Key Points
  • In the treatment of GORD, review patients:
    • after four to eight weeks of initial full-dose PPI treatment
    • if PPI medicines were initiated in hospital
  • Consider a step-down approach for the maintenance of symptoms:
    • reduce the dose
    • adopt intermittent symptom-driven use
    • trial cessation
  • Due to high prevalence of extended use of PPIs, rare but potentially serious adverse effects are often observed.

Proton Pump Inhibitors – How much for how long?

The considerable benefits and perceived safety of proton pump inhibitors (PPIs) in the management of acid-related gastrointestinal (GI) disorders means they are often used for long periods without ongoing review.

In Australia the use of PPIs increased 1318% between 1995 and 2006.1 Currently there are enough PPIs dispensed to treat seven percent of the Australian population every day.2 This translates to 1.6 million Australians taking a PPI daily.

Despite their perceived safety, emerging evidence suggests PPIs are associated with a range of rare but serious adverse effects. These include osteoporosis and fractures, hypomagnesaemia, interstitial nephritis, enteric infection and community acquired pneumonia. This therapeutic brief advocates the benefits of a step-down approach: reducing the dose, adopting intermittent use or trialling cessation, while maintaining adequate symptom control.

Prescribing for gastro-oesophageal reflux disease (GORD)

The initial course of treatment usually involves the prescribing of a full-dose PPI (see table 1) for four to eight weeks, after which treatment should be reviewed.3,4 If response is adequate, consider ‘stepping-down’ to maintenance dose, switching to intermittent dosing or trialling cessation (see table 1). For many patients symptoms will have resolved and extended treatment may be unnecessary. If response is inadequate after two to four weeks, check adherence.

If adherence to the PPI is satisfactory, then endoscopy may be required to exclude other conditions.3,5 If after endoscopy no underlying cause is found, it may be necessary to double the dose for four weeks before ‘stepping-down’ to the lowest effective dose or trialling cessation.4 Patients initiated on PPIs in hospitals should be reviewed as they may not require ongoing treatment following discharge. Ongoing use of PPIs may expose patients to adverse effects.

Table 1: Initial and maintenance proton-pump inhibitors therapy for gastro-oesophageal reflux disease







(Losec®, Acimax®, Meprazol®, Ozmep®, Omepro®, Omepral®, Maxor®, Pemzo®, Probitor®) tablet, capsule

Zoton FasTabs®, Zopral®, Lanzopran®) tablet, capsule

(Somac®, Ozpan®, Gastenz®, Salpraz®, Pantofast®, Pantoloc®, Panto®, Sozol®, Suvacid®) tablet, granules

(Pariet®) tablet

(Nexium®) tablet

Initial therapy (full-dose PPI)3,4





20mg *

Maintenance therapy (lower dose PPI)





See note**

Not all strengths and formulations of PPIs are included in the Table. Table excludes injections.

* While many patients may be initially treated with esomeprazole 40mg, 20mg is recommended initial therapy3,4; esomeprazole 40mg is appropriate if endoscopy reveals severe erosive disease or ulceration in previously untreated patient3 or response to esomeprazole 20mg is inadequate after initial 4 weeks.4 The advantage of starting on 20mg esomeprazole is that it reduces the number of steps required in the step-down process.

** Step-down strategy: 10mg omeprazole is appropriate step-down therapy from 20mg esomeprazole.

Step-down strategies and PPI withdrawal plan

In patients who have had an adequate response to initial full-dose PPI therapy, it is appropriate to cease or reduce PPI therapy using a ‘step down’ approach:

tickReduce the dose

A recommended approach is to prescribe either half the daily dose or alternate daily dosing, depending on patient preference. At least 80% of patients with GORD presenting with healed oesophagitis can achieve symptomatic remission with lower (maintenance) doses of PPIs.6 Refer to Table 1 for dosing advice.

tickIntermittent symptom-driven PPI

As an example, use omeprazole 10mg or equivalent on days when symptoms occur. This dosage controls symptoms in most people with endoscopy negative GORD.7

tickTrial cessation

In a significant minority of patients (up to 30%) symptoms will not return after cessation of PPI therapy.5 The decision to cease therapy should be guided by symptom control and each patient’s ability to report return of symptoms.

If the initial attempt to step-down or discontinue PPI therapy is unsuccessful, the PPI may be continued for a few weeks before considering another attempt to reduce the dose or cease treatment.8

Following cessation, antacids, histamine H2 receptor antagonists (H2RAs) or PPIs at the lowest effective dose may be used as needed for the relief of mild, occasional reflux symptoms.3

Rebound activation of proton pumps resulting in rebound acid hypersecretion may occur following cessation of PPIs.9,10 Gradual dose tapering or switching to alternate day therapy for one to two weeks before cessation may prevent rebound symptoms.11

What to discuss with your patient

  • Patients with mild or infrequent symptoms can often be managed with simple non-drug measures. Advise patients about lifestyle modifications as appropriate, such as weight loss, moderation of alcohol consumption, smoking cessation, elevation of bed head and avoidance of precipitating foods.3
  • Patients achieving good symptom control may be hesitant to trial dose reduction or cessation. For these patients it may be worthwhile highlighting that by using a step-down approach it is often possible to maintain symptom relief while avoiding potential adverse effects.12
  • Encourage patients to try again if attempt to step-down PPI therapy is unsuccessful.
  • Advise patients to adopt symptom-driven use of antacids, antacid/alginate combination, H2RAs or low-dose PPIs for the relief of mild, occasional acid-related GI disorders.3,5 Patients should also be informed of the need for assessment in the case of recurrent symptoms.

Adverse effects

The high prevalence of extended use of PPIs means that rare but potentially serious adverse effects are being seen more often.


Recent meta-analyses and regulatory agencies have identified an association between use of PPIs and fractures, including hip and spinal fractures.13,14 This may be due to impaired calcium absorption.13 Patients at risk of osteoporotic fractures are advised to maintain an adequate intake of calcium and vitamin D. Bone mineral density tests are recommended for high-risk patients using a high-dose PPI on a long-term basis.15 These may include older patients and postmenopausal females.

Acute interstitial nephritis

Acute interstitial nephritis (AIN) is a rare adverse event (approximately 8 cases per 100,000 patient years in one study).16 The TGA has warned that PPIs are now a leading cause of AIN in Australia.17


Clinicians should be alert to the possibility of PPI-associated hypomagnesaemia. Patients may present with clinical symptoms such as nausea and vomiting, anorexia, weakness and fatigue, dizziness, decreased mobility, paraesthesia or severe muscle cramps.18 Use of magnesium supplements may be insufficient to correct a magnesium deficiency associated with long-term PPI use, and the PPI may need to be discontinued.19

Enteric infection

PPIs may increase susceptibility to enteric bacterial infection, including Clostridium difficile infection due to the reduction in gastric acidity.20 The use of probiotics for the prevention or treatment of Clostridium difficile is not warranted.4 The US Food and Drug Administration recommends patients using PPIs contact their health professional if they develop persistent diarrhoea.21 Patients using PPIs may be at increased risk of traveller’s diarrhoea, and the ongoing need for PPI therapy in patients travelling to high risk areas should be reviewed.20


Epidemiological studies suggest an association between use of PPIs and both community and hospital-acquired pneumonia, possibly due to the reduction in gastric acidity which allows bacterial colonization. The greatest risk of developing pneumonia happens shortly after initiating treatment.22

Vitamin B12 deficiency

Long-term use of PPIs may decrease the absorption of Vitamin B12, although the clinical relevance is uncertain.4

PPIs and clopidogrel

Regulatory agencies have warned that PPIs, particularly omeprazole and esomeprazole, may reduce the antiplatelet effect of clopidogrel.23,24 However, a recent meta- analysis has not found strong evidence to suggest that the interaction is clinically significant.25

When is long term treatment appropriate?

Some patients may require long term treatment with PPIs. This includes patients with severe oesophagitis, oesophageal stricture or scleroderma, Zollinger-Ellison syndrome or Barrett’s oesophagus.12 Patients who require long-term treatment with a NSAID, including low-dose aspirin, may be co-prescribed a low-strength PPI for ulcer prophylaxis in some circumstances.3 Prophylaxis with a PPI may also be clinically appropriate in other patients at high risk of bleeding.

Further information:

Gastroenterological Society of Australia


  1. Hollingworth S, Duncan EL, Martin JH. Marked increase in proton pump inhibitors use in Australia. Pharmacoepidemiol Drug Saf 2010; 19(10): 1019-24.
  2. OECD (2011), “OECD Health Data: Pharmaceutical market", OECD Health Statistics (database). doi: 10.1787/data-00545-en [accessed 07 June 2012]
  3. Therapeutic Guidelines. Gastrointestinal Version 5. Melbourne; 2011.
  4. Rossi S (Editor). Australian Medicines Handbook. Australian Medicines Handbook Pty Ltd. Adelaide; 2012.
  5. Gastroenterological Society of Australia. Gastro-Oesophageal Reflux Disease in Adults.2011 [accessed 25 June 2012]; Available from:
  6. Tytgat GN. Review article: treatment of mild and severe cases of GERD. Aliment Pharmacol Ther 2002; 16 Suppl 4:73-8.
  7. Dent J, Talley NJ. Overview: initial and long-term management of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2003; 17 Suppl 1:53-7.
  8. Zarowitz BJ. The challenge of discontinuing proton pump inhibitors. Geriatr Nurs 2011; 32(4): 276-8.
  9. 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(1): 80-7.
  10. 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; 105(7): 1531-7.
  11. Vakil N. Prescribing proton pump inhibitors: is it time to pause and rethink? Drugs 2012; 72(4): 437-45.
  12. NPS - Better Choices, Better Health. NPS Prescribing Practice Review 45: Proton pump inhibitors: step-down to symptom control.2009 [accessed 25 June 2012]; Available from:
  13. Eom CS, Park SM, Myung SK, et al. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med 2011; 9(3): 257-67.
  14. European Medicines Agency (EMA). Pharmacovigilance Working Party (PhVWP) Monthly report on safety concerns, guidelines and general matters - Proton-pump inhibitors – Risk of bone fracture. 2012 [accessed 25 June 2012]; Available from:
  15. Talley NJ, Jung HK, Jiang X, Locke GR. Is there an increased risk of hip fracture in patients on long-term PPI therapy? Nat Clin Pract Gastroenterol Hepatol 2007; 4:420-1.
  16. Simpson IJ, Marshall MR, Pilmore H, et al. Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology (Carlton) 2006; 11(5): 381-5.
  17. Therapeutic Goods Administration (TGA). Proton pump inhibitors and acute interstitial nephritis. Medicines Safety Update 2011 [accessed 25 June 2012]; Available from:
  18. Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM 2010; 103(6): 387-95.
  19. Therapeutic Good and Administration (TGA). Risk of hypomagnesaemia with proton pump inhibitors. Medicines Safety Update 2011 [accessed 25 June 2012]; Available from:
  20. Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther 2011; 34(11-12): 1269-81.
  21. Food and Drug Administration (FDA). Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). 2012 [accessed 25 June 2012]; Available from:
  22. Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ 2011; 183:310-9.
  23. Food and Drug Administration (FDA). Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). 2009 [accessed 25 June 2012]; Available from:
  24. European Medicines Agency (EMA). Interaction between clopidogrel and proton-pump inhibitors CHMP updates warning for clopidogrel-containing medicines. 2010 [accessed 25 June 2012]; Available from:
  25. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Can J Gastroenterol 2010; 31(8): 810-23.

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Key Points
  • In the treatment of GORD, review patients:
    • after four to eight weeks of initial full-dose PPI treatment
    • if PPI medicines were initiated in hospital
  • Consider a step-down approach for the maintenance of symptoms:
    • reduce the dose
    • adopt intermittent symptom-driven use
    • trial cessation
  • Due to high prevalence of extended use of PPIs, rare but potentially serious adverse effects are often observed.