Review of the Popular Stomach-Acid Suppressant Proton Pump Inhibitor Drugs

Proton pump inhibitors (PPIs) are currently one of the mainstays for treatment of stomach-acid disorders.[1] In 1989, omeprazole (PRILOSEC) was the first of this drug class to be approved by the Food and Drug Administration (FDA).[2] Since then, five other PPIs have gained approval (see Table below for a list of these drugs; one PPI, omeprazole, is also marketed in combination with the antacid sodium bicarbonate). All PPIs are available in oral forms, and four are available over the counter. Additionally, three PPIs also are available in intravenous form.

Prescription PPIs are approved to treat heartburn associated with gastroesophageal reflux disease over a few weeks. Some of these drugs also are approved to treat other conditions, including the following: (1) erosive esophagitis (inflammation and erosion of the esophagus), (2) peptic (stomach or duodenum) ulcers (including those caused by nonsteroidal anti-inflammatory drugs [NSAIDs]), (3) conditions in which the stomach makes too much acid (including Zollinger-Ellison syndrome) and (4) stomach infection caused by a bacteria called Helicobacter pylori (taken with certain antibiotics).[3]

Over-the-counter PPIs are approved only for a maximum of 14 days of treatment for heartburn that occurs at least two days a week.[4] PPIs often are overused, particularly for unapproved conditions, such as dyspepsia (indigestion) and vague digestive disorders.[5]

With over 121 million fills for just four generic PPIs and one brand-name prescription PPI in 2016, these drugs are among the most commonly prescribed drugs in the U.S.[6] Despite their popularity, these drugs have been linked to various, sometimes severe, adverse effects, especially with long-term use.

Public Citizen’s Health Research Group has long warned about the serious risks of PPIs and was partially successful in petitioning the FDA to include related warnings on the labeling of these drugs.[7] We have designated all these drugs as Limited Use.

Oral Prescription and Over-the-Counter ProtonPump Inhibitors (PPIs)*

*All PPIs are classified as Limited Use.
**Over-the-counter PPI brands

Benefit but with rebound acidity

PPIs are effective for relieving symptoms and healing lesions in the inner stomach lining associated with stomach-acid disorders because these drugs inhibit the secretion of the acid.[8],[9] Notably, PPIs are more potent stomach-acid inhibitors than histamine-2 receptor blockers (H2 blockers), including cimetidine (TAGAMET HB) and ranitidine (ZANTAC), a group of drugs that partially prevents the production of stomach acid. PPIs usually take several days to start working;[10] H2 blockers work more quickly but have a relatively short duration of action (up to eight hours).[11]

As indicated in our 2011 FDA petition,[12] research shows that upon stopping PPIs after taking them for a month or more, patients make even more stomach acid than they did before they started these drugs, a phenomenon known as rebound acid oversecretion. This can cause acid reflux symptoms to return at an even greater intensity than before therapy, prompting patients to retake these drugs, leading to long-term dependence. This can happen even in healthy people.[13]

Multiple serious adverse effects

PPIs are safe for short-term use;[14] the adverse effects for such use are generally mild and include headaches and gastrointestinal disturbances (abdominal pain, constipation, diarrhea, nausea and vomiting). However, PPI makers did not generally examine most of the uses of these drugs for longer than 12 months.[15]

Evidence from postmarketing studies has linked the long-term use of PPIs to several serious adverse effects. These drugs increase the risk of a severe type of diarrhea caused by Clostridium difficile infection in the intestines.[16] PPIs also can cause low magnesium levels in the blood (which can lead to life-threatening heart rhythm disorders) if these drugs are taken for three months or longer. Osteoporosis (bone thinning) leading to fractures of the hip, wrist and spine can occur among people who take multiple daily doses for a year or longer. PPIs also can cause acute interstitial nephritis (a type of kidney disease) at any time during treatment, as well as certain types of lupus erythematosus (an autoimmune disorder in which the body’s immune cells attack other cells or organs). Vitamin B12 deficiency can occur after more than three years of use. Using PPIs for more than one year has been linked to an increased risk of fundic gland polyps (masses of cells in the bottom of the stomach).

Additionally, PPIs interact with other drugs, including the blood thinner clopidogrel (PLAVIX) and the immunosuppressive drugs methotrexate (OTREXUP, RASUVO, TREXALL, XATMEP) and mycophenolate mofetil (CELLCEPT), which can interfere with the effectiveness and safety of these drugs.[17]

Information (including warnings) on these adverse effects and drug interactions was added to the labeling of PPIs after our 2011 petition to the FDA; five of these updates were requested in our petition.[18],[19] Unfortunately, the FDA required only general warnings for all of these adverse effects, despite our request for blackbox warnings (the most prominent warnings that the agency can require) for two adverse effects: fractures and low magnesium levels in the blood. The agency did not grant our request for new warnings on PPI labeling regarding the risk of long-term dependency and pneumonia, despite the extensive related evidence cited in our petition. In April 2019, the FDA identified a potential signal for rebound acid oversecretion associated with PPIs in an exploratory analysis of its Adverse Event Reporting System but noted that “no action is necessary at this time.”[20]

Importantly, recent evidence reveals additional serious adverse effects that, as of press time, have not been added to PPI labeling. For example, a large long-term observational study using data from the Department of Veterans Affairs showed that new users of prescription PPIs had a 25% higher risk of death than those taking H2 blockers.[21] Additional evidence links long-term use of PPIs to chronic kidney disease[22] and neurological adverse effects (mainly dementia and depression).[23]

What You Can Do

If you have a serious stomach-acid disorder (including peptic ulcers) or are taking NSAIDs, taking a PPI can be beneficial or even lifesaving.

However, if you have heartburn, your symptoms may improve with diet and lifestyle changes (eating smaller meals; not eating too close to bedtime; avoiding certain “trigger” foods and drinks, including alcohol, coffee, chocolate and fatty foods; and raising the head of the bed at night). If your symptoms do not resolve with these strategies, seek medical attention. It is best to try antacids[24] (such as aluminum hydroxide and magnesium hydroxide [MAALOX]) first, then H2 blockers before using a PPI.

If you require a PPI, take the lowest dose possible for your condition for the shortest possible duration. Ask your doctor for an “exit strategy” for your PPI that decreases your dose gradually to avoid rebound acid oversecretion.
 

References

[1] Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: A comprehensive review. Gut Liver. 2017;11(1):27-37.

[2] AstraZeneca Pharmaceuticals LP. Label: omeprazole (PRILOSEC). December 2016. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a1b077e6-b070-43f2-a98e-380cc635419d&type=display. Accessed May 8, 2019.

[3] Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: A comprehensive review. Gut Liver. 2017;11(1):27-37.

[4] AstraZeneca Pharmaceuticals. Label: omeprazole (PRILOSEC OTC). April 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021229Orig1s033lbl.pdf. Accessed May 8, 2019.

[5] Novotny M, Klimova B, Valis M. PPI long term use: risk of neurological adverse events? Front Neurol. 2019;9(Jan 8):1142.

[6] Symphony Health. Top 200 drugs – 2016. https://symphonyhealth.com/wp-content/uploads/2017/04/Top-200-Drug-List-2016.pdf. Accessed May 8, 2019.

[7] New warnings on common heartburn drugs: Too little — and, for some, too late. Worst Pills, Best Pills News. February 2015. /newsletters/view/945. Accessed May 8, 2019.

[8] Chapman DB, Rees CJ, Lippert D, et al. Adverse effects of long-term proton pump inhibitor use: A review for the otolaryngologist. J Voice. 2011;25(2):236-240.

[9] Bruley Des Varannes S, Coron E, Galmiche JP. Short and long-term PPI treatment for GERD. Do we need more-potent anti-secretory drugs? Best Pr Res Clin Gastroenterol. 2010;24(6):905-921.

[10] AstraZeneca Pharmaceuticals LP. Label: esomeprazole (NEXIUM). June 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f4853677-1622-4037-688b-fdf533a11d96&type=display. Accessed May 8, 2019.

[11] Chapman DB, Rees CJ, Lippert D, et al. Adverse effects of long-term proton pump inhibitor use: A review for the otolaryngologist. J Voice. 2011;25(2):236-240.

[12] Public Citizen. Petition urging FDA to add warnings to proton pump inhibitors. August 23, 2011. https://www.citizen.org/sites/default/files/1964.pdf. Accessed May 8, 2019.

[13] Reimer C, Søndergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009;137(1):80-87.

[14] Novotny M, Klimova B, Valis M. PPI long term use: risk of neurological adverse events? Front Neurol. 2019;9(Jan 8):1142.

[15] AstraZeneca Pharmaceuticals LP. Label: esomeprazole (NEXIUM). June 2018. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=f4853677-1622-4037-688b-fdf533a11d96&type=display. Accessed May 8, 2019.

[16] Ibid.

[17] Ibid.

[18] Public Citizen. Petition urging FDA to add warnings to proton pump inhibitors. August 23, 2011. https://www.citizen.org/sites/default/files/1964.pdf. Accessed May 8, 2019.

[19] New warnings on common heartburn drugs: Too little — and, for some, too late. Worst Pills, Best Pills News. February 2015. /newsletters/view/945. Accessed May 8, 2019.

[20] Food and Drug Administration. Potential signals of serious risks/new safety information identified by the FDA Adverse Event Reporting System (FAERS): July - September 2018. April 29, 2019. https://www.fda.gov/drugs/fda-adverse-event-reporting-system-faers/potential-signals-serious-risksnew-safety-information-identified-fda-adverse-event-reporting-system-20. Accessed May 20, 2019.

[21] Xie Y, Bowe B, Li T, et al. Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open. 2017;7(6):e015735.

[22] Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238-246.

[23] Novotny M, Klimova B, Valis M. PPI long term use: risk of neurological adverse events? Front Neurol. 2019;9(Jan 8):1142.

[24] Food and Drug Administration. Over-the-counter (OTC) heartburn treatment. March 5, 2018. https://www.fda.gov/drugs/drug-information-consumers/over-counter-otc-heartburn-treatment. Accessed May 8, 2019.