There are many reasons why you might not respond to proton pump inhibitors (PPIs), ranging from not taking medications as prescribed to having genes that change the way your body metabolizes PPIs.

Gastroesophageal reflux disease (GERD) is estimated to affect anywhere from 18–28% of people in North America.

Lifestyle changes like quitting smoking and avoiding trigger foods are sometimes enough to improve GERD symptoms. Doctors often recommend medications if changing lifestyle habits alone isn’t effective.

Proton pump inhibitors (PPIs) have been the gold standard medical treatment of GERD for over 25 years. PPIs offer relief for about 60% of people, but the remaining 40% still have persistent symptoms.

Let’s examine potential reasons why GERD may not respond to PPIs as well as treatment options for people who don’t experience significant symptom relief.

GERD is called “refractory” if it doesn’t respond to PPIs for at least 8–12 weeks. There are many reasons why GERD may not respond to PPIs. Here are some of the possible reasons.

Not taking medications as prescribed

GERD may not respond to PPIs if they’re not taken as prescribed.

PPIs should normally be taken 30–60 minutes before a meal, but potentially more than half of people take PPIs incorrectly.

Most doctors recommend that once-daily PPIs should be taken as soon as you wake up in the morning. For twice-daily PPIs, the second dose is usually taken before dinner.


Not having a response to PPIs can be a sign that you may not have GERD. Esophageal pH monitoring is the gold standard technique for differentiating GERD from other conditions. It involves inserting a tube into your esophagus through your nose for 24 hours.

Other conditions that may mimic GERD include:

Genetic factors

PPIs are primarily metabolized (processed) by your liver. Genes that change your expression of an enzyme called CYP2C19 can change how your body breaks down and uses PPIs. About 2–5% of people of European and African ancestry and 15% of people of Asian ancestry are classified as “poor metabolizers.”

Functional esophageal disorders

Functional esophageal disorders are symptomatic conditions that aren’t caused by a known underlying disease or anatomical condition. The presence of a functional esophageal disorder may complicate GERD treatment.

Functional esophageal disorders associated with GERD include:

Functional heartburn

Functional heartburn is when you experience GERD symptoms but without the evidence of high acid levels in your esophagus.

Esophageal hypersensitivity

Esophageal hypersensitivity is when you are highly sensitive to anything in your esophagus. This can be from sources like stomach acid, temperature, and pressure.

Underlying conditions

Some underlying conditions may reduce the effectiveness of PPIs. Here are some examples:

  • Delayed stomach emptying: Delayed stomach emptying may increase pressure in your stomach, which can increase your backflow of stomach acid.
  • Lower esophageal sphincter (LES)difficulties: Your LES is a band of muscle that creates a barrier between your stomach and esophagus. Difficulties with this sphincter can cause acid to leak into your esophagus.
  • Weakly acidic or nonacidic reflux: Weakly acidic or nonacidic reflux occurs when the acidity of your esophagus is above the threshold for acid reflux, but you still have symptoms.

Worsening GERD symptoms while on PPIs might be due to rebound acid secretion. Rebound acid secretion occurs when your body produces more stomach acid than before treatment. It’s thought to occur due to elevations in the hormone gastrin.

Rebound acid secretion primarily occurs when you stop taking PPIs.

If you have GERD that doesn’t respond to PPIs, a doctor may recommend other medications or surgery.


A doctor may recommend:


Surgery is considered the last resort treatment. Several techniques are available, such as:

  • Fundoplication: Your surgeon wraps part of your stomach called the fundus around your esophagus to reinforce your sphincter. Success rates have been reported from 67–95% of people who receive this treatment.
  • Magnetic sphincter augmentation: A magnetic band of metal beads called the LINX device is wrapped around your sphincter to help reduce the backup of stomach acid.

Learn more about surgical options for GERD.

Here are some frequently asked questions people have about PPI-refractory GERD.

What is the strongest PPI for GERD?

Omeprazole was the first PPI on the market. Several other PPIs like lansoprazole, rabeprazole, and pantoprazole have been found to have similar effectiveness and rates of side effects.

What happens if PPIs don’t help GERD?

If you don’t respond to PPIs, a doctor may recommend:

  • other medications like H2 blockers
  • tests to confirm whether you have GERD or another condition
  • surgery

It’s important to visit a doctor for regular checkups if you’re taking PPIs to treat GERD. It can take a few days for PPIs to take their full effect.

In a 2021 study, researchers found evidence that most people who had a response to PPIs within 4 weeks also had a response within 2 weeks.

A doctor may recommend changing medications if you don’t notice an improvement in your symptoms within 2 weeks.

PPIs are the gold standard treatment for GERD that doesn’t respond to lifestyle changes alone. Although PPIs can be effective, many people don’t experience relief.

Not taking your PPIs as prescribed is one of the most common reasons why you may not notice your symptoms improve. Other factors like the presence of underlying conditions and misdiagnosis can also contribute.