Is There a Real Long-Term Benefit to Proton Pump Inhibitors in Functional Dyspepsia?

Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs globally, with their use becoming almost instinctive for any patient reporting upper gastrointestinal (GI) discomfort. Yet, the distinction between justified use and habitual overprescribing becomes particularly hazy in the context of functional dyspepsia (FD)—a condition characterized by chronic upper GI symptoms without identifiable structural or biochemical abnormalities.

Although PPIs are often the first-line therapy, a growing body of evidence suggests that their long-term benefit in FD is questionable, with diminishing efficacy over time, potential adverse effects, and unclear justification for chronic use. The central question arises: Are we providing long-term therapeutic value—or exposing patients to unnecessary risks?

Understanding Functional Dyspepsia: The Diagnosis of Exclusion

Functional dyspepsia is defined by the Rome IV criteria and is characterized by the following features:

• Persistent or recurrent upper abdominal discomfort or pain
  
  
• Postprandial fullness
  
  
• Early satiety
  
  
• Epigastric burning
  

Importantly, these symptoms are not attributable to identifiable structural diseases such as ulcers, malignancies, or infections like Helicobacter pylori. FD is estimated to affect 10–20% of the general population and often coexists with other functional gastrointestinal disorders, notably irritable bowel syndrome (IBS).

Its pathophysiology is multifactorial and may include:

• Disordered gastric motility
  
  
• Visceral hypersensitivity
  
  
• Psychological comorbidities, including anxiety and depression
  
  
• Subtle inflammatory or immune dysfunction
  

Why Are PPIs Used in Functional Dyspepsia?

PPIs are prescribed under the premise that gastric acid contributes to symptom generation. Their widespread use in FD can be attributed to several clinical assumptions:

• Acid suppression might alleviate upper GI symptoms
  
  
• PPIs are easily accessible, relatively inexpensive, and perceived as safe
  
  
• Many patients report symptom improvement after empirical use
  

Consequently, many clinicians continue PPI therapy long after excluding peptic ulcers or reflux disease—often because the patient "feels better." However, this raises a critical concern: Does transient symptom relief justify indefinite pharmacologic intervention?

The Short-Term Evidence: Yes, PPIs Work—To a Degree

There is some evidence supporting the short-term efficacy of PPIs in FD:

• Several randomized controlled trials (RCTs) have demonstrated modest improvements—about 10–20% greater than placebo
  
  
• Patients with overlapping reflux symptoms appear to derive the most benefit
  
  
• Symptom relief is generally seen within the first 4–8 weeks
  
  
• The number needed to treat (NNT) is relatively low in specific subpopulations
  

In summary, short-term use is defensible in carefully selected patients, especially those with acid-related symptom profiles.

The Long-Term Reality: Benefits Decline, Risks Increase

Beyond the 8–12 week mark, especially in the absence of coexisting GERD or ulcer disease, the role of PPIs in FD becomes increasingly uncertain.

1. Symptom Rebound After Withdrawal

A well-documented phenomenon is rebound acid hypersecretion after stopping PPIs. This may create a false perception of “relapse,” leading both patients and providers to resume or continue therapy unnecessarily, even when the original benefit was marginal.

2. Declining Efficacy Over Time

Longitudinal studies indicate that symptom control achieved during initial therapy often diminishes over time. Many patients experience recurrent or persistent symptoms despite ongoing acid suppression—highlighting that acid may not be the central pathophysiologic driver in FD for most individuals.

The Hidden Price: Long-Term PPI Risks

Despite their perceived safety, prolonged PPI use is not without consequences. Emerging evidence links long-term therapy with a variety of complications:

Microbiome Disruption
PPIs alter gastric pH and thereby disrupt normal gut microbiota, potentially contributing to small intestinal bacterial overgrowth (SIBO) and increasing susceptibility to infections like Clostridioides difficile.

Malabsorption Syndromes
Chronic acid suppression impairs the absorption of critical micronutrients such as calcium, magnesium, iron, and vitamin B12. Over time, this may lead to clinically significant deficiencies, particularly in elderly or nutritionally vulnerable populations.

Renal Complications
Observational data have associated PPIs with an increased risk of chronic kidney disease (CKD) and acute interstitial nephritis. While causality remains under investigation, the correlation is concerning enough to warrant caution.

Fracture Risk
Reduced calcium absorption due to hypochlorhydria may compromise bone mineral density, increasing the risk of osteoporotic fractures—especially in older adults on long-term therapy.

Potential Gastric Neoplasia
Though controversial, some studies have linked chronic PPI use to the development of fundic gland polyps and, in certain high-risk populations, a potential increase in gastric cancer risk. This is likely multifactorial and not solely attributable to acid suppression.

Alternatives to Long-Term PPI Use in Functional Dyspepsia

Given the modest benefits and non-trivial risks of chronic PPI use, clinicians should consider other evidence-based interventions:

H. pylori Testing and Treatment
In some patients, especially in endemic areas, eradication of H. pylori can lead to significant symptom resolution—even if the initial presentation doesn’t overtly suggest infection.

Prokinetics
For patients with delayed gastric emptying or motility-related symptoms, agents like domperidone, itopride, or newer prokinetics like prucalopride can be useful. Their efficacy is often higher in postprandial distress syndrome (PDS) subtypes.

Tricyclic Antidepressants (TCAs)
Low-dose TCAs such as amitriptyline can reduce visceral hypersensitivity and provide symptom relief, particularly in patients without reflux features. They offer benefit beyond acid suppression by modulating the brain–gut axis.

Cognitive Behavioral Therapy (CBT)
As psychological factors play a significant role in FD, particularly in those with treatment-refractory symptoms, CBT has shown measurable improvements in symptom perception and patient quality of life.

Dietary Modifications
Several dietary strategies—smaller, more frequent meals; low-fat intake; and FODMAP reduction—may help certain subgroups, particularly those with FD–IBS overlap. Personalized dietary interventions based on symptom diaries can be valuable.

So, Should PPIs Ever Be Used Long-Term in FD?

Yes—but with strict clinical judgment. Long-term use may be appropriate in:

• Patients who experience clear, documented symptom recurrence upon withdrawal
  
  
• Those with proven overlapping GERD or endoscopic abnormalities
  
  
• Individuals with low risk of long-term complications
  
  
• After thorough discussion regarding risk–benefit ratios and ongoing evaluation
  

For the majority of FD patients, a step-down approach or discontinuation following initial relief is more prudent.

Revisiting the Physician’s Role

PPI therapy is often continued passively—nobody stops it simply because no one has reassessed the indication. Yet as stewards of pharmacologic safety, clinicians should proactively:

• Periodically re-evaluate the ongoing necessity of PPI therapy
  
  
• Educate patients on both benefits and risks of chronic use
  
  
• Initiate weaning protocols once control is achieved
  
  
• Consider non-acid suppressive therapies as first-line agents in non-reflux functional dyspepsia
  

Key Takeaways for Clinicians

• Proton pump inhibitors may offer mild to moderate symptom relief in functional dyspepsia in the short term.
  
  
• Long-term efficacy in FD is limited, and chronic use should not be routine.
  
  
• Continued PPI use may be harmful due to nutrient deficiencies, renal risks, infection, and potential neoplastic concerns.
  
  
• The underlying mechanisms of FD are largely non-acid related; hence, management should be multifaceted.
  
  
• A deprescribing culture should be cultivated—clinicians must lead discussions, offer alternatives, and individualize therapy duration based on careful assessment.
  

This nuanced approach ensures that therapeutic decisions align not only with the evidence base but also with the evolving understanding of functional dyspepsia and the broader context of patient safety.