PPI Stopped Working: Tolerance Onset? Ideas & Solutions

Proton-pump inhibitors (PPIs) are medications that induce profound and prolonged reduction of stomach acid production by irreversibly inhibiting the H+/K+-ATPase proton pump.

These medications are utilized as monotherapy or adjunct interventions for the treatment of: gastroesophageal reflux disease (GERD) & laryngopharyngeal reflux (LPR); Barrett’s esophagus; eosinophilic esophagitis; gastritis; gastrinomas; dyspepsia; peptic ulcer; Zollinger-Ellison syndrome; and H. Pylori infection.

Although PPIs are very effective when used appropriately and consistently – some individuals report that PPIs stop working either suddenly or after a prolonged period of time (such that the beneficial acid reducing effect fades).

Why a PPI stopped working… (Possibilities)

According to Domingues et al. (2014): PPI therapy failure may occur in up to 42% of patients.

The main causes of therapeutic failure include: non-acid or weakly acid reflux; genotypic differences; comorbid medical conditions; incorrect diagnosis; and/or poor treatment compliance (i.e. adherence).

There are various reasons that PPIs stop working after providing an initial therapeutic effect.

1. Overpowering & offsetting PPI effect

Diet & Lifestyle: Reversion back to acid reflux-inducing habits (thinking that the PPI will cancel everything out).

Common is the scenario wherein individuals present with bad acid reflux – and initiate PPI therapy while simultaneously making healthy modifications to diet and lifestyle (as an adjunct).

This combination tends to provide significant reflux control and symptom relief (typically within weeks).

However, after the reflux has been under control for a while – some individuals begin to take the relief for granted because they feel “normal” again.

Although they continue taking the PPI – they revert back to the problematic diet & lifestyle choices that led to the reflux and predictably report that the “PPI stopped working.”

The reality is that poor diet/lifestyle choices overrode the effect of the PPI.

Medications, supplements, drugs: CYP2C19 enzyme interactions. Acidic or increase stomach acidity. Capable of altering GI and/or esophageal sphincter pressure/function.

In some cases, individuals may start new medications and/or supplements while using a PPI and assume that these substances won’t affect the PPI’s efficacy.

The reality is that some drugs/supplements may: (1) alter CYP2C19 function (altering PPI metabolism and subsequent efficacy); (2) increase stomach acidity; and/or (3) alter GI and/or esophageal sphincter pressure/function.

Medical doctors and/or pharmacists may not be aware of every medication/supplement that a patient is using (particularly if some are unreported or purchased OTC) – yet some of these may interact with or overpower the effects of PPIs to cause the PPI to stop working.

In other cases, medical doctors and/or pharmacists may know about every medication/supplement that a patient is using – but might be unaware that certain substances can cause or exacerbate reflux (due to lack of formal research) – such that patients are never told to discontinue usage and/or try lower risk alternatives.

2. Exacerbation of medical conditions (unrelated to the PPI)

Reflux-inducing conditions

Functional GI disorders; eosinophilic esophagitis; H. Pylori infection; hiatal hernia; digestive disorders; binge eating disorder; etc.

All these conditions could worsen reflux irrespective of PPI therapy.

Example #1: Hiatal hernia becomes larger due to a combination of gaining significant weight and/or straining while lifting an object – such that there’s now greater acid backflow up the esophagus than before.

Example #2: Someone with H. Pylori might derive a bit of benefit from standalone PPI therapy –then might find that it stops working or fails to fully manage the condition… this is because more meds are needed.

Conditions that could worsen reflux

Sleep disorders (e.g. sleep apnea); neuropsychiatric disorders (e.g. anxiety, bipolar, depression, schizophrenia); obesity (or being overweight); allergies; autoimmune conditions; cancers; etc.

All these conditions could worsen reflux irrespective of PPI therapy.

If you aren’t properly managing other aspects of your health – it could directly or indirectly worsen reflux such that you perceive the PPI has stopped working (despite the PPI eliciting the exact same effect it always has).

Esophageal hypersensitivity (?)

Esophageal hypersensitivity may cause individuals to believe a PPI has stopped working due to the fact that the esophagus has become hypersensitive due to psychiatric and/or neurological conditions.

Treatment of the hypersensitivity with a neuromodulatory agent like amitriptyline tends to generate improvement and may complement the PPI’s acid-reducing effect.

3. Administration specifics & adherence

Among many patients who derive initial benefit from PPIs followed by a loss of effect (i.e. PPI stops working) – there are problems with: (1) administration specifics; (2) dosing (high vs. low; once vs. twice daily); and/or (3) adherence (compliance).

PPIs often fail over a long-term due to patients not taking them as directed. (R)

Chheda & Postma (2008): “Nearly half of all patients seen at a voice and swallowing center were not compliant with optimal PPI usage.” (R)

Administration specifics: Many PPI users are unaware of the importance of following a strict PPI administration regimen.

  • Fasted state: PPIs need to be administered in a fasted state (on an empty stomach) for maximal effect.
  • 30-60 minutes before eating: PPIs should be administered 30-60 minutes before eating. Waiting significantly longer than 60 minutes before eating after taking a PPI may also reduce its effect.
  • Morning is optimal: PPIs tend to provide most significant benefit when administered first thing in the morning (right after waking up).
  • Protein-rich meal (post-administration): To optimize the effect of the PPI, it is recommended to consume a protein-rich meal ~30-60 minutes after the PPI is taken.
  • Standalone: PPIs should NOT be combined with other substances or used with other medications – as this may interfere with the PPIs absorption, bioavailability, metabolism, and overall effect.
  • Consistent times: PPIs should be consistently administered at the same time(s) each day – rather than at 7 AM one day – then 11 AM the next – as this may cause small “gaps” in acid reduction (such as to transiently induce reflux and interfere with healing).
  • Daily use (no skipping days): PPIs tend to require at least several days to reach peak effect – and are recommended for daily use. Administering PPIs “as needed” or infrequently (e.g. every-other-day) – especially after a period of consistent use – may explain why they stopped working.
  • Twice daily (AM & PM): If reflux is severe, it is often recommended to use PPIs twice daily (pre-breakfast & pre-dinner ~10-12 hour spacing). Why? Sometimes a single dose of PPI therapy provides incomplete/insufficient symptom management.

Note: The only exception to some of the aforementioned guidelines is dexlansoprazole (Dexilant) – which can be administered with or without food (food has no impact on its effect).

PPI Dosing: Using too low of a PPI dose relative to acid production and symptoms may provide insufficient reflux relief and/or make individuals believe the PPI is no longer working.

Some individuals require (1) high-dose PPI therapy (others only require low-dose PPI therapy) and (2) twice daily PPI therapy (rather than once-daily PPI therapy).

Gunaratnam et al. (2006): 54% of patients with poorly controlled GERD are dosed suboptimally and only 12% are dosed in a manner that maximized acid suppression. (R)

  • Adjust dose (?): A gastroenterologist can help you determine whether your PPI dose is sufficient. Obviously if you haven’t noticed sufficient symptom relief with ongoing treatment, it’s possible that
  • Twice daily (?): Some individuals may benefit from twice daily dosing due to insufficient or incomplete symptom relief with once-daily dosing. Evidence suggests that twice-daily PPI dosing yields the most marked increase in pH>4 time. (R)

Adherence (compliance): A majority of patients with GERD are relatively adherent to PPI therapy, however, adherence failure is a common reason PPIs stop working.

One report states that ~20-50% of patients with “PPI failure” present lack of compliance to PPI therapy (i.e. they aren’t taking the PPI as instructed). (R)

Some people may take a PPI for a while and experience partial or complete symptom remission – but then either consciously or inadvertently discontinue PPI therapy or become less strict with adherence over a long-term.

For example, a person might transition from taking PPIs once daily to taking PPIs every other day – and then report the PPI doesn’t seem to work as well as it did before.

In this scenario – we have a person who’s experiencing acid reflux (possibly rebound acid hypersecretion) on the days he/she skips PPIs which could induce some esophageal irritation and/or damage.

This may lead the person to erroneously conclude that the PPI doesn’t really seem to work anymore – when the reality is that the loss of therapeutic effect is from a less strict dosing regimen (poorer compliance).

4. Altered PPI pharmacokinetics

Reduced PPI bioavailability

This can be caused by suboptimal administration timing (time of day & relative to food intake) and altered PPI metabolism (CYP450).

This could be a reason as to why a subset of individuals claim that their PPIs stop working after a specific period of time.

For example: If you were taking a PPI in the morning ~30-60 minutes before meals and it was working well – but switched to taking your PPI only in the afternoon ~10 minutes before meals – then this may reduce its effect.

Altered PPI metabolism (CYP450)

Most PPIs are metabolized by CYP2C19 enzymes in the liver.

It’s possible that ongoing PPI therapy may alter concentrations of CYP2C19 enzymes as a result of chronic administration – such that the PPI is metabolized with greater/lesser efficiency than it was when a person first started treatment.

Altered PPI metabolism via time-related CYP2C19 activation changes could affect: bioavailability, distribution, and onset of PPI action – thus explaining why the PPI is no longer working (or working as well as it once did).

5. Long-term PPI complications

Bacterial overgrowth (SIBO): PPIs can sometimes cause small-intestinal bacterial overgrowth (SIBO) – particularly when used for a long-term. SIBO might exacerbate reflux leading users to conclude that the PPI stopped working.

Dysbiosis: Evidence suggests that PPIs can cause gut dysbiosis. Dysbiosis may play a role in causing reflux to occur. Perhaps dysbiosis-related reflux offsets the efficacy of the PPI. (R)

Vitamin/mineral deficiencies: Long-term PPI use may interfere with vitamin/mineral absorption – thus causing deficiencies. Deficiencies in specific vitamins/minerals may have systemic effects (such as within the GI tract) and this could offset the benefit of the PPI.

Delayed gastric emptying of solids: Evidence suggests that PPIs can delay gastric emptying of solids. (R) Delayed gastric emptying of solids might cause an increase in reflux to negate some of the initial benefit derived from the PPI.

Neuropsychiatric effects (?): PPIs may directly and/or indirectly (via the gut-brain axis) alter neurochemistry to induce or exacerbate neuropsychiatric effects (e.g. anxiety, depression, cognitive dysfunction, etc.). Neuropsychiatric effects could worsen reflux and offset the initial benefit from the PPI.

6. Switching PPIs (?)

Occasionally, some individuals may switch from one PPI to another due to cost-savings; better side effect profile; and/or more flexible administration options (e.g. with dexlansoprazole).

However, these individuals may fail to administer an equipotent dose of the new PPI (consistent with the acid reduction provided by the old PPI).

This is likely uncommon, but could occur and would explain why the patient perceived a PPI as having “stopped working.”

Misdiagnosis as a reason PPIs stop working…

If PPIs are being utilized properly/consistently and they “stop working” – it is important to reassess the accuracy of the initial diagnosis/condition for which PPIs were prescribed.

For example, someone might receive a “GERD” (gastroesophageal reflux disease) diagnosis from a non-specialist but may actually have eosinophilic esophagitis (only to be detected via endoscopic examination by a gastroenterologist).

Obviously if someone was diagnosed with GERD but actually had eosinophilic esophagitis (a condition caused by non-IgE-mediated immune responses to certain foods) – PPI therapy might only provide some benefit and/or may stop working (particularly if the eosinophilic esophagitis flared up).

Proper management of eosinophilic esophagitis by avoiding certain foods (elimination diet) in addition to an adjunct PPI – may fully reverse the symptoms.

Note: Individuals diagnosed by a non-specialist (i.e. gastroenterologist) should be encouraged to get a second opinion from a gastroenterologist for the sake of diagnostic clarity. Findings may reveal why the PPI stopped working or provided only limited/short-term benefit.

Do PPIs cause tolerance or tachyphylaxis?

No. There’s no evidence to support the idea that PPIs cause tolerance or tachyphylaxis.

This is why PPIs are the mainstay long-term treatment for reflux conditions/diseases.

Kinoshita et al. (2018): “PPIs are effective for long-term acid inhibition, especially during the daytime period, because of their lack of tolerance phenomenon. PPIs are considered to be long-range marathon runners and not short-range track sprinters.” (R)

David C. Metz (2008): “These drugs [PPIs] to not engender tachyphylaxis, or loss of efficacy, over time, and patients rarely require dose escalation to maintain efficacy.” (R)

Obviously if PPIs did cause tolerance, then this would explain why PPIs eventually stop working. However, there’s no evidence that PPIs actually cause tolerance.

(This differs from H2 antagonists a.k.a. “H2 blockers” which can cause tolerance onset within ~2 weeks of consistent usage.)

It is theoretically possible that PPIs could somehow cause pharmacokinetic (e.g. via CYP450 enzymes) or pharmacodynamic tolerance via physiologic adaptation to the regular presence of proton-pump inhibitors and sustained proton-pump inhibition.

Pharmacokinetic tolerance to PPIs

Would cause the PPI to be metabolized at an atypical rate and thus could significantly reduce PPI potency and/or duration of effect.

All common PPIs (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole) are metabolized primarily by CYP2C19 enzymes in the liver – and function as CYP2C19 inhibitors.

Dexlansoprazole and Pantoprazole are also metabolized by CYP3A4 (to a lesser extent than CYP2C19).

Pharmacokinetic tolerance to PPIs would present as altered metabolism of PPIs as a function of treatment time (e.g. long-term daily use of PPIs alters CYP2C19 enzyme expression and thus PPI metabolism – which influences PPI efficacy).

Whether this actually occurs in select individuals remains unclear. At this time there are no formal data to support this idea – but it seems plausible.

Note: Individuals with certain genetic polymorphisms affecting CYP2C19 expression and/or those using drugs that induce CYP2C19 may find that PPIs diminish in efficacy over time.

Pharmacodynamic tolerance to PPIs

Would cause the PPI to lose its efficacy in magnitude of proton-pump inhibition with continued use – such that dosage increases would be required to maintain efficacy. (There is no evidence that this occurs.)

Some argue that pharmacodynamic tolerance to PPIs occurs to some extent given that “rebound hyperacidity” is observed upon discontinuation – and this is proportionate to the dosage of PPI used during treatment (e.g. high doses = greater rebound hyperacidity).

According to David C. Metz (MD)… (R)

“In suppressing acid, PPIs stimulate the body’s feedback loop that tries to reactivate acid secretion.

If the drug is removed, there is a potential risk of rebound hypersecretion, creating a sort of dependency on the drug because the body is acclimated to having acid suppressed.

In addition, ongoing feedback stimulation creates a need for ongoing therapy to control symptoms, and higher initial doses are more likely to activate this feedback response.

It is important to start patients, when clinically indicated, on the lowest effective maintenance dose of PPI.”

Additionally, some might argue that clinical trials for PPIs may have lacked sufficient duration to induce and ultimately detect tolerance. Perhaps tolerance onset occurs after 1-2+ years of consistent/daily therapy.

That said, long-term studies haven’t reported any significant decrease in PPI efficacy over time – even at stable doses. For this reason, pharmacodynamic tolerance to PPIs probably doesn’t occur.

Moreover, it is important to realize that the phenomenon of “rebound hyperacidity” during PPI cessation is NOT evidence of pharmacodynamic tolerance to PPIs (which would inevitably result in diminished and lost efficacy during treatment).

Rebound hyperacidity is merely a physiological recalibration post-PPI therapy… PPIs reduce gastric acid and this causes hypergastrinemia and the growth of histamine-releasing enterochromaffin-like (ECL) cells during treatment – such that when stopped, there’s heightened acid production for ~3 weeks.

What to do if PPIs “stop working”…

Obviously if your PPI stops working – you should contact a medical doctor (preferably a gastroenterologist) and discuss why it may have stopped working.

None of the ideas listed below should be considered medical advice.

1. Confirm accurate diagnosis

Verify that you actually have a medical condition that requires a PPI (proton-pump inhibitor) and consider getting a second-opinion from a gastroenterologist to confirm the initial diagnosis.

It is preferred that all individuals with GI symptoms undergo a series of gastrointestinal exams (e.g. endoscopy, 24-hour pH monitoring, etc.) – for the sake of diagnostic clarity.

Additional tests may be recommended to rule out conditions like H. Pylori, Eosinophilic Esophagitis, and Functional GI Disorders (e.g. functional dyspepsia).

Why? Because in these conditions – other medications are needed in addition to the PPI for complete symptom relief.

2. Optimize PPI administration (or switch to dexlansoprazole)

Most individuals using PPIs are completely oblivious to optimal PPI administration recommendations.

In some cases, medical doctors don’t even bother discussing the importance of administration specifics on PPI efficacy (they just say “take this PPI daily and see if it helps”).

  • Take first-thing in the morning: PPIs should be administered first thing in the morning after waking up – as there may be a circadian component to acid production and degree of proton-pump inhibition by the PPI.
  • Take while fasted (empty stomach): PPIs (with the exception of dexlansoprazole) should be administered in a fasted state. Even dexlansoprazole may benefit from being taken fasted due to the fact that individuals may administer the medication late (too long after eating) such that acid has already increased and inflicted damage.
  • Eat a protein-rich breakfast 30-60 minutes later: After the first (AM) dose of a PPI, it is recommended to consume a protein-rich breakfast – as protein may improve the PPI’s ability to inhibit proton-pumps.
  • Twice daily administration (AM pre-breakfast & PM pre-dinner): Some individuals benefit more from divided dosing (e.g. 20 mg omeprazole AM & 20 mg omeprazole PM) more than a single large dose (e.g. 40 mg omeprazole AM).
  • Second dose (pre-dinner): Many don’t know how to optimize the second dose of a PPI… Ideally: (1) No calories at least 2 hours prior & (2) consume dinner 30-60 minutes after (just like the morning PPI).
  • Increase dosing (ask doctor about this): Some individuals are on too low of a PPI dose for it to adequately reduce acid levels. Ask your doctor whether increasing your PPI dose may be worth trying.
  • Be consistent with dosing: Don’t skip days & take at same times each day – set reminders/alarms if forgetful.
  • Don’t take with medications/supplements: Avoid administering other medications, supplements, OTC drugs, etc. at the same time as a PPI. Why? They may interfere with PPI absorption or metabolism – and thus decrease its effect. Schedule different times to take other substances that you need.

Note: Dexlansoprazole is easiest for most individuals to use simply because they don’t need to pay as much attention to administration timing relative to food intake – as the presence of food in the stomach has no impact on dexlansoprazole efficacy.

3. Lifestyle & dietary modifications

Do not expect PPIs to necessarily “do all the work” in managing acid reflux conditions like GERD and LPR.

  • Zero alcohol, caffeine, nicotine, chocolate: No exceptions. If reflux is severe there’s no need to even think about these substances. All cause reflux by altering LES pressure (causing it to relax) which enables reflux. They may also increase stomach acid production and disrupt sleep – causing reflux to worsen.
  • Zero smoke exposure: Smoking and breathing in smoke (e.g. bonfires, second-hand smoke, etc.) are all terrible for reflux. Smoke causes the stomach to produce more acid, can increase inflammation/oxidative stress, and may dry out mucosal membranes (which may increase damage from reflux episodes).
  • No food 3-4+ hours before bed: Consuming any calories too close to bedtime can increase rates of nocturnal reflux via increasing: stomach acid/gases and LES pressure during sleep. Additionally, during sleep the body is not upright – making it easier for acid to backflow up the GI tract and inflict damage.
  • 4-8 small meals rather than 1-3 large meals: Intermittent fasting is generally terrible for most people with reflux conditions. Consuming 4-8 small meals spaced evenly throughout the day helps keep the stomach from getting “too full.” Larger meals increase pressure against the lower esophageal sphincter (LES) and cause reflux.
  • Loose clothing (nothing tight): Tight clothing can increase intra-abdominal pressure and thus reflux episodes.
  • Anxiety/stress reduction: Keep anxiety/stress to a minimum any way you can – including meditation, nature walks, reducing work, etc.
  • Sleep on left side: The single most optimal sleep position for individuals with reflux. Right side and stomach are the worst positions for reflux.
  • Elevate head of bed (6-inch incline): This can be done with “bed risers” which can be purchased on Amazon. If you’re handy – you could also make these for yourself.

4. Evaluate medications & supplements

Talk to a medical doctor and/or pharmacist about the medications, supplements, and other drugs (e.g. OTC, illicit, etc.) you use to ensure that they do NOT interact with or diminish the effect of your PPI.

  • Rule out interactions: Ensure meds/supps aren’t interacting with the PPI (ask a pharmacist and/or medical doctor).
  • Avoid unnecessary substances: Don’t take any meds/supps that are not medically necessary (ask your doctor).
  • Check if reflux-inducing: Determine whether medications/supplements used increase acidity and/or reflux episodes (via altered GI or esophageal sphincter function).
  • Don’t take at same time as PPI: This should be obvious – but co-administration/ingestion of other substances could interfere with PPI efficacy.
  • Check if interact with CYP2C19: Any medications that are metabolized by CYP2C19 enzymes in the liver could alter its expression over time. Altered CYP2C19 expression could influence the metabolism and subsequent efficacy of PPIs.

5. Switch PPIs (?)

I think many doctors have patients (who complain that the PPI stopped working) switch PPIs as some sort of a placebo test.

Logically it makes zero sense that switching PPIs would provide benefit if one stopped working – assuming equipotent dosing.

Why? Because PPIs are functionally similar and are metabolized by the same hepatic enzyme (CYP2C19).

In theory, it’s possible that dexlansoprazole and pantoprazole (metabolized by CYP3A4 in addition to CYP2C19) could have subtle disparities in efficacy for some users relative to equipotent-dosed omeprazole, esomeprazole, lansoprazole, and rabeprazole due to CYP3A4 involvement in metabolism – but this is unlikely.

Why would this occur? Perhaps due to rare outliers in CYP2C19 and/or CYP3A4 expression (mediated by genetics) – thus influencing metabolism speed. Expression of these isoenzymes can also be influenced by co-administered meds/drugs/supplements that interact with them.

Switching from one PPI to another could provide benefit if the dosage of the PPI switched to is not equipotent.

For example, switching from 40 mg pantoprazole to 40 mg omeprazole will provide a stronger acid reducing effect – and thus might alleviate symptoms.

(This might be further enhanced if administered in divided doses (e.g. AM & PM) rather than as a standalone AM dose.)

How is this possible? Omeprazole 20 mg is roughly equivalent (in potency) to 40 mg pantoprazole.

Therefore, 40 mg omeprazole will [usually] provide a stronger effect than 40 mg pantoprazole.

Don’t our bodies adapt to the specific chemical composition of the PPI?

It is hypothetically possible (although extremely unlikely) that bodies adapt to the specific chemical makeup of PPIs (e.g. omeprazole) such that administering a different PPI (e.g. pantoprazole) from the one that stopped working – will reinstate therapeutic action.

However, this is most likely complete BS – and there’s no evidence to support the idea.

If this were true, there would likely be some degree of “cross tolerance” between omeprazole & esomeprazole (which is not usually reported in the anecdotes I’ve found).

Moreover, if this truly occurred, individuals would eventually be able to switch back to the initial PPI that stopped working after using a different PPI for several months (yet some individuals report switching back provides zero effect even after months – which defies logic).

Anecdotes (PPI stopped working)

Included below are anecdotes from various individuals reporting that PPIs stopped working unexpectedly.

Generally, one or more of the following usually account for why PPIs stop working: suboptimal lifestyle/diet choices; using medications that worsen reflux; poor PPI compliance; improper and/or inconsistent PPI dosing/administration; and unmanaged medical conditions.

In some cases, reflux occurs secondary to a medical condition like eosinophilic esophagitis or H. Pylori such that PPIs may provide some initial benefit – but worsening of the medical conditions may eventually offset this benefit (such that the PPI seemingly “stops working”).

Anecdote 1

Tolerance to GERD medications is getting awful in my case. Started with lansoprazole (15 mg/daily) and worked well for about 2 years.

Then I had to increase to twice daily. Eventually it just stopped working.

(Almost like I wasn’t taking pills at all – because every GERD symptom returned).

Switched to pantoprazole and it worked well for 8 months – then stopped working. Switched to esomeprazole and it stopped working after 4 months.

Tried Ranitidine and it stopped working after a few months.

Trying to switch back to other meds (e.g. lansoprazole) provides no benefit.

My thoughts?

Logically this makes ZERO sense.

I’m not denying this individual’s subjective experience, but there’s no reason that lansoprazole would stop working but pantoprazole would work – followed by esomeprazole…

They are all metabolized by CYP2C19 and have nearly identical levels of protein binding %.

It is possible that other medications and/or supplements were added to the equation that altered CYP2C19 metabolism (but this was not mentioned).

Anecdote 2

PPIs stopped working and GERD progressed enough that it became refractory to drug therapy.

It’s time to stop treatment of the symptoms with PPIs and find the root cause of GERD and address it.

My thoughts?

Finding the “root cause” of GERD is sometimes not possible or multifactorial.

It is possible that if significant weight was gained that this increased the size of a preexisting hiatal hernia such as to worsen GERD.

However, medications such as PPIs should theoretically still function to reduce stomach acid if used properly.

Anecdote 3

Was on pantoprazole for 4-5 years to treat heartburn.

Endoscopy revealed hiatal hernia and I was diagnosed with GERD.

Took the meds and was fine for the most part “eating what I want” up until now.

About a month ago I started getting very intense heartburn.

Doctor said to change diet so I did but the heartburn persisted while taking pantoprazole.

Stopped taking pantoprazole and switched to Pepcid (famotidine) along with a strict diet but still don’t feel “normal.”

GP thinks PPI tachyphylaxis may have occurred.

My thoughts?

Pantoprazole likely never stopped working here.

There’s no evidence that PPI tachyphylaxis occurs – but it warrants consideration in this case with long-term (4-5 years of use).

The fact that this individual ate whatever they wanted on pantoprazole was problematic – as highly acidic foods/drinks may have contributed to a resurgence of reflux symptoms.

What likely happened was diet/lifestyle caused an increase in reflux that overrode the pantoprazole’s acid reducing effect (at whatever dose was administered).

Anecdote 4

Have been on PPIs for a long time: esomeprazole, omeprazole, pantoprazole, etc.

Currently have been taking pantoprazole for several years – but suddenly it seems less effective.

Have had some other “health issues” so am not sure if it’s related.

(Individual admits to also having 2-3 cups of coffee a day and 3-5 beers a week. Also states that “diet could be better” and that he/she deals with “some anxiety issues”).

My thoughts?

Could easily be related to other “health issues” and/or medications used to treat those other health issues (if any were administered).

Less effective is not the same as ineffective or “stopped working.”

Perhaps a dosage increase for pantoprazole and review of this individuals’ medications (to ensure none are exacerbating reflux) would be of benefit.

Diet, lifestyle, and anxiety could also be exacerbating reflux and decreasing the efficacy of pantoprazole.

Anecdote 5

PPI stopped working and I’m scared.

Started taking PPI over a month ago and tried increasing the dosage above 20 mg per day but got “extremely sick” so couldn’t do it.

Remained patient and for a while I began to feel almost normal.

Suddenly from one day to the next I felt really sick again.

Before PPI therapy: extreme nausea, unable to sleep more than 1 hour a night, unable to eat, anxiety, felt horrible.

I feel like the PPI is not working anymore or not as much.

My thoughts?

Unlikely that the “extreme sick” feeling is from the PPI.

That said, could try a different PPI in case of some sort of rare reaction to this specific PPI.

Individual may also benefit getting evaluated by a gastroenterologist to rule out conditions like functional dyspepsia (psychological component) and infection (e.g. H. Pylori).

Assuming nothing serious is found – individual likely needs a combination of PPI and anxiolytic.

Anecdote 6

I went from September to now before my meds seemed to have stopped working (40 mg pantoprazole per day).

Measuring my meals has helped “tremendously” with regard to symptom reduction.

My thoughts?

Seemed to have stopped working doesn’t mean stopped working.

Individual might benefit from twice daily dosing rather than once-daily.

Smaller meals should be continued with low acid foods.

Anecdote 7

Been on esomeprazole for a long-term (14 years) and prior to treatment had heartburn, pain, vomiting, etc.

Have a hiatal hernia and was initially prescribed ranitidine and pantoprazole – neither helped so tried esomeprazole and it worked.

Recently have been struggling with reflux again (heartburn, chest pain, acid in throat, etc.) despite taking esomeprazole.

My thoughts?

Individual reports following healthy diet/lifestyle modifications in addition to esomeprazole.

It’s possible that hiatal hernia worsened or that transient diet/lifestyle changes explain the worsening of reflux.

Medications and/or supplements might be a factor as well.

Doesn’t make much sense that esomeprazole would work consistently for 14 years and suddenly stop.

Twice daily dosing may be superior for this individual.

Anecdote 8

Have been on omeprazole for a full month to treat esophagitis associated with GERD.

It worked very well and have had no acid for weeks, however, this week I noticed it suddenly stopped working and the past few days I’ve woken up with acid in my mouth.

Nothing has changed in diet or lifestyle. Am frustrated and discouraged.

My thoughts?

It’s extremely unlikely that omeprazole would “suddenly stop working” after 1 month – as there’s no viable mechanism by which tachyphylaxis would occur so rapidly.

Obviously the medication was working very well in controlling acid but something likely changed in this user’s life – even if he/she is unaware (e.g. eating times, stress level, sleep position, sleep quality/duration, medications/supplements, routine, etc.).

Anecdote 9

Have been on lansoprazole (30 mg) daily in the morning and it was working – then suddenly it feels like it stopped working.

Gastritis significantly worsened and feels like pre-medication (baseline).

I’m not sure about the cause as diet hasn’t been anything unusual and don’t have any major stress/anxiety.

My thoughts?

User admitted that “hormonal fluctuations” have affected her gastritis – and that she deals with anxiety issues.

It’s possible that a combination of hormonal fluctuations AND anxiety are increasing gastritis symptoms and overriding the effect of lansoprazole.

Perhaps a dosage increase and/or switch to another medication (for a placebo-like effect) might be useful here – along with daily tracking of meal sizes & time between meals.

Anecdote 10

My PPIs stopped working for GERD and I can’t see a doctor for more than a month.

I’ve successfully eaten “keto” and even once completely dropped my PPIs for a few months while eating that way.

I’ll drop the regular evening martini and chocolate.

I have had problems sleeping.

My thoughts?

The PPIs likely didn’t “stop working” – but may have been overpowered by diet and lifestyle choices.

This individual is on a “keto” diet which might help some cases of reflux – but not all (sometimes the lack of fiber makes things worse due to constipation and prolonged GI motility).

Poor sleep can cause an increase in stress, inflammation, and anxiety – and can exacerbate GERD.

Individual may benefit from a sleep study (rule out sleep apnea) and possibly sleep medications.

The “martini” (alcohol & acidic) and “chocolate” (theobromine) in the evening could negatively affect sleep and might be the primary reason for poor sleep along with increased reflux – especially if ingested late at night.

Switching PPIs for a placebo-like effect may be worthwhile as well.

What do I think about these anecdotes?

They provide ZERO evidence that PPIs objectively “stopped working.”

In some of the cases, it’s possible that diagnoses were inaccurate (particularly if diagnoses made without gastroenterological examination) or partially inaccurate (e.g. reflux is occurring but it’s secondary to another condition like functional dyspepsia or eosinophilic esophagitis) – but this is unlikely.

It is plausible that some of these individuals had comorbid albeit untreated medical conditions (e.g. obesity, sleep apnea, insomnia, hormone imbalances, anxiety disorders) – which could exacerbate preexisting acid reflux and/or other GI symptoms.

It’s also possible that certain individuals were using dietary supplements, medications, or other drugs that may have interfered with the pharmacokinetics of PPIs (such as via CYP2C19 metabolism) which might reduce its effect at the dosage that initially worked well.

For some of these individuals, adherence to daily PPI administration may have been an issue – and perhaps administration specifics (e.g. taking after meals instead of 30-60 minutes before) and/or dosages were suboptimal.

In most of these cases, it is highly likely that a combination of diet, lifestyle, medication/supplement use, poor adherence, suboptimal administration and/or dosing – caused the PPIs do “stop working.”

For example, several individuals openly admitted to ingesting chocolate, coffee, and alcohol – all of which are known to cause and exacerbate reflux.

The fact that switching to different PPIs provided relief in some of these cases suggests a legitimate placebo effect (assuming equipotent dosing of the new PPI as the former PPI) probably occurs.

A nocebo effect may also occur for some – as switching back to a PPI that stopped working (even if the switch is done months/years later) was reported to provide no benefit (which is unlikely assuming dosage was adequate).

Furthermore, there’s zero consistency in the times of when PPIs stopped working (some report the loss of effect after 14+ years, others after 4-5+ years, and others after just one month).

This indicates that there’s no predictability in average duration of treatment before loss of effect occurs – which would be expected if “tolerance” truly occurred.

Have you noticed that PPIs stopped working over time?

If you experienced this, feel free to leave a comment explaining

  • Why do you think your PPI stopped working?
  • How long did it take before your PPI stopped working?
  • Which PPI did you use? What was the dose?
  • Did you adhere to PPI therapy? (e.g. daily administration with no “PPI breaks”)
  • Did you administer PPIs optimally? (e.g. morning, same time each day, fasted administration, proper administration relative to meals, protein rich meal 30-60 minutes after the PPI, etc.)
  • Do you think other medications or supplements and/or medical conditions may have reduced the effect of your PPI?
  • Did you make any changes in diet/lifestyle that may have offset the effect of the PPI?
  • Have you switched PPIs to determine whether a different PPI would provide better effect?
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