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Short and long-term PPI treatment for GERD. Do we need more-potent anti-secretory drugs?

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Because the reflux of the acidic gastric content into the esophagus plays a major role in the pathogenesis of symptoms of GERD and lesions of erosive esophagitis, acid suppression with a proton pump inhibitor (PPI) is currently the mainstay of anti-reflux therapy. There is a strong correlation between the degree of acid suppression provided by a given drug and its efficacy. The superiority of PPIs over other drugs (antacids, prokinetics and H2-receptor antagonists) has now been established beyond doubt, both for short- and long-term treatment. However, there are still some unmet therapeutic needs in GERD; hence, patients with non-erosive reflux disease (NERD) are less responsive to PPIs than those with erosive esophagitis. Moreover, the efficacy of PPIs in patients with atypical symptoms is frequently limited to the relief of associated heartburn or regurgitation. With respect to safety, although most studies on short- and long-term PPI use have provided reassuring data, recent reports have drawn attention to potential side effects or drug–drug interference. Better healing rates in the most severe forms of esophagitis, or a faster onset of symptom relief, may require optimization of acid suppressive therapy with regard to the daily course of acid secretion, especially during the night. Different pharmacological approaches can be considered, with the ultimate goals of achieving faster, stronger and more-sustained acid inhibition. How a better pharmacological profile may translate into clinical benefit should now be tested in appropriate, controlled studies.

Introduction

According to the Montreal definition, gastroesophageal reflux disease (GERD) is a condition that develops when reflux of the stomach contents into the esophagus causes troublesome symptoms and/or complications [1]. GERD impacts quality of life (HR-QOL) and reduces work productivity [2], [3], [4]. Hence, moderate reflux symptoms occurring more than once a week impair HRQOL and can be considered as GERD, irrespective of the presence or absence of mucosal breaks at endoscopy [5]. Because the reflux of the acidic gastric content into the esophagus plays a major role in the pathogenesis of GERD symptoms and erosive esophagitis (EE) lesions, acid suppression is currently the most-effective drug therapeutic approach. During the last two decades, the superiority of proton pump inhibitors (PPIs) over other drugs (antacids, prokinetics and H2-receptor antagonists) has been established beyond doubt by many pharmacological studies and large clinical trials [6], [7]. PPIs are now considered as the mainstay of anti-reflux medical therapy and are extensively prescribed, not only by gastroenterologists and GPs but also by non-GI specialists such as cardiologists, pneumologists or ENT specialists. Due to the high prevalence of GERD, they represent a huge economic burden, far beyond the treatment of the most-frequent malignancies [8]. However, despite the unprecedented commercial success of this class of drugs, there remain some unmet needs in GERD therapy. For example, it has become increasingly evident that there are subgroups of patients less- (or un-) responsive to PPIs, such as those with so-called non-erosive reflux disease (NERD) or atypical manifestations. Regarding safety, although most studies on short/long-term PPI use have provided reassuring data, recent reports have highlighted potential side effects or drug–drug interference.

GERD treatment can be subdivided into acute treatment, during which healing of esophagitis lesions and/or symptom control is the aim, and a maintenance phase during which the maintenance of healing and/or symptom control should be achieved. In this chapter, we have chosen to review recent data (published after 2000) on PPI efficacy and to discuss more extensively the long-term strategies available for GERD treatment, as well as the shortcomings and limitations of current PPIs. For older studies, the reader is referred to a previous issue of Best Practice in Gastroenterology [9], [10].

Section snippets

PPI pharmacology: what is new and what is relevant to the clinic?

Five PPI molecules are available on the market in most developed countries, omeprazole, lansoprazole, pantoprazole, rabeprazole and the more-recently developed S-enantiomer of omeprazole, esomeprazole. Some special formulations are also available, such as the lansoprazole disintegrated tablets which may be more convenient to some patients [11].

All current PPIs are substituted benzimidazoles which interact with gastric H+/K+ ATPase (the proton pump), the enzyme constituting the final step in the

The objectives

The objectives of short-term PPI therapy are rapid symptom relief and the healing of mucosal breaks in the case of EE. Most clinical trials have evaluated efficacy after 4 or 8 weeks of daily PPI administration at different doses and dosing frequencies (usually once daily).

Esophageal lesion healing is the most objective outcome measure and, due to the better grading system offered by the Los Angeles classification, results from different studies can be more-reliably compared than in the past.

Long-term management with PPI therapy

GERD is a chronic, relapsing disease. Once healing of mucosal breaks and sufficient symptom relief have been achieved by initial therapy, the main goals of long-term management are to maintain symptom control and prevent lesion recurrence, allowing a return to a nearly-normal quality of life. Recent cohort studies have shown that GERD can progress with time [59], [60] and in some cases complications develop, making prevention of these complications another important objective. In many patients,

Atypical symptoms

The degree of association and causal relationship with reflux is highly variable between the different syndromes, and also from one patient to another. These atypical symptoms are often isolated (i.e. without associated heartburn or regurgitation) making the diagnosis more difficult. In patients with atypical GERD manifestations, the success rate of acid suppressive therapy with PPI is rather low (if any) and mainly limited to the suppression of esophageal symptoms (heartburn, regurgitation and

PPIs long-term safety

In a non-life-threatening disorder like GERD, safety is a crucial issue. In this context, several concerns have been raised recently, suggesting possible PPI-related adverse events in long-term users. All these potential risks are not specific to GERD [113] but GERD is the most-frequent indication for long-term PPI use. Although PPIs are certainly over-prescribed, the magnitude of this misuse is difficult to quantify [114].

The risk of increased incidence of neoplasms under PPI therapy has been

Do we need more-potent antisecretory drugs in GERD?

In GERD, there is a strong, significant correlation between the degree of acid suppression provided by a given drug and its rate of efficacy [127], [128]. As previously indicated, the level of inhibition of gastric acidity achieved by a standard, once-daily dose of any available PPI is highly variable during the 24 h period, being maximal after meals while nocturnal acidity persists, especially during the second part of the night [128]. In addition, due to their pharmacological mechanism of

Conflict of interest statement

None declared.

Acknowledgements

Astra zeneca (research) Movetis (consulting)Given Imaging (consulting)Mauna kea Technologies (research support) Jansen Cilag (research).

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