#94902: Gastroesophageal Reflux Disease in Adults

Hoarseness occurs more frequently in patients with weekly GERD symptoms. Patients with chronic laryngitis often lack typical GERD symptoms of heartburn and regurgitation, but esophageal inflammation is present in 19% to 40%. Abnormal esophageal presence of acidic reflux was found in 55% to 79% of patients with chronic hoarseness and 18% to 70% of those with posterior laryngitis [16,19,20,21].

GERD is the third most common cause of chronic cough in adults, after postnasal drip and asthma. The frequency of chronic cough in patients with no, infrequent, or frequent GERD symptoms is 11%, 15%, and 22%, respectively. GERD may be the primary cause in 10% of patients with chronic cough [16,17,22].

Non-cardiac chest pain is recurrent chest pain that can be difficult to distinguish from ischemic heart pain, diagnosed after a cardiac cause is excluded. GERD is the most important esophageal cause of non-cardiac chest pain [16]. In a community study, 53% of patients with non-cardiac chest pain experienced heartburn and 58% experienced acid regurgitation. Non-cardiac chest pain was reported by 37% of patients with at least weekly heartburn symptoms, 30.7% with infrequent heartburn (less than weekly), and 7.9% of those without GERD symptoms. Around 50% of patients with non-cardiac chest pain show abnormal esophageal acid exposure [23].

GERD is present in 50% to 80% of adults with asthma, and 65% to 77% of adults with asthma report GERD-related symptoms [24]. Roughly 35% of patients with asthma show abnormal esophageal pH [25]. In 341 patients with severe or difficult-to-treat asthma despite standard treatment, 46.3% were diagnosed with GERD at 12- to 15-year follow-up [26]. The prevalence of asthma in patients with GERD increased over five years, from 4.5% to 7.8% [27].

The prevalence of functional chest pain is unknown and is largely inferred from studies of non-cardiac chest pain. Population surveys estimate the lifetime prevalence of functional chest pain at 19% to 33%, but this includes chest pain from GERD, eosinophilic esophagitis, and esophageal motor disorders [23,28].

Within non-cardiac chest pain cohorts, 50% to 60% have GERD, 15% to 18% have esophageal dysmotility, and 32% to 35% have functional chest pain. The prevalence appears gender-equal but is higher in patients younger than 55 years of age [29].

The prevalence of heartburn is difficult to estimate because its diagnosis is linked to ambulatory reflux testing and PPI response, both of which have limited ability to differentiate from GERD [30]. As many as 21% to 39% of patients with heartburn refractory to PPI undergoing pH-impedance monitoring fulfill the criteria for functional heartburn [31]. Up to 70% of patients with heartburn have normal endoscopy findings and are categorized by the presence or absence of abnormal acid exposure, symptom-reflux association, and PPI response [32]. Functional heartburn is found in roughly 50% of PPI nonresponders and 25% of PPI responders [7,33].

The epidemiology of reflux hypersensitivity is unknown but can be inferred from the NERD population. An estimated 37% to 60% of patients with NERD have normal esophageal presence of acidic reflux (measured by ambulatory pH testing) off their PPIs. Less than 10% show acid sensitivity [7,34,35]. Reflux hypersensitivity is very common and together with functional heartburn accounts for more than 90% of cases of heartburn refractory to twice-daily PPI. Additionally, it affects primarily young to middle-aged women, commonly overlaps with another FGID, and often is associated with some type of psychological comorbidity [36].

Functional dysphagia is considered the least prevalent functional esophageal disorder, but the true prevalence is unknown. A population survey of functional disorders estimated that 7% to 8% of dysphagia was unaccounted for by exclusionary criteria, and another study found 0.6% of patients with functional GI disorder complained of frequent dysphagia [7,37,38].

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for anti-inflammatory, analgesic, and antipyretic effects. NSAIDs act by inhibiting cyclo-oxygenase-1 and -2 (COX-1 and COX-2). COX is an enzyme that converts arachidonic acid to inflammatory mediators (e.g., prostaglandins, thromboxanes). By blocking this conversion, NSAIDs reduce pain and inflammation [61]. However, prostaglandins are important for GI protection and other normal physiologic processes. NSAIDs are associated with adverse GI effects ranging from dyspepsia, heartburn, and abdominal discomfort, to peptic ulcer with life-threatening or fatal complications from upper GI bleeding and perforation. Symptoms are unreliable indicators of upper GI mucosal damage, and risks are similar for short-course and long-term NSAID therapy. NSAIDs are also associated with cardiovascular, hepatic, and renal adverse effects [62].

Combining NSAIDs and selective serotonin reuptake inhibitors (SSRIs) increases the risk of upper GI bleeding greater than either drug alone. NSAIDs with SSRIs can markedly decrease serotonin platelet content, which impairs platelet aggregation in response to injury. This can prolong bleeding time, increase gastric acid secretion, and potentially promote ulcers and perforation. Combining SSRIs and NSAIDs should be avoided, if possible [63,64,65,66].

The recommended approach to mitigate upper GI risk is switching to or initiating the COX-2 inhibitor-dominant NSAID celecoxib and starting a PPI [67]. PPIs can reduce or resolve GERD-like symptoms of heartburn and dyspepsia and are more effective than histamine-2 receptor antagonists (H2RAs). Treatment adherence should be assessed, especially in the elderly [62].

NSAID-induced GI toxicity can also involve non-gastric intestinal ulceration and bleeding. PPIs do not prevent, and may aggravate, intestinal damage by inducing gut dysbiosis. Celecoxib has better intestinal tolerability than other NSAIDs, but this advantage is partially lost by adding a PPI [68,69,70]. Given the GI and cardiovascular risk profiles of NSAIDs, the appropriateness of NSAID prescriptions should be assessed. These agents are indicated to control inflammation and pain, rather than pain alone [62].

Increased GERD symptoms are also associated with beta-adrenergic agonists, anticholinergics, nitrates, phosphodiesterase type 5 (PDE5) inhibitors, theophylline, calcium channel blockers, and benzodiazepines [61].

Esophageal mucosa damage can be induced by commonly prescribed drugs, but this is under-appreciated due in part to sparse attention in the published research. Drug-­induced esophagitis is characterized by dysphagia, chest pain, and/or odynophagia. Endoscopic findings of ulcers or erosions are usually confined to the middle third of the esophagus [71]. Antibiotics (e.g., doxycycline, amoxicillin, ciprofloxacin, metronidazole, rifaximin) are the primary cause of drug-induced esophagitis and are potentially more damaging than NSAIDs [3,72]. Drug-induced esophagitis is a self-limiting side effect that can be resolved by removing the causative agent and providing supportive therapy [73].

Infrequent or occasional gastroesophageal reflux is normal, particularly after a large meal. The reflux is diluted with saliva, and the esophagus clears the diluted refluxed acid with peristaltic action (a part of esophageal motility). A fully functioning LES, with normal pressure and a normal frequency of transient relaxation episodes, is a crucial physiologic defense against damage from reflux. The LES performs this function with assistance from the diaphragmatic crura, which relies on gastroesophageal junction positioning in the abdomen. This abdominal positioning enables the crura to essentially function as an external sphincter [50].

The crura and LES normally relax during swallowing. Relaxations not initiated by swallowing are termed transient LES relaxations. Transient LES relaxations are also part of normal LES function unrelated to swallowing or peristaltic action, but allow gas to be vented from the stomach (belching) as a normal function. Gastric distention can trigger reflux during transient relaxation and may underlie postprandial reflux [4,60].

Normal LES function is illustrated by air swallowing when drinking carbonated beverages in the upright position. The ingested air accumulates in the proximal stomach to cause distention. This elicits transient relaxations of the LES, allowing the ingested gas (air) to be vented as a belch. Air swallowing during eating and drinking is normal [78].

To function properly, the LES sustains a higher than normal tone from increased calcium, mediated by excitatory cholinergic neurons. The resting LES has higher intracellular levels of calcium than adjacent esophageal muscle, and decreased LES calcium levels are found in GERD [50].

Persons without GERD have a balance between the aggressive forces associated with injury and irritation of the esophagus and the defensive forces that impede reflux and help clear the refluxate. The primary aggressive forces are reflux causticity and volume burden, and defensive forces are related to the antireflux barrier, clearance mechanisms, and tissue resistance at the cellular level [79].

In parietal cells that line the stomach wall, proton pumps produce stomach acid by moving hydrogen ions from the parietal cell into the stomach lumen against a concentration gradient. Proton pump release of acid is prompted by signaling from acetylcholine, released by vagal nerve endings; gastrin, a local hormone produced by G cells in the antrum; and histamine, produced by enterochromaffin-like cells in the stomach wall [80]. Gastric acid kills micro-organisms, assists digestion, and facilitates absorption of iron, calcium, and vitamin B12 [81]. It also plays a crucial role in filtering out bacteria and in preventing development of enteric infections [82].

As discussed, PPIs are the foundation of GERD management. They directly inhibit hydrogen ion exchange and acid release prompted by all three stimulatory signaling agents, thus blocking the proton pump. H2RAs only block H2 receptors on the parietal cells, leaving gastrin and acetylcholine as potential signaling stimuli. PPIs are more potent inhibitors of gastric acid secretion than H2RAs [80].

Reflux occurs when the normal function of antireflux barriers between the stomach and esophagus become impaired. GERD develops when reflux of gastric contents is large or aggressive enough to cause troublesome symptoms and/or complications and adversely affect health-related quality of life [62]. The primary factor in GERD pathogenesis is defective function of the LES and the diaphragmatic crura antireflux barrier [52].

LES incompetence results in frequent transient LES relaxations, defined as LES relaxation occurring in absence of swallowing, lasting longer than 10 seconds, and associated with crural diaphragm inhibition [83]. Frequent or longer-lasting transient LES relaxations result in reflux of gastric fluid through the gastroesophageal junction. Most reflux events (about 90%) occur during transient LES relaxations rather than low resting LES pressure [52,83]. Mechanisms more likely with hiatal hernia include low gastroesophageal junction pressure, strain, or air swallow-associated reflux [83].

Symptoms develop when offensive factors in reflux make repeated contact with esophageal mucosa [62]. Potential esophageal injury from reflux increases as more elements of esophageal defense break down [84]. With LES compromise, increasing contact with caustic, corrosive reflux elements can induce esophageal mucosal injury and degrade esophageal mucosal defense by impairing mucosal resistance and esophageal clearance of acid and reflux [52]. Other pathogenic factors can include delayed gastric emptying and hiatal hernia [62]. As discussed, pathophysiologic mechanisms of GERD are exaggerated in obese patients [85].

In patients with GERD, reflux markedly increases after meals due to increased transient LES relaxations to accommodate food-induced gastric expansion. Despite the buffering effect of food, the pH of reflux into the distal esophagus is acidic due to a "pocket" of unbuffered gastric acid that accumulates in the proximal stomach after meals and serves as a reservoir for acid reflux [62,86].

As discussed, GERD causes reflux esophagitis, reflux esophagitis causes Barrett esophagus, and the metaplasia of Barrett esophagus predisposes to esophageal adenocarcinoma. Until recently, the presumed cause of reflux esophagitis was caustic, chemical injury induced by acid and pepsin in reflux. Repeated exposure made the esophageal squamous epithelium permeable to acid, causing epithelial cell death that triggers a proliferative response to repair epithelial injury [87].

Reflux esophagitis is now shown to develop as a cytokine-mediated inflammatory injury. Instead of direct destruction of epithelial cells, acid and bile salts in reflux induce these cells to release pro-inflammatory cytokines. The cytokines initially attract T lymphocytes that trigger the basal cell proliferation characteristic of GERD-induced injury. The inflammatory cells recruit neutrophils to the site of injury, ultimately mediating the epithelial damage [87].

Barrett esophagus develops through metaplasia, a process whereby one type of tissue replaces another type of tissue. Acid and bile reflux damages the squamous mucosa of the distal esophagus. This mucosal damage can heal through regeneration of more squamous epithelium, or through columnar metaplasia, whereby columnar cells replace the damaged squamous cells [87,88].

Non-acidic elements of reflux (e.g., pepsin, trypsin) also induce esophageal mucosal injury, esophagitis, and GERD. Most patients with NERD show non-acid-reflux-induced alteration in esophageal epithelium. Dilation of spaces between adjacent esophageal epithelial cells is the hallmark feature of microscopic esophagitis and increases penetration of hydrogen ions, pepsin, and bile into esophageal sub-mucosa. Non-acid reflux is mostly alkaline from the presence of duodeno-gastric biliary reflux. Acid and duodeno-gastric biliary reflux act synergistically to induce lesions and increase the risks of Barrett esophagus and esophageal adenocarcinoma [89]. PPIs are very effective at healing inflammation caused by acid reflux but do not suppress duodeno-gastric biliary reflux [87,88].

Most reflux events do not produce GERD symptoms, but symptom-producing events tend to involve lower pH, longer acid clearance time, and higher total acid exposure. In some cases, weekly acidic or non-acidic reflux can also produce symptoms [60,90].

The relationship between symptom severity and endoscopic findings is non-linear. Severe GERD symptoms can occur with negative endoscopic findings, while endoscopic findings of erosive esophagitis, Barrett esophagus, hemorrhagic esophageal stricture, or esophageal adenocarcinoma can be asymptomatic [60,91].

In patients with chronic pain or upper GI disorders without obvious pathology on imaging, the symptoms are termed "functional," a reference to the apparent lack of structural pathology (and explanation). Functional pain symptoms are now known to reflect durable abnormalities in peripheral and CNS pain signaling and processing. This also explains functional esophageal symptoms.

Reflux events become bothersome and distressing through complex mechanisms. Proteinase-activated receptor 2 (PAR2) and transient receptor potential vanilloid-1 (TRPV1) are thought to play key roles. Esophageal expression of PAR2 is activated by acid or weakly acidic reflux exposure. PAR2 releases interleukins (IL-8, IL-1b) and other inflammatory cytokines, promoting inflammatory injury in the esophageal mucosa [92,93]. The sensation of heartburn is generated by visceral sensory neurons within the deep layers of esophageal mucosa [87]. When activated by PAR2, acid, and other inflammatory mediators, visceral sensory neurons upregulate the expression of chemosensitive receptors TRPV1 and acid-sensing ion channel 3 (ASIC3), which release pain mediators that generate heartburn symptoms [94,95]. Repeated activation can induce inflammatory and neuroinflammatory effects and promote visceral hypersensitivity [96]. Elevated levels of IL-8 are found in biopsy specimens from patients with GERD and NERD, and high levels of IL-8 in biopsies of patients with NERD predict symptomatic recurrence [97,98,99].

Psychologic stress can increase the perception of heartburn and aggravate GERD symptoms [41]. Acute stress can enhance sensitivity to intraesophageal acid perception in patients with reflux esophagitis or NERD, and greater emotional response to stress correlates with increased perceptual response to acid [100,101]. Previous reports have revealed that low quality of life was severe in patients with extraesophageal symptoms. The quality of life of patients with GERD is also associated with psychologic factors [41,102,103].

Reflux-related esophageal disorders fall on a spectrum, based on interaction between esophageal hypersensitivity and acid exposure and its contribution to reflux symptoms. On one end, symptom contribution from abnormal acid exposure dominates erosive esophagitis; on the other end, contribution from hypersensitivity dominates functional heartburn. Acid exposure and hypersensitivity both contribute to symptoms in reflux hypersensitivity and NERD (Table 1) [7].

Patients with functional esophageal disorders present with reflux-related esophageal symptoms (e.g., heartburn, chest pain) not adequately explained by structural, inflammatory, or major motor abnormalities. In these patients, clinical findings typically include [6,7]:

Structural, motor, or inflammatory abnormality can be present, but a pathologic finding is not sufficient or necessary for diagnosis.

In the context of normal or borderline functional testing, symptom perception is driven by mechanisms that include hypersensitivity from peripheral and/or central sensitization, altered central processing of visceral stimuli, and altered autonomic activity. Altered pain perception with heightened visceral sensitivity and symptom perception and lowered symptom thresholds to chemical, mechanical, or emotional stimuli are consistently shown [1,104].

Esophageal tissue injury, inflammation, and repetitive mechanical stimuli can all sensitize peripheral afferent nerves. Esophageal hypersensitivity can remain long after resolution of the original insult [7,105].

Psychologic features are an important aspect of functional esophageal disorders. With recurrent or long-standing states of psychologic stress, centrally mediated processes can alter autonomic nervous system activity and modulate spinal transmission of nociceptive signals. Peripherally, gut mucosa permeability can be altered by mast cell degranulation [106]. These mechanisms contribute to exaggerated perception of physiologic stimuli [7].

Upper GI Endoscopy

Endoscopy identifies and documents reflux-related esophageal mucosal damage; the presence and severity of reflux disease complications, such as erosive esophagitis, Barrett esophagus, or peptic ulcers; and anatomic abnormalities, such as hiatal hernia, masses, and strictures [116]. Upper GI endoscopy is the most common initial test in patients with GERD symptoms and PPI nonresponse and is performed urgently in patients with alarm features [1,117]. This procedure consists of an endoscope being fed down the esophagus into the stomach and duodenum, where a small camera sends video images to a monitor screen for close inspection of the esophageal lining [118].

Endoscopic findings of esophagitis, esophageal erosion, eosinophilic esophagitis, or Barrett esophagus are highly suggestive of chronic esophageal epithelial exposure to reflux [52]. Erosive esophagitis is visually graded during endoscopy using Los Angeles (LA) classification [32].

GERD is diagnosed when endoscopy shows erosive esophagitis, and further testing is usually not needed. However, esophagitis is present in only 33% of patients with GERD symptoms and the absence of esophagitis does not rule out GERD. Patients with negative endoscopy should receive functional assessment [79].

Esophageal Biopsy

Esophageal biopsy specimens allow histologic assessment of esophageal mucosal injury. Biopsies are obtained during endoscopy to confirm or rule out suspicions of eosinophilic esophagitis (suggested by esophageal symptoms) or Barrett esophagus (suggested during endoscopy) [79]. Biopsies can also identify dilated distal intercellular spaces, a possible mechanism of GERD symptoms. Esophageal biopsy is not recommended in suspected GERD with normal endoscopy [79].

pH Monitoring

pH monitoring in the distal esophagus measures the extent of acid exposure using either a trans-nasal catheter (24 hours) or wireless, capsule-based pH testing (48 hours) [1,116,118,119]. The capsule-based approach is preferred because it increases detection. Extension of pH monitoring to 96 hours is an option. This increases pathologic findings and diagnostic yield over 24- and 48-hour pH monitoring in more complex patients [120].

Wireless pH monitoring uses a small capsule, endoscopically attached to the esophageal wall, to record and transmit pH data to a receiver worn on the belt. Patients push a button when experiencing symptoms. The capsule detaches and is excreted 7 to 10 days later [118].

pH monitoring measures:

Esophageal acid exposure time is the most useful indicator of pathologic acid reflux. Off-PPI testing assesses symptom provocation by acid reflux events; on-PPI testing measures persistent esophageal acid exposure despite PPI acid suppression [52].

In patients with GERD symptoms, NERD is diagnosed with negative endoscopy and pathologic acid reflux. Further testing is performed when endoscopy and pH monitoring are negative.

Esophageal Impedance Monitoring

Non-acid reflux is undetectable by standard pH monitoring but can induce symptoms in patients with GERD or functional esophageal disorders and is common in patients maintained on PPIs [52]. Impedance monitoring is a valuable test in patients with suspected GERD but negative pH testing, atypical or extraesophageal symptoms, or refractory GERD [4].

Esophageal impedance monitoring detects changes in the resistance of electrical current on a catheter placed into the esophagus. Impedance monitoring is usually combined with pH monitoring to record antegrade or retrograde movement of liquid and gas into the esophagus and to identify reflux as acidic, weakly acidic, or weakly alkaline [4]. Acid reflux is defined as a pH <4 in the esophagus; non-acid reflux is pH >4. The latter includes weakly acidic (4 <pH<7) and weakly alkaline (pH ≥7) reflux [1].

High-Resolution Esophageal Manometry

Functional assessment of the LES and the esophageal body is performed by esophageal manometry. High-resolution manometry (HRM) is often used with esophageal impedance; some devices combine both. HRM uses a catheter, inserted transnasally, with closely spaced sensors that measure the intraluminal pressure of the entire esophagus during swallowing [83]. In patients with GERD symptoms or NERD with poor PPI response, HRM identifies altered esophageal motility, impaired LES function, and/or transient LES relaxations to explain symptom persistence [59,121]. HRM is also valuable in excluding possible underlying esophageal motility disorders [122]. HRM is combined with 48-hour pH testing to assess patients with [1,79]:

It should also be conducted before antireflux surgery for diagnostic confirmation. The British Society of Gastroenterology finds HRM superior to standard manometry in terms of reproducibility, speed of performance, and ease of interpretation [119].

Gastric Scintigraphy

Gastroparesis (delayed gastric emptying) is an important contributor to GERD symptoms in many patients. These patients generally have negative endoscopy findings and greater odds of PPI nonresponse. With suspicion of gastroparesis, a four-hour gastric emptying scintigraphy is used [116,123].

Barium Swallow

The ACG does not recommend the use of a barium swallow solely as a diagnostic test for GERD.

(https://journals.lww.com/ajg/fulltext/2022/01000/acg_clinical_guideline_for_the_diagnosis_and.14.aspx Last Accessed: September 9, 2024)

Level of Evidence/Strength of Recommendation: Low/Conditional

Achalasia is an esophageal motility disorder with incomplete LES relaxation, increased LES pressure, and esophageal body aperistalsis, leading to poor clearance and esophageal dilation. Aside from dysphagia to solids and liquids, patients with achalasia may experience heartburn and regurgitation. Barium swallow with HRM can differentiate achalasia and other esophageal motility disorders from GERD [52].

Primary regurgitation and reflux symptoms (e.g., reflux into throat and mouth, wet burps, choking on liquid or food reflux) may reflect esophageal dysmotility or rumination syndrome. The step-wise diagnostic process outlined by the AGA starts with endoscopy to detect mechanical obstruction, eosinophilic esophagitis, or hiatal hernia [79]. With negative endoscopy, esophageal HRM is used. With meal-related regurgitation or suspected rumination syndrome, postprandial HRM is indicated.

In these patients, PPI response is less than 50%, because symptoms often result from reflux burden/volume instead of reflux acidity [124]. Reflux volume can reflect esophagogastric junction distensibility [52]. With hypotensive gastroesophageal junction or impaired esophageal motility on HRM, the next step is to assess with pH-impedance testing.

With abnormal reflux on PPI, dose-escalation benefit is unlikely and treatment addresses other pathophysiology [79]. With incompetent gastroesophageal junction and/or hiatal hernia, antireflux surgery is indicated to restore antireflux barrier function. Without hiatal hernia or hypotensive gastroesophageal junction, patients may still benefit from antireflux surgery. Transient LES relaxations may drive reflux with normal gastroesophageal junction pressure and anatomy; in these patients, use baclofen for reflux inhibition.

Pain (e.g., chest pain, heartburn, throatburn) is a primary symptom of GERD, and PPI response is often sufficient to guide management [79]. In cases of PPI nonresponse, endoscopy is used to explore alternative diagnoses. With negative endoscopy, pH-impedance testing off-PPI should be done to assess esophageal acid exposure, type of reflux event, and reflux/symptom correlation [79].

With normal impedance testing findings, functional heartburn or chest pain is the likely diagnosis, so HRM should be done to rule out esophageal motility disorders. Patients with positive HRM may have reflux hypersensitivity or refractory GERD (abnormal acid exposure with or without reflux symptom correlation) [7]. With confirmed pathologic acid exposure, pH-impedance testing on-PPI is used to assess PPI-refractory reflux mechanism (e.g., impaired gastric acid suppression, continued reflux, functional overlap) [79,125]. For patients with functional heartburn/chest pain or reflux hypersensitivity, pain modulators and behavioral therapies are indicated to target visceral hypersensitivity. Patients with reflux hypersensitivity may also require PPIs and baclofen for reflux inhibition.

Aerophagia is a functional GI disorder of repetitive troublesome belching and abdominal discomfort from excessive air swallowing, also associated with visceral hypersensitivity [78,116]. Other belching syndromes include [78,116]:

It is important to distinguish supragastric from gastric belching, because supragastric belches do not originate from the stomach, making transient LES relaxation therapy ineffective.

The first step in assessing these patients is the use of HRM/impedance testing to differentiate belching type, rumination syndrome, or GERD [79,116,126,127]. PPIs may reduce heartburn or chest pain with a transient LES relaxation-mediated belching syndrome. If only belching is present (not other reflux symptoms), PPIs should be discontinued. Patients with supragastric belching or rumination syndrome should be referred to behavioral therapy or a speech pathologist.

If postprandial HRM/impedance is negative for gastric belching, pH-impedance testing is indicated to assess belching pattern and reflux burden [79]. With normal reflux burden and gastric belching, patients may benefit from reflux inhibition with baclofen. Patients with gastric belching and abnormal reflux burden may benefit from the addition of PPIs. Antireflux surgery should be used cautiously in belching syndromes, as the risks of gas bloat and worsening supragastric belching can be substantial.

In the context of presumed GERD, prominent ENT and/or respiratory symptoms are challenging; non-reflux cause is likely. PPI response is comparable to placebo in randomized trials [19]. The extent of symptom association with GERD guides initial management [15,79]. Without close symptom association, clinicians should focus on non-reflux causes. With closer symptom association, pH-impedance testing off-PPI should be used to guide management decisions. Patients with normal results are unlikely to benefit from PPI dose escalation, but patients with abnormal esophageal acidity may benefit from antireflux procedures, with the caveat that symptoms are more refractory.

Functional chest pain is a subtype of non-cardiac chest pain. Initial cardiac evaluation is required in both, because history and physical examination do not reliably differentiate esophageal from cardiac chest pain. Functional chest pain is defined as recurring, unexplained, retrosternal chest pain of presumed esophageal origin, not explained by reflux disease or other mucosal or motor processes and with pain differing from heartburn [7].

Clinical Evaluation and Diagnosis

After exclusion of a cardiac cause, further workup is necessary and is guided by common underlying causes of non-cardiac chest pain and clinical evaluation findings [7,129]. With high prevalence in GERD, a high-dose PPI trial is used to assess for a possible GERD trigger of chest pain. With PPI nonresponse, pH-impedance testing off-PPI is recommended if suspicion of GERD remains. Endoscopy with biopsy is recommended to rule out eosinophilic esophagitis and Barrett esophagus. HRM may be considered when GERD is ruled out, because major motor disorders are exclusion criteria.

In order to diagnose functional chest pain, all of the following criteria must be present [7,128]:

The definition of functional heartburn has evolved from a NERD-spectrum disorder in Rome III to a stand-alone functional esophageal diagnosis in Rome IV [130]. The current diagnosis emphasizes a lack of conclusive evidence for GERD; the absence of symptom-reflux correlation and PPI nonresponse alert to a possible functional disorder [7].

Clinical Evaluation and Diagnosis

Functional heartburn is diagnosed after careful history identifies heartburn as the dominant symptom and stepwise evaluation is negative for GERD, eosinophilic esophagitis, and esophageal motor disorders. Most patients are identified by PPI nonresponse, a core diagnostic criterion [7,131]. After nonresponse to PPI trial, endoscopy and esophageal biopsies are used, regardless of esophageal mucosa appearance, to assess for reflux esophagitis, Barrett esophagus, eosinophilic esophagitis, or a nonpeptic inflammatory process. pH-impedance testing is used to identify acidic reflux and symptom/reflux correlation.

Diagnosis of NERD is made when there is evidence of abnormal esophageal acid exposure. When symptoms correlate with weakly acidic/non-acidic reflux events, the diagnosis is reflux hypersensitivity. Functional heartburn is diagnosed with normal esophageal acid and no symptom/reflux correlation. Diagnostic criteria are [7,128]:

GERD (proven by endoscopy and pH testing) and PPI nonresponse may reflect [7]:

Reflux hypersensitivity describes heartburn or chest pain symptoms, endoscopy negative for reflux injury, and pH-impedance testing negative for abnormal acid burden but positive for symptom triggering by non-acidic reflux [7].

Clinical Evaluation and Diagnosis

As with functional chest pain and functional heartburn, an empiric PPI trial begins the diagnostic process for reflux hypersensitivity. Partial or poor PPI response points to functional heartburn or reflux hypersensitivity. Endoscopy should be used to rule out esophagitis, Barrett esophagus, and eosinophilic esophagitis [131].

A reflux hypersensitivity diagnosis hinges on sensitivity to reflux events. Acid parameters should be in the normal range on- and off-PPI [132]. Reflux hypersensitivity differs from functional heartburn by significant symptom/non-acidic reflux correlation [7,35]. The diagnostic criteria are [7,128]:

A PPI response does not exclude this diagnosis.

Globus describes a persistent or intermittent nonpainful sensation of a lump or a foreign body in the throat. The symptom is commonly episodic, not associated with dysphagia or odynophagia, and frequently improves with eating and swallowing [7].

Clinical Evaluation and Diagnosis

The diagnosis is made primarily by eliciting a compatible clinical history and ruling out an identifiable cause (e.g., structural lesion, GERD, major motor disorder). There must be no dysphagia and no alarm features. Initial evaluation should include physical examination of the neck followed by laryngoscopic examination of the pharynx. After localized structural or inflammatory causes are excluded, the workup may proceed with an empiric trial of PPI therapy for four to eight weeks [7]. If the patient responds, the management shifts to GERD. For non-response to PPI, endoscopy may be considered to identify an alternative cause. Manometry may be helpful to rule out a major motor disorder; however, there are limited data to support a distinct motor pattern associated with globus. Patients not responding to PPI and without an identifiable cause in the oropharynx and esophagus are diagnosed with globus [7]. The diagnostic criteria are [7,128]:

Functional dysphagia is a sensation of abnormal bolus transit through the esophageal body in the absence of structural, mucosal, or motor abnormalities to explain the symptom. Diagnosis requires exclusion of oropharyngeal mechanisms of dysphagia, structural lesions in the tubular esophagus, GERD, eosinophilic esophagitis, and major motor disorders [7].

Clinical Evaluation and Diagnosis

Careful history should be obtained for patients with suspected functional dysphagia to exclude oropharyngeal dysphagia and to detect conditions that mimic or contribute to dysphagia (e.g., globus, xerostomia, odynophagia) [7,133,134,135]. PPI trial and upper endoscopy with biopsy can exclude GERD and eosinophilic esophagitis. Barium contrast using solid boluses is indicated to detect subtle strictures often overlooked on endoscopy and other obstructive processes, such axial hiatal hernias.

In the absence of structural lesions, HRM should be used to exclude major motor disorders. During HRM, multiple rapid swallows, water drinking, or food ingestion can improve detection of obstructive motor mechanisms that explain dysphagia. Borderline or minor motor disorders are compatible with functional dysphagia.

The diagnostic criteria for functional dysphagia are [7,128]:

Esophageal erosions are observable during endoscopy and visually graded using the LA classification, which provides endoscopic stratification of esophagitis severity [32,79]:

Mucosal breaks are areas of slough or erythema with discrete demarcation from adjacent, more normal-looking mucosa. In a validation study, severity of esophageal acid exposure was significantly related to the severity grade of esophagitis. Pretreatment esophagitis grades A through C were significantly related to heartburn severity, PPI treatment outcomes, and risk for symptom relapse off of PPIs [32]. Because there can be significant interobserver variability for mild erosive esophagitis (LA grade A), many experts only consider grades B or higher as objective evidence of GERD [79].

Eosinophilic esophagitis is a chronic disorder characterized by an aberrant inflammatory response involving local production of eotaxin-3, a chemokine that attracts eosinophils to the esophageal mucosa. Eosinophils cause local tissue damage and recruit and/or activate other effector cells, such as mast cells, which facilitate esophageal fibrous remodeling [136]. Progressive loss of tissue elasticity from inflammatory cell infiltration can elicit motor abnormalities [3,137].

Patients with eosinophilic esophagitis that does not respond to PPIs are diagnosed with "true eosinophilic esophagitis;" good PPI response or abnormal acid reflux on pH testing results in a diagnosis of GERD. The term "PPI-responsive eosinophilic esophagitis" was coined for the latter group, despite nearly identical clinical, endoscopic, and histologic features in both groups [136]. GERD is associated with eosinophilic esophagitis and should be ruled out by pH testing [52].

Therapy in patients with PPI-responsive eosinophilic esophagitis can reverse the inflammatory signature, but PPI response as diagnostic exclusion for eosinophilic esophagitis has been controversial [136]. In 2017, the first practice guidelines that eliminated the eosinophilic esophagitis vs. PPI-responsive eosinophilic esophagitis dichotomy were published, and in 2018, an international consensus conference adopted the updated criteria [138,139]. In this guideline, diagnostic criteria for eosinophilic esophagitis are organized into three categories [138]:

As noted, reflux injury to the esophageal squamous epithelium can lead to Barrett esophagus, a metaplastic process whereby the squamous cells are replaced by columnar epithelium-containing goblet cells [52]. Patients with Barrett esophagus may experience heartburn, regurgitation, or less commonly, dysphagia or a globus sensation, but others remain asymptomatic [49].

The ACG states that Barrett esophagus diagnosis requires endoscopic detection of columnar metaplasia plus biopsy confirmation of metaplasia with goblet cells [140]. In contrast, the British Society of Gastroenterology and the GERD Society Study Committee in Japan state that the presence of goblet cells is not required to diagnose Barrett esophagus, with diagnosis based solely on endoscopic detection of columnar metaplasia [49,141,142].

Weight gain and weight loss are associated with an increase and decrease in reflux symptoms, respectively, in both normal and overweight individuals [58]. Weight loss in overweight or obese patients with GERD symptoms is one of the most strongly supported lifestyle modification interventions. Several randomized controlled trials and well-designed observational studies have shown reduced reflux symptoms and esophageal acid exposure with weight loss, with a dose-dependent decreased presence of reflux symptoms following weight reduction [150].

The American Association of Clinical Endocrinologists and American College of Endocrinology recommend all overweight or obese patients with GERD should undergo weight loss, with the goal loss of 10% of body weight or greater. PPI therapy should be administered during dietary and weight-loss interventions [151]. Bariatric and other surgical options for obese patients may be considered.

The recumbent position is associated with worsening of esophageal pH values and GERD symptoms. Several randomized controlled trials have demonstrated improvement in GERD symptoms and esophageal pH values with head-of-bed elevation. Wood or cement blocks may be placed under the feet of the bed to raise the head end 6 to 10 inches. Wedges can also be inserted between the mattress and box-spring to elevate the body from the waist up and are available at drugstores and medical supply stores. Stacking pillows is ineffective [15,150]. Some patients may invest in adjustable beds that allow for easy personalization of this elevation. Patients with nocturnal GERD symptoms may find substantial relief from head-of-bed elevation and avoiding meals three hours before bedtime, especially foods with high fat content [50].

Tobacco smoking reduces LES pressure and salivary bicarbonate secretion, which facilitates reflux and decreases acid buffering [150]. However, smoking cessation has shown inconsistent benefits in GERD [15]. A large prospective study of 29,610 participants found smoking cessation was associated with decreased severe reflux symptoms in normal-weight individuals on PPI treatment (versus those who continued daily smoking), but no effect was found in overweight or obese individuals. This was thought to reflect the minimal added contribution from smoking compared with obesity in GERD pathophysiology, with smoking a more important factor in non-obese individuals [152].

Consumption of chocolate and carbonated beverages has been found to decrease LES pressure, but cessation of these agents does not necessarily raise LES pressure, decrease transient relaxations, or improve GERD symptoms [50]. Clinicians routinely recommend patients with GERD avoid coffee and caffeinated beverages, but whether coffee or caffeine itself is a factor in the pathophysiology of GERD is unclear; studies show conflicting results [58].

Protein and dietary fat have shown opposite effects on the LES; protein ingestion increases LES pressure, and fat ingestion decreases LES pressure. Ingestion of total fat, saturated fat, and cholesterol were higher in patients with GERD symptoms than those without symptoms in one study, but this effect only held in patients with BMI >25 [58,153,154].

A study examined dietary guideline adherence in 317 patients with GERD and whether adherence was related to reflux symptom severity and frequency. Compared with GERD-free controls, patients with GERD, even with moderate-severe or frequent symptoms, were as likely to consume tomato products and large-portion meals and were significantly more likely to consume soft drinks and tea and eat fried and high-fat foods. The results held when PPI users were excluded. If dietary modification is effective in reducing GERD, the results suggest substantial potential for nondrug interventions for many patients with GERD [155]. BMI was not analyzed separately.

Clinical trials have failed to consistently capture the aggravating effect of the consumption of chocolate, carbonated beverages, alcohol, coffee/caffeine, spicy foods, tomatoes or tomato sauce, citrus, or fatty foods on GERD symptoms. The equivocal findings are partly due to methodology problems [156]. More recent evidence supports the role of certain trigger foods, while population studies endorse decreased reflux symptoms with specific diets [149]. Specific foods or beverages are clearly GERD symptom triggers for some patients. When triggers are identified, their avoidance can bring considerable symptom relief [15].

Interestingly, a comparison of patients with GERD who performed Ramadan fasting and those who did not found significant reductions in GERD symptoms and severity in the fasting group before the end of the month compared with the non-fasting group [157].

Common medications that facilitate decrease in LES pressure and increase in transient relaxations include beta-adrenergic agonists, anticholinergics, nitrates, PDE-5 inhibitors (e.g., sildenafil, tadalafil), theophylline, calcium channel blockers, and benzodiazepines [50]. As discussed, regular use of NSAIDs is linked to a range of adverse GI effects; concurrent use of NSAIDs and SSRIs further elevates risks of upper GI ulceration and bleeding [114]. In patients prescribed these medications, possible contribution to GERD symptoms should be discussed. It is also worth revisiting if a patient has poor response to acid suppressant medications to determine if therapeutic alternatives are feasible.

NSAIDs should be discontinued whenever possible. If this is not feasible, PPI therapy should be initiated and NSAID dose reduction considered. PPIs are more effective than H2RAs in reducing NSAID-induced upper GI injury [158].

Misoprostol is a prostaglandin analogue also used for gastroprotection during NSAID use and is approved by the U.S. Food and Drug Administration (FDA) for prevention of NSAID-induced ulcer disease. Misoprostol is more effective than H2RAs in preventing NSAID-induced mucosal injury and equally effective as PPI in ulcer prevention with NSAID use. However, GI side effects, especially diarrhea, can limit patient tolerability [158].

Antacids are popular for treating occasional mild episodes of reflux and use different combinations of three basic salts—magnesium, calcium, and aluminum—with hydroxide or bicarbonate ions to neutralize gastric acid [10]. Antacids only provide quick, short-acting relief for 30 to 60 minutes, do not promote healing of erosive esophagitis, and only neutralize acid already secreted [84]. The role of antacids in the treatment of GERD is limited to patients with known triggers or breakthrough symptoms not effectively controlled by other medications. If used, antacids should be taken after each meal and at bedtime. Patients should receive education on the differences between occasional indigestion and GERD so they do not try to self-treat and subsequently fail to achieve relief [50].

Cimetidine, famotidine, and nizatidine are currently the FDA-approved H2RA agents for the treatment of GERD and are available over the counter. A fourth H2RA, ranitidine, was withdrawn from the U.S. market in 2020 [159]. H2RAs decrease gastric acid secretion in a reversible fashion by blocking the action of histamine on H2 receptors of gastric parietal cells. The inhibition of acid secretion results in an increase in gastric pH and a decrease in pepsin activity [159]. Over-the-counter formulations are available at a dose that is typically half the lowest standard prescription dosage [50].

This class of drugs is uniformly safe and well tolerated. The risk of adverse effects is slightly increased with cimetidine because it interacts with cytochrome P-450, potentially leading to drug-drug interactions [84].

Taken in standard divided doses, H2RAs can achieve symptom relief in some patients with milder or intermittent GERD. However, H2RAs have a dose ceiling; dose escalation above the recommended range does not further improve response. Over-the-counter H2RAs are particularly useful when taken before reflux. The peak potency of antacids and H2RAs is similar, but H2RAs have a much longer duration of action—up to 10 hours [84].

The ACG practice guidelines recommend H2RA use as a maintenance option in patients without erosive disease if patients experience heartburn relief [15]. A main limitation of H2RAs is tachyphylaxis (development of tolerance), often within two weeks of daily use. This pharmacologic phenomenon results in declining acid suppression and limits the regular use of H2RAs in clinical practice [160].

GERD and NERD

Numerous clinical trials have shown PPIs to be superior to H2RAs, antacids, and sucralfate in alleviating GERD symptoms. PPIs result in a significantly faster healing rate of peptic ulcers (12% per week) and heartburn (11.5% per week) compared with H2RAs (6% and 6.4% per week, respectively) [158]. Long-term PPI maintenance is also more effective in preventing recurrence of reflux esophagitis (80% PPIs vs. 49% H2RAs) and esophageal strictures (46% PPIs vs. 30% H2RAs) [67].

A meta-analysis of 98 randomized controlled trials evaluated PPI and H2RA effectiveness after four to eight weeks in adults with GERD. Effectiveness (defined as esophageal healing and GERD symptom relief) and tolerability (defined as discontinuation from ineffectiveness, adverse effects, or non-adherence) was calculated for low- and high-dose daily use; high doses were uniformly more effective [168]. The agent with top-ranked effectiveness was esomeprazole (40 mg/day), followed by rabeprazole (40–50 mg/day) and pantoprazole (80 mg/day). Best tolerability was noted with omeprazole (40 mg/day), then pantoprazole (40 mg/day), lansoprazole (60 mg/day), and the H2RA ranitidine (1,200 mg/day), which, as stated, is no longer marketed in the United States. However, sponsorship bias was detected. Higher PPI outcomes in studies with pharmaceutical company funding may have led to overestimated esophageal healing efficacy [168].

Once-daily PPIs for eight weeks heals reflux esophagitis in more than 80% of patients, and this is further improved by twice-daily dose escalation. Esomeprazole achieves higher short-term healing rates of reflux esophagitis than omeprazole, lansoprazole, and pantoprazole, but this advantage is negligible in less severe esophagitis. PPIs are effective for symptom relief in erosive and non-erosive disease, but efficacy in reducing regurgitation is considerably lower than with heartburn [169,170].

The belief that PPIs have lower efficacy in NERD was dispelled by a meta-analysis showing that PPI efficacy for NERD was comparable to erosive disease when functional testing using pH-HRM or pH-impedance testing was added to confirm NERD after negative endoscopy findings [62,171].

GERD practice guidelines and review papers often state that PPIs lack meaningful differences in potency. However, a comparative study of PPI efficacy in intragastric pH control, measured by percentage of time at pH >4 over 24 hours, found relative potencies, compared with omeprazole (1.00; reference), of 0.23 for pantoprazole, 0.90 for lansoprazole, 1.60 for esomeprazole, and 1.82 for rabeprazole [172]. This pharmacodynamic non-equivalence should be considered when prescribing or switching PPIs [62].

Short-term PPIs are generally well-tolerated, with infrequent adverse reactions including flatulence, headache, diarrhea, abdominal pain, and nausea. These reactions are often self-limiting or can be addressed by switching to a different agent [162].

Extraesophageal Manifestations

In contrast to typical symptoms, PPI efficacy in extraesophageal manifestations of GERD is less clear-cut. PPIs are usually given twice-daily for extended periods, but evidence is not strong enough to allow clear recommendations to be made for patients with only extraesophageal symptoms. Nonetheless, an empiric PPI trial can be the initial approach to diagnose and treat the potential underlying cause of extraesophageal disease [62].

As noted, GERD is the most common and best-studied cause of non-cardiac chest pain, and PPIs are the initial pharmacologic approach in these patients. Patients with non-cardiac chest pain and endoscopic or pH-monitoring evidence of GERD tend to improve, but not resolve, with PPI therapy. In contrast, GERD-negative patients show little or no PPI response. The therapeutic benefit of PPIs in patients with chronic cough is demonstrated, but efficacy in reflux laryngitis is much weaker. Asthma and GERD often coexist, and while asthma medications can trigger GERD, PPIs may improve asthma control [62].

Dyspepsia

Dyspeptic symptoms are common in patients with GERD, especially with frequent reflux-related symptoms. In these patients, PPI therapy improves epigastric pain, belching, bloating, and early satiety, but lacks benefit with nausea and vomiting [173]. PPI efficacy in functional dyspepsia occurs at standard doses, but long-term PPI therapy for functional dyspepsia is not indicated [62].

Dyspeptic symptoms may worsen with PPI therapy or new symptoms (especially postprandial fullness) may emerge from PPI-induced inhibition of gastric motility and delayed gastric emptying. In these cases, patients should be switched to the H2RA nizatidine. In addition to antisecretory activity, this agent displays cholinergic-like activity and accelerated gastric emptying [62,174].

Optimizing PPI Use

To achieve maximum response, it is important that patients receive correct instructions on how to use PPIs. The timing of PPI administration is essential. Patients are usually initiated on once-daily dosing, which must be taken 30 to 60 minutes before the first meal of the day, as the agents are most effective after a prolonged fast (i.e., overnight). Proton pumps are highly active during the postprandial period, and with a plasma half-life of one to two hours, PPIs reach peak concentration at the time of a meal [107,158]. If increased acid suppression is required, a second dose taken 30 to 60 minutes before the evening meal is more effective than doubling the morning dose [107].

With initial therapy, patients must adhere to daily use. The antisecretory action of PPIs increases with consecutive daily dosing, and full steady-state acid inhibition is achieved after four to five days. Steady-state acid inhibition is lost with non-adherence to daily use [158].

Treatment Duration and Discontinuation

With evidence that links long-term PPI use to potential risks, GERD practice guidelines recommend PPI dose reduction or discontinuation in some patients. In 2017, the AGA recommended that after a three- to six-month treatment course with good PPI response, patients with uncomplicated GERD should attempt to stop or reduce PPIs because patients who cannot reduce PPIs face the likelihood of lifelong PPI use [67]. In these patients, esophageal pH-impedance monitoring distinguishes acid-related disorders from a functional syndrome. The best candidates for this strategy may be patients with primarily atypical symptoms and those who lack obvious predisposition to GERD from central obesity or large (>3 cm) hiatal hernia.

PPIs can be very difficult to quit, and 75% to 90% of patients with GERD relapse in the initial six months after PPI discontinuation. This is attributed to the chronicity of GERD and NERD and contribution from PPIs, as abrupt cessation may be followed by rebound acid hypersecretion and symptom exacerbation [62,107,175].

Before continuing a likely long-term PPI treatment, or for patients already on long-term PPIs, an attempt to stop PPI therapy should be considered. Tapering is more effective as a discontinuation strategy than abrupt withdrawal, patient education, or lifestyle modifications [176]. Weight loss can also be an effective strategy in obese/overweight patients. One study found 54% of patients remaining adherent to a hypocaloric diet were able to stop PPIs, and 32% reduced their PPI dose by 50% [177].

PPIs can induce parietal cell proliferation to promote a hyperacidity state after discontinuation. This rebound hyperacidity can create a dependence on continued PPI use [178]. In a study of 120 healthy volunteers, rebound acid hypersecretion occurred after 8 weeks of PPI treatment, and 44% experienced acid-related symptoms 9 to 12 weeks after discontinuation. The authors concluded patients should taper off PPIs more gradually than is commonly suggested [179]. These results have been replicated in other studies as well [60,180,181].

Because relapse frequency and severity are highly variable among patients, long-term PPI maintenance should be individualized based on clinical characteristics of the patient. Strategies include continuous/daily use, intermittent cycles of daily use, and on-demand/symptom-driven therapy. Infrequent reflux symptoms are less likely to be chronic and may respond to a different approach [62].

An alternative approach is a PPI step-down, in which the dose is reduced to determine the minimum needed. This involves a gradual reduction in dose or frequency and may include a goal of switching to "as-needed" therapy. The step-down approach allows patients to implement lifestyle modifications and find the lowest dose they need for adequate symptom control [107]. While full-dose PPIs are superior to half-dose in maintaining remission, step-down dosing with esomeprazole 20 mg maintained a significantly higher proportion of patients with GERD in symptomatic remission than lansoprazole 15 mg or pantoprazole 20 mg [169]. Because PPIs do not correct the underlying esophageal motor abnormalities of GERD, patients may require continuous acid suppression treatment to maintain remission [62].

The AGA guideline for long-term use of PPIs concludes the best current approaches to mitigate potential risks of long-term PPIs are to avoid prescribing when PPIs are not indicated and to reduce their use to the minimum dose when PPIs are indicated [67]. The AGA states most patients with uncomplicated GERD can reduce from twice-daily to once-daily PPI dosing, 33% can successfully transition from PPIs to H2RAs, and 16% are able to transition off all acid suppression. Patients with non-erosive disease who cannot transition off PPIs are usually satisfied with on-demand PPI therapy. Because PPI reduction is often successful in uncomplicated GERD, it is recommended that clinicians periodically re-evaluate patients to ensure they are taking the lowest dose sufficient to manage their condition [67].

Patients with complicated GERD (e.g., erosive disease) are usually unable to successfully reduce PPIs. Patients with good symptom control from daily PPIs who cannot reduce face lifelong PPI therapy. Assessment for an acid-related disorder with esophageal pH-impedance monitoring is recommended. This testing shows a subset of patients with poor correlation between symptoms and acidic reflux events, and strenuous efforts should be made to discontinue or reduce PPIs in these patients [67].

A Canadian guideline was published in 2017 to help clinicians identify when to taper or stop PPI therapy. In adults with upper GI symptoms who have completed a minimum four-week course of PPI treatment with resolution of upper GI symptoms, the following is recommended [114]:

Criteria have also been proposed that may predict greater success halting PPIs in elderly patients living in care facilities. PPI discontinuation outcomes were evaluated in 27 elderly residents (mean age: 80 years) taking a PPI for more than six months who met all of the following criteria: 1) no indication for long-term PPIs; 2) not currently experiencing GI symptoms; 3) no previous PPI discontinuation without success; and 4) no anxiety when medications are discontinued. PPIs were stopped without taper with participants receiving medical monitoring and support. After eight weeks, 70% remained asymptomatic and did not need PPIs to manage GI symptoms [182].

With Barrett esophagus of any mucosal length, long-term PPI use for potential chemopreventive effects against neoplastic transformation is advocated by the ACG and the AGA, but is not recommended by the British Society of Gastroenterology [67,140,183]. The evidence supporting this practice is inconsistent. A meta-analysis of observational studies found PPI use associated with a 71% reduction in risk of esophageal adenocarcinoma and/or high-grade dysplasia in Barrett esophagus, but another study concluded standard PPI therapy was unable to normalize esophageal exposure to acid in most patients with Barrett esophagus [184,185]. Individually tailored maximal acid suppression is needed to control GERD and to achieve any chemopreventive effect in Barrett esophagus [62].

Agents with prokinetic properties are proposed as adjunctive medications for PPI nonresponse when delayed gastric emptying is a suspected symptom contributor. Metoclopramide and domperidone are selective dopamine receptor antagonists that may improve esophageal peristalsis, accelerate esophageal acid clearance, increase LES basal pressure, and improve gastric emptying. Other possible agents include revexepride (investigational in the United States), prucalopride, and mosapride [160].

A select group of PPI nonresponders may benefit from adjunctive promotility agents. However, mosapride, the most-studied agent, is not approved in the United States. Domperidone reduced symptom scores better than PPI alone, but is also not approved and carries significant arrythmogenic risks [160]. Metoclopramide is associated with several adverse effects and use in GERD has been limited by safety concerns [196,197]. In patients with persistent GERD symptoms despite PPI treatment, two randomized controlled trials found revexepride no more effective than placebo in controlling regurgitation and reflux [198,199]. A small randomized controlled trial of prucalopride in patients with GERD and ineffective esophageal motility suggested this drug may be useful in augmenting peristalsis in these patients [200].

Baclofen acts as an agonist of gamma-aminobutyric acid (GABA) type B receptors and is prescribed to decrease transient LES relaxation-related acidic and non-acidic reflux episodes [160]. Baclofen physiologically inhibits transient LES relaxations, and studies measuring baclofen effects with pH-impedance monitoring show significant reductions in postprandial acid- and non-acid-related symptoms in patients with heartburn by reducing transient LES relaxations, increasing LES tone, and decreasing reflux episodes. Studies have also demonstrated that baclofen reduces the number of postprandial and non-acid reflux events, nocturnal reflux activity, and belching episodes [50,52]. In patients with symptomatic GERD treated with daily omeprazole plus baclofen 10 mg or placebo, baclofen significantly reduced the rates of heartburn (46% vs. 4%) and regurgitation (54% vs. 4%) [201]. Baclofen may be particularly beneficial for patients with abnormally high non- or weakly-acidic reflux events [160]. However, baclofen requires adherence to twice or three times daily dosing, and common side effects include drowsiness, fatigue, and confusion [107].

Especially in patients with NERD, PPI response is often partial or limited and symptom relief requires additional medications. Esophageal mucosal protection from acidic and non-acidic contents is another approach to PPI nonresponse. Some of these agents target the gastric acid pocket in the proximal stomach, a contributor to the pathogenesis of postprandial reflux [202].

Alginates

Alginate is a polysaccharide derived from seaweed that binds water in the acid pocket to form a viscous gel, displacing the acid pocket distally below the diaphragm. Sodium bicarbonate, often added to alginate, is converted to carbon dioxide and forms bubbles trapped within the gel. This changes the gel to a lighter substance that rises to the surface of gastric contents and floats, hence the term "raft-forming agent." Alginates offer a supplemental mechanism of acid suppression [203,204].

Gaviscon is a common raft-forming alginate formulation. In a randomized controlled trial of 136 patients with persistent reflux symptoms taking once-daily PPIs, adding alginate (10 mL four times/day) for seven days led to significantly greater reductions in reflux score and number of nights with symptoms than placebo [205].

A review of 14 studies in patients with NERD or atypical GERD symptoms found alginate-based therapies more effective in resolving reflux symptoms than placebo or antacids, and somewhat less effective than PPIs or H2RAs [204]. This review evaluated alginate monotherapy, but in practice, alginates are typically added to PPIs. Alginate-antacid formulations show efficacy comparable to single-dose omeprazole in patients with NERD [202].

Mirgeal is an alginate formulation that combines glycyrrhetinic acid and anthocyanosides, both of which have mucosal protective properties. Use in combination with PPIs showed greater reflux symptom control in patients with NERD and poor PPI response compared with alginic acid plus PPI [160].

Sucralfate

Sucralfate is a salt of sucrose sulfate and aluminum hydroxide that creates a physical barrier to block esophageal mucosa exposure to, and diffusion of, hydrochloric acid, pepsin, and bile salts. As an add-on to PPIs, sucralfate can further reduce GERD symptoms and may help induce mucosal healing and reduce recurrent esophagitis during maintenance therapy [202,206].

Hyaluronic Acid and Chondroitin Sulfate

Hyaluronic acid is involved in several key processes, including cell signaling and wound repair and regeneration. Chondroitin sulfate has possible benefits in inflammatory diseases. Formulations that combine hyaluronic acid and chondroitin sulfate have been introduced and evaluated as treatment of reflux disease [207].

In adults with NERD and poor PPI response, hyaluronic acid/chondroitin sulfate (four times per day) for 14 days led to significantly greater reductions in heartburn and regurgitation symptom intensity than placebo. Onset of effect within 30 minutes was more frequent with hyaluronic acid/chondroitin sulfate than placebo (60% vs. 30%). Complete remission was attained by 50% with hyaluronic acid/chondroitin sulfate and 10% with placebo [207].

A larger randomized controlled trial evaluated improved symptom relief with hyaluronic acid/chondroitin sulfate plus PPI compared with PPI alone in 154 patients with NERD. After two weeks of hyaluronic acid/chondroitin sulfate or placebo, significant reduction in total symptom score (on measures of heartburn, acid regurgitation, retrosternal pain, and acid taste in mouth) was reached by 52.6% with hyaluronic acid/chondroitin sulfate and 32.1% with placebo. The synergistic effect of hyaluronic acid/chondroitin sulfate and PPI treatment suggests mucosal protection added to acid suppression could improve symptom control in patients with NERD [164].

Based on current knowledge, mucosal protective compounds cannot replace PPIs, but show promise in PPI-refractory GERD or NERD in combination with PPIs [160,202]. The ACG states there is no role for sucralfate or other membrane-protectors, but these agents may represent the only effective medication protection against biliary reflux injury of the esophageal mucosa [15,89].

Compared with healthy subjects, patients with non-cardiac chest pain demonstrate higher pain sensation with esophageal exposure to balloon distension, acid infusion, and electrical and thermal stimulation [208]. In these patients, esophageal hypersensitivity results from sensitization of both peripheral afferent nerves (peripheral sensitization) and spinal dorsal horn neurons (central sensitization). Esophageal hypersensitivity and objective pathology can occur together; around 30% of patients with non-cardiac chest pain have abnormal esophageal findings on HRM [209].

Most PPI-refractory patients have NERD or functional symptoms, making treatment with pain modulators a reasonable option. Antidepressants are the most-studied medications for this indication and include tricyclic antidepressants (e.g., imipramine, nortriptyline), SSRIs (e.g., sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), and trazodone. Doses used are lower than in depression, and randomized controlled trials have found them effective in reducing esophageal pain, especially in patients with esophageal hypersensitivity [210]. Antidepressants act by modulating the esophagus-brain axis. Patients with NERD and painful heartburn received functional magnetic resonance imaging (off-PPI) after 21 days of nortriptyline or placebo. Acid-induced activation in prefrontal cortex, caudate, insula, cingulate, and hippocampus brain areas were significantly reduced with nortriptyline compared with placebo [211].

A systematic review of 15 randomized controlled trials found that, compared to baseline, antidepressants increased esophageal pain thresholds 7% to 37%, reduced functional chest pain 18% to 67%, and reduced heartburn in patients with GERD 23% to 61%. Antidepressants modulate esophageal sensation, reduce functional chest pain, and may benefit a subgroup with GERD [212]. In these patients, PPI therapy can (and should) be discontinued when ineffective. The clinical relevance of distinguishing functional heartburn from esophageal hypersensitivity is unclear [213].

In patients with non-cardiac chest pain, chest pain was reduced by 50% to 63% with venlafaxine, sertraline, or imipramine, compared with 1% to 15% in those randomized to placebo. This improvement was independent of effects on depression. Side effects are the main drawback with antidepressant therapy for esophageal hypersensitivity and can adversely impact their tolerability and lead to discontinuation. Antidepressant study drop-out rates as high as 53% have been reported in this population, highlighting the need for safer, more tolerable drugs [1,214].

Vonoprazan

A novel potassium-competitive acid blocker, vonoprazan, has demonstrated more potent and sustained acid suppressive effects than the PPIs lansoprazole, esomeprazole, and rabeprazole [160]. The metabolism of vonoprazan is not impacted by genetic polymorphisms of CYP2C19, which impair the efficacy of some PPIs. Vonoprazan was comparable to lansoprazole for the treatment of erosive esophagitis and overall shows more favorable pharmacodynamic and pharmacogenetic properties compared to PPIs. As stated, vonoprazan received FDA approval in 2023 based on phase III clinical trials that demonstrated it to be noninferior to PPIs as a component of H. pylori eradication regimens [146].

Melatonin

Melatonin is an important signaling molecule in gut motility and gut-liver communication, and the esophageal mucosa possesses large numbers of melatonin-binding sites [60]. Exogenous melatonin is thought to control GERD symptoms by stimulating production of nitric oxide and prostaglandin E2, inhibiting gastric acid secretion, reducing inflammatory cytokines, and preventing acid/pepsin-induced esophagitis. Melatonin is not conventional therapy but may represent an alternative for patients lacking benefit from PPIs [50].

Clinical trials in GERD are limited, but published results suggest improvements in heartburn, epigastric pain, and LES function [50]. Ramelteon is a melatonin (MT) receptor agonist with high affinity for MT1 and MT2 receptors, essentially a pharmaceutical version of melatonin that is FDA-approved for insomnia [159]. Ramelteon is considerably more expensive than melatonin but is produced under quality control not found with melatonin supplements, because the quality and purity of supplements are unregulated in the United States. In one study, patients with frequent heartburn and/or regurgitation and chronic insomnia received ramelteon 8 mg or placebo before bed for four weeks. Ramelteon led to significant decreases in symptom scores (vs. placebo) for daytime heartburn, night-time heartburn, 24-hour heartburn, and 24-hour acid regurgitation. Insomnia severity scores were significantly reduced with ramelteon compared with placebo. Ramelteon also led to improvements in sleep efficiency and sleep latency. No significant adverse events were observed [215].