Learn about the benefits, symptoms, and risks of long-term use of Proton Pump Inhibitors (PPIs). Discover alternative strategies and precautions for PPI users. Weigh the benefits and risks of PPI use and importance of individualized treatment plans.

1. Introduction to Proton Pump Inhibitors (PPIs)

Overview of PPIs

Proton Pump Inhibitors (PPIs) are a class of medications that have revolutionized the management of acid-related disorders, becoming the mainstay treatment for these conditions [Mari et al., 2023]. PPIs work by inhibiting the enzyme responsible for producing gastric acid in the stomach, thereby reducing the amount of acid present in the digestive system. This makes PPIs highly effective in treating various acid-related disorders, such as gastroesophageal reflux disease (GERD), peptic ulcer disease, and erosive esophagitis.

Common uses and indications

PPIs are commonly prescribed for a range of acid-related disorders, including GERD, peptic ulcers, and erosive esophagitis. They are also used to prevent gastrointestinal bleeding in patients at risk, such as those taking nonsteroidal anti-inflammatory drugs (NSAIDs) or antiplatelet medications [Ben-Eltriki et al., 2023]. In the context of coronary artery disease (CAD), PPIs are often prescribed alongside antiplatelet medications to reduce the risk of gastrointestinal bleeding [Teperikidis et al., 2023]. Some common PPIs include Protonix, Nexium, and Prilosec.

Mechanism of action

PPIs exert their therapeutic effects by irreversibly inhibiting the hydrogen-potassium ATPase enzyme (also known as the proton pump) in the parietal cells of the stomach. This inhibition results in a significant reduction in gastric acid secretion, leading to an increase in gastric pH and a decrease in the overall acidity of the stomach. By reducing the acidity in the stomach, PPIs promote healing of damaged tissues in the esophagus and stomach, alleviate symptoms such as heartburn, and prevent complications associated with acid-related disorders [Snady, 2023].

2. Benefits of Long-term PPI Use

Effective Treatment for Acid-Related Disorders

Proton Pump Inhibitors (PPIs) are widely prescribed medications for the treatment of acid-related disorders, such as gastroesophageal reflux disease (GERD), peptic ulcers, and Barrett’s esophagus. Long-term use of PPIs has been shown to be effective in managing these conditions and reducing the risk of complications. For example, a study by Snady H. demonstrated that the combination of high-dose PPIs and cryoablation led to complete ablation of Barrett’s esophagus in 100% of patients, with a low rate of adverse events and recurrence (Snady, 2023). This suggests that long-term PPI use can be beneficial in preventing the progression of Barrett’s esophagus to esophageal adenocarcinoma.

Prevention of Gastrointestinal Bleeding

PPIs have been shown to be effective in preventing gastrointestinal bleeding, particularly in patients with a history of peptic ulcers or those taking antiplatelet medications. In a ChatGPT powered umbrella review, Teperikidis et al. found that PPI use was associated with a reduced risk of major adverse cardiovascular events (MACE) in patients with coronary artery disease who were also taking antiplatelet medications (Teperikidis et al., 2023). This suggests that long-term PPI use may be beneficial in preventing gastrointestinal bleeding in high-risk patients.

Reduction in Risk of Esophageal Cancer

Long-term PPI use has been associated with a reduced risk of esophageal cancer, particularly in patients with GERD or Barrett’s esophagus. In the study by Snady H., the combination of PPIs and cryoablation led to a significant reduction in the risk of esophageal adenocarcinoma in patients with Barrett’s esophagus (Snady, 2023). This suggests that long-term PPI use may be beneficial in preventing the development of esophageal cancer in high-risk patients.

However, it is essential to weigh the benefits of long-term PPI use against the potential risks and side effects. As noted in a study by Thurber et al., higher-quality data is needed to better understand PPI-associated risks of adverse effects, such as bone fractures, kidney disease, gastrointestinal infections, and nutrient deficiencies (Thurber et al., 2023). Until then, healthcare professionals should carefully consider the long-term use of PPIs and weigh the risks and benefits for each patient.

3. Symptoms and Side Effects of PPI Use

Common Side Effects

Proton Pump Inhibitors (PPIs) are widely used to manage various gastric acid-related conditions, such as gastroesophageal reflux disease (GERD), gastritis, esophagitis, Barrett’s esophagus, and peptic ulcer disease, among others [Maideen NMP., 2023]. While PPIs are generally considered safe and effective, they can cause some common side effects. These may include headache, diarrhea, constipation, abdominal pain, nausea, and vomiting [Snady H., 2023]. Most of these side effects are mild and often resolve on their own without the need for medical intervention.

Less Common but Serious Side Effects

In addition to the common side effects, long-term use of PPIs has been associated with some less common but potentially serious side effects. These include renal disorders (acute interstitial nephritis, acute kidney injury, chronic kidney disease, and end-stage renal disease), cardiovascular risks (major adverse cardiovascular events, myocardial infarction, stent thrombosis, and stroke), fractures, infections (Clostridium difficile infection, community-acquired pneumonia, and Coronavirus disease 2019), micronutrient deficiencies (hypomagnesemia, anemia, vitamin B12 deficiency, hypocalcemia, hypokalemia), hypergastrinemia, and cancers (gastric cancer, pancreatic cancer, colorectal cancer, hepatic cancer) [Maideen NMP., 2023]. It is important for healthcare providers to be aware of these potential risks and monitor patients on long-term PPI therapy accordingly.

Withdrawal Symptoms and Rebound Acid Hypersecretion

One concern with the long-term use of PPIs is the potential for physical dependence and withdrawal symptoms. Rebound acid hypersecretion (RAHS) is a phenomenon where acid production in the stomach increases significantly after discontinuation of PPI therapy, leading to a recurrence or worsening of symptoms [Helgadottir H, Bjornsson ES., 2023]. This can make it difficult for patients to stop using PPIs, even when they no longer have a clear indication for their use.

In a study of patients with GORD who underwent laparoscopic magnetic sphincter augmentation (MSA) using the LINX® device, 88% of patients were able to completely stop or reduce their PPI medication by at least 75% after the procedure [Nehra D, et al., 2023]. This suggests that alternative treatments, such as MSA, may help bridge the therapeutic gap between PPI medication and more invasive surgical options like Nissen fundoplication.

In conclusion, while PPIs are effective in managing gastric acid-related conditions, their long-term use can be associated with a range of side effects, some of which can be serious. Healthcare providers should be aware of these potential risks and monitor patients on long-term PPI therapy accordingly. Additionally, patients should be informed of these risks and encouraged to explore alternative treatment options when appropriate.

4. Risks and Controversies Associated with Long-term PPI Use

Increased risk of dementia

Long-term use of Proton Pump Inhibitors (PPIs) has been associated with an increased risk of dementia. A study published in 2023 found that elderly patients in British Columbia, Canada, who were on long-term PPI therapy had a higher prevalence of dementia compared to those who were not on PPIs (Ben-Eltriki et al., 2023). However, more high-quality research is needed to establish a definitive causal relationship between PPI use and dementia risk.

Potential link to gastric and colorectal cancer

Some studies have suggested a potential link between long-term PPI use and an increased risk of gastric and colorectal cancer. A review article published in 2023 reported that long-term PPI use was associated with an increased risk of gastric cancer, pancreatic cancer, colorectal cancer, and hepatic cancer (Maideen, 2023). However, the evidence is not conclusive, and further research is needed to establish a clear causal relationship between PPI use and cancer risk.

Kidney damage and mortality

Long-term PPI use has also been linked to kidney damage and increased mortality. A study conducted in British Columbia found that older adults on long-term PPI therapy had an increased risk of acute renal injury, chronic kidney disease, and death (Ben-Eltriki et al., 2023). Another review published in 2023 reported that PPI use was associated with acute interstitial nephritis, acute kidney injury, chronic kidney disease, and end-stage renal disease (Maideen, 2023). However, as with other risks associated with PPI use, more high-quality research is needed to establish a definitive causal relationship between PPI use and kidney damage or mortality.

Possible association with Parkinson’s disease

There is limited evidence suggesting a possible association between long-term PPI use and Parkinson’s disease. However, the available data is not sufficient to establish a clear causal relationship, and more research is needed to explore this potential association.

In conclusion, long-term use of PPIs has been associated with several risks and controversies, including increased risk of dementia, potential links to gastric and colorectal cancer, kidney damage, and possible association with Parkinson’s disease. However, more high-quality research is needed to establish definitive causal relationships between PPI use and these risks. Clinicians should carefully weigh the benefits and risks of long-term PPI use for each patient and consider alternative strategies and precautions when appropriate.

5. Alternative Strategies and Precautions for PPI Users

Alternative Strategies and Precautions for PPI Users

Given the potential risks and controversies associated with long-term PPI use, it is essential to consider alternative strategies and precautions for managing acid-related disorders. These may include lifestyle modifications, alternative medications, and regular monitoring and check-ups.

Lifestyle Modifications

Lifestyle changes can help alleviate symptoms of acid reflux and GERD, reducing the need for PPIs. Some recommendations include maintaining a healthy weight, avoiding trigger foods, eating smaller meals, not lying down immediately after eating, and elevating the head of the bed. Smoking cessation and limiting alcohol consumption can also help improve symptoms.

Alternative Medications

For patients who require acid suppression therapy but are concerned about the long-term use of PPIs, alternative medications may be considered. Histamine type 2-receptor antagonists (H2RAs) are one option, although they may not be as effective as PPIs in treating severe cases of GERD. Additionally, some researchers are exploring the potential of chitosan nanoparticles for GERD treatment, which may offer targeted drug delivery and controlled release in the esophagus, although more research is needed in this area [Herdiana Y., 2023].

Monitoring and Regular Check-ups

For patients who require long-term PPI use, regular monitoring and check-ups with healthcare providers are essential. This can help ensure that the medication is still necessary and that the benefits continue to outweigh the risks. Deprescribing, or the process of reducing or stopping PPI use, may be considered in some cases. Successful deprescribing strategies have been linked to clear and simple de-escalation protocols and proper training of physicians responsible for deprescribing [Del-Pino M, Sanz EJ., 2023].

Targeted quality improvement strategies have been shown to reduce unnecessary PPI and H2RA use in hospitalized patients across a large health system. These strategies include standardization of stress ulcer prophylaxis care pathways, evidence-based order set modifications, technology-driven support, and clinical pharmacy metric performance to goal [Wiggins EH, Burgess LH, Kramer J., 2023].

Considerations for PPI Users

It is important for patients and healthcare providers to weigh the benefits and risks of long-term PPI use on an individual basis. Some patients may require long-term PPI therapy for specific medical conditions, while others may be able to manage their symptoms with lifestyle modifications and alternative medications. Regular monitoring and check-ups can help ensure that PPI therapy remains appropriate and safe for each patient.

In conclusion, alternative strategies and precautions for PPI users can help mitigate the potential risks associated with long-term use. By considering lifestyle modifications, alternative medications, and regular monitoring, patients and healthcare providers can work together to develop individualized treatment plans that balance the benefits and risks of PPI therapy.

6. Recent Trends and Insights in PPI Use

Shifts in Acid Suppression Drug Utilization

A systematic review of global PPI use in the general population found that nearly one-quarter of adults use a PPI, with 63% of users being less than 65 years old, 56% being female, and 75% being of “White” ethnicities. The study also found that nearly two-thirds of users were on high doses (≥ defined daily dose (DDD)), 25% of users continued PPIs for more than one year, and 28% of these continued for more than three years (Shanika et al., 2023). These findings indicate a widespread use of PPIs and a growing concern regarding long-term use.

In another study conducted in the Republic of Srpska, the utilization of medicines for the alimentary tract and metabolism (group A/ATC classification) increased by almost threefold in a 12-year period, which was consistent with the total medicine utilization. Pantoprazole was the most prescribed medicine among the PPIs. More than half of family physicians prescribed PPIs with antibiotics, and only 53/239 physicians noticed some adverse reactions of PPIs in their patients. Approximately 45% of patients were using PPIs for a long period of time (>6 months) (Stojaković et al., 2022).

Concomitant Use of Antiplatelet Agents and PPIs

The use of PPIs among elderly populations in British Columbia, Canada, was found to be alarmingly high, with 62% having a cumulative exposure exceeding two years and 42% exceeding five years. The recommended treatment duration for common indications such as reflux esophagitis and duodenal and gastric ulcers is 4-12 weeks. Only 13.5% of the elderly population were dispensed PPIs for 90 days or less (Ben-Eltriki et al., 2023). This overutilization of PPIs is often a result of failure to re-evaluate the need for continuation of therapy and may lead to serious harm from long-term PPI exposure.

Debate on PPIs and Gastric Cancer

The prescriptive appropriateness of PPIs in polypharmacy is a controversial topic, as PPIs are often overprescribed, and the risk of prescribing errors and adverse drug reactions increases for each additional drug added to therapy. An observational prospective study evaluated the implementation of a validated PPIs deprescription flow chart in a real-life internal ward setting. The study found that the percentage of patients with a prescriptive/deprescriptive pathway conforming to that of the flow chart was 70.4%, with low symptomatologic recurrences (Baiardi et al., 2023). This suggests that multidisciplinary management of PPIs deprescription protocols can show high adherence by prescribers in real-life hospital settings and low recurrence events.

In a study conducted in Saudi Arabia, the use of omeprazole in noncritically ill pediatric patients was deemed appropriate in only 38.6% of the study population, indicating overuse of the medication in the institution (Alosaily et al., 2023). Further research is needed to confirm this on a nationwide scale and to address the potential risks associated with the inappropriate use of PPIs in pediatric populations.

7. Conclusion

Conclusion

Long-term use of Proton Pump Inhibitors (PPIs) has been a topic of debate among healthcare professionals due to the potential benefits and risks associated with their use. PPIs are effective in treating acid-related disorders, preventing gastrointestinal bleeding, and reducing the risk of esophageal cancer. However, several studies have reported potential risks and adverse effects associated with their long-term use, including increased risk of dementia, gastric and colorectal cancer, kidney damage, and possible association with Parkinson’s disease [Ben-Eltriki et al., 2023; Teperikidis et al., 2023; Thurber et al., 2023].

Given the conflicting evidence and potential risks, it is essential for healthcare professionals to carefully weigh the benefits and risks of long-term PPI use for each patient. Individualized treatment plans should be developed, considering alternative strategies and precautions such as lifestyle modifications, alternative medications, and regular monitoring and check-ups [Cost-effectiveness of Celecoxib versus Non-steroidal Anti-inflammatory Drugs plus Proton-pump Inhibitors for Treating Osteoarthritis in Algeria].

Moreover, the overutilization of PPIs, particularly in elderly populations, highlights the need for healthcare providers to re-evaluate the necessity of long-term PPI therapy and consider de-escalation strategies when appropriate [Alosaily et al., 2023]. Further research is needed to better understand the relationship between PPI use and the associated risks, as well as to identify potential confounding factors and underlying mechanisms.

In conclusion, the long-term use of PPIs should be carefully considered, taking into account the potential benefits and risks for each patient. Healthcare professionals should remain vigilant in monitoring patients on long-term PPI therapy and be open to adjusting treatment plans as needed. By doing so, they can help ensure that patients receive the most appropriate and effective care for their acid-related disorders.

References

References

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Ben-Eltriki M, Chhabra M, Cassels A, Wright JM. (2023). Inappropriate Use of Proton Pump Inhibitor Among Elderly Patients in British Columbia: What are the Long-term Adverse Events?.

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Teperikidis E, Boulmpou A, Potoupni V, Kundu S, Singh B, Papadopoulos C. (2023). Does the long-term administration of proton pump inhibitors increase the risk of adverse cardiovascular outcomes? A ChatGPT powered umbrella review.

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Shanika LGT, Reynolds A