Article Archive
January/February 2014

Recognizing Proton Pump
Inhibitor Risk

By Mark D. Coggins, PharmD, CGP, FASCP
Today’s Geriatric Medicine
Vol. 7 No. 1 P. 6

Proton pump inhibitors (PPIs) effectively suppress gastric acid and are used to prevent and treat conditions such as gastroesophageal reflux disease (GERD), erosive esophagitis, and NSAID-induced ulcers. PPIs’ proven effectiveness and favorable safety profile have contributed to their widespread use, second only to statins in terms of total drug expenditure worldwide.1 In the United States, PPIs are the third highest selling class of medications, with an annual cost of $13.9 billion per year.2,3

Despite their popularity, increasing debate surrounds inappropriate PPI use and the associated safety concerns, both of which contribute to unnecessary health care costs while placing patients at risk of serious side effects. In fact, about two-thirds of PPI use may be inappropriate.3,4 The Centers for Medicare & Medicaid Services (CMS) Medicaid Integrity Group has issued a statement noting that PPIs are widely prescribed outside of FDA-approved product labeling for indication, age, dosage, or duration.5

General Medical Concerns With PPIs

Rebound Hypersecretion
PPI use often continues because increased gastric acid hypersecretion can occur when it ceases,1 as is the case in 60% to 90% of patients taking PPIs for at least two to three months. Rebound hypersecretion symptoms, which occur when the body’s normal gastric acid has been suppressed and then recurs when PPI use ends, can take that long (or longer) to resolve, depending on the previous dose and duration of therapy.

To avoid the condition, a patient’s PPI dose may need to be reduced initially, followed by reducing the frequency of administration. For example, if a patient initially takes 40 mg of a PPI twice daily, the dose should be decreased to 20 mg twice daily and then the frequency should be reduced to daily followed by every other day, with decreases occurring approximately every week (or at longer intervals, if necessary).

Additionally, patients could use antacids or H2 blockers such as ranitidine or famotidine for breakthrough symptoms.

Osteoporosis and Fracture Risk
Data from seven epidemiologic studies prompted the FDA to revise PPI warning labels to include safety information about the possible increased risk of hip, wrist, and spine fractures with the use of these medications. Patients over the age of 50 also appear to be at increased fracture risk. Increased risk appears to depend on dose and/or duration, with patients receiving high doses and/or long-term therapy (more than one year) having a greater risk. 

PPIs also may reduce the effectiveness of bisphosphonate medications used to help prevent hip fractures. Patients over the age of 70 taking PPIs with the bisphosphonate alendronate experienced a significantly increased fracture risk, and when PPI therapy was given together with alendronate for two years or more, the potential hip fracture protection was negated.6

It is believed that decreased calcium or vitamin B12 absorption contributes to PPI-related hip fractures. Patients taking PPIs who are at risk of osteoporosis are encouraged to supplement with calcium citrate and vitamin D.

Infection Risk
It is believed that the increased pH resulting from PPI gastric suppression encourages bacterial growth with even short-term PPI use (less than one week), increasing infection risk.

The increasing occurrence of Clostridium difficile (C diff) infections in hospitals and nursing homes is of tremendous concern, with a mortality rate of 6.9% at 30 days after diagnosis and 16.7% at one year. Nationally, the estimated cost per infection ranges from $6,000 to $9,000, and the estimated total cost per year ranges from $1 billion to $1.6 billion.7

PPI use has been linked to increases in C diff infections and diarrhea, with patients taking PPIs having a 1.4 to 2.75 times greater risk of developing the infection than patients not receiving PPI therapy. One in 533 hospitalized patients taking PPIs develops a C diff infection. One study indicated that patients with no recent hospitalization have an increased C diff infection risk after only two days of PPI use, while patients with a hospital admission within the previous 30 days have an increased risk after only one day of therapy. Additionally, patients being treated for a C diff infection while taking a PPI have a 42% greater risk of infection within 90 days.8

The incidence of pneumonia also may increase with PPI use; patients on mechanical ventilators taking PPIs are at greatest risk. One additional case of hospital-acquired pneumonia occurs for every 111 non-ICU patients treated with PPIs for at least three days.2

Conflicting data on the risk of community-acquired pneumonia and PPI use have emerged. A recent study indicated that short-term PPI use, but not chronic use, may be associated with a higher risk of community-acquired pneumonia.1

Magnesium Depletion
PPI use lasting more than one year can decrease magnesium absorption, which can be of concern in patients taking other medications that lower magnesium levels, such as diuretics. Low magnesium levels also may adversely affect patients taking cardiac medications, including those receiving digoxin, who are at greater risk of digoxin toxicity.1

Patients being considered for long-term PPI use should be tested for a baseline magnesium level and then undergo periodic evaluations throughout the course of PPI therapy, especially if they are taking digoxin. It is important to monitor for symptoms of hypomagnesmia, which include muscle cramps, heart palpitations, dizziness, tremors, and seizures.

Supplementation with an over-the-counter product such as Slo-Mag or MagOx may be indicated, and if magnesium levels do not improve with supplementation, the PPI may need to be changed to a H2 blocker.

Reducing Inappropriate Use Across Care Settings
PPI overuse in both ICUs and general hospital units often results from inappropriate stress ulcer prophylaxis. While PPIs can reduce stress ulcer bleeding risk in ICU patients, their use should be limited to critically ill patients with specific risk factors (see below).1-4 These patients then should be assessed daily, with PPI therapy discontinued once risk factors are resolved.1

There is no evidence to support PPI use for stress ulcer prophylaxis in medical or surgical (non-ICU) patients considered at low risk of stress ulcers.1 In this setting, PPIs should be used only for documented FDA-approved diagnoses warranting treatment. Despite this recommendation, studies indicate the following8:

• Forty percent to 70% of all hospital patients receive PPI therapy.

• Two-thirds of PPI orders are given without an adequate indication.

• In one-half of hospital cases, PPIs are ordered on admission, and only one-half of these orders are discontinued on hospital discharge.

Improved medication reconciliation processes are needed, and pharmacists, nurses, and discharge planners must increase their focus on PPI use occurring throughout a patient’s hospital stay and on the patient’s discharge back into the community or, in many cases, nursing home care. Failure to discontinue PPI use on discharge has been shown to result in a large number of patients inappropriately receiving long-term PPI therapy, with an increased risk of adverse events. 

The hospital discharge planning team can assist by ensuring a diagnosis validating postdischarge PPI use is documented, and if PPI therapy was started for stress ulcer prophylaxis while the patient was hospitalized, have the order discontinued on discharge.

When patients are discharged from the hospital and admitted to long term care facilities, the admission team should have processes in place to ensure a supporting indication exists for PPI therapy along with any information concerning the severity of symptoms and length of therapy. If this information is not present, the discharging hospital should be contacted to determine the indication for PPI use.

Physicians in ambulatory care settings and nursing homes often are hesitant to discontinue PPI therapy ordered by other physicians, especially when it is not clear why a PPI was prescribed. The supporting indication for PPI use along with details about the duration of therapy are essential for health care providers to adequately evaluate PPI use.

In the outpatient setting, the lack of supporting documentation or supporting indication for PPI use is common. Physicians and other providers often inadequately evaluate long-term PPI use in patients with mild GERD symptoms or dyspepsia despite guidelines recommending ongoing evaluation. It is also common for providers to minimize PPI safety concerns, fail to discuss long-term risks with patients, overlook PPI use in follow-up examinations, and reflexively refill prescriptions without adequate reassessment. 

To minimize the inappropriate PPI use across settings, new prompts for interventions are needed to increase discussions between providers and patients about the benefits and risks of PPI therapy while also improving the ongoing monitoring and evaluation of patient symptoms, with increased focus and consideration for step-down therapy or on-demand dosing. 

General Recommendations
PPIs provide superior efficacy and should continue to be recommended as first-line agents per evidence-based guidelines for many upper gastrointestinal (GI) conditions, including ulcers, severe GERD, NSAID-associated GI bleeding prophylaxis, erosive gastritis, and Barrett’s esophagus.1

Despite the benefits seen with PPI use, health care providers must increase their awareness of the associated risks and implement strategies such as the following to ensure appropriate use1-5,9,10:

• Patients should use the lowest dose for the shortest duration possible to appropriately treat a specific condition.

• PPIs should be taken 30 to 60 minutes prior to breakfast (and dinner if twice-daily therapy is required) to maximize effectiveness.

• Patients should not maintain long-term acid suppression therapy without ongoing symptom evaluation and dose-reduction or drug-discontinuation consideration.

• When used in combination with anti-infective medications to eradicate Helicobacter pylori, PPI discontinuation should be considered after 14 days. 

• The treatment of duodenal ulcers or nonerosive reflux disease may require only four weeks of PPI therapy.

• For patients with GERD, a trial reduction should be considered after eight to 12 weeks of PPI therapy if there is documented or suspected erosive reflux disease.

• When treating GERD symptoms, step-up dosing strategies should be considered, which include starting with H2 blockers twice daily and if symptoms are not adequately controlled, discontinuing the H2 blocker and beginning once-daily PPI therapy, increasing to twice daily if symptoms continue.

• Step-down dosing strategies, such as tapering the PPI dose every seven days for patients with GERD or achieving maintenance dosing for other GI disorders, should be considered. For example, if a PPI initially is dosed at twice daily, taper to once daily for seven days then every other day for seven days, resulting, if possible, in an attempt at trial discontinuation. Alternatively, attempt a taper to maintenance doses of H2 blockers. In both cases, if symptoms reemerge, the dose should be increased to the lowest effective dose of PPI or H2 blocker required to control symptoms.

• Consideration should be given to trying to control GERD symptoms with cost-effective patient-on-demand PPI dosing rather than routine dosing schedules. 

• H2 blockers and antacids may be useful for addressing mild symptoms, nighttime symptoms, or indigestion/heartburn.

• Lifestyle modifications to help minimize medication use should be encouraged, such as eating smaller meals, quitting smoking, not eating two to three hours before bedtime, raising the head of the bed 4 to 6 inches, maintaining a normal weight, and avoiding foods that worsen symptoms.

• Patients may have a false sense of safety with over-the-counter PPIs since they are widely available without a prescription. They should be advised of potential risks and instructed to contact their physician if symptoms do not relieve after two weeks of use.

Need for Improved Education
Concerns about PPI overuse led the CMS’ Center for Program Integrity to develop an educational program (available at The program includes several useful educational resources, including a PPI fact sheet intended to promote appropriate prescribing behaviors within FDA-approved guidelines and specific dosing charts.9

— Mark D. Coggins, PharmD, CGP, FASCP, is director of pharmacy services for more than 300 skilled nursing centers operated by Golden Living and a director on the board of the American Society of Consultant Pharmacists. He was recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.


Risk Factors for ICU Stress Ulcer Prophylaxis
Patients should have at least one of the following:

• coagulopathy;

• mechanical ventilation for more than 48 hours;

• a Glasgow coma score of 10 or lower;

• hepatic or renal failure;

• history of gastrointestinal ulcer or bleed within one year of admission;

• multiple trauma;

• partial hepatectomy;

• spinal cord injury;

• thermal injury over more than 35% of body surface area;

• transplantation perioperatively in the ICU; or

• two or more of these risk factors: sepsis, an ICU stay of more than one week, occult bleeding lasting at least six days, or high-dose corticosteroids (more than 250 mg/day of hydrocortisone).

— Source: ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health Syst Pharm. 1999;56(4):347-379.

Prescription and Over-the-Counter Proton Pump Inhibitors

Generic Name

Prescription Brand Name

Over-the-Counter Brand Name




Esomeprazole magnesium





Prevacid 24HR




Omeprazole magnesium


Prilosec OTC

Omeprazole and sodium bicarbonate


Zegerid OTC

Pantoprazole sodium



Rabeprazole sodium



*Over-the-counter versions of omeprazole are the magnesium salt.


1. Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of proton pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol. 2012;5(4):219-232.

2. Fohl AL, Regal RE. Proton pump inhibitor-associated pneumonia: not a breath of fresh air after all? World J Gastrointest Pharmacol Ther. 2011;2(3):17-26.

3. Katz MH. Failing the acid test: benefits of proton pump inhibitors may not justify the risks for many users. Arch Intern Med. 2010;170(9):747-748.

4. Hamzat H, Sun H, Ford JC, Macleod J, Soiza RL, Mangoni AA. Inappropriate prescribing of proton pump inhibitors in older patients: effects of an educational strategy. Drugs Aging. 2012;29(8):681-690.

5. Proton pump inhibitors: use in adults. Centers for Medicare & Medicaid Services website. August 2013. Accessed November 22, 2013.

6. Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med. 2011;171(11):998-1004.

7. Clostridium difficile (C. difficile) infections. Virginia Department of Health website. Last updated November 5, 2013. Accessed November 28, 2013.

8. Dial SM. Proton pump inhibitor use and enteric infections. Am J Gastroenterol. 2009;104:S10-S16.

9. Program integrity proton pump inhibitor education materials. Centers for Medicare & Medicaid Services website. Last modified September 23, 2013. Accessed November 22, 2013.

10. 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;16(9):e228-234.