, Volume 72, Issue 4, pp 437–445 | Cite as

Prescribing Proton Pump Inhibitors

Is it Time To Pause and Rethink?
Current Opinion


Proton pump inhibitors (PPIs) are among the most widely used agents in the world. The prevalence of reflux disease is increasing, as is the incidence of oesophageal adenocarcinoma, a complication that is strongly correlated with chronic reflux disease. Although these agents are generally safe, a number of potential side effects have been described and a careful assessment of the risks and benefits of PPI therapy is required in all patients being prescribed long-term therapy.

Overutilization of PPIs is a problem in clinical practice and needs further attention. PPI use has been associated with osteoporosis and bone fracture, hypomagnesaemia, the development of gastric polyps, enteric infections, interstitial nephritis and pneumonia. Patients on long-term therapy should be periodically evaluated for the indications for continued therapy. Despite widespread publicity in the lay press, and regulatory guidance regarding a number of associations, the evidence for serious side effects is poor and the risk of confounding remains a real possibility for many associations. Patients are more concerned about the absolute risk of developing a complication than a relative risk. The absolute risk of all the complications attributed to PPIs is low and patients who need long-term PPI therapy need a clear discussion of the available data on the risk of therapy and also a discussion of the risk of continued reflux.



No sources of funding were used to conduct this study or prepare this manuscript. Nimish B. Vakil is a consultant of Astra Zeneca, Takeda, Ironwood; stockholder of Meridian and Orexo; and has received research support from Astra-Zeneca, XenoPort.


  1. 1.
    Heidelbaugh JJ, Goldberg KL, Inadomi JM. Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Am J Manag Care 2010 Sep; 16(9): e228–34PubMedGoogle Scholar
  2. 2.
    Godman B, Sakshaug S, Berg C, et al. Combination of prescribing restrictions and policies to engineer low prices to reduce reimbursement costs. Expert Rev Pharmacoecon Outcomes Res 2011 Feb; 11(1): 121–9PubMedCrossRefGoogle Scholar
  3. 3.
    IMS. IMS health reports US prescription sales grew 5.1 percent in 2009, to $300.3 billion [media release; online]. Available from URL: http://www.imshealth.com/portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=d690a27e9d5b7210VgnVCM100000ed152ca2RCRD&vgnextchannel=41a67900b55a5110VgnVCM10000071812ca2RCRD&vgnextfmt=default [Accessed 2011 Oct 1]
  4. 4.
    El-Serag HB. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol 2007; 5(1): 17–26PubMedCrossRefGoogle Scholar
  5. 5.
    Dubois RW, Aguilar D, Fass R, et al. Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life, and work productivity. Aliment Pharmacol Ther 2007; 25(4): 487–500PubMedCrossRefGoogle Scholar
  6. 6.
    Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med 2001; 161(1): 45–52PubMedCrossRefGoogle Scholar
  7. 7.
    Jung HK. Epidemiology of gastroesophageal reflux disease in Asia: a systematic review. J Neurogastroenterol Motil 2011 Jan; 17(1): 14–27PubMedCrossRefGoogle Scholar
  8. 8.
    Lagergren J, Bergström R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999 Mar 18; 340(11): 825–31PubMedCrossRefGoogle Scholar
  9. 9.
    Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. J Natl Cancer Inst 2008 Aug 20; 100(16): 1184–7PubMedCrossRefGoogle Scholar
  10. 10.
    Nguyen DM, El-Serag HB, Henderson L, et al. Medication usage and the risk of neoplasia in patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2009 Dec; 7(12): 1299–304PubMedCrossRefGoogle Scholar
  11. 11.
    Guda NM, Vakil N. Proton pump inhibitors and the time trends for esophageal dilation. Am J Gastroenterol 2004 May; 99(5): 797–800PubMedCrossRefGoogle Scholar
  12. 12.
    El-Serag HB. Temporal trends in new and recurrent esophageal strictures in Department of Veterans Affairs. Am J Gastroenterol 2006 Aug; 101(8): 1727–33PubMedCrossRefGoogle Scholar
  13. 13.
    Hoorn EJ, van der Hoek J, de Man RA, et al. A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis 2010 Jul; 56(1): 112–6PubMedCrossRefGoogle Scholar
  14. 14.
    Cundy T, Dissanayake A. Severe hypomagnesaemia in longterm users of proton-pump inhibitors. Clin Endocrinol (Oxf) 2008; 69(2): 338–41CrossRefGoogle Scholar
  15. 15.
    Mackay JD, Bladon PT. Hypomagnesaemia due to protonump inhibitor therapy: a clinical case series. QJM 2010 Jun; 103(6): 387–95PubMedCrossRefGoogle Scholar
  16. 16.
    Schlingmann KP, Weber S, Peters M, et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6,a new member of the TRPM gene family. Nat Genet 2002; 31: 166–70PubMedCrossRefGoogle Scholar
  17. 17.
    Hansen KE, Jones AN, Lindstrom MJ, et al. Do proton pump inhibitors decrease calcium absorption? J Bone Miner Res 2010 Dec; 25(12): 2786–95PubMedCrossRefGoogle Scholar
  18. 18.
    Wright MJ, Sullivan RR, Gaffney-Stomberg E, et al. Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J Bone Miner Res 2010 Oct; 25(10): 2205–11PubMedCrossRefGoogle Scholar
  19. 19.
    O’Connell MB, Madden DM, Murray AM, et al. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 2005 Jul; 118(7): 778–81PubMedCrossRefGoogle Scholar
  20. 20.
    Targownik LE, Lix LM, Leung S, et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010 Mar; 138(3): 896–904PubMedCrossRefGoogle Scholar
  21. 21.
    Yu EW, Blackwell T, Ensrud KE, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 2008 Oct; 83(4): 251–9PubMedCrossRefGoogle Scholar
  22. 22.
    Gray SL, LaCroix AZ, Larson J, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern Med 2010 May 10; 170(9): 765–71PubMedCrossRefGoogle Scholar
  23. 23.
    Targownik LE, Leslie WD. The relationship among proton pump inhibitors, bone disease and fracture. Expert Opin Drug Saf 2011 Nov; 10(6): 901–12PubMedCrossRefGoogle Scholar
  24. 24.
    Ngamruengphong S, Leontiadis GI, Radhi S, et al. Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2011 Jul; 106(7): 1209–18PubMedCrossRefGoogle Scholar
  25. 25.
    Kwok CS, Yeong JK, Loke YK. Meta-analysis: risk of fractures with acid-suppressing medication. Bone 2011 Apr 1; 48(4): 768–76PubMedCrossRefGoogle Scholar
  26. 26.
    Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med 2011; 171(11): 998–1004PubMedCrossRefGoogle Scholar
  27. 27.
    Poulsen AH, Christensen S, McLaughlin JK, et al. Proton pump inhibitors and risk of gastric cancer: a populationbased cohort study. Br J Cancer 2009 May 5; 100(9): 1503–7PubMedCrossRefGoogle Scholar
  28. 28.
    Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology 2000; 118: 661–9PubMedCrossRefGoogle Scholar
  29. 29.
    Schenk BE, Kuipers EJ, Nelis GF, et al. Effect of Helicobacter pylori eradication on chronic gastritis during omeprazole therapy. Gut 2000 May; 46(5): 615–21PubMedCrossRefGoogle Scholar
  30. 30.
    Lundell L, Miettinen P, Myrvold HE, et al. Lack of effect of acid suppression therapy on gastric atrophy. Nordic Gerd Study Group. Gastroenterology 1999 Aug; 117(2): 319–26Google Scholar
  31. 31.
    Lundell L, Havu N, Miettinen P, et al., Nordic GERD Study Group. Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial. Aliment Pharmacol Ther 2006 Mar 1; 23(5): 639–4PubMedCrossRefGoogle Scholar
  32. 32.
    van Soest EM, van Rossum LGM, Dieleman JP, et al. Proton pump inhibitors and the risk of colorectal cancer. Am J Gastroenterol 2008; 103: 966–73PubMedCrossRefGoogle Scholar
  33. 33.
    Robertson DJ, Larsson H, Friis S, et al. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case control study. Gastroenterology 2007; 133: 755–60PubMedCrossRefGoogle Scholar
  34. 34.
    Stewart CA, Termanini B, Sutliff VE, et al. Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy. Aliment Pharmacol Ther 1998; 12: 83–98PubMedCrossRefGoogle Scholar
  35. 35.
    Sarzynski E, Puttarajappa C, Xie Y, et al. Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci 2011 Aug; 56(8): 2349–53PubMedCrossRefGoogle Scholar
  36. 36.
    Hutchinson C, Geissler CA, Powell JJ, et al. Proton pump inhibitors suppress absorption of dietary non-heme iron in hereditary hemochromatosis. Gut 2007; 56: 1291–5PubMedCrossRefGoogle Scholar
  37. 37.
    Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004; 57: 422–8PubMedCrossRefGoogle Scholar
  38. 38.
    den Elzen WPJ, Groeneveld Y, de Ruijter W, et al. Longterm use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther 2008; 27: 491–7CrossRefGoogle Scholar
  39. 39.
    Geevasinga N, Coleman PL, Webster AC, et al. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol 2006 May; 4(5): 597–604PubMedCrossRefGoogle Scholar
  40. 40.
    Vakil N. Acid inhibition and infections outside the gastrointestinal tract. Am J Gastroenterol 2009; 104: S10–6CrossRefGoogle Scholar
  41. 41.
    Laheij RJF, Sturkenboom MCJM, Hassing R-J, et al. Risk of community-acquired pneumonia and use of gastric acidsuppressive drugs. JAMA 2004; 292: 1955–60PubMedCrossRefGoogle Scholar
  42. 42.
    Gulmez SE, Holm A, Frederiksen H, et al. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med 2007; 167: 950–5PubMedCrossRefGoogle Scholar
  43. 43.
    Sarkar M, Hennessy S, Yang YX, et al. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008; 149: 391–8PubMedCrossRefGoogle Scholar
  44. 44.
    Dublin S, Walker RL, Jackson ML, et al. Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population-based case-control study. Pharmacoepidemiol Drug Saf 2010 Aug; 19(8): 792–802PubMedCrossRefGoogle Scholar
  45. 45.
    Yang YX, Metz D. Safety of proton pump exposure. Gastroenterology 2010; 139: 1115–27PubMedCrossRefGoogle Scholar
  46. 46.
    Redelmeier DA, McAlister FA, Kandel CE, et al. Postoperative pneumonia in elderly patients receiving acid suppressants: a retrospective cohort analysis. BMJ 2010; 340: c2608PubMedCrossRefGoogle Scholar
  47. 47.
    Dial S. Proton pump inhibitor use and enteric infections. Am J Gastroenterol 2009; 104: S10–6PubMedCrossRefGoogle Scholar
  48. 48.
    Paredes-Sabja D, Bond C, Carman RJ, et al. Germination of spores of Clostridium difficile strains, including isolates from a hospital outbreak of Clostridium difficile-associated disease (CDAD). Microbiology 2008; 154: 2241–50PubMedCrossRefGoogle Scholar
  49. 49.
    Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007 Sep; 102(9): 2047–56PubMedCrossRefGoogle Scholar
  50. 50.
    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; 137: 80–7PubMedCrossRefGoogle Scholar
  51. 51.
    Juul-Hansen P, Rydning A. Clinical and pathophysiological consequences of on-demand treatment with PPI in endoscopy-negative reflux disease: is rebound hypersecretion of acid a problem? Scand J Gastroenterol 2011 Apr; 46(4): 398–405PubMedCrossRefGoogle Scholar
  52. 52.
    Metz DC, Pilmer BL, Han C, et al. Withdrawing PPI therapy after healing esophagitis does not worsen symptoms or cause persistent hypergastrinemia: analysis of dexlansoprazole MR clinical trial data. Am J Gastroenterol 2011 Nov; 106(11): 1953–60PubMedCrossRefGoogle Scholar
  53. 53.
    Niv Y. Gradual cessation of proton pump inhibitor (PPI) treatment may prevent rebound acid secretion, measured by the alkaline tide method, in dyspepsia and reflux patients. Med Hypotheses 2011 Sep; 77(3): 451–2PubMedCrossRefGoogle Scholar
  54. 54.
    Batuwitage BT, Kingham JG, Morgan NE, et al. Inappropriate prescribing of proton pump inhibitors in primary care. Postgrad Med J 2007 Jan; 83(975): 66–8PubMedCrossRefGoogle Scholar
  55. 55.
    Ramirez E, Lei SH, Borobia AM, et al. Overuse of PPIs in patients at admission, during treatment, and at discharge in a tertiary Spanish hospital. Curr Clin Pharmacol 2010 Nov; 5(4): 288–97PubMedCrossRefGoogle Scholar
  56. 56.
    Zink DA, Pohlman M, Barnes M, et al. Long-term use of acid suppression started inappropriately during hospitalization. Aliment Pharmacol Ther 2005 May 15; 21(10): 1203–9PubMedCrossRefGoogle Scholar
  57. 57.
    Pace F, Porro GB. On-demand PPI therapy in GERD. Curr Treat Options Gastroenterol 2008 Feb; 11(1): 35–42PubMedCrossRefGoogle Scholar
  58. 58.
    Lobo FS, Wagner S, Gross CR, et al. Addressing the issue of channeling bias in observational studies with propensity scores analysis. Res Social Adm Pharm 2006 Mar; 2(1): 143–51PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2012

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA

Personalised recommendations