Diseases of the Esophagus (2004) 17, 197–204 © 2004 ISDE

Review article

Blackwell Publishing, Ltd.

Pharmacologic management and treatment of gastroesophageal reflux disease M. Storr,1 A. Meining2 1

Department of Internal Medicine II – Standort Großhadern, Ludwig-Maximilians University and Klinikum Innenstadt der LMU, Munich, Germany

2

SUMMARY. Gastroesophageal reflux disease (GERD) is one of the most common diagnoses in daily practice. Diagnosis can be made on symptom evaluation, on pH-monitoring or on endoscopic findings. In contrast to commonly held opinion there is no strong evidence that lifestyle factors are a dominant factor in the pathophysiology of GERD. The various agents currently used for treatment of GERD include mucoprotective substances, antacids, H2-blockers and proton pump inhibitors. This article gives an overview of the pharmacological management of GERD and focuses on the differential therapy of endoscopy-negative GERD, GERD with esophagitis and maintenance therapy. KEY WORDS: gastroesophageal reflux disease (GERD), treatment.

esophageal pH (24-h pH monitoring) has led to great improvement in the ability to diagnose reflux disease and reflux associated complications. The endoscopic classification of GERD is shown in Table 1. Endoscopic examination, the gold standard of the diagnostic procedures, permits both visualization and classification of esophagitis, as well as diagnostic biopsy of the esophageal mucosa for the known complications of GERD: Barrett’s esophagus and adenocarcinoma or other differential diagnoses like squamous cell carcinoma. But since in up to 25% of patients with endoscopy positive GERD, pH monitoring records normal acid exposure, the limitation of this investigation in the diagnosis of GERD has to be recognized.2 Since the examinations are somewhat, uncomfortable for patients and expensive, and since the proton pump inhibitors (e.g. omeprazole) exert profound acid inhibition and excellent symptom-relieving capacity, a short-term treatment with omeprazole (20 mg t.i.d) as a diagnostic test for reflux disease appears efficient with a fairly high sensitivity of 75% but a poor specificity of 55% owing to the placebo effect.3,4 A number of therapeutic options including pharmacological treatment, surgery and modification of lifestyle have been suggested as therapy for patients suffering from GERD. For pharmacologic management in daily practice there is a consistent hierarchy of effectiveness of the available short and long-term therapies. Whereas lifestyle measures have only a limited role in GERD treatment, proton pump inhibitor

INTRODUCTION Gastroesophageal reflux disease (GERD) is one of the most common diagnoses in daily practice. In industrial nations between 10 and 20% of the population complain of heartburn, the most reliable symptom of GERD, at least once a week and 4–10% report daily onset. In the USA an investigation in Olmsted County, Minnesota, discovered, that 17.8% of the inhabitants complain about frequent (weekly) heartburn and 42.4% complain about any heartburn.1 GERD is defined by the presence of physical complications attributed to gastroesophageal reflux (esophagitis, asthma, aspiration pneumonia, laryngitis) or by the occurrence of reflux induced symptoms that can be severe enough to impair quality of life. A well-structured symptom analysis is necessary since 30–50% of GERD patients have a negative endoscopic examination. It is well accepted that heartburn that occurs in the absence of endoscopic reflux esophagitis is most likely due to gastroesophageal reflux although the term ‘heartburn’ is unreliably interpreted by patients. The introduction of fiber optic instruments and ambulatory devices for continuous monitoring of

Address correspondence to: Dr med. Martin Storr, II. Medizinische Klinik, Ludwig-Maximilians University Munich, Germany, Marchioninistr.15, 81377 Munich, Germany. Tel: + 089 7095 2281; Email: [email protected] 197

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Table 1 Classification of reflux esophagitis according to Savary and Miller (1978) (I–IV) and direct comparison to the Los Angeles classification (A–D) Classification

Savary and Miller

Los Angeles Classification

Stage I/A

One or more longitudinal non-confluent mucosal lesions with erythema, often covered with exudate above or extending from the gastroesophageal junction. Confluent erosive and exudative mucosal lesions that do not cover the entire circumference of the esophagus. Circumferential erosive and exudative mucosal lesions covering the whole esophageal mucous membrane.

One or more mucosal breaks confined to the mucosal fold, each no longer than 5 mm.

Stage II/B Stage III/C Stage IV/D

Chronic mucosal lesions such as ulcerations with or without stricture formation.

(PPI) therapy is considered the initial medical treatment of choice because of its clearly superior efficacy compared with the other pharmacological options.

One or more mucosal breaks longer than 5 mm confined to the mucosal fold but not continuous between two folds. Mucosal breaks that are continuous between the tops of two or more mucosal folds but that involve less than 75% of the esophageal circumference. Extensive mucosal breaks engaging at least 75% of the esophageal circumference.

Table 2 Pathophysiologic mechanisms of gastroesophageal reflux disease Barrier function

PATHOPHYSIOLOGICAL BACKGROUND Gastroesophageal reflux describes the retrograde movement of gastric contents through the lower esophageal sphincter (LES) to the esophagus. Pathologic reflux is characterized as frequent reflux episodes (> 50 episodes/24 h) of longer duration (> 3 episodes longer than 5 min) with increased acid fraction time (pH < 4 for > 4%/24 h), can occur during day and/or night and may cause symptoms and inflammation or mucosal injury of the esophagus.5 To date it has been accepted that the dominant mechanism of symptom production in reflux disease is abnormal prolonged contact of the esophageal mucosa with acid and pepsin but there is also evidence that in a minority of patients normal levels of acid and pepsin reflux may trigger reflux-induced symptoms.6,7 Symptom and pH-monitoring studies have shown that symptoms are most frequent after meals when most reflux occurs.8 In contrast to commonly held opinion there is no strong evidence that lifestyle factors are a dominant factor in the pathophysiology of GERD. However, since red and white wine and coffee cause a significant increase of GER due to a decrease in LESP, it cannot be ruled out that disadvantageous factors may precipitate GERD and that individual patients may benefit from lifestyle modification.9,10 Formerly GERD was attributed to hypotonic LES and/or deficient or delayed esophageal acid clearance (Table 2). The importance of hypotonic LES has been reported in patients with higher grades of esophagitis, whereas in the majority of patients with mild GERD or endoscopy-negative GERD transient lower esophageal sphincter relaxations (TLESRs) are believed to be the underlying disorder. Esophageal clearance is dependent on voluntarily induced primary peristalsis (approximately 60 times per hour) and on secondary peristalsis that occurs

Acid clearance Mucosal defense

Gastric emptying

Abdominal pressure

Lower esophageal sphincter Basal lower esophageal sphincter pressure Transient lower esophageal sphincter relaxations Crural diaphragm Hiatal hernia Peristaltic action of tubular esophagus Saliva production Pre-epithelial (mucus, bicarbonate) Epithelial (tight cell contacts, ion exchanger) Postepithelial (blood supply) Ulceration or stricture Neuromuscular disorders Idiopathic gastroparesis Pyloric dysfunction Obesity Pregnancy

Gastric hypersecretion Genetic predisposition?

in the absence of a pharyngeal swallow and which can be elicited by esophageal distension or acidification such as reflux. Delayed clearance is reported in patients with chronic severe reflux disease. Hiatus hernia is believed to be a promoting factor for GERD since a hiatal hernia lowers the LESP, increases the frequency of TLESRs, increases ‘stress reflux’ (reflux during an increase in intra-abdominal pressure overwhelming the low LESP) and delays acid clearance due to repeated reflux from the hernial sac during swallow-induced LES relaxations.11 Recent observations that GERD may occur in patients without hypotonic LES or hiatus hernia discovered the TLESRs, which are now believed to be the underlying disorder causing pathological reflux in the majority of GERD patients. TLESR refers to episodes of LES relaxation that occur unrelated to swallowing, with the LESP decreasing to gastric level for at least 10 s (TLESRs occur normally 2–6 times/ per hour). Gastric distension due to postprandial fullness or intragastric air causing increased intragastric pressure is believed to be one of the main factors triggering TLESRs but the understanding of TLESRs is still incomplete. The physiological

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role of TLESRs seems to be venting the gastric lumen to allow escape of excessive air, thus representing an abortive belch reflex.12 Pharmacological options influencing TLESRs would be useful in GERD treatment but larger randomized, placebo-controlled trials investigating how TLESRs can be modulated in GERD patients are needed. However, promising pharmacological research may result in new pharmacological options (CCKA antagonist loxiglumide; NO-synthase inhibitor L-NNA; GABAB receptor agonist baclofen) for a causal GERD treatment. A small placebo-controlled trial on GERD patients demonstrated that baclofen, given orally 90 min before a meal, reduces the number of TLESRs and the rate of reflux episodes but had no effect on esophageal acid exposure.13 Influencing TLESRs remains a challenge and future pharmacological investigations should focus on this since it would be, for the first time, a treatment of the underlying disorder.

TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE (GERD) The diagnosis of GERD can be made on symptom evaluation, on pH-monitoring or on endoscopic findings. It remains controversial whether endoscopic evaluation is routinely necessary in patients with moderate GERD symptoms, but in patients with atypical or severe symptoms such as dysphagia, hematemesis or weight loss an endoscopic examination is necessary to exclude esophageal stricture, peptic ulcer or malignancy. The commonly used approach treating GERD patients employs the neutralization or suppression of intragastric acidity whereby the gastric reflux into the esophagus is rendered non-irritating to the esophageal mucosa. This approach does not influence the underlying disorder since in most GERD patients pathogenesis includes an increase in TLESR occurrence. In some patients uncomplicated GER may be treated by modification of lifestyle, comedications and eating habits in an early stage of GERD. These modifications include elevating the head of the bed, losing weight, avoiding strong stimulators of acid secretion (e.g. coffee, alcohol), avoiding certain drugs (e.g. anticholinergics), specific foods (fats, chocolate) and smoking, all of which will reduce LESP. There are a wide range of substances that have been reported to affect the LESP or TLESRs and an overview is given in Table 3.14 However, there is little evidence that lifestyle modifications are effective in GERD patients. For the short-term and for maintenance therapy there is a clearly established hierarchy of efficiency among the available medical treatments and the drugs should be used in a step down regimen (Fig. 1).

Table 3 Agents that modify the lower esophageal sphincter pressure (LESP)

Decreases LESP Hormones

Cholecystokinin Secretin Progesterone Glucagon Neurotensin Gastrin Neurotransmitter VIP Dopamine CGRP NO Drugs Atropine N-buthylscopalamine Cimetropiumbromide Theophylline Nitrate Dopamine Ca2+-antagonists Loperamide Molsidomine -arginine Beta-adrenergics Benzodiazepines Botulinum toxin Food components Alcohol Fat Chocolate Peppermint Acid

Influences number of transient lower esophageal sphincter relaxations Cholecystokinin +

Nitric oxide + GABA – Atropine – Morphine – Loxiglumide – (CCK-A antagonist) Anesthesia – NO-antagonists – Baclofen –

Fat + Cold stress – Gastric distension + Acid + Gas +

+, Increases number of transient lower esophageal sphincter relaxations; –, decreases number of transient lower esophageal sphincter relaxations.

Fig. 1 Step-down strategy for the therapy of gastroesophageal reflux disease – step-down for symptom relief and mucosal healing. (PPI: proton pump inhibitor; OTC: over the counter.)

Within this hierarchy antacids and mucoprotective agents occupy the lower level, prokinetics and H2-antagonists the intermediate level and PPIs are the most effective. Antacids Antacids are probably the most widely used agents, especially as over-the-counter drugs for the treatment of mild gastroesophageal reflux. Their beneficial effect is mainly due to the neutralization of acid and to

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some extent also to a mucoprotective effect, but therapy with antacids is inferior to other therapeutic options. Some antacids produce CO2, which will increase gastric pressure and therefore might enhance TLESR incidence. The beneficial effect of these drugs is limited since they do not suppress acid production and therefore produce only temporary relief. These drugs can also cause side-effects such as obstipation or diarrhea due to their content of aluminum or magnesium. Their therapeutic benefit lies primarily in the symptomatic control of sporadic reflux episodes since they offer the advantage of prompt relief and in reflux treatment during pregnancy. Mucoprotective agents Mucoprotectives including sucralfate and algine acid are thought to provide a protective coating on esophageal mucosal lesions. Due to more potent drugs, the value of mucoprotectives in GERD treatment is low and they only might be used in very mild GERD since they are inferior to the other therapeutic options and since they are not cost effective in the treatment of GERD.15 Prokinetics Metoclopramide was shown to increase LESP, esophageal contraction amplitude and gastric emptying. Because of its effect on LESP and gastric emptying metoclopramide can be used in GERD. However, the long-term use of this drug is limited by its side-effects on the central nervous system due to the dopamine D2 receptor blockade.16 The effect of domperidone on esophageal motility is similar to the effect of metoclopramide but, due to its chemical structure, domperidone does not penetrate into the central nervous system and therefore lacks central side-effects. Domperidone has positive effects in patients with GERD, however, its effect is inferior to that of H2-antagonists or PPIs.17 Cisapride is a prokinetic agent that seems to increase the release of acetylcholine from enteric neurons and hence stimulates muscle action mainly via an action on the 5-HT4 receptor but, in contrast to metoclopramide and domperidone, has no antidopaminergic properties. In patients with GERD, cisapride increases LESP and has proven to be as effective as ranitidine in symptomatic relief and in mucosal healing in patients with mild or moderate esophagitis.18 The effects of cisapride seem to be superior to other prokinetic agents but since cisapride in higher doses has recently been reported to induce prolongation of the QT interval and consequently cardiac arrhythmia and torsades de pointes tachycardia in critically ill patients, it is no longer available.19 Mosapride is a novel prokinetic agent enhancing upper but not lower gastrointestinal motility by

stimulating 5HT4 receptors. In a first clinical study mosapride (40 mg; q.i.d.) significantly reduced acid reflux into the esophagus, proven by pH-monitoring.20 H2-antagonists H2-antagonists such as cimetidine, ranitidine, famotidine and nizatidine are widely used and accepted for the treatment of GERD and their effectiveness has been clearly documented in double-blinded, placebo-controlled studies. H2-antagonists effectively block basal and meal stimulated gastric acid secretion and thus prevent acid reflux into the esophagus although to a lower degree than PPIs. The H2antagonists are eliminated by hepatic metabolism and urinary excretion therefore dosage should be reduced in patients with any degree of hepatic or renal impairment. Since 1995 H2-antagonists are available over the counter in the US and are extensively used for GERD treatment. H2-antagonists given in standard dosage for 12 weeks sufficiently relieves symptoms and cause mucosal healing in 50–75% of patients with grade I–II GERD.17 Healing rates under H2-antagonists are related to the severity of esophagitis with success rates of only 30–50% for patients with grade III–IV GERD, therefore H2antagonists should be considered for sporadic or mild GERD only.21 Proton pump inhibitors (PPI) PPIs are so far the most potent agents for the treatment of reflux esophagitis. These drugs are effective in healing reflux esophagitis and relieving related symptoms. Several studies have demonstrated the superiority of PPIs over H2-antagonists or prokinetics in the treatment of GERD. PPIs provide symptomatic relief and are superior to H2-antagonists in nonerosive GERD.22 In a randomized, prospective, placebo-controlled study on 221 patients with symptomatic non-ulcerative esophagitis or with heartburn without esophagitis, omeprazole (20 mg) was found to be superior to cimetidine (400 mg; q.i.d.) for the relief of all grades of heartburn in GERD after 4 weeks of treatment, whether or not the patient had unequivocal endoscopic esophagitis (66% versus 31%).23 PPI treatment is also superior to therapy with prokinetics in the treatment of symptoms in patients with GERD, regardless of the presence of erosive esophagitis.24 These results for symptomatic endoscopy-negative GERD have been demonstrated by many authors and the meta-analysis of Chiba et al. clearly demonstrates the superiority of PPI treatment over H2-antagonists in both relieving symptoms and healing esophagitis.17 For severe esophagitis even high doses of H2antagonists do not appear to be as effective as PPIs. In a randomized, double-blinded study on patients

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with symptomatic, endoscopically confirmed erosive GERD, omeprazole (20 mg) was superior to cimetidine (400 mg; q.i.d.) in healing esophagitis after 8 weeks (71% versus 35%) and was superior in inducing a regression to normal, of pathological changes in histology (67% versus 48%).25 Based on efficacy, safety and cost-effectiveness, PPIs should be the drug of choice for the treatment of patients with endoscopically confirmed erosive GERD.26 In patients who fail to respond to PPIs correct administration (before breakfast) should be confirmed before establishing changes in therapy. Further therapeutic steps may include a second dose of H2-antagonist or PPI in the evening; a change to another brand of PPI; and endoscopic evaluation as well as pH-monitoring while on medication to confirm ongoing acid reflux in order to further increase PPI dosage. Maintenance therapy in GERD treatment is necessary since GERD is a chronic disease and most patients (50–90%), especially those with higher grades of esophagitis, will relapse once therapy is discontinued. Maintenance therapy after omeprazole (40 mg) induced healing was investigated in a randomized, prospective study on 175 patients with endoscopically confirmed reflux esophagitis. In this clinical trial omeprazole (20 mg) was more effective than ranitidine (150 mg; t.i.d). After 12 months 80% of the patients in the omeprazole group were still in remission compared with 49% in the ranitidine group.27 As with initial therapy, the study by Vigneri et al. demonstrated that PPI are superior to H2antagonists or prokinetics in maintenance therapy once the initial therapy was successful. Therefore a PPI should be the drug of choice in the maintenance therapy after erosive GERD lesions have healed.2,29 Special considerations Endoscopy-negative reflux disease

Most GERD patients do not present Barrett’s esophagus or esophageal mucosal breaks (erosions or ulcerations) in endoscopic examination.30 One has to keep in mind that most GERD patients are endoscopynegative and that symptom frequency and intensity are poor predictors for mucosal lesions. Endoscopic examination permits both visualization and classification of esophagitis as well as diagnostic biopsy of the esophageal mucosa for the known complications of GERD: Barrett’s esophagus and adenocarcinoma. Since the examinations are invasive for the patients and expensive, and since PPIs exert profound acid inhibition and excellent symptomrelieving capacity, a short-term treatment trial with omeprazole in standard or high dosage as a diagnostic test for reflux disease appears efficient.31 In patients unresponsive to PPI therapy and with

negative findings at the endoscopic examination, pH-monitoring might be necessary to discover the correct diagnosis. Though a large number of GERD patients are endoscopically negative, most of the clinical studies were focused on patients with GERD and esophagitis. Recently a large randomized, controlled clinical trial demonstrated that the efficacy of pharmacological treatment is similar in GERD both with and without esophagitis. PPIs are superior to either H2-antagonists, prokinetics or placebos.32 GERD with esophagitis

In patients with erosive esophagitis, therapy should start with a PPI (in severe grade IV esophagitis a double dose of PPI should be used) and subsequent trials of step down of therapy should be made as soon as symptoms or esophagitis are under control.1,3,34 When cost calculations are based on patients with GERD and esophagitis, there is a clear cost advantage for treatment with a PPI rather than with a H2-antagonist.35 Cost effectiveness studies demonstrated that the most effective initial therapy for reflux disease is also the most cost-effective since drug related costs are only part of the cumulative costs of reflux disease management. When treatment periods of 8–12 month are taken into account the higher utilization of medical resources occurring as a result of failure of less effective therapies substantially outweighs the greater costs of a more effective drug.36,37 These calculations are limited to patients with esophagitis and to date no comparable calculations for patients with endoscopicallynegative GERD exists although they are the largest group of GERD patients. Population-based cost calculations for all GERD patients, including endoscopynegative patients, remain to be established since future calculations including also mild stages of GERD might argue against the step-down approach in GERD treatment for cost related reasons.35 There is a clear dose–response relationship for treatment with PPIs but from cost calculations it does not seem necessary to start with a higher than standard dose of PPI in GERD treatment.38 For the majority of patients PPI at the standard dose once daily for 4 to 8 weeks is the most appropriate treatment. PPI at a higher dose can be used with benefit in patients not completely healed or symptomfree after 8 weeks or who are known to have disease that is resistant to treatment. Maintenance therapy

There are a number of studies demonstrating that H2-antagonists or a prokinetic monotherapy for maintenance is inferior to a combination of both and that both the monotherapy and the combination are significantly less effective than therapy with PPI. The hierarchy of effectiveness of treatment is

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essentially the same for initial and maintenance therapy in all GERD patients. In long-term treatment of patients without severe esophagitis step down therapy is recommended as soon as symptoms are under control in order to minimize drug related costs. Since data for endoscopynegative GERD and for patients with reflux esophagitis grade A or B have shown relapse rates from 50 to 90% after withdrawal of drug therapy, a withdrawal of any maintenance therapy can not be recommended.39 Since cost optimization does not only include drug related costs but also the costs of repeated endoscopy, step down maintenance therapy should be stepped down to the least costly medication capable of controlling symptoms without repeat endoscopy, which is a low dose or on-demand PPI.40 Symptom relief in maintenance therapy is a reliable predictor of healing of esophagitis, thus the success of step down therapy may be determined by symptom control alone and the Geneval workshop suggests that the reduction to less than two heartburn episodes per week is associated with healing of esophagitis.15 For severe esophagitis (grades C/D) a step down of initial PPI therapy during maintenance is not acceptable since a pharmacotherapy other than full dose PPI is unlikely to prevent relapse of esophagitis in these patients.41 In patients with mild esophagitis or without esophagitis, maintenance therapy may be stepped down to half dose PPI or PPI on demand. General considerations Cost calculations revealed that treatment of GERD with PPI provides the best cost efficacy compared with treatment with other drugs. Interestingly PPI therapy shows 90% healing rates after 8 weeks not only in untreated patients but also in GERD patients unresponsive to high dose H2-antagonist therapy. The approach to minimizing costs in the management of reflux disease by introducing trial PPI therapy without endoscopic evaluation should be left to the experienced practitioner and to date there are no data from controlled studies regarding this procedure. For a long period a ‘step-up’ protocol in GERD treatment was state of the art. The step up regimen started with antacids followed by prokinetics, H2-antagonists and then PPIs. The 1997 Geneval GERD workshop suggested the ‘step-down’ therapy in GERD treatment. Therapy should be started with a PPI and step-down of therapy is suggested when symptoms are effectively controlled or when mucosal lesions are healed.15 There is ongoing debate regarding which drug regimen should be chosen for GERD treatment. Either ‘step-down’ starting with a PPI and eventually converting treatment to a cheaper H2-antagonist when remission is achieved or ‘step-up’ starting with

inexpensive drugs. When choosing the right therapy for each individual patient, the overall direct costs of treatment, which are often higher due to unnecessarily delayed effective therapy with PPIs, should be considered rather than comparing the costs of each individual capsule or tablet. When further calculating indirect costs due to patients’ satisfaction (lost working days) and long-term complications of GERD, the necessity of a fast and sufficient treatment, which should be a PPI, becomes obvious. A step-up regimen might be useful in patients with very mild, intermittent symptoms in the absence of esophageal mucosal injury. When talking about cost calculations, it has to be recognized that although the clinical effectiveness for treatment of GERD appears essentially the same for all available PPIs, the relative cost effectiveness of treatment of patients with GERD will depend on the relative acquisition costs of the PPIs, which vary in each country. Home care Reflux disease in home-care patients is more problematic due to a number of additional difficulties. The diagnostic procedure is often accompanied by a number of technical investigations (pH-monitoring; upper endoscopy) that might present a transport challenge and be limited due to immobility or a lack of patient compliance. Therefore many decisions have to be made on clinical symptoms by the patient and the knowledge of the visiting physician rather than investigation reports. If transportation is only a minor problem, a specialized center should be chosen to avoid unnecessary second visits due to missing investigations or due to missing specialists in treatment of GERD in elderly or home care patients. If home-care patients receive enteral nutrition by a nasogastric or nasojejunal tube, the tubes have to be regarded as predisposing conditions to pathologic reflux and a sufficient treatment with PPI should be initiated. Since home-care medicine is aggravated by a number of difficulties the visiting physician should be aware of the fact that GERD is a common problem and even more so in bedridden patients who might not complain of heartburn. Though PPIs are costly they should be prescribed generously also in home-care patients when GERD is suspected.

CONCLUSION According to its high prevalence GERD is a common problem in daily practice. To date TLESRs (75%) and decreased LESP (20%) are believed to be the major motility disorders underlying GERD. The main symptoms are heartburn and-non-cardiac chest pain. There are powerful medications for GERD

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treatment and endoscopic diagnosis should not be neglected since even minor symptoms could be the first signal for another differential diagnostic disease (e.g. carcinoma). As reflux of acid is regarded to be the major aggressive factor acting on the esophageal mucosa, therapy has concentrated on the blockade or neutralization of gastric acid. However, there is some evidence that prokinetics can also be beneficial in the treatment and prophylaxis of GERD. The various agents currently used for treatment of GERD include mucoprotective substances, antacids, H2blockers and PPIs. Although these drugs are effective, they do not necessarily influence the underlying causes of the disease by improving the esophageal clearance, increasing the LESP or reducing the frequency of TLESRs. To date it seems to be reasonable to combine these drugs with a prokinetic drug to restore the defective motility patterns, but prokinetics probably do not influence the incidence of TLESRs and therefore newer drugs are needed to specifically treat this motility disorder. In acute as well as long-term treatment of reflux esophagitis, treatment with PPI shows the best results compared with other drugs, and also has the best cost-efficacy if the treatment of complications is taken into account. PPI should therefore be the preferred drug in treatment of more severe forms of erosive GERD. References 1 Locke G R, Talley N J, Fett S L et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population study in Olmsted County, Minnesota. Gastroenterology 1997; 112: 1448 –56. 2 Quigley E M M. 24-hour pH monitoring for gastroesophageal reflux disease: already standard but not yet gold? Am J Gastroenterol 1992; 87: 1071–5. 3 Young M, Sanowski R, Talbert G et al. Omeprazole administration as a test for gastroesophageal reflux. Gastroenterology 1992; 102: 192. 4 Johnsson F, Weywadt I, Solhaug J et al. One-week omeprazole treatment in the diagnosis of gastro-esophageal reflux disease. Scand J Gastroenterol 1998; 33: 20. 5 Storr M, Meining A, Allescher H D. Pathophysiology and pharmacological treatment of gastroesophageal reflux disease. Dig Dis 2000; 18: 93–102. 6 Johnston B T, Collins J S, McFarland R J et al. Are esophageal symptoms reflux-related? A study of different scoring systems in a cohort of patients with heartburn. Am J Gastroenterol 1994; 89: 497 – 502. 7 Shi G, des Varannes S B, Scarpignato C et al. Reflux related symptoms in patients with normal esophageal exposure to acid. Gut 1995; 37: 457–64. 8 Gudmundsson K, Johnsson F, Loelsson B. The time pattern of gastroesophageal reflux. Scand J Gastroenterol 1988; 23: 75–9. 9 Meining A, Classen M. The role of diet and lifestyle measures in the pathogenesis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2000; 95: 2692–7. 10 Pehl C, Pfeiffer A, Wendl B et al. Different effects of white and red wine on lower esophageal sphincter pressure and gastroesophageal reflux. Scand J Gastroenterol 1998; 33: 118– 22. 11 Kahrilas P J, Shi G, Manaka M et al. Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology 2000; 118: 688–95.

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