, Volume 71, Issue 18, pp 2381–2389 | Cite as

Gastro-Oesophageal Reflux Disease

Beyond Proton Pump Inhibitor Therapy
Current Opinion


Gastro-oesophageal reflux disease (GORD or GERD) is a very common disorder, and advancement in drug development over the years has markedly improved disease management. Proton pump inhibitors (PPIs) remain the mainstay of treatment for GERD due to their profound and consistent inhibitory effect on acid secretion. However, PPIs do not reduce the number of reflux events and do not provide long-term cure for GERD. In addition, although the safety profile of PPIs is excellent, recent population-based studies have suggested that long-term PPI use may be associated with a variety of adverse events. They include osteoporosis-related hip and spine fractures, community-acquired and nosocomial pneumonia, various enteric and non-enteric infections, fundic gland polyps and many others. Consequently, there is growing interest by patients and physicians alike in current, as well as future, non-PPI-related therapeutic strategies for GERD. This includes repositioning histamine H2 receptor antagonists and prokinetics in our current GERD therapeutic algorithms and a resurgence of non-medical therapeutic modalities for GERD, such as anti-reflux surgery, endoscopic treatment, alternative and complementary medicine and psychological interventions. Furthermore, there will be renewed efforts in further developing new medical and non-medical therapeutic modalities for GERD.



Dr Fass has received research support from AstraZeneca and Reckitt-Benckiser and served as a speaker for Takeda, and as a consultant for Shire, Takeda, Vecta and Reckitt-Benckiser. Dr Hershcovici has no conflicts of interest that are directly relevant to the content of this article. No sources of funding were used in the preparation of this article.


  1. 1.
    Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005 May; 54(5): 710–7PubMedCrossRefGoogle Scholar
  2. 2.
    Locke 3rd GR, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997 May; 112(5): 1448–56PubMedCrossRefGoogle Scholar
  3. 3.
    Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976 Nov; 21(11): 953–6PubMedCrossRefGoogle Scholar
  4. 4.
    Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002 May; 122(5): 1500–11PubMedCrossRefGoogle Scholar
  5. 5.
    Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997 Jun; 112(6): 1798–810PubMedCrossRefGoogle Scholar
  6. 6.
    Fass R, Shapiro M, Dekel R, et al. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease. Where next? Aliment Pharmacol Ther 2005 Jul 15; 22(2): 79–94CrossRefGoogle Scholar
  7. 7.
    Moore JM, Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease: real or imagined? Curr Opin Gastroenterol 2010 Jul; 26(4): 389–94PubMedCrossRefGoogle Scholar
  8. 8.
    Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004 Oct 27; 292(16): 1955–60PubMedCrossRefGoogle Scholar
  9. 9.
    Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004 Jul 6; 171(1): 33–8PubMedCrossRefGoogle Scholar
  10. 10.
    Keszthelyi D, Jansen SV, Schouten GA, et al. Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study. Aliment Pharmacol Ther 2010 Nov; 32(9): 1124–8PubMedCrossRefGoogle Scholar
  11. 11.
    Lombardo L, Foti M, Ruggia O, et al. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010 Jun; 8(6): 504–8PubMedCrossRefGoogle Scholar
  12. 12.
    Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology 2010 Oct; 139(4): 1115–27PubMedCrossRefGoogle Scholar
  13. 13.
    McColl KE. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol 2009 Mar; 104 Suppl. 2: S5–9PubMedCrossRefGoogle Scholar
  14. 14.
    Furlanetto TW, Faulhaber GA. Hypomagnesemia and proton pump inhibitors: below the tip of the iceberg. Arch Intern Med 2011 Aug 8; 171(15): 1391–2PubMedCrossRefGoogle Scholar
  15. 15.
    Reimer C, Sondergaard B, Hilsted L, et al. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009 Jul; 137(1): 80–7PubMedCrossRefGoogle Scholar
  16. 16.
    Niklasson A, Lindstrom L, Simren M, et al. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebo-controlled trial. Am J Gastroenterol 2010 Jul; 105(7): 1531–7PubMedCrossRefGoogle Scholar
  17. 17.
    Laine L, Hennekens C. Proton pump inhibitor and clopidogrel interaction: fact or fiction? Am J Gastroenterol 2010 Jan; 105(1): 34–41PubMedCrossRefGoogle Scholar
  18. 18.
    Fass R, Hixson LJ, Ciccolo ML, et al. Contemporary medical therapy for gastroesophageal reflux disease. Am Fam Physician 1997 Jan; 55(1): 205–12, 17–8PubMedGoogle Scholar
  19. 19.
    Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology2000 Feb; 118 (2 Suppl. 1): S9–31PubMedCrossRefGoogle Scholar
  20. 20.
    Wang WH, Huang JQ, Zheng GF, et al. Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: a meta-analysis. World J Gastroenterol 2005 Jul 14; 11(26): 4067–77PubMedGoogle Scholar
  21. 21.
    Johnson NJ, Boyd EJ, Mills JG, et al. Acute treatment of reflux oesophagitis: a multicentre trial to compare 150 mg ranitidine b.d. with 300mg ranitidine q.d.s. Aliment Pharmacol Ther 1989 Jun; 3(3): 259–66PubMedCrossRefGoogle Scholar
  22. 22.
    Kahrilas PJ, Fennerty MB, Joelsson B. High-versus standard-dose ranitidine for control of heartburn in poorly responsive acid reflux disease: a prospective, controlled trial. Am J Gastroenterol 1999 Jan; 94(1): 92–7PubMedCrossRefGoogle Scholar
  23. 23.
    Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998; 115(6): 1335–9PubMedCrossRefGoogle Scholar
  24. 24.
    Fackler WK, Ours TM, Vaezi MF, et al. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002; 122(3): 625–32PubMedCrossRefGoogle Scholar
  25. 25.
    Kahrilas PJ, Dent J, Lauritsen K, et al. A randomized, comparative study of three doses of AZD0865 and esomeprazole for healing of reflux esophagitis. Clin Gastroenterol Hepatol 2007 Dec; 5(12): 1385–91PubMedCrossRefGoogle Scholar
  26. 26.
    Zhang Q, Lehmann A, Ridga R, et al. Control of transient lower oesophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in patients with gastro-oesophageal reflux disease. Gut 2002; 50(1): 19–24PubMedCrossRefGoogle Scholar
  27. 27.
    Koek GH, Sifrim D, Lerut T, et al. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut 2003 Oct; 52(10): 1397–402PubMedCrossRefGoogle Scholar
  28. 28.
    Vela MF, Tutuian R, Katz PO, 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 Jan; 17(2): 243–51PubMedCrossRefGoogle Scholar
  29. 29.
    Gerson LB, Huff FJ, Hila A, et al. Arbaclofen placarbil decreases postprandial reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol 2010 Jun; 105(6): 1266–75PubMedCrossRefGoogle Scholar
  30. 30.
    Boeckxstaens GE, Beaumont H, Mertens V, et al. Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease. Gastroenterology 2010 Aug; 139(2): 409–17PubMedCrossRefGoogle Scholar
  31. 31.
    Boeckxstaens GE, Beaumont H, Hatlebakk JG, et al. Efficacy and tolerability of the novel reflux inhibitor, AZD3355, as add-on treatment in GERD patients with symptoms despite proton pump inhibitor therapy [abstract]. Gastroenterology 2009 May; 136 (5 Suppl. 1): A–436Google Scholar
  32. 32.
    Frisby CL, Mattsson JP, Jensen JM, et al. Inhibition of transient lower esophageal sphincter relaxation and gastroesophageal reflux by metabotropic glutamate receptor ligands. Gastroenterology 2005 Sep; 129(3): 995–1004PubMedCrossRefGoogle Scholar
  33. 33.
    Keywood C, Wakefield M, Tack J. A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease. Gut 2009 Sep; 58(9): 1192–9PubMedCrossRefGoogle Scholar
  34. 34.
    Partosoedarso ER, Abrahams TP, Scullion RT, et al. Cannabinoid 1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets. J Physiol 2003 Jul 1; 550 (Pt 1): 149–58PubMedCrossRefGoogle Scholar
  35. 35.
    Beaumont H, Jensen J, Carlsson A, et al. Effect of delta9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans. Br J Pharmacol 2009 Jan; 156(1): 153–62PubMedCrossRefGoogle Scholar
  36. 36.
    Scarpellini E, Blondeau K, Boecxstaens V, et al. Effect of rimonabant on oesophageal motor function in man. Aliment Pharmacol Ther 2011 Mar; 33(6): 730–7PubMedCrossRefGoogle Scholar
  37. 37.
    Hershcovici T, Fass R. Transient lower oesophageal sphincter relaxation reducers: have we hit a brick wall? Aliment Pharmacol Ther 2011 Jun; 33(11): 1256–7; author reply 7-8PubMedCrossRefGoogle Scholar
  38. 38.
    Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American gastroenterological association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 2008 Oct; 135(4): 1383–91PubMedCrossRefGoogle Scholar
  39. 39.
    Masci E, Testoni PA, Passaretti S, et al. Comparison of ranitidine, domperidone maleate and ranitidine+domperidone maleate in the short-term treatment of reflux oesophagitis. Drugs Exp Clin Res 1985; 11(10): 687–92PubMedGoogle Scholar
  40. 40.
    Kim YS, Kim TH, Choi CS, et al. Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study. World J Gastroenterol 2005 Jul 21; 11(27): 4210–4PubMedGoogle Scholar
  41. 41.
    Scarpellini E, Vos R, Blondeau K, et al. The effects of itopride on oesophageal motility and lower oesophageal sphincter function in man. Aliment Pharmacol Ther 2011 Jan; 33(1): 99–105PubMedCrossRefGoogle Scholar
  42. 42.
    Ruth M, Hamelin B, Rohss K, et al. The effect of mosapride, a novel prokinetic, on acid reflux variables in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1998 Jan; 12(1): 35–40PubMedCrossRefGoogle Scholar
  43. 43.
    Cho YK, Choi MG, Han HW, et al. The effect of mosapride on esophageal motility and bolus transit in asymptomatic volunteers. J Clin Gastroenterol 2006 Apr; 40(4): 286–92PubMedCrossRefGoogle Scholar
  44. 44.
    Boulant J, Fioramonti J, Dapoigny M, et al. Cholecystokinin and nitric oxide in transient lower esophageal sphincter relaxation to gastric distention in dogs. Gastroenterology 1994 Oct; 107(4): 1059–66PubMedGoogle Scholar
  45. 45.
    Zerbib F, Bruley Des Varannes S, Scarpignato C, et al. Endogenous cholecystokinin in postprandial lower esophageal sphincter function and fundic tone in humans. Am J Physiol 1998 Dec; 275 (6 Pt 1): G1266–73PubMedGoogle Scholar
  46. 46.
    Choung RS, Ferguson DD, Murray JA, et al. A novel partial 5HT3 agonist DDP733 after a standard refluxogenic meal reduces reflux events: a randomized, double-blind, placebocontrolled pharmacodynamic study. Aliment Pharmacol Ther 2008 Mar 1; 27(5): 404–11PubMedCrossRefGoogle Scholar
  47. 47.
    Krarup AL, Ny L, Astrand M, et al. Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment Pharmacol Ther 2011 May; 33(10): 1113–22PubMedCrossRefGoogle Scholar
  48. 48.
    del Genio G, Tolone S, del Genio F, et al. Total fundoplication controls acid and nonacid reflux: evaluation by pre- and postoperative 24-h pH-multichannel intraluminal impedance. Surg Endosc 2008 Nov; 22(11): 2518–23PubMedCrossRefGoogle Scholar
  49. 49.
    Kahrilas PJ. Surgical therapy for reflux disease. JAMA 2001 May 9; 285(18): 2376–8PubMedCrossRefGoogle Scholar
  50. 50.
    Galmiche JP, Hatlebakk J, Attwood S, et al. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial. JAMA 2011 May 18; 305(19): 1969–77PubMedCrossRefGoogle Scholar
  51. 51.
    Schwartz MP, Smout AJ. Review article: the endoscopic treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2007 Dec; 26 Suppl. 2: 1–6PubMedCrossRefGoogle Scholar
  52. 52.
    Spechler SJ, Lee E, Ahnen D, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001 May 9; 285(18): 2331–8PubMedCrossRefGoogle Scholar
  53. 53.
    Louis H, Deviere J. Ensocopic-endoluminal therapies: a critical appraisal. Best Pract Res Clin Gastroenterol 2010 Dec; 24(6): 969–79PubMedCrossRefGoogle Scholar
  54. 54.
    Cadiere GB, Buset M, Muls V, et al. Antireflux transoral incisionless fundoplication using EsophyX: 12-month results of a prospective multicenter study. World J Surg 2008 Aug; 32(8): 1676–88PubMedCrossRefGoogle Scholar
  55. 55.
    Hoppo T, Immanuel A, Schuchert M, et al. Transoral incisionless fundoplication 2.0 procedure using EsophyX for gastroesophageal reflux disease. J Gastrointest Surg 2010 Dec; 14(12): 1895–901PubMedCrossRefGoogle Scholar
  56. 56.
    Kim MS, Holloway RH, Dent J, et al. Radiofrequency energy delivery to the gastric cardia inhibits triggering of transient lower esophageal sphincter relaxation and gastroesophageal reflux in dogs. Gastrointest Endosc 2003 Jan; 57(1): 17–22PubMedCrossRefGoogle Scholar
  57. 57.
    Arts J, Sifrim D, Rutgeerts P, et al. Influence of radio-frequency energy delivery at the gastroesophageal junction (the Stretta procedure) on symptoms, acid exposure, and esophageal sensitivity to acid perfusion in gastroesophagal reflux disease. Dig Dis Sci 2007 Sep; 52(9): 2170–7PubMedCrossRefGoogle Scholar
  58. 58.
    Corley DA, Katz P, Wo JM, et al. Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial. Gastroenterology 2003 Sep; 125(3): 668–76PubMedCrossRefGoogle Scholar
  59. 59.
    Bonavina L, Saino GI, Bona D, et al. Magnetic augmentation of the lower esophageal sphincter: results of a feasibility clinical trial. J Gastrointest Surg 2008 Dec; 12(12): 2133–40PubMedCrossRefGoogle Scholar
  60. 60.
    Bonavina L, DeMeester T, Fockens P, et al. Laparoscopic sphincter augmentation device eliminates reflux symptoms and normalizes esophageal acid exposure: one- and 2-year results of a feasibility trial. Ann Surg 2010 Nov; 252(5): 857–62PubMedCrossRefGoogle Scholar
  61. 61.
    Zou D, Chen WH, Iwakiri K, et al. Inhibition of transient lower esophageal sphincter relaxations by electrical acupoint stimulation. Am J Physiol Gastrointest Liver Physiol 2005 Aug; 289(2): G197–201PubMedCrossRefGoogle Scholar
  62. 62.
    Dickman R, Schiff E, Holland A, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ther 2007 Nov 15; 26(10): 1333–44Google Scholar
  63. 63.
    Nojkov B, Rubenstein JH, Adlis SA, et al. The influence of co-morbid IBS and psychological distress on outcomes and quality of life following PPI therapy in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2008; 27(6): 473–82PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  1. 1.Southern Arizona VA Health Care SystemTucsonUSA
  2. 2.Department of Medicine, Section of GastroenterologyUniversity of ArizonaTucsonUSA

Personalised recommendations