EDUCATION PRACTICE. How Do I Handle the Patient With Noncardiac Chest Pain? Clinical Scenario

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9: EDUCATION PRACTICE How Do I Handle the Patient With Noncardiac Chest Pain? AMINDRA S. ARORA and DAVID A. KATZKA Division of Gastroenterology and Hepatology, Mayo Foundation, Rochester, Minnesota This article has an accompanying continuing medical education activity on page e35. Learning Objectives At the end of this activity, the learner will know the evaluation, the causes, and the treatment options for patients with chest pain of esophageal origin. Podcast interview: A Clinical Scenario 48-year-old woman presents to you with a 6-month history of intermittent chest pain occurring several times per week. The pain is intermittent and more likely after meals but not exclusively, lasts about 15 minutes, and is squeezing in nature and severe enough to interrupt normal activity. There is no associated dysphagia, heartburn, voice hoarseness, sore throat, regurgitation, or weight loss. She denies an increase in anxiety or stress. Her physical examination is unremarkable with normal blood pressure and heart rate, clear lungs, normal heart tones and abdominal examination, and no reproducible tenderness over the chest. Routine blood work including thyroid function testing was normal. She has had a chest radiograph, an echocardiogram stress test that was negative, and carries no personal or family risk factors for coronary artery disease. She was placed on twice-daily proton pump inhibitors (PPIs) for 1 month with slight improvement. She presents to you for further evaluation. The Problem Chest pain is a common symptom in many esophageal diseases and uniformly more than 30% of patients undergoing coronary angiography for angina-like pain have normal cardiac findings. Unfortunately, the commonality of esophageal disease as a cause of noncardiac chest pain (NCCP) has not been sought uniformly in clinical practice. For example, a recent Olmsted county population based study followed up patients with a diagnosis of NCCP and showed that most patients did not undergo a gastrointestinal evaluation. Furthermore, lack of confirmation of esophageal causes had further consequences in that patients with NCCP thought to be resulting from a gastrointestinal cause still experienced subsequent cardiac events. As a result, from the outset it is imperative to exclude a cardiac cause of the chest pain before pursuing a noncardiac cause (eg, esophageal cause) for the pain. In a large series of patients with gastroesophageal reflux disease (GERD), chest pain was reported in 25% to 60% of cases. Indeed, data from some literature have suggested that up to 80% of subjects with NCCP have some form of esophageal abnormality, of which GERD is most common. Other studies, however, have failed to identify an esophageal cause in almost 40% of patients with chest pain despite use of ph monitoring and provocative testing including balloon distention. Unfortunately, not only might it be difficult to differentiate chest pain of esophageal origin from cardiac origin, it also is difficult to attribute chest pain to a specific esophageal disorder based on clinical characteristics of the pain. A response of chest pain to acid-suppressing medications or a presentation with typical gastroesophageal reflux (GER) symptoms are helpful but by no means completely reliable in predicting the presence of GER-associated NCCP and differentiating GER from cardiac ischemia. In this brief clinical case scenario we define the following: (1) what specific diagnoses cause NCCP; (2) what diagnostic modalities are available for the evaluation of patients with NCCP; and (3) what are the most effective treatments for those patients with either GERD-related or -unrelated NCCP. Esophageal Disorders That Cause Chest Pain Gastroesophageal Reflux Disease GER is the most common cause of NCCP. It is estimated that 60% of these patients will have abnormal findings on prolonged ambulatory ph monitoring. Indeed, Hewson et al reported that 48% of patients with NCCP had an abnormal ambulatory ph study although this increased to 60% if a positive symptom index also was taken into account. In young patients with NCCP, a prevalence of GERD diagnosed using endoscopy and/or 24-hour esophageal ph monitoring was 30%. Even in patients with proven coronary artery disease and atypical chest pain, 67% had proven GERD as documented by ph studies, of these the majority had marked improvement of their symptoms on antisecretory therapy. A more recent study also showed that patients with symptomatic documented coronary artery disease have less chest pain on a PPI as compared with placebo. Abbreviations used in this paper: DES, diffuse esophageal spasm; GERD, gastroesophageal reflux disease; LES, lower esophageal sphincter; NCCP, noncardiac chest pain; PPI, proton pump inhibitor by the AGA Institute /$36.00 doi: /j.cgh

2 296 ARORA AND KATZKA CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 4 Figure 1. Suggested algorithm for evaluation and treatment of NCCP after cardiac causes have been excluded. A role for gastroesophageal reflux in NCCP is also suggested by the favorable response of these patients to acid-suppressing therapy. For example, a randomized controlled trial of patients with NCCP, with documented GER, showed that more than 80% of patients had symptomatic improvement on twice-daily omeprazole as compared with 6% who were on placebo over the course of 2 months. Although such studies presumably have shown efficacy of PPIs as a result of their ability to reduce acid reflux, more recent data using esophageal impedance monitoring also suggest that nonacid reflux also may contribute to esophageal symptoms probably through esophageal mechanoreceptors as opposed to chemoreceptors, which detect acid. This might explain a lack of response of chest pain to acidsuppressing therapy in some patients. Furthermore, some investigators also have postulated a role of bile reflux in patients with chest pain. Whether the proven efficacy of fundoplication in chest pain is a result of suppression of acid or of all reflux, as suggested by these findings, is unclear. It is also unclear why patients with reflux experience chest pain as opposed to heartburn, although there is common overlap of these 2 symptoms in the same patient. One explanation of reflux-induced chest pain is derived from a study of patients using high-frequency intraluminal endoscopic ultrasonography. In this study, patients with chest pain showed longer durations of contraction of the longitudinal muscle when compared with patients with heartburn. These findings give credence to the older concept of reflux-induced esophageal spasm or dysmotility. Other investigators have postulated that patients with NCCP may have an alteration in autonomic function leading to chest pain and tachycardia. Hypersensitive Esophagus Patients with a hypersensitive esophagus are defined by the presence of a normal-appearing esophagus, physiological esophageal acid exposure on ambulatory ph monitoring, but a positive symptom association or index. These patients often describe typical reflux symptoms and the assumption is that these patients do have acid reflux as the root cause of their chest pain but sensory thresholds for esophageal afferent neurons are such that they give rise to reflux sensation in the presence of normal amounts of acid reflux. Their symptom index stands in contrast to patients with gastroesophageal reflux for whom a substantial percentage of acid reflux episodes are asymptomatic. As a result, episodes of reflux not typically felt by healthy volunteers and patients with GERD will be sensed by patients with this hypersensitive disorder. Furthermore, although

3 April 2011 ESOPHAGEAL CHEST PAIN 297 symptomatic reflux episodes in GERD patients with normal esophageal sensation might be perceived as heartburn or mild chest discomfort, those with a hypersensitive esophagus will perceive similar quantities of acid reflux as more painful. Why these patients have altered esophageal sensory thresholds is unclear. Some investigators have suggested that this esophageal hypersensitivity is part of a larger disorder of visceral and perhaps somatic hypersensitivity as evidenced by concomitant functional disorders such as irritable bowel syndrome, fibromyalgia, and related pain syndromes. Although the pathogenesis of chronic pain syndromes and NCCP are poorly understood, it seems that pain hypersensitivity to both non-noxious stimuli (allodynia) and noxious stimuli (hyperalgesia) is present. Some investigators have explained this hypersensitivity by showing that an increase in esophageal chemoreceptor sensory pain function occurs in response to previous sensitizing acid exposures. Other investigators, using cerebral evoked potentials, have shown that this sensitization may be either a sensory afferent or cortical process. It is also interesting to consider that chest pain in these patients may be reproduced by showing a lower sensory and pain threshold to esophageal balloon distention. This would fit with data suggesting that mechanical distention of the esophageal lumen by nonacid refluxate is enough of a stimulus to cause chest pain. Data attempting to show whether this mechanosensitivity is enhanced by previous mucosal acid exposure is conflicting. Functional Heartburn Functional heartburn is different from hypersensitive esophagus in the sense that there is no clear evidence that acid reflux is the cause of the chest pain. The ROME III committee defines functional heartburn by the following criteria: (1) midline chest pain or discomfort that is not burning in quality; (2) absence of GERD; and (30) absence of an esophageal motility disorder. The etiology of functional heartburn or chest pain is unclear. Some investigators have postulated that psychologic factors may be important. For example, studies of patients with NCCP have shown that traits such as somatization, anxiety, panic disorder, poor coping strategy, and major depression are common in these patients. Interestingly, one study confirmed that somatization in patients with NCCP is associated with chest pain in the absence of increased esophageal sensitization to acid. On the other hand, other data have shown that these psychologic factors may lead to changes in esophageal sensory thresholds. Even so, there is most likely also a factor of esophageal hyperalgesia, similar to patients with a hypersensitive esophagus. This is shown by low thresholds of pain to esophageal balloon distention and abnormal cerebral evoked potential and brain imaging in response to balloon distention in patients with functional heartburn. Another potential etiology, as discussed earlier, is suggested by symptoms induced by the reflux of nonacidic components but it is unclear how commonly this accounts for symptoms in patients with functional chest pain, particularly in the presence of effective gastric acid inhibition. Esophageal Motor Disorders The attribution of chest pain to esophageal motility disorders has been difficult because the definition and classification of these disorders has undergone extensive change over the past 3 decades. For example, although nutcracker esophagus was a clearly defined disorder at one point, its clinical relevance is now commonly questioned. Similarly, diffuse esophageal spasm (DES), once considered one of the most common causes of chest pain, is now viewed as a relatively rare disorder and one in which it is difficult to come to a consensus definition. Furthermore, if one looks at manometric evaluations of patients with NCCP, approximately 70% will have a normal study result. A Brazilian study showed that the most common motor disorder seen in NCCP was a hypotensive lower esophageal sphincter (LES) tone. Only when dysphagia is present with NCCP does the chance of diagnosing an esophageal motility disorder increase substantially to 45%. With this in mind, however, esophageal motility disorders remain important in the differential diagnosis of noncardiac chest pain. Achalasia Chest pain is seen in up to 60% of patients with achalasia. Although dysphagia or regurgitation commonly accompanies the chest pain, chest pain alone may be a presenting symptom of achalasia in up to 5% of patients with achalasia. In contrast, within groups of patients undergoing manometric evaluation for chest pain, achalasia is uncommon and present in approximately 2% of patients studied. On the other hand, if dysphagia accompanies chest pain, then 35% of patients will be diagnosed with achalasia. Many investigators have tried to define subgroups of achalasia that are more likely to be associated with chest pain. Earlier studies used the term vigorous achalasia to describe this variant, defined typically by high-amplitude esophageal body contractions putatively associated with an earlier form of achalasia. Unfortunately, reliable prediction of chest pain on the basis of this variant when compared with other forms of achalasia has not been shown. More recently, with the Chicago classification of achalasia, Pandolfino et al ascribed the type III form of achalasia to those patients with chest pain. This high-resolution manometric definition consists generally of prolonged sustained contractions defined by prolonged pressurization. How well this pattern reliably predicts the occurrence of chest pain is unclear. The etiology of chest pain in achalasia is also unclear and may be different from the motility dysfunction. This is suggested by studies showing that therapies effective for dysphagia such as injection of botulinum toxin and pneumatic dilation do not always lead to improvement of the chest pain in patients with achalasia despite improvement in dysphagia and regurgitation. There are reports of a beneficial effect of Heller myotomy on achalasia-related chest pain although results have been inconsistent. Diffuse Esophageal Spasm As discussed, the definition of DES has changed considerably over the past 3 decades. As a result, it is difficult to suggest how commonly this entity presents with chest pain given the marked change in earlier definitions that most likely encompassed many types of motility abnormalities to the present definition in which DES has become a relatively rare diagnosis by the establishment of more strict criteria. Specifically, earlier manometric definitions included simultaneous contractions on more than 10% of wet swallows with accompanying, but not required, criteria of repetitive contractions or contrac-

4 298 ARORA AND KATZKA CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 4 tions of increased duration or amplitude. As a result, this liberal definition of DES accounted for 10% of patients with NCCP. On the other hand, when a stricter definition of DES is used and described manometrically by simultaneous contractions ( 20% of wet swallows), with/without repetitive, prolonged, high-amplitude contractions, or LES abnormalities (incomplete relaxation and high resting pressure), this leads to an estimate of a 2% prevalence of DES in patients with NCCP. Interestingly, similar to achalasia, when dysphagia accompanies chest pain, this prevalence increases to 10%, which follows the suggestion of some that DES may be a variation or a form fruste of an achalasia-like syndrome. Evidence that further supports this concept is derived from the high-velocity contractions that are recorded manometrically in DES patients, the common appearance of simultaneous contractions, and the evolution of this disease into achalasia as described in some patients. With newer technology, it is also important to consider that some investigators are redefining DES. For example, with high-resolution manometry, diffuse esophageal spasm is defined by pressurization front velocity of more than 8 cm/s in more than 20% of swallows. With this definition, DES becomes an even rarer disorder found in only 1.5% of all patients undergoing study. Other investigators defined DES radiographically by nonperistaltic lumen-obliterating contractions commonly associated with impaired opening of the gastroesophageal junction on barium esophagography. A recent study has defined esophageal spasm by cholinergic provocation of longitudinal muscle contraction concordant with chest pain as observed during highfrequency endoluminal ultrasonography. As has always been an issue with DES, without a clear understanding of its pathophysiology or gold standard it remains difficult to define yet remains a potentially viable diagnosis when evaluating patients with noncardiac chest pain. Nutcracker Esophagus Although nutcracker esophagus originally was defined as the occurrence of high-amplitude esophageal peristaltic contractions associated with chest pain and viewed as a spastic disorder of the esophagus, critical evaluation over the years has downplayed its roles. Reasons for this have included the common finding of nutcracker physiology in patients with GERD, the difficulty in ascribing chest pain to these manometric abnormalities in a precise and timed relationship, and the finding of this manometric pattern in asymptomatic patients. Lately, however, with the use of newer technology for studying esophageal motility, nutcracker esophagus is having a potential rebirth. Specifically, intraluminal high-resolution endoscopic ultrasonography studies have shown cholinergic-stimulated asynchrony between circular and longitudinal muscle contraction, which is a unique pattern of movement when compared with healthy controls. Furthermore, the use of high-resolution manometry has led to a completely new classification of patients with nutcracker esophagus based on pressure velocity and magnitude (Table 1). Other investigators have suggested that further patient stratification by the magnitude of contraction amplitude in patients with nutcracker patterns more reliably predicts the association of chest pain to this disorder, with the finding of the highest contraction amplitudes being the most predictive. With this changing target it is difficult to ascribe a prevalence of nutcracker esophagus in patients with NCCP. One study suggested an approximate 10% prevalence Table 1. Classification of Esophageal Motility Disorders Duration of contraction, s Mean distal contractile Peak contractile index, mm Hg/s/cm (DCI) a pressure, mm Hg Presence of peristalsis, % wet swallows LES relaxation (to gastric baseline), Y/N LES pressure, mm Hg Esophageal disorder Normal Y (220) 7 Ineffective esophageal motility 10 Y Failure of peristalsis in distal esophagus Nutcracker phenomenon Y or DES Variable, can be 45 Y Can be Achalasia Usually 45 N Absent No contraction seen Isolated hypertensive LES 45 Variable 70 NOTE. Adapted from Pandolfino et al and Spechler and Castell. DCI, distal contractile integral. a Quantifies the pressure, duration, and length of the smooth muscle esophagus (mm Hg/s/cm). It is calculated by multiplying 3 variables: (1) the length of the distal esophagus (from the transition zone to the proximal aspect of the esophagogastric junction) in cm; (2) the mean esophageal amplitude in mm Hg; and (3) the time taken to reach the gastroesophageal junction in seconds.

5 April 2011 ESOPHAGEAL CHEST PAIN 299 in patients with NCCP who had an abnormal esophageal manometry. It is also still not clear what the pathophysiology of chest pain is in patients with nutcracker esophagus and it may be multifactorial. For example, in addition to acid reflux and motor dysfunction, one study also showed esophageal hypersensitivity to balloon distention in these patients. Nevertheless, it is a diagnosis that currently should be considered in these patients even if defined and specific treatments are lacking. Eosinophilic Esophagitis Eosinophilic esophagitis presenting solely as chest pain appears to be rare, found in only 1 of 105 patients in one series of PPI-unresponsive patients with reflux symptoms. It also is unclear from symptom studies of eosinophilic esophagitis if presentation with chest pain alone is likely because dysphagia is present in more than 80% of adult patients with eosinophilic esophagitis. This is an important consideration because diagnosis of eosinophilic esophagitis is only by endoscopy, which is likely to be a low-yield test when searching for eosinophilic esophagitis in patients with chest pain as their only symptom. Diagnostic Modalities Used in the Evaluation of Noncardiac Chest Pain Symptom Evaluation The symptoms associated with GERD have not been well studied even though it would be an inexpensive method of diagnosing GERD. The problem of basing diagnoses on symptoms alone is that it lacks sensitivity and specificity in general. A German study showed that only heartburn and acid regurgitation were highly specific symptoms in patients with documented GERD (89% and 95%, respectively) but the sensitivity was very low (38% and 6%, respectively). A recent study by Dent et al used a Reflux Disease Questionnaire, which was completed by the family practitioner after the patient visit. The sensitivity of this questionnaire in detecting GERD (as judged by ambulatory ph study and endoscopy) was moderate at 62%. It also was noted that less than half of patients with documented GERD selected heartburn or regurgitation as their main symptom. Unfortunately, symptomatic evaluation of GERD is neither specific nor sensitive when compared with objective data from ph studies or endoscopy. The Proton Pump Inhibitor Test The PPI test, when it was first reported in 1998, held great promise as being both a diagnostic step and a therapeutic modality for patients with NCCP. Since this study, several studies have been performed confirming the value of this test in patients with esophageal acid exposure as a cause of chest pain. Overall, the 7-day PPI test for NCCP has a sensitivity of more than 70% and a specificity of more than 85% as defined by ambulatory ph monitoring. Two recent meta-analyses of randomized controlled trials in NCCP again showed good sensitivity and specificity, thereby confirming the role of the PPI test as an excellent first-line measure for patients with NCCP. It also is cost effective as a first step when compared with other testing such as ph monitoring or endoscopy and avoids the risk of potentially invasive testing. Studies using this method advocate twice-daily dosing for at least 7 days and possibly up to 2 months depending on the frequency of chest pain. To maximize accuracy of the test, a few caveats must be considered. First, depending on the PPI use, patients must take their PPI in a correct fashion relative to meals. Second, it is possible that nighttime chest pain may not be diagnosed as well by the PPI test given the well-known lack of reliable nocturnal acid suppression by most PPIs. Third, if the trial of PPI use has minimal effect with regard to relief of chest pain then the PPI should be discontinued. Conversely, if the PPI trial is effective at relieving chest pain, an attempt should be made to taper the dose to a once-daily PPI. In some patients, the PPI may be discontinued altogether in time. Radiography The utility of barium esophagography for the evaluation of NCCP is dependent on the specific diagnosis that is being sought. For gastroesophageal reflux, radiographic signs tend to be either insensitive or nonspecific. More reliable markers of GERD such as a peptic stricture are found in only 10% to 20% of patients with GERD in general. This number is likely to be far lower in patients with chest pain caused by GERD. On the other hand, common radiographic signs such as provoked or unprovoked free reflux of barium, the presence of a hiatal hernia, or ineffective esophageal motility are nonspecific and commonly seen in normal volunteers. Indeed, ambulatory ph testing of patients with free reflux of barium does not distinguish those patients with or without acid reflux, although studies with multichannel impedance testing have not yet been performed. On the other hand, barium esophagography is an excellent test for diagnosing motility disorders of the esophagus such as achalasia and what may be equivalents of early achalasia or DES, such as a corkscrew esophagus. As discussed, these diseases, let alone radiographic findings, are generally uncommon and should not warrant barium studies as a primary test for evaluation of NCCP unless dysphagia also is present. Endoscopy The role of endoscopy is limited as a diagnostic tool in patients with noncardiac chest pain. In patients with NCCP, endoscopy showed evidence of erosive esophagitis in less than 25% of patients and nearly all had minimal changes of esophagitis (grade 1). By using a national database looking at NCCP and GERD, Dickman et al showed that an endoscopic evaluation for NCCP was normal in 44% of cases compared with 38% of GERD patients having a normal endoscopy. Furthermore, patients with NCCP had less mucosal abnormalities when compared with the GERD group; 19% of the NCCP had esophagitis versus 27.8% in the GERD group and 4% of NCCP patients had Barrett s as compared with 9% of patients with GERD. It seems that endoscopy as a tool to determine the cause of NCCP is limited and when compared with the PPI test is far more expensive. On the other hand, if a patient has dysphagia accompanying chest pain, then the yield on endoscopy is potentially much higher. Potential diagnoses, as discussed, would include reflux with a peptic stricture, eosinophilic esophagitis, and achalasia. Esophageal Manometry Esophageal manometry may be an important test when considering dysmotility disorders affecting the esophagus as a

6 300 ARORA AND KATZKA CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 4 cause of NCCP. A study from a tertiary center showed that 28% of patients with non GERD-related NCCP have some form of motility disorder but whether the identified disorder will be a certain cause of a patient s chest pain is difficult to determine for many of these disorders. These studies showed that the majority of patients with NCCP had a relatively normal manometry (72%). Even so, the manometric abnormalities noted were nonspecific, characterized by nutcracker esophagus or a nonspecific motility disorder predominantly (48% and 36%, respectively). Very few cases of achalasia or diffuse spasm were seen (2% and 10%, respectively). Furthermore, patients rarely report symptoms of chest pain during the study despite abnormalities being present. A more practice-representative study using the Clinical Outcome and Research Initiative study further showed that 70% of patients evaluated for NCCP had a normal esophageal motility study and that a hypotensive LES was the most common abnormality found on testing. A low LES pressure may predispose to GERD and this study reinforced the notion that NCCP is predominantly a GERD-driven issue. Based on these data the American Gastroenterological Association guidelines do not recommend esophageal manometric testing in patients with NCCP alone without concomitant dysphagia and/or strong suspicion of achalasia. This guideline was based on the premise that both NCCP and abnormal motility studies are both intermittent events and the chance of both occurring together would be low. Even when using ambulatory esophageal manometry and ph in hospitalized patients with chest pain attacks, more than 40% had symptoms that correlated with acid reflux and the manometry did not lead to further diagnoses. High-Resolution Manometry High-resolution manometry allows for continuous measurements from a large number of closely spaced sensors with software that is capable of analyzing large volumes of pressure data and is easier to perform than a regular esophageal manometric study because a pull-through is not necessary. The only study reported to date using this technology in patients with possible NCCP was in 2008 by Pandolfino et al. They described a classification of esophageal motility using highresolution esophageal motility, although the report did not state the findings based on symptoms. They stated that patients with chest pain were more likely to have an increase in the distal contractile integral, a combined way of looking at the pressure, duration, and length of the distal esophagus pressure wave but no other data on chest pain patients were presented. At present, there are no data to show an increased diagnostic yield of high-resolution manometry when compared with standard manometry in the evaluation of patients with noncardiac chest pain. On the other hand, if there is suspicion of achalasia, diffuse esophageal spasm, or nutcracker esophagus, high resolution manometry might supply some prognostic information that standard manometry will not. Regarding overall use in these patients, the same guidelines that apply to standard manometry in the American Gastroenterological Association technical review should be applied to high-resolution manometry. Ambulatory ph/impedance Testing The benefit of ambulatory ph testing in evaluating patients with NCCP is to determine the presence of GERD and also if the symptoms correlate with acid exposure in the distal esophagus. Studies using ph monitoring in patients with chest pain showed that more than 50% of patients will have increased esophageal acid exposure. Unfortunately, the documentation of a strong symptom index in patients with reflux-induced chest pain is not as strong when compared with studies of patients with more typical GERD symptoms such as heartburn. This is important to keep in mind because a positive symptom index is found in only about half of the patients with NCCP at best, whereas other investigators have not shown this favorable a result. Consequently, some investigators advocate the use of wireless ph monitoring systems that can record esophageal ph for 48 to 72 hours (with a battery change) as a more sensitive test for chest pain association in these patients. The ability to monitor the ph in the distal esophagus for longer time periods has clearly increased the likelihood of detecting reflux events. Monitoring over 48 hours did increase the sensitivity and specificity to nearly 85% when compared with evaluation at 24 hours (sensitivity, 69%; specificity, 90%). Furthermore, the symptom index and symptom-associated probability scores increased the yield of a positive score by 15% over a 48-hour period as compared with 24-hour data. One interesting area of ph monitoring is in the analysis of weakly acid reflux episodes, which are reflux episodes at a ph of 4 to 7 and their association with reflux symptoms. In one study, 30% of heartburn symptoms in patients with nonerosive reflux disease were associated with weakly acid reflux episodes. Whether this applies specifically to chest pain is not known. The most crucial question in the use of ambulatory ph monitoring is whether it should be performed on or off therapy. For patients with daily symptoms preferably multiple times per day, we tend to perform the study off therapy in an attempt to establish symptom correlation. For those patients with less frequent symptoms, a study performed on therapy will at least document the efficacy of the PPIs to suppress gastric acid and thereby suggest that when symptoms do occur, they are not from esophageal acid exposure. In some patients, testing both on and off PPI therapy may need to be performed. The use of multichannel intraluminal impedance monitoring allows the evaluation of esophageal exposure to gastric reflux (both acid and nonacid) and the symptoms that may be attributable to this reflux. This has been shown to have practical importance in reflux because the presence of the bolus alone in the esophagus, most likely through mechanoreceptors, may cause heartburn. Similarly, nonacidic components of gastric refluxate such as bile acids and pepsin also have been suggested to cause reflux symptoms in the presence of acid suppression. A recent study examining the role of nonacid reflux in patients with nonerosive reflux disease was able to classify patients as having a sensitive esophagus rather than functional heartburn based on a normal acid exposure but a positive symptom score; however, these patients had reflux-like symptoms and chest pain was not described. Based on the data at this time, there is little to suggest that an impedance ph study would be of more benefit than a standard ambulatory ph study in patients with NCCP, particularly in guiding therapy. Part of the reason for this is that there are no prospective data in patients with chest pain such that confirming the presence of medically unresponsive nonacid reflux with impedance measurement should mandate fundoplication or use of medications that augment LES pressure and/or decreased transient

7 April 2011 ESOPHAGEAL CHEST PAIN 301 LES relaxations. Nevertheless, this area of study may increase in importance because a number of studies have shown that patients with functional heartburn (normal endoscopy and ph study) are more sensitive to gastric refluxate in the esophagus as compared with patients with documented esophagitis. Other Modalities High-Frequency Endoluminal Endoscopic Ultrasound It is clear that dysfunction of the circular and longitudinal smooth muscle of the esophagus can result in alteration of the esophageal amplitude and wave form. As discussed, patients with nutcracker phenomenon (high-amplitude esophageal contractions) have been shown to have asynchrony in longitudinal and circular smooth muscle contraction. Furthermore, administration of a cholinergic agent increases the amplitude of the peristaltic wave as well as the thickness of the esophageal wall in normal human study patients and prior studies have shown that edrophonium (a cholinomimetic agent) caused chest pain in patients with NCCP. In addition to these studies, the use of endoscopic ultrasonography also has shown that a group of NCCP patients had sustained muscular contractions of longer than 68 seconds during chest pain periods. These sustained contractions noted on endoscopic ultrasonography were secondary to isometric contraction of the circular muscle, which did not cause luminal constriction and was not related to contraction of the longitudinal muscles. Unfortunately, these are highly sophisticated techniques currently performed for research purposes in only one medical center and thus cannot be used in clinical practice. Provocative Testing There is no clear clinical role for provocative testing in patients with NCCP. Early testing such as infusion with 0.1 N HCl for reflux or induction of esophageal spasm with shortacting acetylcholinesterase inhibitors was neither sensitive nor specific. Studies using esophageal balloon distention to evoke and study esophageal sensory thresholds for pain with or without a functional magnetic resonance imaging of the brain are difficult to perform and standardize and should be confined to research purposes, although some have advocated a place for this testing in routine clinical medicine. Treatment Options for NCCP Gastroesophageal Reflux Treatment for suspected GERD should start with twicedaily PPIs. Depending on the type of PPI used, it may be important to advise patients to take the medication 30 before breakfast and dinner for 1 to 2 months. If there is a favorable response, patients may try to reduce the PPI to once daily. For patients with continued chest pain unresponsive to PPIs but with proven persistent acid reflux with strong symptom correlation on ambulatory ph monitoring, fundoplication may be considered. Fundoplication, however, rarely is required in these patients although the role of antireflux surgery in patients with NCCP has not been studied well. A number of retrospective studies have shown that antireflux surgery can relieve NCCP, however, those patients with typical GERD experienced better long-term chest pain relief than those with atypical GERD symptoms. These retrospective studies from tertiary centers found that patients with atypical GER did poorly and that complications did occur including death. The feeling in general is that the surgical outcome may be poor if patients have failed PPI treatment and have symptoms that are not associated with reflux episodes. Interestingly, an uncontrolled study has shown that a positive symptom index (not always associated with acid reflux) may predict those who will do well after fundoplication. At present, the data are not available to suggest antireflux surgery in patients with atypical GERD symptoms and poor response to PPIs. Motor Disorders Treatments for underlying esophageal motor disorders are disease specific. For achalasia, treatments aimed at relief of dysphagia unfortunately do not relieve chest pain. More specifically, although treatments such as injection of botulinum toxin, pneumatic dilation, and Heller myotomy are effective in relieving dysphagia, chest pain commonly is unaltered after successful outcome. Part of the reason for this is a lack of understanding of the pathophysiology of chest pain in achalasia. Agents such as anticholinergics (eg, hyoscyamine sublingually), nitrates (isosorbide dinitrate or nitroglycerin tablets), and calcium channel antagonists (nifedipine 10 mg orally or sublingually) may be tried but there are no controlled data to support their efficacy in chest pain derived from achalasia. A similar regimen is suggested for diffuse esophageal spasm but, again, without clear proof of efficacy. One study advocated the use of multiple injections of botulinum toxin injection throughout the esophageal body but this was an uncontrolled trial of 29 patients with NCCP, although there was an improvement in symptoms over several months. For patients with nutcracker esophagus, the first step is to evaluate for gastroesophageal reflux either by ph monitoring or treatment with PPIs, given their common association. If reflux is not shown to exist in these patients, then medications similar to those used in DES and achalasia may be tried. Anecdotal experience also has suggested some success with low-dose tricyclic antidepressants, similar to those patients with hypersensitive esophagus and functional heartburn. Hypersensitive Esophagus and Functional Heartburn The first-line treatment for patients with hypersensitive esophagus is acid suppression. This may be a difficult task in these patients because their esophageal sensitivity almost mandates complete control of gastric acid secretion to prevent the reflux of any acid into the esophagus. Acid suppression also will not relieve those symptoms associated with nonacid reflux. Medications used to decrease transient LES relaxations such as GABA antagonists (eg, baclofen) may be tried preprandially but side effects such as fatigue often prohibit use of these agents. Fundoplication has been reported to be effective in these patients but data are limited to a small uncontrolled trial of 19 patients. Tricyclic antidepressants have been used for decades for chronic pain syndromes. These medications decrease the pain thresholds in normal subjects through both peripheral and central neural pathways and possibly involve several chemical mediators including acetylcholine, serotonin, and norepineph-

8 302 ARORA AND KATZKA CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 4 rine. Studies have been performed in normal volunteers showing that low doses of tricyclic antidepressants will increase the threshold for pain sensation in response to esophageal balloon distention. As a result, small studies have shown a benefit of tricyclic antidepressants for the treatment of NCCP. It is unclear if these patients have hypersensitive esophagus or functional heartburn. Tricyclic antidepressants may be started at 10 mg before bedtime and increased by 10 mg weekly to the point of efficacy, side effects, or 50 mg. Dividing the doses into morning and evening doses sometimes may prove effective. Trazodone also has been used for NCCP with some effect. Starting doses are 10 to 25 mg and may be increased to 50 to 75 mg. Recent studies have included the use of selective serotonin reuptake inhibitors such as sertraline, paroxetine, and citalopram, and have shown that there is a decrease in feeling esophageal pain during balloon distension in healthy volunteers and that patients with NCCP are less symptomatic while taking these medications. It is unclear if the beneficial effect of selective serotonin reuptake inhibitors is secondary to esophagealspecific effects or to overall improvement in global assessment. Trials specifically examining the role of serotonin in NCCP are lacking. Sertraline did decrease chest pain scores in patients with NCCP in a 2-month trial starting at 50 mg/day and increasing up to 200 mg (side effects of restlessness and delayed ejaculation was noted). Recently, a study showed that the serotonin-norepinephrine reuptake inhibitor, venlafaxine (75 mg/ day) improved chest pain symptoms in young patients with NCCP. The use of paroxetine was evaluated in patients with NCCP and no change in patient-reported pain was noted although the clinical global impression as judged by a physician did improve in those patients on treatment. Psychological and Alternative Medicine Treatments Patients with NCCP show a higher frequency of psychological distress, but whether this is a result of NCCP or a cause is difficult to determine. However, cognitive behavioral therapy may improve symptoms in patients with NCCP, and these benefits may be sustained for several months after ceasing therapy. Hypnotherapy also has been shown to be effective in improving pain and well-being in patients with NCCP. Other alternative therapies including acupuncture and transcutaneous nerve stimulation have not been studied formally although a survey has suggested that patients with NCCP would willingly try these avenues. Adenosine Receptors It has been shown that adenosine is involved in accentuating somatic and visceral pain perception. In healthy volunteers, intravenous adenosine induced chest pain at lower esophageal distension volumes, and induced visceral hypersensitivity. In an open-label study theophylline (at 6 mg/kg/day in 2 divided doses), an adenosine antagonist, improved pain thresholds in patients with NCCP who were being studied with esophageal balloon distension. A more recent study by the same group showed that oral theophylline (200 mg twice daily) did improve chest pain symptoms significantly in patients with NCCP. The mechanism by which theophylline reduced NCCP in patients with a hypersensitive esophagus is unknown as yet. Conclusions The diagnosis of NCCP often is challenging given the large number of potential diagnoses and the difficulty in identifying a specific etiology. The first and foremost goal in evaluating patients with NCCP is to definitively exclude a cardiac cause. Once this has been done these patients should be evaluated for gastroesophageal reflux either by empiric treatment with a PPI or with ambulatory ph monitoring, often combined with endoscopy. Standard or high-resolution esophageal manometry may be helpful to evaluate for achalasia and diffuse esophageal spasm but these are not commonly found, particularly in the absence of dysphagia. Although nutcracker esophagus may be re-emerging in the esophageal world, its physiological significance is still unclear. Finally, esophageal sensory disorders must be considered a likely cause in these patients either in the form of the hypersensitive esophagus or functional heartburn. Given the range of disorders with distinct pathophysiologies, treatment strategies are disease specific, although often not well proven in terms of efficacy but for treatment of GERD. 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