Introduction

Gastroesophageal reflux disease (GERD) is a clinical syndrome that develops when the reflux of stomach contents into the esophagus, oral cavity, and/or lung causes troublesome symptoms and/or complications [1]. Heartburn, defined as a retrosternal burning sensation, and regurgitation, defined as the perception of flow of refluxed gastric contents into the mouth or hypopharynx, are the characteristic symptoms of GERD and are sufficiently descriptive to be diagnostic without endoscopy. GERD may be further classified based on the presence or absence of esophageal erosions on endoscopic evaluation as erosive reflux disease (ERD) or non-erosive reflux disease (NERD), respectively [1]. GERD-induced esophageal injury may lead to complications including esophageal stricture, Barrett’s esophagus, and rarely esophageal adenocarcinoma. The spectrum of GERD-related symptoms also includes extra-esophageal manifestations such as chronic cough, hoarseness, asthma, and dental erosions [1]. The prevalence of GERD in Western societies has been estimated at 10–20%, whereas in Asia the prevalence is estimated to be less than 5% [2]. It is estimated that more than 50 million Americans experience heartburn two or more days per week [3]. The burden of GERD-related symptoms negatively affects patient quality of life, and symptoms occurring at least twice weekly have been associated with an increase in work absenteeism, a decrease in productivity and physical functioning, and low scores on sleep scales [4]. The management of patients with chronic GERD is aimed at reducing symptoms, improving quality of life, promoting healing and maintenance of healed erosive esophagitis, and preventing complications. This review will provide an overview of the current medical management options for patients with GERD (Table 1). As empiric therapy of uninvestigated GERD is much more common in the clinical setting, the following sections discuss management options for empiric therapy unless specifically noted otherwise.

Table 1 Options for medical management of patients with gastroesophageal reflux disease
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Lifestyle modification (Table 2)

Lifestyle interventions are frequently the initial therapeutic approach to provide relief of mild, infrequent GERD symptoms. This approach relies on counseling patients regarding modifiable factors that can provoke or exacerbate GERD symptoms by decreasing esophageal acid exposure. These recommendations include weight loss, head-of-bed (HOB) elevation, tobacco and alcohol cessation, avoidance of late-night meals, and cessation of foods that can potentially aggravate reflux symptoms such as caffeine, coffee, chocolate, carbonated beverages, spicy foods, and foods high in acid or fat [5].

Table 2 Effect of lifestyle modification on esophageal physiology and GERD symptoms
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Although these lifestyle modifications are frequently recommended, the data supporting many of these recommendations are weak [6]. Despite the potential benefits of dietary modification, no studies to date have demonstrated improvement in GERD symptoms with cessation of coffee, caffeine, chocolate, spicy foods, or fatty foods [5]. Likewise, tobacco and alcohol cessation have not been shown to reduce GERD symptoms [6]. Although data suggest that carbonation lowers LES pressure, a recent systematic review found insufficient evidence to conclude that the consumption of carbonated beverages causes or exacerbates GERD symptoms [7]. Avoiding meals before bedtime can reduce supine gastroesophageal reflux, but a beneficial effect on GERD symptoms has not been demonstrated [8]. HOB elevation during sleep can improve GERD symptoms and distal esophageal acid exposure as a result of improved esophageal clearance rather than a reduction in the number of reflux events [9, 10]. The association between increasing body mass index (BMI) and GERD symptoms has been well established [11–13]. Even modest weight gain in subjects with a normal BMI has been associated with the development of GERD [11], and weight loss has been correlated with a reduction in GERD symptoms [12, 14]. A recent prospective cohort study of overweight and obese subjects demonstrated a significant reduction in GERD symptom scores in men who achieved ≥10% body weight loss and in women who achieved ≥5% body weight loss [15]. Lifestyle modifications can continue to be recommended as initial therapy for mild, infrequent GERD symptoms, but their role in moderate or severe GERD remains unproven.

Pharmacologic therapy

Pharmacologic agents for patients with persistent symptoms despite lifestyle interventions include non-absorbable agents (antacids and alginate formulations), histamine-2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), prokinetic agents, and inhibitors of transient lower esophageal sphincter relaxations (TLESRs). The initial approach to pharmacologic therapy would ideally be based on the presence or absence of reflux esophagitis; however, endoscopic evaluation of all patients with GERD symptoms is impractical and unjustifiable given its high prevalence and low morbidity [16].

Antacids

Antacids have been available over-the-counter for many years and remain frequently used to treat symptomatic GERD, despite the introduction of acid-suppressing medications [17]. Antacids comprise a group of inorganic, relatively insoluble salts of aluminum, calcium, magnesium, or sodium [18]. The previous belief that antacids work by raising the pH of gastric contents, which effectively increases the pH of the esophageal refluxate, has been challenged by more recent studies demonstrating that antacids relieve heartburn by neutralizing acid within the esophagus and exert no significant effect on intragastric pH [19]. While antacids can provide prompt and effective relief of heartburn, the effect is often short-lived. The lack of gastric acid neutralization allows repeated exposure of acidic contents to the esophagus with each subsequent reflux episode and leads to recurrent heartburn symptoms [17]. Despite their widespread use, scientific evidence supporting the use of antacids to treat GERD remains limited. Three studies in the 1980s compared antacids with placebo for the treatment of GERD [20–22]. Two studies evaluated the effect of antacids on the healing rates of esophagitis and found no improvement compared to placebo [21, 22]. Two studies found an improvement in symptoms with antacids compared to placebo, though in only one study was the effect significant [20, 21]. Antacids remain a treatment option for patients with mild, infrequent symptoms (<weekly) and may provide adjunctive benefit in patients with persistent symptoms despite acid-suppressing therapy.

Alginate

An alternative approach to acid suppression or neutralization in the treatment of symptomatic GERD is to impede the flow of refluxate into the esophagus. Symptomatic acid reflux commonly occurs after eating, despite the rise in gastric pH as a result of the buffering effect of food [23]. The recent discovery of the acid pocket, an area of relatively unbuffered, highly acidic secretion localized to the proximal stomach post-prandially, likely explains the discrepancy between the relatively high intragastric pH and low pH of refluxate observed after eating [24, 25]. Alginates are natural polysaccharide polymers that precipitate to form a low-density viscous gel of near-neutral pH on contact with gastric acid [26, 27]. The alginate gel floats on top of the gastric contents, displacing the acid pocket away from the gastroesophageal junction, and creates a mechanical barrier (“raft”) to reduce reflux for up to 4 h after ingestion [28]. Imaging studies have confirmed that alginate rafts localize to the acid pocket and significantly reduce reflux compared to non-raft-forming antacids [26, 29]. Antacid formulations with alginate are significantly more likely than placebo or antacids but less likely than PPI or H2RA to achieve resolution of GERD symptoms [30]. Alginate–antacid formulations, typically marketed under the brand name Gaviscon, should be considered an alternative therapy to other antacids in patients with infrequent (<weekly), mild symptoms, especially if symptoms occur predominantly after eating, or breakthrough symptoms on anti-secretory agents.

Histamine-2 receptor antagonists, proton pump inhibitors, and prokinetics

In patients with frequent (≥weekly) or more bothersome symptoms, antacids and alginates are generally considered inadequate therapy to achieve treatment goals. H2RAs and PPIs work by decreasing gastric acid production rather than through acid neutralization or inhibition of reflux. These medications have been extensively studied in randomized controlled trials and meta-analyses for the treatment of GERD. In multiple head-to-head trials, PPIs have consistently proven superior to H2RAs in resolution of GERD symptoms, healing of esophagitis, prevention of symptom relapse at 6 months, and maintenance of symptom remission beyond 6 months [31]. A Cochrane systematic review of 32 trials with over 9700 participants found that PPI therapy was superior to H2RAs and prokinetics for the relief of heartburn in patients with non-erosive disease [32]. Meta-analyses have not demonstrated a clinically significant difference in the improvement of symptom relief between different PPIs [33]. Multiple studies have demonstrated the superior healing rates and decreased relapse rates with PPI therapy compared to H2RA or placebo for the treatment of ERD [16, 34, 35]. Given these findings, expert consensus guidelines recommend PPI therapy be used to treat all patients with erosive esophagitis [5].

While PPI therapy provides the highest level of symptom relief, healing of esophagitis, and maintenance of symptom remission, considerable controversy exists regarding the optimal initial strategy for the pharmacologic treatment of uninvestigated GERD. Proponents of a “step-up” approach suggest that beginning with less potent, less expensive medications and reserving more potent, more expensive medications if initial therapies fail, is more practical and economical [36]. In contrast, advocates of “step down” therapy argue that starting with a PPI and switching to a less expensive medication only after symptom resolution provides better prompt symptom resolution in a cost-effective manner, with PPI-free remission rates of 50–80% without sacrificing quality of life [16, 37, 38].

Overall, PPI therapy provides symptom relief in approximately 70–80% of patients with ERD and 50–60% with NERD [5]. Multiple risk factors have been associated with lack of symptom control including presence of hiatal hernia, extra-esophageal manifestations, longer duration of symptoms, obesity, and poor medication compliance [39]. The efficacy of acid suppression with PPI therapy is influenced by the timing of administration in relation to eating, with the exception of dexlansoprazole [40]. Maximal acid suppression occurs when PPIs are taken prior to eating, optimally 15–30 min prior to a meal [41]. Despite this recommendation, a recent study found that 54% of patients used PPIs suboptimally (>60 min prior to meals, after meals, as needed, or at bedtime) [42]. Given the high rate of suboptimal PPI dosing, patients with refractory symptoms must be instructed on the optimal administration of PPIs before recommending adjustments in therapy [5]. Despite limited data to support the practice [43], switching between PPIs is commonly tried in clinical practice when symptom control is suboptimal. Increasing the frequency of PPI dosing from once to twice daily dosing in patients with refractory symptoms can result in significant symptomatic improvement; however, only a minority of patients (22–26%) achieve complete resolution of symptoms [44].

In patients with a partial response to twice daily PPI therapy, the addition of an H2RA may improve acid control by decreasing nocturnal acid breakthrough [45–47]. Considerable controversy exists regarding the duration of this effect, with studies demonstrating that tachyphylaxis to H2RA is common after 1 week of therapy [46], whereas other studies found tachyphylaxis developed in a minority (<30%) of patients after 4 weeks of combination therapy [45, 47]. The addition of bedtime H2RA therapy to daytime PPI therapy may be considered in selected patients with evidence of ongoing nocturnal reflux; however, on-demand dosing may be required in patients who develop tachyphylaxis.

Prokinetic medications theoretically improve the esophageal clearance of refluxate by augmenting esophageal peristalsis [48]. Metoclopramide, a centrally acting dopamine receptor antagonist, is the only prokinetic currently available in the USA, and increases LES pressure in healthy subjects and in patients with GERD [49]. Despite these effects, studies of metoclopramide have failed to show improvement in esophageal acid exposure, symptom control, or healing of esophagitis, either as exclusive or adjunctive therapy [50, 51]. Metoclopramide may cause CNS side effects including drowsiness, agitation, irritability, depression, dystonic reaction, and rarely (<1% of patients) tardive dyskinesia [52]. Given its lack of proven efficacy and worrisome side-effect profile, metoclopramide is currently not a recommended treatment of GERD in the absence of coexisting gastroparesis [5].

Patients with refractory symptoms despite PPI therapy warrant further investigation [5]. Those with typical esophageal symptoms should be evaluated with upper endoscopy to exclude non-reflux-related esophageal disorders, principally eosinophilic esophagitis, and to identify patients with persistent erosive disease. Not all patients with symptoms refractory to PPI therapy will have GERD, and therefore, it is important to differentiate those with persistent reflux as the etiology of ongoing symptoms from those with non-reflux-related causes. Reflux monitoring with pH or pH-impedance testing should be performed in patients who have had a negative endoscopic evaluation [5]. If pathologic acid exposure is not documented in patients who undergo testing while off anti-secretory therapy, the underlying diagnosis of GERD should be reconsidered. Patients who undergo testing while on anti-secretory therapy with evidence of ongoing reflux (acid or non-acid) and strong symptom correlation require a discussion regarding the treatment options available for refractory GERD, which may include surgical management. Detailing the rationale and interpretation of reflux testing on versus off acid suppressing therapy is beyond the scope of the current review.

Inhibitors of transient lower esophageal sphincter relaxations (TLESRs)

TLESRs are the most common mechanism of gastroesophageal reflux [53–55]. While PPI therapy significantly reduces esophageal acid exposure, PPIs do not change the absolute number of reflux episodes [56]. Persistent symptoms in patients on PPIs may result from weakly acidic (pH > 4) or weakly alkaline refluxate [56]. In these patients, further reduction of esophageal acid exposure is unlikely to occur with increased gastric acid suppression. A shift toward inhibiting TLESRs to reduce reflux may be an alternative approach to improve symptoms. Multiple neurotransmitters and receptors have been implicated in the modulation of TLESRs including γ-aminobutyric acid (GABA), metabotropic glutamate receptor 5 (mGluR5), nitric oxide, opioids, anticholinergic agents, cholecystokinin, and cannabinoid receptors of which GABA and mGluR5 appear to represent the dominant signaling pathways [57, 58]. Baclofen, a GABA-B agonist, is the only medication currently available that has demonstrated efficacy in reducing TLESRs and gastroesophageal reflux [59–61]. However, baclofen has not been found to greatly improve GERD symptoms [59, 62]. A trial of baclofen at a dosage of 5–20 mg three times daily before meals may be considered in patients with positive symptom correlation to documented reflux despite PPI therapy [5, 48]. Its use is often limited by common side effects, including nausea, sedation, dizziness, and fatigue [48].

Summary

The initial medical management of GERD is dictated by symptom frequency and severity with treatment focused on improving symptoms and reducing complications. Patients with mild, infrequent symptoms should be counseled regarding lifestyle modification including weight loss, head-of-bed elevation, and avoidance of late-night meals. Antacids alone or in combination with alginate can provide fast symptomatic relief but are not appropriate for patients with frequent or severe symptoms. Antacid formulations containing alginate are more effective at treating postprandial symptoms than antacids alone. The mainstay of pharmacologic therapy for GERD remains acid suppression with PPIs, which provide superior symptom control and healing of erosive disease compared to H2RAs. In patients with erosive disease, PPI therapy is mandatory. Whether a “step up” or “step down” strategy is used in the initial treatment of uninvestigated GERD, maintenance therapy should use the least potent acid-suppressing regimen that controls symptoms. In patients with a partial response to PPI therapy, the addition of H2RA may be considered at bedtime if nocturnal symptoms are present. Prokinetic agents have no role in the management of GERD in the absence of coexisting gastroparesis. While there are limited options available for PPI refractory GERD, inhibition of TLESRs with the use of baclofen or surgical management may be considered in carefully selected patients. Additional studies are needed to gain further insight into the pathophysiology of GERD to discover new therapeutic targets for drug development in the future.