:10.1016/j.cgh.2015.06.02626122764
  • FrazzoniM, de BortoliN, FrazzoniL, et al. Impairment of chemical clearance and mucosal integrity distinguishes hypersensitive esophagus from functional heartburn. J Gastroenterol. 2017;52:444–451. . doi:10.1007/s00535-016-1226-927241210
  • WoodlandP, Shen OoiJL, GrassiF, et al. Superficial esophageal mucosal afferent nerves may contribute to reflux hypersensitivity in nonerosive reflux disease. Gastroenterology. 2017;153:1230–1239. doi:10.1053/j.gastro.2017.07.01728734832
  • WoodlandP, Batista-LimaF, LeeC, et al. Topical protection of human esophageal mucosal integrity. Am J Physiol Gastrointest Liver Physiol. 2015;308(12):G975–G980. doi:10.1152/ajpgi.00424.201425907692
  • SonmezS, CoyleC, SifrimD, et al. Duration of adhesion of swallowed alginates to distal oesophageal mucosa: implications for topical therapy of oesophageal diseases. Aliment Pharmacol Ther. 2020;52:442–448. . doi:10.1111/apt.1588432548849
  • BlackshawLA, BordinDS, BrockC, et al. Pharmacologic treatments for esophageal disorders. Ann N Y Acad Sci. 2014;1325:23–39. doi:10.1111/nyas.1252025266012
  • ManabeN, HarumaK, ItoM, et al. Efficacy of adding sodium alginate to omeprazole in patients with nonerosive reflux disease: a randomized clinical trial. Dis Esophagus. 2012;25:373–380. doi:10.1111/j.1442-2050.2011.01276.x22050449
  • ReimerC, LødrupAB, SmithG, et al. Randomised clinical trial: alginate (Gaviscon Advance) vs. placebo as add-on therapy in reflux patients with inadequate response to a once daily proton pump inhibitor. Aliment Pharmacol Ther. 2016;43:899–909. doi:10.1111/apt.1356726909885
  • Di SimoneMP, BaldiF, VasinaV, et al. Barrier effect of Esoxx(®) on esophageal mucosal damage: experimental study on ex-vivo swine model. Clin Exp Gastroenterol. 2012;5:103–107. doi:10.2147/CEG.S3140422767997
  • SavarinoV, PaceF, ScarpignatoC; Esoxx Study Group. Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation. Aliment Pharmacol Ther. 2017;45:631–642. . doi:10.1111/apt.1391428116754
  • ViazisN, KeyoglouA, KanellopoulosAK, et al. Selective serotonin reuptake inhibitors for the treatment of hypersensitive esophagus: a randomized, double-blind, placebo-controlled study. Am J Gastroenterol. 2012;107:1662–1667. doi:10.1038/ajg.2011.17921625270
  • OstovanehMR, SaeidiB, HajifathalianK, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil. 2014;26:670–678. doi:10.1111/nmo.1231324533896
  • LimsrivilaiJ, CharatcharoenwitthayaP, PausawasdiN, et al. Imipramine for treatment of esophageal hypersensitivity and functional heartburn: a randomized placebo-controlled trial. Am J Gastroenterol. 2016;111:217–224. doi:10.1038/ajg.2015.41326753892
  • ForceliniCM, TomiozzoJC, FarréR, et al. Effect of nortriptyline on brain responses to painful esophageal acid infusion in patients with non-erosive reflux disease. Neurogastroenterol Motil. 2014;26:187–195. doi:10.1111/nmo.1225124188252
  • MainieI, TutuianR, AgrawalA, et al. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg. 2006;93:1483–1487. doi:10.1002/bjs.549317051602
  • BroedersJA, DraaismaWA, BredenoordAJ, et al. Oesophageal acid hypersensitivity is not a contraindication to Nissen fundoplication. Br J Surg. 2009;96:1023–1030. doi:10.1002/bjs.668419672931
  • FrazzoniM, ConigliaroR, MelottiG. Reflux parameters as modified by laparoscopic fundoplication in 40 patients with heartburn/regurgitation persisting despite PPI therapy: a study using impedance-pH monitoring. Dig Dis Sci. 2011;56:1099–1106. doi:10.1007/s10620-010-1381-420737211
  • SpechlerSJ, HunterJG, JonesKM, et al. Randomized trial of medical versus surgical treatment for refractory heartburn. N Engl J Med. 2019;381:1513–1523. . doi:10.1056/NEJMoa181142431618539
  • FrazzoniM, PiccoliM, ConigliaroR, et al. Refractory gastroesophageal reflux disease as diagnosed by impedance-pH monitoring can be cured by laparoscopic fundoplication. Surg Endosc. 2013;27:2940–2946. doi:10.1007/s00464-013-2861-323436097