Review ArticleThe appropriate use of proton pump inhibitors (PPIs): Need for a reappraisal
Introduction
Although the discovery of Helicobacter pylori (H. pylori) infection as the cause of peptic ulcer has dramatically changed our understanding of this common disease, gastric acid remains a relevant pathogenetic factor in many disorders of the esophagus and the gastro-duodenal region [1]. The pathophysiological alterations leading to gastroesophageal reflux disease (GERD) are responsible for the presence of acid in a wrong place [2], [3], [4], while acid hypersecretion or the direct effect of normal acid on a damaged gastro-duodenal mucosa maintains a crucial role in inducing a variety of disorders of the upper digestive tract [5].
The search for acid neutralization has consumed generations of gastroenterologists and surgeons, but a continuing and fruitful research has allowed us to synthesize several pharmacological agents capable of strongly controlling the production of acid from the parietal cells of the stomach and further acid-suppressive agents are being developed [6], [7], [8]. Indeed, the advent of powerful inhibitors of gastric acid secretion has revolutionized our therapeutic approach to the acid-related diseases with the great result of rendering surgery progressively more and more obsolete.
The two main classes of drugs used to treat acid-related disorders include histamine type 2 receptor antagonists (H2RAs), that block the histamine receptor on parietal cells thereby reducing hydrogen ion release and PPIs, that inhibit the hydrogen pump in the parietal cell directly, independently of any membrane receptor stimulation [9]. Because of their well documented superiority in relieving symptoms and healing mucosal lesions, PPIs have rapidly replaced H2RAs in treating any clinical acid-related condition. In fact, H2RAs have a relatively short duration of action (4–8 h) and produce an incomplete inhibition of post-prandial gastric acid secretion [10]. So, at least twice daily doses of these drugs are necessary to obtain a good control of acid. Moreover, they present the pharmacodynamic phenomenon of tolerance, which develops within two weeks of repeated administration, resulting in a progressive decline of acid suppression [11]. On the contrary, PPIs control both basal and food-stimulated acid secretions producing more complete and longer-lasting acid suppression than H2RAs (10–18 h) and, moreover, tolerance to them has never been observed [12].
Since their introduction in clinical practice, PPI use continues to grow and this constant increase cannot be only explained by the simple substitution of H2RAs, but also by an endless expansion in the overall market of antisecretory drugs [13]. More recently, the loss of patent protection and the availability of PPIs as generic drugs in many countries have permitted to reduce the price of them, but this fact has further contributed to their increasing use [14].
The continuous expansion of the PPI market has risen many concerns about the possible inappropriate prescribing of these drugs and has created an important problem for many regulatory authorities of various countries and continents [15]. This issue is particularly relevant in consideration of the excessive cost for both patients and governments and the potential risk for iatrogenic harm due to adverse events or drug interactions in polymedicated individuals.
In keeping with the above reflections, we believe that a reappraisal of the appropriate use of PPIs can be useful for both general practitioners and hospital clinicians in order to reduce the dangerous overutilization of these drugs. The aim of this review is to provide a summary of current information on the appropriate use of PPIs, taking into account the guidelines published in medical literature and based on the results of many clinical trials on the treatment of upper digestive disorders and the related meta-analyses and systematic reviews. To identify relevant studies, a computerized (Medline) and manual literature search was performed for the period up to August 2016, with particular focus on the past 15 years. We used the following terms: acid-related diseases, GERD, gastro-esophageal reflux disease, acid reflux, NERD, non-erosive reflux disease, hypersensitive esophagus, impedance–pH testing, Barrett's esophagus, H. pylori infection, duodenal ulcer, H. pylori-negative duodenal ulcer, NSAID-induced ulcer, iatrogenic gastric ulcer, acid hypersecretory conditions, Zollinger–Ellison syndrome, functional dyspepsia, NSAID-induced dyspepsia, stress ulcer, critically ill patients, intensive care units, treatment and prevention of acid-related disorders, overutilization of PPIs, overuse of antisecretory drugs, and costs of overprescribing PPIs. They were used alone or in combination with the following terms: pathophysiology, treatment, management, PPIs, proton pump inhibitors, H2-blockers, potential harms, documented benefits, inappropriate prescription, cost-effectiveness, and PPI expenditure. We critically reviewed all full-text papers and relevant abstracts published in English. The reference lists from identified papers were searched to identify any additional studies that may have been missed during the process.
Section snippets
Accepted indications for PPI use
The Food and Drug Administration (FDA) in USA [16] and the National Institute for Clinical Excellence (NICE) in UK [17] published guidance on the use of PPIs in the following well defined indications:
- 1.
healing of erosive esophagitis and maintenance of this healing
- 2.
GERD with its various clinical manifestations (non-erosive reflux disease = NERD, ascertained extra-esophageal symptoms, esophageal strictures and Barrett's esophagus)
- 3.
treatment of H. pylori infection in combination with antibiotics
- 4.
Gastroesophageal reflux disease (GERD)
PPIs have become the antisecretory drug of choice in this disease because they have been shown to be significantly more effective than H2RAs not only in healing esophageal erosions but also in relieving typical reflux symptoms [18]. The original studies comparing these two pharmacological agents were performed in patients with erosive esophagitis and the healing of mucosal lesions was considered the primary endpoint to assess the efficacy of acid-suppressive drugs [19]. However, in recent years
Eradication of H. pylori infection
It is now recognized that H. pylori colonizes about half of the world's population and is a cause of acute gastritis, chronic gastritis and most cases of duodenal ulcer [37], [38]. Its eradication represents a permanent cure of duodenal ulcer disease with disappearance of both recurrences and complications [39]. Therapeutic regimens include at least two antibiotics and twice daily doses of PPIs for 7–14 days [40]. The addition of PPIs synergizes with the antibiotics and many clinical trials have
H. pylori-negative duodenal ulcers
Although H. pylori infection is an important factor in the etiology of non-NSAID-induced duodenal ulcer disease, it cannot be excluded that other factors, such an increased acid secretion and defective mucosal defensive mechanisms, may be involved and should not be overlooked or discounted [43]. In a review study [44] the proportion of duodenal ulcers that are H. pylori-negative has been reported to be higher in USA and Australia (20%–50%) than in Europe (3%–12%). The precise causes of H. pylori
Non-steroidal anti-inflammatory drugs (NSAIDs)
Altered gastric mucosal defense may be the primary culprit of gastric ulcer, where normal or decreased basal and stimulated acid secretions are generally found [1]. A damaged and weak mucosa may also explain the propensity for NSAID-induced ulcers to occur in the stomach. As further mechanism involving acid in gastric injury, it has been shown that the administration of NSAIDs for one month in patients with rheumatoid arthritis increases significantly intragastric acidity compared with baseline
Pathologic hypersecretory conditions
The best characterized acid hypersecretory condition is the Zollinger–Ellison syndrome (ZES), which is caused by a gastrin producing tumor (gastrinoma) that results in gastric acid hypersecretion. To-day PPIs are the antisecretory therapy of choice and must be given continuously without time limit [56]. They are able to control acid secretion and prevent complications in most patients with ZES, although very high doses of medication may be necessary [57], especially in patients with MEN-1, a
Critically ill patients on prolonged mechanical ventilation
Stress ulcers are most commonly located in the proximal stomach and may occur in patients admitted in intensive care units (ICUs) mainly as result of an ischemic damage and altered mucosal defense, thereby acid can be only implicated as a secondary factor. However, current guidelines approved the use of PPI as stress ulcer prophylaxis (SUP) in ICU patients at high risk of gastrointestinal bleeding, such as those who require mechanical ventilation for more than 48 h or those with coagulopathy [59]
Functional dyspepsia (FD)
According to Rome IV criteria [62], this is a condition that significantly impacts on usual activities of a patient and is characterized by one or more symptoms related to the central upper part of the abdomen that remain unexplained after a routine clinical evaluation. They are represented by epigastric pain or epigastric burning (epigastric pain syndrome = EPS) or nausea, early satiation, postprandial fullness, bloating (postprandial distress syndrome = PDS). The pathogenetic role of acid
Potential consequences and costs of PPI overprescription
There is no doubt that PPI use continues to grow every year in almost all industrialized countries [73] and this has risen many concerns about the appropriateness of their use. Many studies have been published on the rate of inappropriateness of PPI therapy in both hospitals and primary care ambulatories and the increased costs related to their overuse.
Table 3 reports the rates of overprescription in both hospitalized and ambulatory patients treated with antisecretory drugs, mainly PPIs. It
Conclusions
The advent of PPIs has revolutionized the treatment of acid-related disorders and millions of patients have benefitted from them given on both a short- and a long-term basis. In the last decades they have become the mainstay of antisecretory therapy for many upper digestive diseases, thanks to their efficacy combined with a good safety profile. Several guidelines derived from the therapeutic results obtained in many clinical trials and published as meta-analyses and systematic reviews have been
Authors' contribution
- –
Vincenzo Savarino, MD, PhD: design of the study, writing of the manuscript, approving final version
- –
Pietro Dulbecco, MD, PhD: design of the study, writing of the manuscript, approving final version
- –
Nicola de Bortoli, MD: design of the study, writing of the manuscript, approving final version
- –
Andrea Ottonello, MD: design of the study, writing of the manuscript, approving final version
- –
Edoardo Savarino, MD, PhD: design of the study, writing of the manuscript, approving final version
Financial support
None.
Conflict of interests
The authors state that they have no conflicts of interest.
References (96)
- et al.
Pharmacological control of gastric acid secretion for the treatment of acid-related peptic disease: past, present, and future
Pharmacol. Res.
(2003) - et al.
Clinical pharmacology and safety profile of esomeprazole, the first enantiomerically pure proton pump inhibitor
Dig. Liver Dis.
(2001) - et al.
Potential costs of inappropriate use of proton pump inhibiotrs
Am. J. Med. Sci.
(2014) - et al.
Proton pump inhibitors in GORD. An overview of their pharmacology, efficacy and safety
Pharmacol Res
(2009) - et al.
The lessons learned from randomized clinical trials of GERD
Dig Liver Dis
(2007) - et al.
Combined multichannel intraluminal impedance and pH-metry: a novel technique to improve detection of gastro-oesophageal reflux. Literature review
Dig. Liver Dis.
(2004) - et al.
Partial regression of Barrett's esophagus by long-term therapy with high-dose omeprazole
Gastrointest. Endosc.
(1996) - et al.
The effect of proton pump inhibitors on Barrett's esophagus
Gastroenterol Clin North Am
(2015) - et al.
Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett's esophagus
Clin. Gastroenterol. Hepatol.
(2013) - et al.
Guidelines for the management of Helicobacter pylori infection in Italy: the III Working Group Consensus Report 2015
Dig. Liver Dis.
(2015)
Helicobacter pylori-negative duodenal ulcers: prevalence, clinical characteristics, and prognosis—results from a randomized trial with 2-year follow-up
Am J Gastroenterol
Current indications for acid suppressants in Helicobacter pylori-negative ulcer disease
Best Pract Res Clin Gastroenterol
The Zollinger–Ellison syndrome: dangers and consequences of interrupting antisecretory treatment
Clin Gastroenterol Hepatol
Gastroduodenal disorders
Gastroenterology
Effects of proton pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials
Clin. Gastroenterol. Hepatol.
Overuse of acid-suppressive therapy in hospitalized patients
Am J Gastroenterol
Who is using chronic acid suppression therapy and why?
Am. J. Gastroenterol.
Are proton pump inhibitors really so dangerous?
Dig Liver Dis
Control of gastric acid in health and disease
Gastroenterology
Oesophagealmotility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal reflux disease
Aliment. Pharmacol. Ther.
Esophagogastric junction morphology is associated with a positive impedance–pH monitoring in patients with GERD
Neurogastroenterol. Motil.
Dysmotility and reflux disease
Curr Opin Otolaryngol Head Neck Surg
Proton pump inhibitors and acid-related diseases
Pharmacotherapy
The pharmacokinetics of ilaprazole for gastro-esophageal reflux treatment
Expert Opin. Drug Metab. Toxicol.
Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations
Expert Opin. Drug Metab. Toxicol.
Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs
Gut
The role and limitations of H2 receptor antagonists in the treatment of gastro-esophageal reflux disease
Aliment Pharmacol Ther
Tolerance during dosing with H2 receptor antagonists. An overview
Scand J Gastroenterol
Marked increase in proton pump inhibitors use in Australia
Pharmacoepidemiol Drug Saf
We are using too many PPIs, and we need to stop: a European perspective
Am J Gastroenterol
Overprescribing proton pump inhibitors
Br Med J
Inappropriate prescribing of proton pump inhibitors in primary care
Postgrad. Med. J.
Gastro-oesophageal reflux symptoms, oesophagitis and Barrett's oesophagus in the general population: the Loiano–Monghidoro study
Gut
Management strategy for patientswith gastroesophageal reflux disease: a comparison between empirical treatment with esomeprazole and endoscopy-oriented treatment
Am. J. Gastroenterol.
NERD: an umbrella term including heterogeneous subpopulations
Nat Rev Gastroenterol Hepatol
The role of non-acid reflux in NERD — lessons learned from impedance–pH monitoring in 150 patients off therapy
Am. J. Gastroenterol.
Esophageal baseline impedance levels in patients with pathophysiological characteristics of functional heartburn
Neurogastroenterol. Motil.
Association between baseline impedance values and response proton pump inhibitors in patients with heartburn
Clin. Gastroenterol. Hepatol.
Impedance–pH reflux patterns can differentiate non-erosive reflux disease from functional heartburn patients
J. Gastroenterol.
European Association of Endoscopic Surgery (EAES). EAES recommendations for the management of gastroesophageal reflux disease
Surg. Endosc.
Long-term PPI use: balancing potential harms and documented benefits
Am J Gastroenterol
On-demand therapy for gastroesophageal reflux disease
Am. J. Gastroenterol.
Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett's esophagus
Am. J. Gastroenterol.
Proton-pump inhibitor therapy and the development of dysplasia in patients with Barrett's oesophagus
Med. J. Aust.
Barrett's esophagus: proton pump inhibitors and chemoprevention II
Ann. N. Y. Acad. Sci.
Helicobacter pylori and duodenal evidence suggesting causation
Dig. Dis. Sci.
Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric and duodenal ulcer – a randomized, controlled study
Ann. Intern. Med.
Sequential versus standard triple first-line therapy for Helicobacter pylori eradication
Cochrane Database Syst. Rev.
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