Long-Term Risks with the Use of Proton Pump Inhibitors

Stomach acid has many important functions, for example helping to break down food in the stomach or killing harmful bacteria that have been swallowed. However, too much stomach acid or acid in the wrong place can be very painful and can cause several different health issues, including acid reflux (heart burn) and ulcers.[1]

Proton pump inhibitors (PPIs) are a class of medications used to reduce the amount of acid your stomach produces. PPIs are one of the most commonly prescribed drugs in the U.S. and their use has increased in recent years.

When used once daily over a few days, PPIs can reduce the amount of stomach acid by about two-thirds,[2] making them more potent than other classes of drugs that neutralize stomach acid such as antacids (TUMS, PEPTO-BISMOL and others) or drugs that are less effective at preventing the production of stomach acid, such as histamine-2 receptor blockers (H2 blockers), including cimetidine (TAGAMET HB and generics) and famotidine (PEPCID AC and generics).[3] Unlike antacids and H2 blockers, PPIs take up to a few days before their effect becomes noticeable, which means that they may not be a good choice for patients who need quick relief, for example from heartburn.

PPIs carry a higher risk of serious adverse events than alternative medications. Therefore, they should be reserved to treat patients with serious illnesses, such as peptic ulcer disease, and those taking certain medications known to harm the stomach lining (for example, non-steroidal anti-inflammatory drugs, or NSAIDs).

Available proton pump inhibitors

In 1989, the Food and Drug Administration (FDA) approved omeprazole (PRILOSEC and generics), the first drug of its class in the United States. Over-the-counter formulations of PPIs have been available since 2003.[4] The FDA has approved PPIs in various formulations. One PPI, omeprazole, is also marketed in combination with the antacid sodium bicarbonate (see Table below). All of the PPIs have generic versions.[5]

Public Citizen’s Health Research Group has long warned about the serious long-term risks of PPIs, all of which we have designated as Limited Use drugs. In 2011, we petitioned the FDA, and were partially successful in having the agency strengthen the warnings on the labels of these drugs.[6] For instance, in the FDA’s response to our petition, the agency acknowledged that most of the risks identified in the petition were, in fact, likely side effects of PPI use. The FDA agreed to include warning language for some of these risks on the product labels of all PPIs. However, the agency declined our request to require black-box warnings.[7]

Table: List of Oral Prescription and Over-the-Counter Formulations of PPIs*

*Public Citizen’s Health Research Group has classified all PPIs as Limited Use.
**Over-the-counter PPI brand names.

The FDA has approved over-the-counter PPIs for a maximum of 14 days of treatment for heartburn that occurs at least two days a week.[8] The FDA has approved prescription PPIs for longer periods of time to treat heartburn associated with gastroesophageal reflux disease (GERD).[9],[10] Some PPIs are also approved to treat other conditions, including certain types of erosive esophagitis (inflammation and erosion of the esophagus), peptic (stomach or duodenum) ulcers, including those caused by NSAIDs, Zollinger-Ellison syndrome (a rare condition that causes excessive stomach acid production) and stomach infection caused by a bacteria called Helicobacter pylori (taken together with certain antibiotics).

PPIs are generally safe for short-term use. During short-term use, PPIs are associated with mild adverse events such as pharyngitis (sore throat) and gastrointestinal disturbances, such as abdominal pain, constipation, diarrhea and vomiting.[11]

Important safety concerns on the drug label

Long-term use of PPIs, however, is associated with several serious adverse events.[12] This is of particular concern because these drugs are often taken for longer periods than necessary. Moreover, PPIs are widely and inappropriately prescribed off-label for conditions that do not require treatments with powerful drugs, such as dyspepsia (indigestion) and vague digestive disorders.[13]

Micronutrient deficiencies

Long-term use of PPIs may cause low magnesium levels in the blood, which can lead to severe and life-threatening magnesium deficiency (hypomagnesemia), which can cause abnormal heart rhythms and muscle spasms or tremors.[14],[15] PPIs have also been associated with a decreased absorption of vitamin B12, iron and calcium.

Bone fractures

Possibly because of the decreased levels of calcium associated with long-term treatment, PPI use may also increase the risk of osteoporosis (bone thinning), leading to a higher risk of hip, spine and wrist fractures.[16]

Fundic gland polyps

Especially when taken for more than one year, PPIs have been associated with an increased risk of fundic gland polyps (masses of cells in the bottom of the stomach).

Clostridioides difficile infections

Since the use of PPIs reduces stomach acid production, a larger number of dangerous bacteria may be able survive the passage through the stomach into the intestine and, as a result, cause serious infections.[17] The warning on the PPI label includes an increased risk for severe and often life-threatening infection with the toxin-producing bacterium Clostridioides difficile (C. difficile) even in the absence of antibiotic use; C. difficile infection is associated with antibiotic use. C. difficile infections can cause abdominal pain, severe diarrhea and colitis (an inflammation of the colon). Although not included on the drug label, some evidence also suggests that long-term use of PPIs increases the risks for other infections, such as pneumonia, and bacterial overgrowth in the small intestine.[18]

Kidney injury

There is evidence that treatment with PPIs over longer periods of time may increase the risk for kidney damage, including chronic kidney disease, and can facilitate the progression to end-stage kidney disease.[19] However, the warning on the drug label currently only includes increased risk for acute interstitial nephritis, a specific type of kidney disease.

Interactions with other drugs

PPIs can have several dangerous interactions when taken concomitantly (at the same time) with other drugs. For this reason, PPIs should not be taken together with the oral blood thinners clopidogrel (PLAVIX and generics) and warfarin (JANTOVEN and generics), the heart failure drug digoxin (LANOXIN and generics), the immunosuppressive drugs methotrexate (JYLAMVO, OTREXUP, RASUVO, TREXALL, XATMEP and generics) and mycophenolate mofetil (CELLCEPT and generics) and HIV treatments containing rilpivirine (EDURANT and others).

Additional safety concerns not on drug label

Public Citizen’s Health Research Group has repeatedly raised the safety concerns discussed below in previous Worst Pills, Best Pills News articles[20],[21] and in our 2011 petition to the FDA,[22] however they are not currently included as warnings on the drug label.

Dementia

Although there has been inconsistent evidence in the past,[23] several recent studies have found an association between long-term treatment with PPIs and dementia. A study published in 2023 found an association between an increased rate of dementia with long-term PPI use regardless of the age when treatment with PPIs was started.[24]

Increased risk of death

A systematic review of several studies, published in 2020, suggested that the long-term use of PPIs may be associated with an increased rate of death from any cause in older adults, however the available data for this association are insufficient.[25]

Long-term dependency

One reason long-term use of PPIs may be widespread is that these drugs can cause long-term dependency.[26] When patients discontinue PPIs after they had taken them for more than a month, acid reflux symptoms can return at an even greater intensity. The reason is that patients may produce more stomach acid than they did before they started their treatment.[27] This phenomenon, known as “rebound acid hypersecretion,” often leads patients to continue taking PPIs or to re-starting treatment, leading to long-term reliance.

What You Can Do

Because PPIs are associated with serious adverse events, especially when taken for longer periods of time, these drugs should be taken only for serious conditions (such as peptic ulcer disease and rare diseases where stomach acid secretion is greatly increased) and to protect against the harmful effects of NSAIDs on the stomach lining. Also, keep in mind that because PPIs take several days to take effect, they are not a good option for fast relief of heartburn. If you have a condition or disease for which PPIs are the appropriate treatment, discuss with your clinician how to ensure use of these drugs at the lowest effective dose and for the shortest time necessary. Additionally, ask for an “exit strategy” that decreases your PPI dose gradually to avoid rebound acid hypersecretion.[28]
 

References

[1] Clevland Clinic. Proton Pump Inhibitors. Reviewed September 28, 2023. https://my.clevelandclinic.org/health/articles/proton-pump-inhibitors. Accessed November 22, 2023.

[2] Wolfe MM. Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders. UpToDate. Updated July 27, 2022.

[3] Review of the popular stomach-acid suppressant proton pump inhibitor drugs. Worst Pills, Best Pills News. July 2019. https://www.worstpills.org/newsletters/view/1272. Accessed November 22, 2023.

[4] Hayes KN, Nakhla NR, Tadrous M. Further evidence to monitor long-term proton pump inhibitor use. JAMA Netw Open. 2019;2(11):e1916184.

[5] Mishuk AU, Chen L, Gaillard P, et al. National trends in prescription proton pump inhibitor use and expenditure in the United States in 2002-2017. J Am Pharm Assoc. 2021;61(October 22):87-94.

[6] Public Citizen. Petition urging FDA to add warnings to proton pump inhibitors. August 23, 2011. https://www.citizen.org/article/petition-urging-fda-to-add-warnings-to-proton-pump-inhibitors/. Accessed November 22, 2023.

[7] New warnings on common heartburn drugs: Too little — and, for some, too late. Worst Pills, Best Pills News. February 2015. https://www.worstpills.org/newsletters/view/945. Accessed November 30, 2023.

[8] Procter & Gamble. Label: omeprazole magnesium (PRILOSEC OTC). August 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=35a79458-79f6-44d6-b74c-b4f4aaf0dde0&type=display. Accessed November 22, 2023.

[9] Corvis Pharma. Label: omeprazole (PRILOSEC). March 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022056s026lbl.pdf#page=34. Accessed November 22, 2023.

[10] Wolfe MM. Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders. UpToDate. Updated July 27, 2022.

[11] Eisei. Label: rabeprazole sodium (ACIPHEX). November 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5d103551-978f-472a-9c62-51e6e4dea068&type=display. Accessed November 22, 2023.

[12] Hayes KN, Nakhla NR, Tadrous M. Further evidence to monitor long-term proton pump inhibitor use. JAMA Netw Open. 2019;2(11):e1916184.

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

[14] Corvis Pharma. Label: omeprazole(PRILOSEC). March 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022056s026lbl.pdf#page=34. Accessed November 22, 2023.

[15] Jaynes M, Kumar AB. The risks of long-term use of proton pump inhibitors: a critical review. Ther Adv Drug Saf. 2019;10(November 19):2042098618809927.

[16] Wolfe MM. Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders. UpToDate. Updated July 27, 2022.

[17] Jaynes M, Kumar AB. The risks of long-term use of proton pump inhibitors: a critical review. Ther Adv Drug Saf. 2019;10(November 19):2042098618809927.

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

[19] Wolfe MM. Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders. UpToDate. Updated July 27, 2022.

[20] Review of the popular stomach-acid suppressant proton pump inhibitor drugs. Worst Pills, Best Pills News. July 2019. https://www.worstpills.org/newsletters/view/1272. Accessed November 22, 2023.

[21] Proton pump inhibitors linked to dementia in the elderly. Worst Pills, Best Pills News. August 2016. https://www.worstpills.org/newsletters/view/1049. Accessed November 30, 2023.

[22] Public Citizen. Petition urging FDA to add warnings to proton pump inhibitors. August 23, 2011. https://www.citizen.org/article/petition-urging-fda-to-add-warnings-to-proton-pump-inhibitors/. Accessed November 22, 2023.

[23] Ibid.

[24] Pourhadi N, Janbek J, Jensen‐Dahm C, et al. Proton pump inhibitors and dementia: A nationwide population‐based study. Alzheimers Dement. 2023. doi: 10.1002/alz.13477.

[25] Ben‐Eltriki M, Green CJ, Maclure M, et al. Do proton pump inhibitors increase mortality? A systematic review and in‐depth analysis of the evidence. Pharmacol Res Perspect. 2020;8(5):e00651.

[26] Proton pump inhibitors: Dangerous and habit-forming heartburn drugs. Worst Pills, Best Pills News. November 2011. https://www.worstpills.org/newsletters/view/772. Accessed November 22, 2023.

[27] Targownik LE, Fisher DA, Saini SD. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review. Gastroenterology. 2022;162(4):1334-1342.

[28] Corvis Pharma. Label: omeprazole (PRILOSEC). March 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022056s026lbl.pdf#page=34. Accessed November 22, 2023.