Acid-Suppression Therapy for Gastroesophageal Reflux Disease and the Therapeutic Gap

Pathophysiologic Mechanisms Underlying Gastroesophageal Reflux Disease

A discussion of therapeutic options for management of GERD requires an understanding of the underlying pathophysiology of reflux disease so that relevant therapeutic targets can be identified. Defined as “a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications,” GERD is multifactorial. Anatomic impairment of antireflux defenses, poor clearance of refluxate, compromised mucosal defense mechanisms, slow gastric emptying, underlying motility disturbances, and altered neural sensitivity pathways can all play a role in the generation of troublesome symptoms. Precisely how reflux evolves from a physiologic phenomenon to causing bothersome symptoms and mucosal disease is complex and variable among individuals. At its crux, the presence of a normal esophagogastric junction (EGJ) with a coordinated lower esophageal sphincter (LES) and crural diaphragm (CD) maintains a mechanical barrier, which is indispensable to preservation of normal physiologic function. As such, reflux occurs exclusively during transient lower esophageal sphincter relaxations (TLESRs), is largely restricted to gas, and refluxed fluid is confined to the distal esophagus and rapidly cleared. If there is a disruption to any of the components of the mechanical barrier, normal function may be altered. The presence of a mechanically impaired EGJ, either due to an overt hiatal hernia or disruption of the LES-CD complex, results in an increase in non-TLESR reflux events, poor gas/liquid discrimination during gastric venting, and increased volume and extent of the refluxate leading to regurgitation. Coupled with hypersensitivity, this results in troublesome symptoms. Furthermore, other external factors such as obesity, diet, pregnancy, age, esophageal neuromuscular dysfunction, and trauma can instigate and/or exacerbate these mechanisms.

It is important to note that despite gastric acid secretion being the primary target for pharmacologic therapy, abnormal gastric acid secretion is not a mechanism for pathogenesis of GERD, except in rare cases of true acid hypersecretion as seen with some neuroendocrine tumors. In fact, the level of acid secretion in patients with GERD is similar to that of asymptomatic controls. This highlights one of the main limitations of treatment with PPIs, largely that it does not address the root causes of GERD or the hypersensitivity pathways closely tied to bothersome symptoms.

Management of Gastroesophageal Reflux Disease With Acid-Suppression Therapy

In spite of limitations associated with acid-suppression therapy, their advent has revolutionized GERD treatment. In patients with mild symptoms, on-demand rapid-acting (and short-acting) antacids can be used with or without histamine-2 (H ₂ )-receptor antagonists to achieve adequate symptom response. However, in patients with moderate to severe symptoms or with evidence of mucosal damage, PPIs have become first-line therapy and can be titrated up to twice-a-day dosing for those with an insufficient response to daily dosing. PPIs are so effective in treating esophagitis that definitions of GERD early in the PPI era proposed the inclusion of response (or failure of response) to PPI therapy. Moreover, mucosal manifestations of GERD (except for Barrett metaplasia) can be held in remission with sustained PPI therapy. The problem of refractory mucosal disease has essentially vanished and in its place has emerged the notion of refractory symptoms and syndromes potentially attributable to GERD. By the time a patient is referred to a gastroenterologist for refractory GERD, they have likely been on twice-daily PPI for some time and tried on-demand adjunctive antacid or H ₂ -receptor antagonist therapy. It has become the physician's task to determine whether these are, in fact, refractory patients, or whether there is an alternative diagnosis, such as dyspepsia, functional heartburn, irritable bowel, eosinophilic esophagitis, or a motility disorder as the cause of inadequate response to PPI therapy.

PPI treatment success for potential GERD syndromes is variable, and the best chance for success is in treating those with erosive esophagitis. Typical GERD symptoms (heartburn, regurgitation, and chest pain) also respond relatively well, particularly in patients with esophagitis or with abnormal pH testing off PPI therapy. Atypical symptoms and those with normal pH testing are less likely to respond to PPI therapy and warrant evaluation for other causes before being labeled as PPI nonresponders. There are rare instances of true PPI failures , as defined by persistence of abnormal acid exposure on adequate PPI therapy. In these cases, compliance must be questioned, and optimization of dosage and frequency of PPI therapy can be attempted. In rare cases, reduced bioavailability, rapid metabolism, and PPI resistance can be implicated as a cause for nonresponse, and it is reasonable to switch to a different PPI when such situations are suspected. However, for the majority of patients, the most likely reasons for PPI nonresponse are the absence of GERD as an etiology of their symptoms or persistence of regurgitation and/or hypersensitivity (i.e., not inadequate acid suppression). In partial responders, it appears that increased proximal reflux and hypersensitivity account for the lack of full response. For these reasons, pH testing, either in the form of combined intraluminal pH-impedance monitoring or the radiocapsule technique (Bravo), is a first and crucial step in the evaluation of patients with refractory symptoms, along with exclusion of a symptomatic hiatal hernia. There is continued debate regarding the optimal approach to testing (i.e., on or off therapy and the use of impedance versus pH testing alone), but generally, the chance of establishing a correlation between reflux symptoms and events is greatest when a patient is studied off acid-suppression therapy. Impedance testing can add useful information, particularly when regurgitation is the predominant symptom and nonacid reflux (i.e., adequately acid-suppressed on PPI) is thought to drive the main symptomatology. Thus adequate phenotyping of the PPI nonresponder is critical in identifying appropriate targets for therapy beyond PPIs.

Alternative Pharmacologic and Lifestyle Interventions for Gastroesophageal Reflux Disease

It is common to recommend dietary and lifestyle modifications for patients with symptomatic regurgitation and heartburn, particularly in those with persistent regurgitation on PPI therapy or those with mild symptoms. These alterations can minimize symptoms, but they do little to change the underlying mechanism leading to symptom generation. A more useful recommendation is that of weight loss, particularly in patients with central obesity. From a mechanistic standpoint, obesity promotes GERD by increasing intraabdominal pressure, thereby promoting reflux and the development of a hiatal hernia, and metabolically active visceral fat may also promote Barrett metaplasia via proinflammatory mechanisms. Multiple studies have shown that reductions in body mass index (BMI) and central obesity result in improved GERD symptom control. As such, the importance of weight loss should be highlighted to patients seeking optimization of their GERD management.

Beyond lifestyle modifications and acid-suppression therapy, other medical interventions are available, but their use is limited by side effects and/or minimal efficacy. As adjunctive therapy to PPIs, alginates have been found to have modest benefit in reducing the number of acid reflux episodes and the severity and frequency of heartburn, regurgitation, and nighttime symptoms by creating a pH-neutral raft at the site of the postprandial acid pocket. However, alginate formulations differ between the United States and the world at large, and it is unclear if similar benefit can be achieved from the American preparation, which contains lower concentrations of alginate and higher concentrations of antacid. Prokinetics (e.g., metoclopramide, domperidone, and cisapride), which promote gastric emptying, increase LES pressure, and enhance esophageal clearance, have also been studied as adjunctive therapies, particularly in patients with predominant regurgitation. However, their use has been limited by marginal efficacy and prohibitive safety concerns, including potentially fatal cardiac arrhythmias and irreversible neurologic side effects (tardive dyskinesia). Baclofen, a γ-aminobutyric acid type B (GABA _B ) receptor agonist, has been used to modulate TLESRs, which are, in part, regulated by GABA. Multiple studies have shown that modulating this pathway can lead to improved GERD symptoms and reduction in reflux events, acid exposure, and TLESR rate when compared with placebo. Despite improvement in reflux events and symptoms, use of baclofen is limited by neurologic disturbances, including dizziness, fatigue, and drowsiness. Interestingly, when used at bedtime, the side effect profile is less problematic and may actually aid in reducing nighttime symptoms by improving sleep efficiency. Thus it is reasonable to add baclofen as adjunctive therapy in patients with persistent nighttime symptoms on PPI therapy. Other novel GABA receptor agonists, including lesogaberan and arbaclofen, showed promising results in initial clinical trials, but subsequent phase IIb randomized control studies failed to show sufficient benefit when compared with placebo to warrant further development.

An additional approach to management of refractory GERD symptoms, particularly in patients with predominant hypersensitivity, is to use neuromodulators to target pain-processing pathways and reduce symptom perception. Attempts to target esophageal acid-sensing targets mediated by transient receptor potential cation channel subfamily vanilloid member 1 (TRPV1) receptors, which are activated by acid, capsaicin, and heat and have been implicated in esophageal symptom perception, have not been successful thus far. However, the use of psychotropic agents (particularly low-dose antidepressants), which modulate symptom perception by targeting pain pathways, has yielded encouraging results. There is evidence for both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in modulating these pathways and improving symptoms (and/or quality of life), and these should be considered in patients with a hypersensitivity phenotype. However, note that recent randomized control trials of TCAs have failed to show significant improvements compared with placebo, whereas studies evaluating SSRIs have yielded positive results, suggesting that the latter may be a preferred initial treatment choice.