Pharmacologic management of gastroesophageal reflux disease

The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short-and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.     

Pharmacologic management of gastroesophageal reflux disease

Opinion statement The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short- and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.     

On-demand therapy is a valid strategy in GERD patients: pros and cons

On-demand proton pump inhibitor (PPI) therapy is an attractive option for long-term management of gastroesophageal reflux disease (GERD). Controlled trials in non-erosive reflux disease (NERD) patients have shown sufficient symptom control in most patients with a high rate of willingness to continue treatment and substantial saving on PPI expenditure. However, due to the slow onset of action of PPIs, rescue antacids are often used when symptoms recur and several patients continue to experience some degree of heartburn. On-demand treatment is less cost-saving in patients with esophagitis, and symptomatic/endoscopic relapses occur frequently in severe grades. Data on the prevention of long-term sequelae of on-demand treatment are scarce, only indirect evidence being available. It is suggested that PPI continuous maintenance is more appropriate than on-demand therapy in patients with severe esophagitis, in those with Barrett's esophagus where chronic PPIs may reduce incidence of dysplasia, in uninvestigated elderly patients where esophagitis is more prevalent and it is more frequently complicated with gastrointestinal bleeding and possibly in uninvestigated or NERD patients with frequent clinical relapses. Finally, more appropriate outcome variables should be used in future trials in order to assess efficacy of on-demand treatment adequately.     

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

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 H(2)-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.     

Treatment of gastroesophageal reflux disease in adults: an individualized approach

Until the 1990s, most therapeutic trials in gastroesophageal reflux disease (GERD) focussed upon endoscopic lesions. In fact the correlation between patient symptoms and both the presence and grade of esophagitis is very poor. The classical criteria for the assessment of therapeutic efficacy in GERD have therefore been revised, and there is now a consensus that the relief of symptoms and the long-term control of the disease are the primary aims of therapy for the majority of patients. Proton pump inhibitors (PPIs) represent the mainstay of therapy for patients with non-erosive reflux disease (NERD) as well as esophagitis. Although a stepwise strategy has been recommended in the past, a step-down strategy (starting with a full-dose PPI) appears to be a more cost-effective approach. There are as yet insufficient data to establish the clear superiority of one PPI over others. PPIs have a number of limitations. Symptom relief is significantly inferior in NERD than in erosive esophagitis. The heterogeneity of the NERD group may be one of the most influential factors, but the role of esophageal hypersensitivity has been suggested especially in patients with normal acid exposure. The role of non-acid reflux should also be scrutinized. Long-term control of the disease can be achieved by drug therapy, anti-reflux surgery and now with a variety of endoscopic procedures. The different drug management strategies can be divided into (i) continuous maintenance therapy and (ii) discontinuous therapy which can again be divided into two categories, intermittent and on-demand drug therapy. A case-by-case approach is recommended to determine the personal therapeutic needs and preferences of each individual. Many patients with NERD or mild esophagitis do not require continuous maintenance therapy and recent studies have shown excellent results with different PPI on-demand therapy regimens. Finally when making a choice between different long-term strategies both the clinician and the informed patient have to consider efficacy, safety, tolerability and cost. The potential efficacy of new drugs, especially the GABA(B) agonists and the fast onset acid suppressors, as well as the cost-effectiveness of non-drug strategies (surgery and endoluminal therapies) should be further evaluated.     

Dilated intercellular spaces as a marker of GERD

Gastroesophageal reflux disease (GERD) is typically heralded by the substernal burning pain of heartburn. On endoscopic examination, about one third of GERD subjects with heartburn have erosive disease, and the remainder have nonerosive reflux disease (NERD). Unlike patients with erosive disease, those with NERD (∼ 50%) often do not respond to therapy with proton pump inhibitors (PPIs), raising the question of whether they have NERD and, if they do, whether the cause of their symptoms is similar to those who respond to PPIs. Recently, biopsies established that subjects with heartburn and PPI-responsive NERD, like those with erosive esophagitis, have lesions within the esophageal epithelium known as dilated intercellular space (DIS). In this article, we discuss the physicochemical basis for DIS in acid-injured esophageal epithelium and its significance in GERD. Although DIS is not pathognomic of GERD, it is a marker of a break in the epithelial (junctional) barrier reflecting an increase in paracellular permeability.     

Maintenance therapy of gastroesophageal reflux disease

The aims of treatment of gastroesophageal reflux disease (GERD) are to cure mucosal breaks, control symptoms, and prevent complications (e.g. stricture, Barrett’s esophagus, and esophageal adenocarcinoma). Proton pump inhibitors (PPIs) are known to be the best drugs to cure esophagitis; however, a highrecurrence rate of about 80% was described after the completion of initial therapy. Regretfully, not so many physicians perform maintenance therapy in clinical practice. Histamine H2 receptor antagonists have an insufficient effect in maintenance therapy compared with PPIs; therefore, they could be prescribed for mild reflux esophagitis. Several clinical trials have been conducted to investigate the efficacy of continuous PPI administration maintenance therapy for GERD. Among these trials, recent large-scale studies showed that esomeprazole was equal to or superior to other kinds of PPIs. On the other hand, on-demand PPI studies have been conducted, mainly in patients with nonerosive reflux disease or uninvestigated GERD;however, this strategy was less effective than continuous therapy in many studies. Because on-demand therapy is less expensive, it is worth confirming this strategy in further studies. Studies of maintenance therapy with investigations conducted for as long a period as 5 years have described that PPI maintenance therapy could be considered as effective, safe, and well tolerated.     

Management strategies for gastroesophageal reflux disease

Abstract   In the treatment of gastroesophageal reflux disease (GERD), the most effective treatment option is the use of proton pump inhibitor (PPI), which minimizes the effect of gastric acid on the distal esophagus. Both the step-up and step-down treatment strategies have advantages and disadvantages. Most physicians would like to choose the step-down therapy rather than the step-up therapy. The 'No-step' PPI therapy (i.e. continuous PPI therapy) is another relevant option. After an initial remission, long-term PPI therapy is an appropriate form of maintenance therapy in many patients.
As a treatment plan for non-erosive reflux disease, a standard dose of PPI for 4–8 weeks followed by either the step-down strategy or the on-demand treatment strategy is acceptable. When treating erosive esophagitis, PPI is better than H₂ receptor blockers in healing mucosal breaks and relieving symptoms. Long-term maintenance PPI therapy is reported to be very effective in maintaining the remission of reflux esophagitis for up to 5 years. On-demand PPI is also another good option for a maintenance therapy in erosive esophagitis. In Barrett's esophagus, symptoms seem to be well-controlled with PPIs. Unfortunately, however, PPIs have no effect on the shortening of Barrett's esophagus or in preventing the progression to dysplasia and adenocarcinoma.
In summary, after reviewing existing guidelines a rather simple guideline on the management of GERD is suggested – PPI should be given for 4–8 weeks followed by either on-demand or maintenance PPI therapy according to the clinical severity.     

Functional heartburn and non-erosive reflux disease

Gastroesophageal reflux disease (GERD) is a common disorder in Western countries. For many years our attention has been focused on patients with erosive esophagitis, but in recent times we have realized that endoscopy-negative reflux disease is the most common presentation of this illness, affecting up to 70% of these individuals. Patients with the non-erosive form (NERD) are a heterogeneous group including various subpopulations with different mechanisms for their main symptom of heartburn: reflux of acidic and non-acidic gastric contents, mucosal hypersensitivity, intraesophageal distension by gas, intraduodenal infusion of fat, muscle contractions and psychological abnormalities. As to esophageal acid exposure, patients with NERD can be subdivided into those with abnormal and normal pH testing. The latter group includes patients with a positive correlation between symptoms and reflux events, in whom heartburn can be controlled by proton pump inhibitor (PPI) therapy. According to the recent Rome III criteria, they are still in the realm of GERD. An additional group is called functional heartburn, because this typical symptom is associated neither with an abnormal pH test nor with a positive symptom index. Their response to PPIs is very disappointing. Therefore, there is an increasing consensus on the fact that they do not have GERD and should be treated with drugs other than PPIs.     

Potential options to optimize therapy of gastroesophageal reflux disease with proton pump inhibitors

Proton pump inhibitors (PPIs) are antisecretory agents that are widely used in the short- and long-term management of gastroesophageal reflux disease (GERD) to relieve symptoms, heal esophagitis, and prevent complications, such as strictures and Barrett's esophagus. The total healthcare costs of GERD are high, especially for maintenance treatment. Therefore, the choice of cost-effective therapeutic options is an ineluctable challenge for public health authorities, third-party payers, and patients. In some European Union countries, a recent trend of public health authorities is to promote the choice of less expensive PPIs, regardless of their antisecretory potency--this in spite of the evidence that newer PPIs provide superior symptom relief and esophageal erosion healing compared to earlier drugs. Several large clinical trials have demonstrated the superiority of esomeprazole over other PPIs at standard doses for both initial and continuous maintenance therapy in patients with moderate/severe erosive esophagitis. The non-erosive GERD poses a major challenge as this condition appears more frequently to be less responsive to PPIs. The use of PPIs with the strongest antisecretory properties might reveal to be more adequate and cost-effective, particularly for this indication.     

Effectiveness of proton pump inhibitors in nonerosive reflux disease.

BACKGROUND & AIMS: Little information is available about the efficacy of proton pump inhibitors (PPIs) in patients with nonerosive reflux disease (NERD). We aimed to synthesize available data and determine the effectiveness of PPIs on symptom resolution in patients with NERD. METHODS: A systematic review of the literature identified studies reporting the effects of PPIs in patients with NERD. Heartburn resolution data were pooled across studies. The effectiveness of PPI therapy in inducing complete heartburn resolution was compared in patients with NERD vs. erosive esophagitis (EE). RESULTS: Seven trials evaluating heartburn resolution in NERD were identified. Higher proportions of patients reported achieving sufficient heartburn resolution compared with complete heartburn resolution. The effect of PPIs on sufficient heartburn resolution was observed sooner than was complete heartburn resolution. Therapeutic gain of PPI therapy over placebo ranged from 30% to 35% for sufficient heartburn control and from 25% to 30% for complete heartburn control. Pooled response rates at 4 weeks were significantly higher for patients with EE compared with NERD (56% vs. 37%, P < 0.0001). CONCLUSIONS: PPIs provide a more modest therapeutic gain in patients with NERD as compared with those with EE. A trend in increased therapeutic gain for NERD patients was shown throughout the 4 weeks, suggesting that 4 weeks of follow-up evaluation may be insufficient to show full therapeutic gain in this patient population.     

Sleep dysfunction in patients with GERD: erosive versus nonerosive reflux disease

BACKGROUND: Sleep disturbance has been observed in patients with gastroesophageal reflux disease (GERD), but very few studies have further characterized sleep quality in patients with nonerosive esophageal reflux disease (NERD). This study was undertaken to investigate whether there are differences in sleep quality among patients with erosive esophagitis, NERD, and control subjects. METHODS: We performed symptom severity scoring and upper GI endoscopy in 20 healthy control subjects and 35 GERD patients, including 17 with NERD and 18 with erosive esophagitis. Sleep quality was measured by using Pittsburgh Sleep Quality Index (PSQI). RESULTS: Sleep disturbance was noted in 11 of 17 NERD patients and 12 of 18 patients with erosive esophagitis (P = NS) but none of healthy control subjects. The patient groups, erosive esophagitis and NERD, had greater PSQI scores compared with healthy control subjects (both P < 0.05). Both groups had similar median PSQI score (5.5 vs 6.0; NERD vs erosive esophagitis; P = NS). There was no significant correlation between reflux symptom severity score and PSQI score. CONCLUSIONS: Despite no difference in sleep quality between erosive esophagitis and NERD, NERD can have a significant impact on sleep comparable to erosive esophagitis. It is suggested that NERD should be treated aggressively and at least similarly to erosive esophagitis.     

The proton pump inhibitor test and the diagnosis of gastroesophageal reflux disease

There continues to be significant controversy related to diagnostic testing for gastroesophageal reflux disease (GERD). Symptoms of GERD may be associated with physiologic esophageal acid exposure measured by intraesophageal pH monitoring or pH-impedance monitoring, and a significant percentage of patients with abnormal esophageal acid (or weak acid) exposure have no or minimal clinical symptoms of reflux. On the other hand, endoscopic lesions are only present in a minority of GERD patients. In clinical practice, presumptive diagnosis of GERD is reasonably assumed by the substantial reduction or elimination of suspected reflux symptoms during the therapeutic trial of acid reduction therapy, the so-called proton pump inhibitor (PPI) test. We aimed to assess the optimal cutoff value and duration of this test in GERD patients with and without esophagitis. We conducted a prospective study of 544 patients, endoscopically investigated and treated for 2 weeks with PPIs at double dose, and for an additional 3 months at standard dose. The status of the patient at the end of the study was used as an independent diagnostic standard. We found esophagitis present in 55.8% and absent in 44.2% of patients (corresponding to a diagnosis of nonerosive reflux disease [NERD]). The test was positive in 89.7–97.8% of the patients according to the cutoff or duration of the test used. The sensitivity of the PPI test was excellent, ranging from 95.5 to 98.8%, whereas the specificity was poor, not exceeding 36.3%. Erosive esophagitis patients responded more favorably to the PPI test and subsequent PPI therapy compared with NERD patients. In conclusion, the PPI test is a sensitive but less specific test. Its optimal duration is 1 week, and the optimal cutoff value is a decrease of heartburn score of more than 75%. NERD patients respond less satisfactorily to PPIs, even when functional heartburn patients are excluded and only ‘true’ NERD patients are considered.     

Esomeprazole versus other proton pump inhibitors in erosive esophagitis: a meta-analysis of randomized clinical trials.

BACKGROUND & AIMS: There are limited data comparing the effectiveness of available proton pump inhibitors (PPIs) in erosive esophagitis (EE). We performed a meta-analysis to calculate the pooled effect of esomeprazole on healing rates, symptom relief, and adverse events versus competing PPIs in EE. METHODS: We performed a structured electronic search of MEDLINE and EMBASE and reviewed published abstracts to identify English-language, randomized clinical trials from 1995-2005, comparing rates of endoscopic healing, symptom relief, and adverse events with esomeprazole versus alternative PPIs in the treatment of gastroesophageal reflux disease (GERD)/EE. We then performed meta-analysis to compare the relative risk (RR) of EE healing, symptom relief, and adverse events between study arms and calculated the absolute risk reduction and number needed to treat (NNT) for each outcome. RESULTS: Meta-analysis was performed on 10 studies (n=15,316). At 8 weeks, there was a 5% (RR, 1.05; 95% confidence interval, 1.02-1.08) relative increase in the probability of healing of EE with esomeprazole, yielding an absolute risk reduction of 4% and NNT of 25. The calculated NNTs by Los Angeles grade of EE (grades A-D) were 50, 33, 14, and 8, respectively. Last, esomeprazole conferred an 8% (RR, 1.08; 95% confidence interval, 1.05-1.11) relative increase in the probability of GERD symptom relief at 4 weeks. CONCLUSIONS: As compared with other PPIs, esomeprazole confers a statistically significant improvement, yet, clinically, only a modest overall benefit in 8-week healing and symptom relief in all-comers with EE. The clinical benefit of esomeprazole appears negligible in less severe erosive disease but might be important in more severe disease.     

Pathophysiology, diagnosis and treatment of non-erosive reflux disease (NERD)

Up to 70% of patients with typical symptoms of gastroesophageal reflux disease (GERD) have neither definite endoscopic oesophageal breaks nor Barrett's oesophagus at upper endoscopy. These patients suffer from non-erosive reflux disease (NERD), also termed endoscopy-negative reflux disease or symptomatic GERD. NERD patients appear as a heterogeneous population with multiple and substantially different mechanisms implicated in the genesis of symptoms. In fact, patients with NERD may be divided into 3 groups on the basis of 24-hour pH monitoring: 1) patients with an abnormal acid exposure time (AET); 2) patients who demonstrate a normal AET, but in whom symptoms and reflux events are significantly correlated (hypersensitive oesophagus) and 3) patients with typical reflux symptoms but in whom all parameters of the pH study are normal. There is no gold standard for the diagnosis of NERD but a well-taken history can be, usually, sufficient to confirm the diagnosis and begin therapy. Thus, the more sensitive tool for the diagnosis of NERD is proton pump-inhibitor (PPI) test. The aims of NERD treatment are: symptoms relieve, restore quality of life and maintain clinical remission. Proton pump-inhibitors (PPIs) in full doses represent the treatment of choice of NERD patients, even if overall, clinical trials showed a lower efficacy in symptoms control when compared to patients with erosive oesophagitis. Patients with NERD often need long-term therapy for symptoms control. 'On demand' PPI therapy has been considered as the most cost-effective strategy for the long-term treatment of NERD. In conclusion, many data indicate that NERD is a disorder in its own right that shares symptoms with other GERD groups. However further studies are needed to better define the natural history and improve the treatment of this disorder.     

"Refractory GERD": acid, nonacid, or not GERD?

Gastroesophageal reflux disease (GERD) is a common condition with 44% of Americans surveyed reporting heartburn at least once a month and 20% once a week (1, 2). However, despite major advances in our understanding of this disease, management of GERD is still a challenge. Proton pump inhibitors (PPIs) are more effective than H2-receptor antagonists (H2RA) in the initial healing of erosive esophagitis, which provide symptom relief and maintenance (3). Due to its established efficacy and safety, PPI treatment is used as the initial "test" in diagnosing GERD in the absence of bleeding, anemia, weight loss, or dysphagia. A single dose of PPI provides adequate symptom relief in most patients; however, dose escalation to twice a day may be needed in some. Patients unresponsive to PPI therapy are often labeled as having "refractory GERD." However, this term is poorly defined and has a different meaning in different countries. More importantly, the cause of "refractory GERD" is poorly understood.     

Mechanisms of heartburn

Heartburn is a typical symptom of GERD. The spectrum of diseases associated with GERD includes reflux esophagitis, Barrett's esophagus and nonerosive reflux disease (NERD). Although acid reflux is the classic cause of heartburn in patients with erosive esophagitis, the relationship between acid and heartburn is far from clear, especially in patients with NERD. Strong evidence exists that weakly acidic reflux and/or non-acid-related events have a significant role in the generation of heartburn. In addition to the role of nonacidic refluxate components, activation of mechanoreceptors and chemoreceptors, and a possible role for central and peripheral sensitization, has been described. Although patients with erosive esophagitis respond well to acid-suppressive therapy, the same does not hold true for those with NERD. NERD represents a major clinical problem, and its management remains a challenge. Discussion of NERD focuses on the mechanisms that cause chest pain in this subgroup of patients. Improved understanding of the pathogenesis underlying heartburn in patients with GERD, in particular those with NERD, will shape our understanding of this condition. Such understanding will serve as a platform for further research and allow additional therapies to be developed for this increasingly encountered clinical condition.     

Proton pump inhibitor resistance,the real challenge in gastro-esophageal reflux disease

Gastro-esophageal reflux disease(GERD)is one of the most prevalent chronic diseases.Although proton pump inhibitors(PPIs)represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief,several studies have shown that up to 40%of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily.Several mechanisms have been proposed as involved in PPIs resistance,including ineffective control of gastric acid secretion,esophageal hypersensitivity,ultrastructural and functional changes in the esophageal epithelium.The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation,upper endoscopy,esophageal manometry and ambulatory pH-impedance monitoring,which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn.Treatment has been primarily based on doubling the PPI dose or switching to another PPI.Patients with proven disease,not responding to PPI twice daily,are eligible for anti-reflux surgery.     

Nonerosive reflux disease

Nonerosive reflux disease (NERD) is the most common phenotype of gastroesophageal reflux disease. By definition, patients with NERD have typical reflux symptoms caused by the intraesophageal reflux of gastric contents but have no visible esophageal mucosal injury. This is in contrast to patients with erosive reflux disease (ERD) or Barrett's esophagus (BE) who have obvious esophageal mucosal injury on endosco-py. Only 50% of patients with NERD have pathologic esophageal acid exposure as detected on 24-h pH monitoring. NERD patients with physiologic esophageal acid exposure and good temporal correlation of symptoms with reflux events are considered to have esophageal hypersensitivity, while patients with no symptom-reflux correlation are considered to have functional heartburn. It is possible yet uncommon for NERD to progress to severe ERD (i.e. LA Grade C or D) or BE. Patients with NERD and pathologic esophageal acid exposure have motor dysfunction and acid reflux abnormalities that are similar to patients with ERD and BE, whereas NERD patients with physiologic esophageal acid exposure have minimal abnormalities and are not much different than healthy controls. The pathological feature most indicative of NERD is the presence of dilated intercellular spaces within squamous epithelium, an ultrastructural abnormality readily identified on transmission electron microscopy but also on light microscopy. A symptomatic response to an empiric trial of high-dose proton pump inhibitor (PPI) therapy is a simple and useful strategy to establish the diagnosis of NERD, although histology and pH monitoring may be useful in confirming the diagnosis. Patients with NERD suffer similar decrements in quality of life as do patients with erosive esophagitis. Therapy is aimed at eliminating or reducing symptoms and improving quality of life. PPIs are the most effective agents for the treatment of NERD although they are less effective in providing symptom relief than in patients with erosive esophagitis. Laparoscopic antireflux surgery is an effective therapy for selected patients with NERD and outcomes are better when performed in high volume centers.     

A critical assessment of the current status of non-erosive reflux disease

Non-erosive reflux disease (NERD) has assumed increasing prominence in studies of gastroesophageal reflux disease (GERD), but it remains a challenge to define NERD precisely and to define its place in the investigation and treatment of GERD. Most simply, NERD may be defined as GERD in an individual who has no evidence of erosions at endoscopy. Unfortunately, the characteristic symptoms of GERD--heartburn and regurgitation--are insufficient to identify all GERD patients and, hence, the diagnosis of NERD is hampered by the lack of clear criteria for the symptomatic diagnosis of GERD. The diagnosis of NERD is hampered further by limited interobserver agreement on the endoscopic diagnosis of erosive esophagitis and by the fact that endoscopy is often performed soon after patients have discontinued therapy. Improvements in endoscopic technology will increase the likelihood of identifying small erosions or other reflux-related lesions; however, this will increase the proportion of patients considered to have erosive esophagitis without defining precisely what constitutes NERD. It is important to recognize that NERD is but one manifestation of GERD and that it, like other manifestations of GERD, is associated with a marked diminution in patients' quality of life. However, this recognition apart, there seems to be little practical benefit or understanding to be gained in clinical practice or clinical research from considering NERD as a distinct entity or from studying NERD patients in isolation. Advances in understanding the pathogenesis of GERD and its symptoms may be better served by categorizing GERD with respect to the spectrum of its histologic, functional, endoscopic and symptomatic manifestations rather than by studying NERD, a manifestation that is characterized solely by the absence of esophageal erosions.