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Jan G Hatlebakk
Haukeland University Hospital
University of Bergen
Since their introduction in around 1990, proton pump inhibitors (PPIs) have become the mainstay of therapy in gastro-oesophageal reflux disease (GORD).
Introduced originally as a healing therapy for peptic ulcer disease, it was only later understood that they had an even greater potential for treating GORD, a chronic disorder in which acid directly causes heartburn or chest pain. Symptoms are induced by the reflux of gastric – and often also duodenal – contents to the distal oesophagus, where this may cause reflux oesophagitis in about 50% of patients.(1)
GORD therapy goals
The most effective therapy for GORD is the suppression of gastric acid secretion,(2) and gastric pH needs to be raised above pH 3–4 to achieve the two main goals of therapy:
The main importance of achieving full healing of mucosal lesions may be to prevent the development of complications such as Barrett’s oesophagus, a premalignant condition that may develop into adenocarcinoma of the oesophagus.(3) The more general benefits of healing, meanwhile, are indicated by the fact that the presence of GORD has been found to reduce health-related quality of life and productivity at work.
PPIs and their effects
Over the past decade, five different PPIs have been introduced to the market in most Western countries. These are:
All these substances are substituted benzimidazole compounds, binding irreversibly to the gastric parietal cell H(+),K(+)-ATPase, the so-called proton pump.
The suppression of acid secretion varies between patients, depending on several factors, including Helicobacter pylori infection status and the genetically determined hepatic metabolism of the drugs via the cytochrome P450 enzymes, with most subjects in Western countries being rapid metabolisers.
The duration of action is usually too short to control gastric acidity throughout 24 hours, resulting in “nocturnal acid breakthrough” during the early hours of the night, which may be followed by gastro-oesophageal reflux in many patients with GORD.(4)
In clinical practice, it may therefore be difficult to achieve full symptom relief with once-a-day dosing of a PPI, particularly in those patients who tend to have reflux when lying down. In such cases, the first step is to split the dosage of the PPI to cover the late evening and night.(5) There is also some data on adding an H(2)-receptor antagonist such as ranitidine at bedtime, which, at least initially, improves acid suppression during the early hours of the night.(6)
A number of recent studies have confirmed the effectiveness of newer-generation PPIs across the spectrum of GORD.
In the EAZEE study, for example, 5,241 adult patients with grades A–D reflux oesophagitis according to the Los Angeles classification were randomised to eight weeks of therapy with either esomeprazole 40mg or lansoprazole 30mg daily.(7)
Healing rates in patients with grades A or B oesophagitis were very similar at between 91.0% and 97.2%.
In patients with grade C or grade D lesions, however, esomeprazole was significantly more effective, which means that the problem of patients who do not heal looks set to become much less of a burden in daily clinical practice.
Furthermore, symptom relief occurred significantly faster with esomeprazole, with a median time until nocturnal heartburn was controlled on just one night, compared with two nights with lansoprazole.
It has recently been shown that the presence of Barrett’s oesophagus is a negative predictive factor for the healing of reflux oesophagitis. This is a practical observation since Barrett’s oesophagus coexists with reflux oesophagitis in 5–10% of patients with chronic reflux oesophagitis.(8)
PPIs on demand?
The use of PPIs only on demand has been investigated in patients both with and without reflux oesophagitis, and has been followed by good patient satisfaction with therapy.(9,10)
It has also been demonstrated that the onset of effect of PPIs is relatively short when adequate doses are given.(11)
GORD and surgery
The extensive prescription of PPIs has not reduced the frequency of antireflux surgery, which is now usually performed as a laparoscopic procedure. Some countries have even seen an increase in surgery, possibly due to some patients being reluctant to accept the prospect of a lifelong intake of medication.
Nevertheless, antireflux surgery is followed in a significant minority of patients by discomfort from dysphagia or the gas-bloat syndrome.
An ongoing Nordic study compares open Nissen fundoplication with maintenance therapy with omeprazole 20–40mg daily. The study has shown comparable efficacy between medical and surgical therapies, but indicates a minor advantage for surgery after seven years of follow-up.(12)
Meanwhile, the safety issues around long-term acid suppression continue to be debated, although accumulating experience is reassuring.(13)
PPIs as diagnostic tool
PPIs have been used extensively as diagnostic tools in dyspeptic patients, since an improvement in symptoms has customarily been taken as an indication of GORD being the underlying cause of the symptoms.
Unfortunately, little research has been done into the validity of this approach, which is commonly used as an alternative to well-established but resource-demanding and sometimes uncomfortable procedures such as upper gastrointestinal endoscopy, manometry and 24-hour pH-metry.
However, in one large Scandinavian multicentre study, Johnsson and co-workers randomised 377 patients with symptoms of GORD to 14 days of therapy with either esomeprazole 40mg each morning or 20mg twice daily, or to placebo.(14) The response of the patients to therapy was compared with findings at upper gastrointestinal endoscopy and 24-hour pH-metry, using a combination of the latter two methods as the reference.
The sensitivity of a complete response or significant improvement in symptoms was satisfactory, at about 79–86% after five days, but specificity was only in the order of 40%, which seriously questions the value of the response to PPIs as supporting the diagnosis of GORD.
Less is known about using PPIs as diagnostic tools in other patient groups, such as patients with chest pain of unknown origin and patients with airway disorders suspected of being associated with GORD.
PPIs are likely to dominate in their role as medical therapy for GORD for many years to come, even as other classes of acid-suppressive medication are being developed. A sixth PPI, tenatoprazole, is undergoing clinical trial at the present time.
With adequate doses of medication, the clinical response to PPIs is excellent in the vast majority of patients suffering from GORD.