Proton-Pump Inhibitor Therapy Induces Acid-Related Symptoms in Healthy Volunteers After Withdrawal of Therapy
Gastroenterology July 2009
Christina Reimer, Bo Sondergaard, Linda Hilsted, Peter Bytzer
Department of Medical Gastroenterology, Koge University Hospital, Copenhagen University, Copenhagen, Denmark
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
Refers to article:
Evidence That Proton-Pump Inhibitor Therapy Induces the Symptoms it Is Used to Treat , 01 June 2009
Kenneth E.L. McColl, Derek Gillen
July 2009 (Vol. 137, Issue 1, Pages 20-22)
"Treatment with a PPI (esomeprazole 40 mg once daily) for 8 weeks induces acid-related symptoms like heartburn, acid regurgitation, and dyspepsia once treatment is withdrawn. The symptoms observed in our trial caused mild to moderate discomfort and appeared for the majority of subjects in the first 2 weeks after withdrawal of PPI. The observation that >40% of healthy volunteers, who have never been bothered by heartburn, acid regurgitation, or dyspepsia, develop such symptoms in the weeks after cessation of PPI is remarkable and has potentially important clinical and economic implications" "The possible implications of RAHS need to be addressed in future studies"
"Conclusion: Acid inhibition with a PPI for 8 weeks induces acid-related symptoms in a significant proportion of asymptomatic subjects when therapy is withdrawn. We find it highly likely that the symptoms observed in this trial are caused by RAHS and that this phenomenon is equally relevant in patients treated long term with PPIs. These results justify the speculation that PPI dependency could be 1 of the explanations for the rapidly and continuously increasing use of PPIs."
Background & Aims
Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI). If RAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications.
A randomized, double-blind, placebo-controlled trial with 120 healthy volunteers was conducted. Participants were randomized to 12 weeks of placebo or 8 weeks of esomeprazole 40 mg/d followed by 4 weeks with placebo. The Gastrointestinal Symptom Rating Scale (GSRS) was filled out weekly. A score of >2 on 1 of the questions regarding heartburn, acid regurgitation, or dyspepsia was defined as a clinically relevant acid-related symptom.
There were no significant differences between groups in GSRS scores at baseline. GSRS scores for acid-related symptoms were significantly higher in the PPI group at week 10 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .023), week 11 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .009), and week 12 (1.3 ± 1.2 vs 1.0 ± 0.3; P = .001). Forty-four percent (26/59) of those randomized to PPI reported ≥1 relevant, acid-related symptom in weeks 9-12 compared with 15% (9/59; P < .001) in the placebo group. The proportion reporting dyspepsia, heartburn, or acid regurgitation in the PPI group was 13 of 59 (22%) at week 10, 13 of 59 (22%) at week 11, and 12 of 58 (21%) at week 12. Corresponding figures in the placebo group were 7% at week 10 (P = .034), 5% at week 11 (P = .013), and 2% at week 12 (P = .001).
PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal. This study indicates unrecognized aspects of PPI withdrawal and supports the hypothesis that RAHS has clinical implications.
Abbreviations used in this paper: CgA, chromogranin, PPI, proton-pump inhibitor, RAHS, rebound acid hypersecretion
The use of proton-pump inhibitors (PPIs) for acid-related symptoms and disorders is extensive and rapidly escalating. In Denmark, the total use of PPIs increased 7-fold from 1993 to 2007. Even in the last 5 years (2003-2007), the use increased substantially from 20 to 33 defined daily doses per 1,000 persons per day. In 2006, approximately 7% of the Danish population was treated with a PPI.1 Although the incidence of new treatments with PPIs remains stable, the prevalence of long-term treatment is rising.2 The reasons for the increasing long-term use are not fully understood.
Treatment with PPIs is initiated mainly by primary care physicians, usually as empirical therapy for dyspeptic symptoms. Empirical PPI therapy for ≥4 weeks in patients with uninvestigated dyspepsia is supported by dyspepsia guidelines.3, 4 Continuous PPI therapy is indicated in cases of severe gastroesophageal reflux disease or as prophylactic therapy for patients who must continue treatment with nonsteroidal anti-inflammatory drugs.5 However, studies have shown that up to 33% of patients who initiate PPI treatment redeem repeated prescriptions without an obvious indication for maintenance therapy.6, 7 Moreover, studies have shown that primary care physicians perceive withdrawal or reduction of long-term PPI treatment as difficult to achieve.8, 9 Recurrence of symptoms of underlying acid-related disease is an obvious explanation for reuptake of PPI therapy, but physiologic changes triggered by the PPI treatment itself, which set off once therapy is withdrawn, could hypothetically lead to aggravation of symptoms or maybe even to new onset of acid-related symptoms. This latter hypothesis is supported by physiologic studies that have implied that treatment with a PPI for ≥8 weeks leads to a temporarily increased capacity to secrete acid after discontinuation of treatment in particular in Helicobacter pylori-negative individuals.10, 11, 12 Rebound acid hypersecretion (RAHS), defined as an increase in gastric acid secretion above pretreatment levels after antisecretory therapy,13 is observed within 2 weeks after withdrawal of treatment and could theoretically lead to acid-related symptoms such as heartburn, acid regurgitation, or dyspepsia that might result in resumption of therapy. A plausible physiologic theory for the rebound phenomenon suggests that long-term, elevated gastric pH caused by blockage of the proton-pumps stimulates compensatory gastrin release. This in turn induces a hypersecretory state or hypertrophy of the enterochromaffin-like cells, reflected by an increased level of chromogranin A (CgA), which results in an increased capacity to stimulate gastric acid secretion that sets off once PPI therapy is withdrawn.11, 14, 15, 16 It is, however, undetermined whether increased acid secretion is of clinical relevance and leads to acid-related symptoms.
We sought to determine the clinical relevance of RAHS to establish whether long-term treatment with a PPI creates a need for continuous treatment. This could add to the increasing long-term use of PPIs and have substantial economic and clinical implications.
The results of our study indicate and support the hypothesis that the RAHS is clinically significant. Treatment with a PPI (esomeprazole 40 mg once daily) for 8 weeks induces acid-related symptoms like heartburn, acid regurgitation, and dyspepsia once treatment is withdrawn. The symptoms observed in our trial caused mild to moderate discomfort and appeared for the majority of subjects in the first 2 weeks after withdrawal of PPI. The observation that >40% of healthy volunteers, who have never been bothered by heartburn, acid regurgitation, or dyspepsia, develop such symptoms in the weeks after cessation of PPI is remarkable and has potentially important clinical and economic implications. Even though symptoms are also observed in the placebo group, indicating increased attention to acid-related symptoms in the overall study population, the difference in the proportion with clinically relevant symptoms between the groups can only be explained by allocation to different interventions. This is supported by the timing of symptoms occurring after blinded withdrawal of PPI in the final 4 weeks of the study in the actively treated group in contrast with the placebo group, where symptoms seemed to occur at random throughout the entire study period.
Strengths and Weaknesses
The strengths of this study are the power and the double-blind, placebo-controlled design, including blinded withdrawal of PPI, making the subjects unaware of when to expect symptoms. Furthermore, the use of on-line reporting of symptoms with a thoroughly validated questionnaire within 24 hours has secured reliable and accurate monitoring of symptoms. One of the limitations of our study is the use of healthy volunteers as study subjects. We cannot be absolutely sure that symptoms develop as a consequence of RAHS to the same degree in patients, who have started PPI therapy because of dyspeptic symptoms. On the other hand, RAHS could be even more relevant in patients with reflux disease or other acid-related disorders. Within this population, it is likely that withdrawal of PPI treatment is difficult to achieve because of rapid recurrence of reflux symptoms that could be aggravated or maybe even provoked by RAHS.
Comparison With Other Studies
Two studies have investigated occurrence of upper abdominal symptoms after withdrawal of treatment with a PPI, but both have only been published in abstract form so far. A small trial in 36 healthy volunteers investigated symptoms after treatment with a PPI for 14 days23 and reported a significantly higher dyspepsia symptom score in a group treated with omeprazole in the 2nd week after withdrawal of treatment. The association between RAHS and the symptoms observed in that trial remains uncertain as a number of studies have failed to document acid rebound after withdrawal of only 2 weeks of PPI treatment.24, 25, 26 In another trial with 48 subjects, a significantly higher proportion (44%) treated with pantoprazole 40 mg developed dyspepsia after withdrawal of 4 weeks of treatment compared with 9% in the placebo group.27
The symptoms observed in our trial have a more established physiologic foundation. Studies of acid output after 8 weeks to 3 months of treatment with different PPIs have shown an increase in basal acid output and maximal acid output 14 days after treatment compared with baseline values.10, 11, 28 In a recent publication by Hunfeld et al,29 studies on RAHS after therapy with PPIs were systematically reviewed. They concluded that there is some evidence for an increased capacity to secrete acid in H pylori-negative subjects after a minimum of 8 weeks of treatment.29 Even though the studies in the review were all uncontrolled and used different measures for acid secretory capacity, we still find it reasonable to claim that the symptoms observed in our trial are related to RAHS. This assumption is somewhat controversial, though. Other explanations than RAHS could be considered, especially because the correlation between gastric acid secretory capacity and acid-related symptoms is questionable. The fact that not all PPI-treated subjects experience acid-related symptoms after withdrawal could lead to the hypothesis that RAHS is only clinically relevant in subjects with a preexisting lower esophageal sphincter dysfunction and consequently the potential to reflux.
However, the fact that we observed a significant difference in both symptom scores and the proportion of subjects with symptoms from the 2nd week after discontinuation of PPI supports an association with RAHS either directly via acid secretion or indirectly via the changes in hormone levels associated with long-term PPI therapy.
Even moderate elevations in P-gastrin exert a trophic effect on the enterochromaffin-like cells and the increased P-CgA concentrations found in our study are likely to reflect functional or proliferative changes of the gastric enterochromaffin-like cells.30, 31 The continued occurrence of acid-related symptoms in the PPI group, even in the final week of the study at a time where P-gastrin levels had normalized, is possibly related to a sustained increased acid secretory capacity, as reflected by the increased levels of P-CgA.
Our study results reveal for the first time that profound acid inhibition with a PPI for 8 weeks induces acid-related symptoms in a significant proportion of subjects after withdrawal of therapy. Even though P-gastrin and P-CgA are only indirect measures of acid secretory capacity, we believe that these results support the hypothesis that RAHS is clinically relevant.
The proposed association is indirectly supported by previous studies showing that withdrawal of H2-receptor antagonist therapy induces dyspeptic symptoms in a proportion of previously asymptomatic subjects.32
It has been hypothesized that a lower gastric acid productive capacity associated with H pylori-induced gastric inflammation may protect infected subjects from development of acid rebound. Results of previous physiologic studies, which included a mixture of subjects with and without H pylori infection, have been contradictory.10, 28, 33
The randomly skewed allocation of the majority of infected subjects to the placebo group in our study does not allow us to determine if the acid rebound phenomenon is clinically significant in infected subjects. However, previous studies have shown that up to 75% of long-term treated patients in our region are not infected with H pylori,34, 35 which make our findings potentially relevant for the majority of these individuals.
We recognize that the difference between the 2 groups in symptom scores is modest. However, considering the timing of symptoms and the double-blind, placebo-controlled design of this study, including blinded withdrawal of PPI, we believe that our findings is a very strong indication of a clinically significant acid rebound phenomenon that needs to be investigated in proper patient populations.
Although we cannot be certain that symptoms with the severity and frequency we observed in our study would make patients resume therapy, we know from clinical studies that even mild symptoms more than once a week constitutes troublesome symptoms.36, 37 The escape antacid medication used by the subjects treated with a PPI in our study attests to the clinical relevance of the observed symptoms. Pharmacoepidemiologic studies have shown that a significant proportion of patients treated long term with a PPI initiate and maintain therapy on uncertain or unapproved indications, such as functional dyspepsia, where the effects of acid-suppressive therapy is controversial.2, 6, 38 Thus, patients with ambiguous symptoms that are not truly acid related may be prescribed a PPI empirically, but may find it difficult to withdraw from therapy because of the development of true acid-related symptoms related to acid rebound, necessitating continued PPI treatment.
The possible implications of RAHS need to be addressed in future studies. Tapering has been investigated in a clinical trial where long-term treated patients were randomised to tapering or instant discontinuation.34 Tapering over 3 weeks did not have a significant effect on the proportion that successfully withdrew treatment compared with instant discontinuation. However, the duration of RAHS is unknown and probably lasts >3 weeks as suggested by the continued presence of acid-related symptoms 4 weeks after discontinuation of therapy (at week 12) in our study. Furthermore, 2 studies have shown increased acid secretory capacity ≥8 weeks after discontinuation of treatment.10, 39
Acid inhibition with a PPI for 8 weeks induces acid-related symptoms in a significant proportion of asymptomatic subjects when therapy is withdrawn. We find it highly likely that the symptoms observed in this trial are caused by RAHS and that this phenomenon is equally relevant in patients treated long term with PPIs. These results justify the speculation that PPI dependency could be 1 of the explanations for the rapidly and continuously increasing use of PPIs.