Rebound Acid Secretion Explained
There is controversy as to whether taking proton pump inhibitors (PPIs) long term results in the user becoming addicted to them in some way. This is based on the following facts:
1. PPIs alter the balancing act in the stomach.
There is a scientific rationale why PPI use can lead to a situation in the stomach that results in rebound increased acid secretion when the drug is withdrawn:
- PPIs block acid secretion in the acid-producing parietal cell in the stomach.
- The decreased acid causes endocrine cells in the stomach to secrete a hormone called gastrin. This signals to the parietal cell that more acid is needed in the stomach, which is normally produced during a meal when the food neutralizes gastric acid.
- In a person taking PPIs, the gastrin has no effect and continues to increase in the blood. When the PPI is withdrawn, the elevated gastrin causes a rebound increase in acid secretion. It is likely that this is temporary and adjusts quickly (within a week or two) as the normal balance between acid production and gastrin production is restored.
2. PPIs help control symptoms in people with GERD or gastric ulcers
Withdrawal of PPIs in those on long term PPIs sometimes causes a recurrence of symptoms. This is not unexpected if the PPIs were used appropriately for treatment of GERD or gastric ulcers. In such a case, removal of PPIs restores gastric acid, which is the cause of symptoms in the first place. The recurrence of symptoms is telling you that PPIs have not cured the underlying disease. They have just controlled the symptoms.
3. Studies validate the concept of rebound acid secretion
Two studies have been reported that validate the concept of rebound acid secretion:
Proton-Pump Inhibitor Therapy Induces Acid-Related Symptoms in Healthy Volunteers After Withdrawal of Therapy (Reimer C. et al Gastroenterology 2009; 137:80-87)
Dyspeptic Symptom Development After Discontinuation of a Proton Pump Inhibitor: A Double-Blind Placebo-Controlled Trial (Niklasson A. et al. Am J Gastroenterology 2010; 105:1531-1537)
In these studies, healthy volunteers without any upper gastrointestinal symptoms were given PPIs or placebo for 4-8 weeks. They were asked to record “dyspepsia and/or heartburn” daily for two weeks before treatment, during treatment, and for six weeks after treatment using a recognized scoring system for severity of these symptoms. Both studies showed an increase in the incidence of dyspepsia in the post-treatment period for the group that had taken PPIs. Only 44% of patients in the treated group developed symptoms, indicating that the effect was seen only in a minority. The symptoms were generally mild and temporary. By the third week after stopping the drug, there was no difference between the treated and placebo groups. The fact that this effect was the result of a rebound acid secretion on stopping PPIs was suggested in one study by the finding of elevated gastrin levels in those who developed symptoms.
Based on these three items of information, we can say that PPIs used long-term produce a change in the gastrin-parietal cell balance that results in a temporary rebound over-secretion of acid when PPIs are withdrawn suddenly.
The clinical significance: What this means for you
The clinical implication of this finding is difficult to analyze accurately. It is important to recognize that different people can interpret these findings differently. The editorial that accompanied the Reimer paper suggested that PPI therapy induces the symptoms it is used to treat. The editorial that accompanied the Niklasson paper was less negative about this phenomenon. So, even experts do not agree on the clinical significance of the changes.
Let me try to put this is what I think is the correct perspective. The clinical significance can be discussed from the point of view of different patient groups:
Group 1: Patients with no symptoms.
These are the two study groups. The controversy has no significance in these groups because they will never take PPIs.
Group 2: Patients who are taking long term PPIs for a valid reason other than GERD.
Patients who have chronic peptic ulcer disease or are taking PPIs to protect against peptic ulcers when using non-steroidal anti-inflammatory drugs need to keep taking PPIs for as long as these indications exist. It is possible that they will experience mild symptoms for a short time if the PPIs are stopped because of rebound acid secretion. This is likely temporary and, if warned that they may occur beforehand, is not likely to cause problems.
Group 3: Patients with a proven or definite diagnosis of GERD.
Proof of GERD is an endoscopic examination that has shown either erosive esophagitis or a columnar lined esophagus. Definite diagnosis of GERD is a combination of heartburn and regurgitation that is highly specific for GERD. In these patients, if PPIs have been effective in controlling heartburn, it is highly likely that removing PPIs suddenly will cause the symptoms to return. The main reason for this is that PPIs have not cured GERD. They have simply controlled heartburn. The heartburn returns because the disease is unmasked by removal of the drug that controlled the symptom. Rebound secretion of excessive acid has a minimal, if any, effect in producing symptoms.
It is important to recognize that this GERD patient population is frequently prescribed PPIs in dosage and frequency that is more than needed. In such a case, good symptom control can be achieved with lower dosage and frequency of PPI use and sometimes even by replacing PPIs with a less powerful acid suppressive drug like an H2 receptor antagonist (like Zantac, Tagamet). RefluxMD will often suggest that patients who are on continuous high dosage PPI treatment for proven or definite GERD should try to gradually decrease the dose. We call this process titration downward of the dose. The objective is to identify the minimum dose of PPIs or H2 receptor antagonists that are required to control symptoms adequately. This is good medicine because PPIs do not cure GERD or stop reflux. They simply control pain. As such, the lower the drug required to control pain, the better.
There are studies that show that many patients who are prescribed PPIs actually cease daily use of PPIs and opt for an “on-demand” drug intake (PPIs or other drugs) with success:
On-demand therapy for gastroesophageal reflux disease (Metz et al. On-demand therapy for gastroesophageal reflux disease. Am J Gastroenterology 2007;102:642-653)
Step-down management of gastroesophageal reflux disease (Inadomi JM et al. Step-down management of gastroesophageal reflux disease. Gastroenterology 2001;121:1095-1100).
Step-down of dosage is unlikely to cause rebound acid secretion that may aggravate symptoms.
There is another phenomenon in patients with proven GERD who try to stop PPI therapy after long-term use. They find that they cannot do this. Their symptoms are actually worse than before they started PPIs. This phenomenon is best explained by a progression of GERD while the patient was on PPIs. PPIs do not stop the progression of GERD. The disease can get worse while the patient on PPIs. As such, if PPIs are stopped, the symptoms are worse than when they were started. Another piece of evidence that GERD progresses while a patient is on PPIs is that many patients who are given PPIs long-term for GERD need to increase their dose and frequency of PPIs with time. PPIs not only fail to cure GERD, they also fail to prevent the progression of GERD. Some physicians attribute the severe symptoms that people experience when they stop PPIs to rebound acid secretion, but this is probably a minor factor (if it is a factor at all).
Group 4: Patients who were diagnosed with GERD in error
It has been estimated that approximately 30% of patients taking long-term PPIs for GERD may not have GERD at all. The original diagnosis of GERD was incorrect. This is not unreasonable if one recognizes that other types of pain can mimic heartburn and heartburn is not specific for GERD (other conditions can cause the symptom of heartburn). Once the PPIs have controlled the symptom, the patient is maintained on the drug long term. This group potentially includes all patients who are taking PPIs with a diagnosis of GERD not been based on an endoscopy that showed erosive esophagitis or a positive pH test.
RefluxMD suggests that patients in this group try a test of PPI withdrawal. The objective is to identify the 30% who are taking PPIs without a need for these drugs. It is in this group that we must be very careful of the potential effect of rebound acid secretion producing symptoms. The patient must expect mild symptoms when PPIs are withdrawn and should be prepared to tolerate them for a period of three weeks. If the symptoms disappear, the likely cause is rebound acid secretion.
In the 70% of these patients who are taking PPIs appropriately because they have GERD, withdrawal of PPIs may cause symptoms that are unbearable or last for more than three weeks. The recurrence of symptoms has nothing to do with rebound acid secretion after PPI withdrawal.
The identification of the 30% of this group of patients is incredibly positive for a variety of reasons: (a) there is a massive cost savings; (b) a large number of patients are prevented from being unnecessarily exposed to the complications of PPI therapy. While these complications are an acceptable risk if PPIs are necessary, the risk is not acceptable if the drugs are used inappropriately.
Group 5: Patients with a diagnosis of Barrett’s esophagus made by endoscopy.
Many of these patients have had symptoms of reflux and been on PPIs long term. They have proven symptomatic GERD and need PPI therapy to control their symptoms.
A small number of patients who have a diagnosis of Barrett’s esophagus have mild or no significant symptoms of GERD. In this group, there is no valid reason for the patient taking PPIs. There is no evidence that use of PPIs will prevent or decrease the likelihood of cancer. This makes sense because acid is not the cause of cancer. Despite the absence of evidence that PPIs decrease the risk of cancer, many physicians will prescribe PPIs long term in Barrett’s patients who do not have symptoms to justify their use. This is not appropriate. PPIs have no effect other than symptom control – they should not be ascribed powers they do not have.
If a patient with Barrett’s esophagus is on PPIs, RefluxMD will ask the question: “Did you have symptoms when you were prescribed PPIs or were the PPIs prescribed to decrease the cancer risk of Barrett’s?” If the PPIs were prescribed for symptom control, RefluxMD will recommend a trial of stepping down the drugs to get to the minimum dosage as in Group 3. If the answer to the question is that PPIs were prescribed for a reason other than symptoms control, RefluxMD will recommend that the patient withdraw PPIs completely. We must be very careful of the potential effect of rebound acid secretion producing symptoms in this situation. The patient must expect mild symptoms when PPIs are withdrawn. They must tolerate these for a period of three weeks. If the symptoms disappear, the likely cause is rebound acid secretion.
Which group are you?
The clinical effect of rebound increase in acid secretion with withdrawal of PPIs is therefore relatively small and limited to a small group of people who are on PPIs for no good reason. When an attempt is made to withdraw PPIs, the rebound effect may produce mild symptoms including heartburn for up to three weeks. The patient must not ascribe these symptoms to GERD. They must tolerate them, knowing about the possibility of rebound acid as their cause. If they disappear, they can conclude they do not need PPIs.