PPIs are widely held to be safe medicines. However, evidence of potentially serious adverse effects merits consideration. By stopping therapy when appropriate — or using PPIs for the shortest time and at the lowest effective dose — the benefit can be preserved and the risk of serious adverse effects reduced.

Starting proton pump inhibitor therapy

Confirm symptoms, refer if necessary

Proton pump inhibitors (PPIs) effectively control heartburn, but many people have a poor understanding of this term. Provide a clear description such as “a burning feeling rising up from your stomach or lower chest towards the neck”.[1]

Refer patients for endoscopy if alarm symptoms (anaemia, difficulty or pain on swallowing, evidence of gastrointestinal bleeding, weight loss or vomiting) are present.[1,2]

Review medicines

Ask patients to bring a list of all their medicines to each visit.[3] Discontinue or reduce the dose of any medicine that could contribute to symptoms (e.g. calcium channel blockers, nitrates, NSAIDs, theophylline[4]) where appropriate.

4–8 weeks of PPI therapy relieves symptoms and heals oesophagitis

Prescribe an initial 4-week course of standard-dose PPI (see Table 1) after excluding alarm symptoms. Initial standard-dose therapy heals oesophagitis in more than 70% of patients.[5]

Review patients after the initial 4-week course. Manually setting electronically-generated prescriptions to the minimum quantity needed can be a trigger for patients to return for review.[6]

An additional 4-week course of standard-dose therapy is appropriate in patients with persistent symptoms. Oesophagitis healing rates are increased by a further 14% if therapy is extended to 8 weeks.[5] Refer patients for endoscopy if response is inadequate after 8 weeks.[2]

Many patients will not need continuous, long-term PPI therapy

Consider a trial cessation or reduced therapy if initial treatment is successful.[1]

Always review the need for ongoing PPI therapy following hospital discharge. Stop the PPI when the initial indication no longer exists and when there is no need for further therapy.

PPI maintenance therapy is not usually necessary after successful eradication of Helicobacter pylori ulcers.[2]

Over-the-counter PPI therapy

PPI therapy does not always require a prescription

Pantoprazole 20 mg (Somac Heartburn Relief) is available over the counter (pharmacist only medicine) for symptomatic relief of heartburn, acid regurgitation and other symptoms associated with GORD.[7]

Pharmacists should ask about symptoms and patient history

Pharmacists should establish whether patients requesting over-the-counter pantoprazole need PPI therapy, provide lifestyle advice and describe treatment options.
Confirm that symptoms occur on two or more days a week. Refer to a doctor for further investigation when:

• alarm symptoms are present, or symptoms are non-specific or atypical
• symptoms occur daily
• the individual is 55 years or older with first-time or long-standing, frequent and troublesome symptoms
• symptoms are not controlled after two weeks of continuous over-the-counter pantoprazole 20 mg
• there is a family history of gastrointestinal cancer, or the individual is receiving long-term NSAID therapy.[8]

Refer to the Pharmaceutical Society of Australia protocol — Provision of pantoprazole as a pharmacist only medicine — for further guidance.[8]

Suggest lifestyle changes

Discuss diet and weight loss

A written record of episodes of reflux and the foods consumed beforehand may help patients to identify specific triggers.

Encourage weight loss in overweight patients. Being overweight or obese is associated with a 1.4- or 1.9- fold greater risk of symptoms of GORD, respectively, compared with normal-weight people.[9]

Target behaviours that contribute to or reduce reflux

Quitting smoking and moderating alcohol consumption should be part of the management plan. Cigarette smoking and alcohol consumption (≥ 7 standard alcoholic drinks per week) are risk factors for GORD.[10]

Patients experiencing night-time symptoms may benefit from elevating the head of their bed.[11]

Table 1. Dose comparison of prescription only proton pump inhibitors

PPI	Standard dose[A]	Low dose[A]
esomeprazole (Nexium)	20 mg daily[B]	20 mg daily
lansoprazole (Zoton)	30 mg daily	15 mg daily
omeprazole (Acimax, Losec, Meprazol, Omepral, Probitor)	20 mg daily	10 mg daily
pantoprazole (Somac)	40 mg daily	20 mg daily
rabeprazole (Pariet)	20 mg daily	10 mg daily

[A] Standard dose refers to the initial therapeutic trial dose that should be used to provide symptom relief and heal erosive disease.[2] Low dose refers to the lower dose recommended for maintenance therapy for gastro-oesophageal reflux disease.[3]

[B] Esomeprazole 20 mg is recommended as the initial therapeutic trial dose to provide symptom relief and heal erosive disease.[2] Esomeprazole 40 mg daily is a PBS-listed restricted benefit for healing of gastro-oesophageal reflux disease, and may be appropriate if there is endoscopically proven erosive disease in a previously untreated patient.[2]

Trial a withdrawal and use step-down strategies

Assess management options at patient review

Determine whether ongoing therapy is required when patients attend for review or request a repeat prescription. Consider reduced PPI therapy in all patients except those with: severe oesophagitis, oesophageal stricture or scleroderma; Barrett’s oesophagus; or Zollinger–Ellison syndrome.

Manage patients with severe disease in consultation with a gastroenterologist.[2] Patients with severe oesophagitis should be treated with ongoing, standard-dose PPI; complications such as strictures will require endoscopic therapy.[1]

What to tell patients about reduced PPI therapy

Patients whose symptoms are well controlled by PPIs may be reluctant to reduce the dose or frequency of their medication. Emphasise that reduced PPI therapy can maintain symptom relief and that:

• symptom-driven therapy will mean taking fewer tablets
• prescription costs may be lower
• there is less risk of unwanted side effects when less medicine is used.

Patient information leaflets — one that allows GPs to detail individual step-down approaches, and the other about PPI use and self-management strategies — are available at: www.nps.org.au/patient_leaflets.

Consider a trial withdrawal if initial PPI therapy is successful

Between 20% and 40% of patients may not require PPI therapy for up to 1 year after successful treatment of GORD.[5] In one small trial, 21% of long-term PPI users previously treated for GORD did not use PPIs during a 1 year follow-up.[12] The comparable figure for patients with dyspepsia or other indications was 48%. Symptom-driven use of PPIs is appropriate if symptoms recur.[1]

Asymptomatic patients maintained on long-term, standard-dose PPI may prefer to step-down to continuous or symptom-driven, low-dose therapy before a trial withdrawal.

Use continuous or symptom-driven low-dose PPI if maintenance therapy is required

Continuous, low-dose maintenance therapy prevents relapse in many patients with healed oesophagitis.[5,13] About 55% of patients with reflux disease remained free of significant symptoms in clinical trials of 6 months to 1 year in duration.[13]

Alternatively, advise patients to take low-dose PPI when troublesome symptoms occur, and to continue until symptoms resolve. Survey data suggest that many patients use PPIs at their discretion, regardless of prescribed instructions.[14,15] In randomised trials of patients with mild to moderate GORD or non-erosive reflux disease, symptom relief and patient satisfaction with low-dose, symptom-driven therapy was similar to that of continuous low-dose therapy.[16,17]

Evidence for serious adverse effects

PPI therapy may be associated with harms

PPIs are generally considered to be safe, but evidence suggests an association between their use and serious adverse effects. These adverse effects may be rare and difficult to predict. PPIs should be prescribed judiciously, for the shortest possible time and at the lowest effective dose, to minimise risk.

PPIs increase the risk of Clostridium difficile infection

PPI use is a risk factor for C. difficile infection, possibly because of the profound reduction in gastric acidity.

In observational studies, PPI therapy was associated with about a 2–3 fold increased risk of C. difficile infection in hospital and community settings.[18-20]

In a case-control study of community-acquired C. difficile infection, antibiotic- and PPI-use were the most important medication-related risk factors.[21]

Acute interstitial nephritis and PPIs

Data collected from 2 Australian teaching hospitals over a 10-year period showed that 18 of 28 cases of biopsy-proven acute interstitial nephritis were associated with PPI use.[22]

The symptoms of acute interstitial nephritis are non-specific; those reported include weight loss, fatigue, malaise, nausea and vomiting.[22,23] A dose–response relationship has not been established and onset may be delayed.[23] Assess renal function by serum creatinine if renal impairment is suspected; withdraw PPI and refer to a nephrologist if confirmed.

Evidence for other possible serious adverse effects

Several studies have suggested that PPIs may reduce the efficacy of clopidogrel, although the evidence is not consistent.[24-28] The US Food and Drug Administration has advised that patients currently taking clopidogrel should continue to do so, while the need for starting or ongoing PPI therapy should be reviewed.[29] Studies are underway to further investigate this potential interaction.

Case–control studies report a modest, but significant, association between long-term PPI use and hip fracture.[30,31] Risk of hip fracture increased with duration of therapy[30,31], and when patients took high doses of PPI for more than 1 year.[30] In Australia, the Adverse Drug Reactions Advisory Committee (ADRAC) has received two reports of pathological fracture and/or osteoporosis associated with PPI use.[32]

Evidence from large case–control studies suggests an association between current PPI use and community-acquired pneumonia.[33-35] The risk was greatest in patients who started treatment within the previous 7 days.[33,34] Those with a longer history of PPI use had a modest, or no, increased risk.

Expert reviewers

A/Prof Geoffrey S Hebbard
Director of Gastroenterology,
Royal Melbourne Hospital and
Associate Professor, Department of Medicine, University of Melbourne, VIC

References

1. Gastroenterological Society of Australia. Gastro-oesophageal reflux disease in adults: guidelines for clinicians. 2008. (accessed 30 October 2008).
2. Therapeutic Guidelines: Gastrointestinal, Version 4: Melbourne: Therapeutic Guidelines Limited, 2006.
3. Department of Veterans' Affairs. PPIs in GORD: Reduce the dose - keep the benefits. Therapeutic Brief 7. (accessed  13 January 2009).
4. Australian Medicines Handbook, 2008.
5. National Institute for Health and Clinical Excellence. Dyspepsia: management of dyspepsia in adults in primary care. Clinical Guideline No. 17. 2004. (accessed 20 January 2009).
6. Fife NHS Board Area Drugs and Therapeutic Committee. Gastro-intestinal. Appendix 1A. Step-down of PPIs in GORD for primary care. 2008. (accessed  13 January 2009).
7. Department of Health and Ageing, Therapeutic Goods Administration. Australian Register of Therapeutic Goods Public Summary 154252: Somac Heartburn Relief pantoprazole (as sodium sesquihydrate) 20 mg tablet blister pack 2008 (accessed  27 January 2009).
8. Pharmaceutical Society of Australia. Provision of pantoprazole as a Pharmacist only medicine for the relief of heartburn and other symptoms of gastro-oesophageal reflux. 2008. (accessed  23 January 2009).
9. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med 2005;143:199-21.
10. Locke GR, 3rd, Talley NJ, Fett SL, et al. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med 1999;106:642-9.
11. Kahrilas P. Medical management of gastroesophageal reflux disease in adults: UpToDate [Online] Wolters Kluwer Healt. (accessed  14 October 2008).
12. Bjornsson E, Abrahamsson H, Simren M, et al. Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial. Aliment Pharmacol Ther 2006;24:945-5.
13. Donnellan C, Sharma N, Preston C, et al. Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease. Cochrane Database Syst Rev 2005:CD003245.
14. Hungin AP, Rubin GP, O'Flanagan H. Long-term prescribing of proton pump inhibitors in general practice. Br J Gen Pract 1999;49:451-3. 
15. Van Soest EM, Siersema PD, Dieleman JP, et al. Persistence and adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther 2006;24:377-85.
16. Bour B, Staub JL, Chousterman M, et al. Long-term treatment of gastro-oesophageal reflux disease patients with frequent symptomatic relapses using rabeprazole: on-demand treatment compared with continuous treatment. Aliment Pharmacol Ther 2005;21:805-12.
17. Janssen W, Meier E, Gatz G, et al. Effects of pantoprazole 20 mg in mild gastroesophageal reflux disease: Once-daily treatment in the acute phase, and comparison of on-demand versus continuous treatment in the long term. Curr Ther Res Clin Exp 2005;66:345-63.
18. 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;171:33-8.
19. Yearsley KA, Gilby LJ, Ramadas AV, et al. Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhoea. Aliment Pharmacol Ther 2006;24:613-9.
20. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007;102:2047-56.
21. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005;294:2989-95.
22. Geevasinga N, Coleman PL, Webster AC, et al. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol 2006;4:597-604.
23. Sierra F, Suarez M, Rey M, et al. Systematic review: Proton pump inhibitor-associated acute interstitial nephritis. Aliment Pharmacol Ther 2007;26:545-53.
    
24. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256-60.
25. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009 doi: 10.1503/cmaj.082001.
26. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44.
27. Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008;48:475-84.
28. Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148 e1-5.
    
29. U.S. Food and Drug Administration Center for Drug Evaluation and Research. Early communication about an ongoing safety review of clopidogrel bisulfite. (accessed  16 March 2009).
30. Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296:2947-53.
    
31. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179:319-26.
    
32. Adverse Drug Reactions Advisory Committee. Proton pump inhibitors and possible fracture risk. Aust Adv Drug Reactions Bull 2009;28:1.
    
33. 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;167:950-5.
    
34. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008;149:391-8.
    
35. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292:1955-60.