The approach to patients with GERD symptoms not responding to medical therapy. *The optimal proton pump inhibitor (PPI) dose threshold to define failure of acid suppression is unknown. Based on the data from Charbel et al., a dose that is either twice the Food and Drug Administration (FDA)-approved dose or a twice daily dose of the FDA indicated dose are the default regimens for defining PPI nonresponders.
How Do You Treat Chest Pain Caused by Acid Reflux?
Response to the patient: Chest pain due to acid reflux is treated by taking medication that stops acid production in your stomach. The medication is called a proton pump inhibitor (PPI). If you have chest pain related to acid reflux that has been confirmed by abnormal pH testings in your swallowing tube and you do not wish to take medications, then an alternative is to undergo surgery. During this procedure done laparoscopically (small incision in your belly), a surgeon will wrap the upper part of your stomach around the distal part of your swallowing tube to tighten your weak lower valve.
Brief Review of the Literature
PPIs are the mainstay therapy for suspected GERD-related chest pain. According to a meta-analysis of seven trials including 232 patients, there was a significantly decreased risk of chest pain continuation after PPI therapy (pooled RR = 0.54, 95% CI 0.41–0.71) when compared to placebo . The overall number needed to treat was 3 to achieve symptomatic response . Patients treated with PPIs were more likely to achieve at least a 50% response than placebo recipients with a statistically significantly lower risk of continued chest pain (pooled RR 0.60, 95% CI 0.44–0.81) . On the other hand, no difference was observed between PPI and placebo in achieving complete resolution of non-cardiac chest pain (pooled RR 0.83, 95% CI 0.66–1.05)  indicating that PPIs substantially improve but do not completely resolve chest pain due to GERD. Another systematic review of the literature suggested that non-cardiac chest pain due to GERD should be treated with double-dose PPI for at least 2 months .
However, no studies have been done comparing the efficacy between once daily PPI to twice daily PPI in patients with non-cardiac chest pain. Based on cost analysis, Fass et al. recommended PPI BID for 8 weeks and in the responders then decreasing the dose to once daily .
Due to the growing concern within the community about possible PPI-related side effects such as dementia or chronic kidney disease, it was recently suggested that PPIs for GERD be discontinued after symptom resolution for longer than 2 weeks. The suggested options are to use H2 receptor antagonists or antacids for infrequent symptoms or intermittent 2–4 week courses of PPIs for symptom recurrence (at least two episodes a week) . Patients who require daily PPIs to control their symptoms should continue them only if the gain in quality-adjusted-life-years with long-term symptom control far exceeds any decrease due to possible rare, serious adverse events . Patients worried about side effects and those whose quality of life is affected should either seek other therapies (surgery) or accept their symptoms .
Several open-label trials have evaluated the efficacy of surgery in patient with non-cardiac chest pain due to GERD . Improvement in chest pain was observed among 58–96% of patients who underwent laparoscopic Nissen fundoplication. Patients with a confirmed association between chest pain and acid reflux by esophageal pH testing had higher response rates to surgery (up to 96%) than those without such an association (up to 65%) . Importantly, the response to PPIs was an important predictor of response to surgery .
There is only one small study that evaluated the efficacy of endoscopic antireflux treatment with endoluminal gastroplication (Endocinch) in patients with atypical GERD symptoms . Improvement in chest pain was observed in 13 of 18 of patients (72%) at 6 months when compared with baseline .
The 2013 consensus of the Esophageal Diagnostic Advisory Panel clearly recommends objective confirmation that GERD is the cause of patients’ symptoms before consideration of surgery (Fig. 3.2) [42, 48]. Required preoperative workup should include upper endoscopy, barium esophagram, pH testing off PPI therapy for at least 7 days, and esophageal manometry . Patients with normal distal esophageal acid exposure on esophageal pH testing have a low likelihood of GERD and poor response to antireflux surgery . A positive symptom index or symptom association probability alone is not sufficient indications for anti-reflux surgery as chest pain is likely due to esophageal hypersensitivity and not GERD . According to recent guidelines by the Society of American Gastrointestinal and Endoscopic Surgeons, objective confirmation of GERD is required before consideration of anti-reflux surgery and surgical therapy should be considered if patients have inadequate control of symptoms on PPIs, severe regurgitation on PPIs, or side effects of PPIs, prefer surgery due to quality of life issues, developed GERD complications such as peptic stricture or Barrett’s esophagus, or have extra esophageal manifestations of GERD such as asthma, hoarseness, cough, and chest pain .
The approach to patients referred for antireflux procedures without a previous confirmed diagnosis of GERD . Reprinted from Dis Esophagus 2013; 26 (8). Richter JE, Pandolfino JE, Vela MF, Kahrilas PJ, Lacy BE, Ganz R, Dengler W, Oelschlager BK, Peters J, DeVault KR, Fass R, Gyawali CP, Conklin J, DeMeester T; Esophageal Diagnostic Working Group. Utilization of wireless pH monitoring technologies: a summary of the proceedings from the esophageal diagnostic working group. pp. 755–65. Copyright 2012 with permission from John Wiley & Sons, Inc.
Chest Pain Due to Esophageal Hypersensitivity
What Is Esophageal Hypersensitivity and Why Does It Cause Chest Pain?
Response to the patient: Some patients experience chest pain due to sensitivity of the nerve fibers within their swallowing tube to repetitive mechanical stimuli, prior tissue injury, or inflammation. The esophagus with such sensitive nerve fibers is called the “hypersensitive esophagus.” Some patients may also experience chest pain due to increased stimuli coming from the brain itself due to anxiety, panic attacks, or depression.
Brief Review of the Literature
Non-cardiac chest pain without evidence of acid reflux, esophageal motility disorders, or eosinophilic esophagitis may be due to visceral hypersensitivity, i.e., “functional chest pain .” This type of chest pain is typically associated with irritable bowel syndrome or other functional disorders in up to 80% of patients . Sensitization of visceral afferents may occur during mucosal injury causing hyperalgesia . The animal and human studies investigating the pathophysiology of esophageal pain in response to various stimuli are described in the section on chest pain due to acid reflux (answer to question 1).
Two mechanisms of esophageal hypersensitivity are proposed: (1) increased esophageal afferent pathway sensitivity and (2) increased secondary cortical processing due to psychological factors such as hypervigilance with normal afferent transmission . Both mechanisms lead to reduced pain thresholds .
Various studies have identified abnormal pain perception via peripheral and central mechanisms in patients with non-cardiac chest pain in response to electrical, mechanical, and chemical stimulus.
Hobson et al. observed that patients with non-cardiac chest pain were characterized by reduced pain thresholds and increased latencies of esophageal evoked potentials in response to electric stimulation when compared to healthy controls . Furthermore, patients with non-cardiac chest pain were divided into three separate phenotypic categories: (1) normal or reduced esophageal evoked potential latencies and reduced pain thresholds, (2) increased esophageal evoked potential latencies with reduced pain thresholds, and (3) normal or increased esophageal evoked potential latencies and normal pain thresholds . Therefore, the authors hypothesized that either increased esophageal afferent pathway sensitivity or abnormality in the secondary cortical processing of esophageal sensory information (central mechanisms of esophageal hypersensitivity) were mechanisms responsible for non-cardiac chest pain . In another study, patients with non-cardiac chest pain were found to experience pain at a twofold lower esophageal electrical stimulation intensities (3.6 ± 1 vs. 7.8 ± 2 mA, p < 0.05) than healthy controls suggesting hypersensitivity (allodynia) to esophageal electrical stimulation .
In their landmark study, Richter et al. observed in 1986 that patients referred by their cardiologists with non-cardiac chest pain were more sensitive to smaller volumes of balloon distension than healthy controls who experienced chest pain at greater distension volumes . In that study, 15 of 18 patients experienced chest pain with balloon volumes of less than 8 mL and all healthy controls with pain (6 of 30 subjects) noted it after balloon volumes of at least 9 mL . There was no difference in balloon pressures or esophageal contractions above the balloon during pain episodes between patients and healthy controls . Therefore it was proposed that esophageal balloon distension triggers esophageal chest pain in susceptible patients due to a lower pain threshold rather than abnormal esophageal contractions . These data were further supported by Rao et al. who showed greater reactivity of the esophagus to balloon distension and a less distensible esophageal wall among patients with non-cardiac chest pain compared to healthy controls evaluated by impedance planimetry . It was suggested that excessive reaction to luminal distension in patients with non-cardiac chest pain might be due to a stiffer esophageal wall . Furthermore, another study by Rao et al. observed that chest pain induced by esophageal balloon distension was not reduced by atropine indicating that the major mechanism responsible for eliciting functional chest pain was hyperalgesia and not motor dysfunction .
A study by Sarkar et al. among 19 healthy volunteers and 7 patients with non-cardiac chest pain found that patients with non-cardiac chest pain had lower baseline electrical pain threshold in the upper esophagus which further decreased and lasted longer after infusion of hydrochloric acid into the distal esophagus when compared with healthy volunteers . In addition, infusion of acid into the lower esophagus decreased the pain threshold to electrical stimulation within the upper esophagus and anterior chest wall in healthy volunteers . The authors postulated that central sensitization may play a role in concurrent visceral and somatic pain hypersensitivity . Another study of ten healthy volunteers found reduced electrical evoked potential latency and electrical pain threshold within nonacid-exposed proximal esophagus suggesting a central increase in afferent pathway velocity . It was postulated that hypersensitivity within the proximal, nonacid-exposed esophagus was due to hyperexcitability within the central visceral pain pathway .
How Can We Distinguish Chest Pain Due to Esophageal Hypersensitivity from Cardiac Chest Pain?
Response to the patient: It is difficult to distinguish between cardiac chest pain and chest pain due to esophageal hypersensitivity based on the description of your pain. If you experience chest pain you should always go to the emergency room to undergo proper evaluation to exclude life-threatening conditions of heart and lungs. After life-threatening conditions have been ruled out you will be referred to the gastroenterologist for further workup.
Brief Review of the Literature
Please refer to answer to question number 2 in the section on chest pain due to acid reflux.
How Do You Diagnose Chest Pain Due to Esophageal Hypersensitivity?
Response to the patient: Please refer to the answer to question number 3 in the section on chest pain due to acid reflux. If your chest pain does not respond to PPIs, your upper endoscopy is normal, the biopsies of samples taken from your esophagus are normal, your pH study is normal, then your chest pain is not due to acid reflux. The doctor will determine next whether you have an abnormal esophageal motility (muscle contractions) that could cause your chest pain. A thin catheter will be inserted through your nose and advanced into your esophagus. You will be asked to swallow sips of water several times and the doctor will check the pressures within your esophagus. If this test is normal, then your chest pain is most likely due to esophageal hypersensitivity.
Brief Review of the Literature
Chest pain due to esophageal hypersensitivity is a diagnosis of exclusion. There is no single gold standard test that allows for the diagnosis of this condition. Recently published Rome IV criteria clearly define the diagnostic criteria for chest pain due to esophageal hypersensitivity (i.e., functional chest pain) . Functional chest pain may be diagnosed if chest pain started at least 6 months before diagnosis, is present at least once a week, and has been present within the last 3 months . It is described as retrosternal pain or discomfort, cardiac causes must be excluded, associated symptoms such as heartburn and dysphagia are absent, and there is no evidence of gastroesophageal reflux, e osinophilic esophagitis, or major esophageal motility disorders .
An esophageal workup should be initiated only after cardiac causes of chest pain (especially coronary artery disease) have been eliminated . Due to the high prevalence of GERD in patients with non-cardiac chest pain, the most cost-effective step is to prescribe high-dose PPI therapy for 8 weeks [38, 44]. Upper endoscopy with biopsies of the esophagus are recommended to exclude erosive or eosinophilic esophagitis as possible causes of chest pain . Nonresponders to high-dose PPI therapy should be offered esophageal pH monitoring off PPIs .
It should be noted that Rome IV classification has proposed a more strict definition of GERD in which only abnormal esophageal acid exposure confirms the diagnosis . Patients with normal esophageal acid exposure but positive chest pain-reflux association (acid-sensitive esophagus) are now classified as having “reflux hypersensitivity” and belong to the functional chest pain group (Fig. 3.3) . Previously, Rome III criteria included acid-sensitive esophagus within non-erosive reflux disease spectrum . The Rome IV classification change evolved from the observation that reflux-symptom association measured only by a positive symptom index or symptom association probability with normal distal esophageal acid exposure often can occur by chance alone . Response to PPIs does not preclude the diagnosis of chest pain due to reflux hypersensitivity .
The association between acid exposure and esophageal hypersensitivity in GERD, reflux hypersensitivity, and functional heartburn . Reprinted from Gastroenterology 2016; 150 (6). Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Functional Esophageal Disorders. pp. 1368–1379. Copyright 2016 with permission from Elsevier
After excluding GERD, the next step is to perform esophageal manometry to determine whether a major esophageal motility abnormality may be causing the chest pain . These would include achalasia, esophagogastric junction outflow obstruction, jackhammer esophagus, diffuse esophageal spasm, or absent peristalsis. If esophageal manometry is normal, then one approach is to perform an esophageal balloon distension test which can reproduce esophageal chest pain in up to 75% of patients with chest pain due to esophageal hypersensitivity . However, the balloon distension test in academic and clinical practice is rarely done. Figure 3.4 presents an algorithm for establishing the diagnosis of chest pain due to esophageal hypersensitivity .
Algorithm for management of esophageal chest pain . Reprinted from Clin Gastroenterol Hepatol. 2014; 12 (8). Coss-Adame E, Erdogan A, Rao SS. Treatment of esophageal (non-cardiac) chest pain: an expert review. pp. 1224–45. Copyright 2014 with permission from Elsevier
How Do You Treat Chest Pain Due to Esophageal Hypersensitivity?
Response to patient: If your chest pain is caused by reflux hypersensitivity, then you may respond to PPIs. In patients not responding to PPI, the recommended treatment for chest pain due to esophageal hypersensitivity includes a variety of antidepressants (tricyclic antidepressants (TCA), serotonin reuptake inhibitors (SSRIs)) or psychological interventions such as cognitive behavioral therapy, coping skills, or hypnosis to decrease pain hypersensitivity.
Brief Review of Literature
It has been suggested that patients w ith an acid-sensitive esophagus may respond to PPI therapy. Among patients with normal upper endoscopy and reflux symptoms responding to PPIs, 26% in one study were found to have a hypersensitive esophagus . However, that study evaluated patients with typical reflux symptoms and it is uncertain whether these findings can be also applied to patients with chest pain due to an acid-sensitive esophagus .
In patients not responding to PPIs, the first line treatment are medications targeting neuromodulation of pain . These include antidepressants such as tricyclic antidepressants (imipramine, amitriptyline), serotonin reuptake inhibitors (sertraline, paroxetine, citalopram), trazodone, or serotonin noradrenergic reuptake inhibitors (venlafaxine) (Table 3.1) . According to a recent systematic review of six randomized placebo controlled trials, venlafaxine (50% vs. 10%; P < 0.001), sertraline (63% vs. 15%; P = 0.02), and imipramine (52% vs. 1%; P = 0.03) but not paroxetine showed statistically significant superiority over placebo in reduction of non-cardiac chest pain . On the other hand, a recent meta-analysis of four randomized placebo controlled trials including 184 patients assessing the efficacy of selective serotonin reuptake inhibitors for non-cardiac chest pain found no difference between active drug and placebo in improving chest pain (standardized mean difference = −0.17; 95% CI = −0.46–0.12) .
A pain modulators for the treatment of functional esophageal disorders 
Class of drug
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