Major Finding: Of 76 patients who had unverified indications for a PPI, 11 were able to discontinue therapy without recurrence of symptoms during the 6 months of follow-up.
Data Source: A standardized search of patients prescribed PPIs by primary care physicians in the previous 12 months in Denmark.
Disclosures: Dr. Bytzer is a speaker or consultant for AstraZeneca Pharmaceuticals, Nycomed, and Orexo. Dr. Reimer has received grant support from and is a consultant to AstraZeneca Pharmaceuticals.
NEW ORLEANS — Patients with gastroesophageal reflux disease are very difficult to wean off proton pump inhibitors, and there is evidence that patients essentially become “addicted” to acid suppression, findings of large study suggest.
Dr. Peter Bytzer of Copenhagen University and Køge (Denmark) Hospital, and Dr. Christina Reimer, also of the university, reported study findings that indicate proton pump inhibitors (PPIs) are nearly impossible to discontinue, even for patients who lack a formal indication for their use.
“We found that discontinuing long-term PPI therapy was possible in only a minority of patients and that the majority experiencing symptom relapse after discontinuing the drug had no abnormal endoscopic findings,” Dr. Reimer said in a poster presentation. “Rapid recurrence of typical reflux symptoms was the main reason for restarting therapy, and 7 days of esomeprazole was helpful, despite the normal endoscopic findings.”
Dr. Bytzer and Dr. Reimer conducted a standardized search of patients prescribed PPIs by primary care physicians in the previous 12 months in Denmark. They identified 901 long-term users (at least 120 tablets), of whom 525 had an endoscopically verified diagnosis of esophagitis, Barrett's esophagus, or peptic stricture or had abnormal pH on monitoring, and therefore were categorized as having an indication for long-term treatment.
The remaining 376 patients were considered to have an unverified indication for a PPI and 76 of them agreed to attempt discontinue the drug. If symptoms recurred within 6 months after PPI withdrawal, patients underwent endoscopy. Those without abnormal findings were then randomized to 7 days of PPI therapy with esomeprazole 40 mg/day or placebo.
Of the 76 patients, 53 (63%) had symptom recurrence within the first week of discontinuing the PPI. The main symptoms were heartburn/acid regurgitation (48%) and dyspepsia (42%), Dr. Reimer reported at a DDW poster session.
On endoscopy, 31 (59%) had no abnormal findings.
Only 11 (14%) discontinued therapy without recurrence of symptoms during the 6 months of follow-up.
The 53 patients asked to restart therapy and were randomized to a PPI or placebo for 7 days; 80% of those taking esomeprazole had treatment success, compared with 13% receiving placebo.
Prescriptions for PPIs have essentially quadrupled in the past 10 years, according to data from the Danish Medicines Agency, Dr. Bytzer noted in a separate presentation at the meeting. “The increase in PPI use is explained by an increase long-term use.”
This hypothesis is supported by evidence of an increased prevalence in acid-related conditions, more liberal prescribing habits—including empirical PPI therapy for unspecific dyspepsia—and PPI “dependency” as a result of acid rebound that requires more and more suppression, he said.
Ironically, studies have suggested that PPIs can actually stimulate acid secretion in healthy volunteers. In a 2007 systemic review, Hunfeld et al. concluded “there is evidence from uncontrolled trials for an increased capacity to secrete acid in [Helicobacter pylori]–negative subjects after 8 weeks of treatment” and “there is no strong evidence for a clinically relevant increased acid production after withdrawal of proton pump inhibitor therapy” (Aliment. Pharmacol. Ther. 2007;25:39-46).
“In other words, once you remove the PPI you get an increased capacity to secrete acid. But is this clinically relevant? Will rebound acid hypersecretion lead to acid-related symptoms?” he questioned.
Apparently, it can. In a blinded withdrawal study conducted by Dr. Bytzer's group, 120 healthy volunteers were randomized to esomeprazole 40 mg or placebo for 8 weeks, after which the esomeprazole group crossed over to placebo for 4 weeks (Gastroenterol. 2009;137:80-7).
After crossing over, these patients experienced a significant increase in dyspepsia, heartburn, and regurgitation at weeks 10, 11, and 12.
These subjects had not had symptoms prior the study and were never on acid reducers. They were unaware of the shift to placebo. After the start of a PPI, gastrin significantly increased, and 44% got significant acid-related symptoms, he reported.
Other investigators have found increases in reflux laryngitis, heartburn, and dyspepsia after discontinuation of PPIs, he added.
To discontinue PPI therapy in long-term users, patients can slowly taper down doses over 3 weeks or so, he suggested, however, he said it remains difficult to discontinue PPI therapy, especially in patients with GERD.