Diagnosis and Management of Functional Heartburn

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1 nature publishing group CLINICAL AND SYSTEMATIC S 53 CME Diagnosis and Management of Functional Heartburn C hr ist ine Hache m, M D 1 and Ni chol as J. Sha he e n, M D, M PH 2 Heartburn is among the most common gastrointestinal symptoms presenting to both generalist physicians and gastroenterologists. Heartburn that does not respond to traditional acid suppression is a diagnostic and therapeutic dilemma. In the era of high utilization of proton pump inhibitors, a substantial proportion of patients presenting to the gastroenterologist with chronic symptoms of heartburn do not have a reflux-mediated disease. Subjects without objective evidence of reflux as a cause of their symptoms have functional heartburn. The diagnostic role of endoscopy, reflux and motility testing in functional heartburn (FH) patients is discussed. Lifestyle modifications, pharmacological interventions, and alternative therapies for FH are also presented. Recognition of patients with FH allows earlier assignment of these patients to different treatment algorithms, which may allow greater likelihood of success of treatment, diminished resource utilization and improved quality of life. Further data on this large and understudied group of patients is necessary to allow improvement in treatment algorithms and a more evidence-based approach to care of these patients. Am J Gastroenterol 2016; 111:53 61; doi: /ajg ; published online 5 January 2016 INTRODUCTION Heartburn, described as retrosternal burning, interferes significantly in the quality of life of many patients, and is a term that both medical and lay people easily recognize. Heartburn affects most of the US population at some time or another with 10 20% of patients complaining of daily heartburn. However, 25 40% of patients complaining of heartburn continue to have symptoms despite daily proton pump inhibitor (PPI) use ( 1,2 ). A substantial proportion of patients with heartburn symptoms who do not respond to PPI therapy have normal esophageal acid exposure, and no correlation between reflux events and their symptoms. This group of patients is termed functional heartburn, to differentiate it from groups in which there is objective evidence of reflux as the etiology of symptoms. Heartburn may be the presenting symptom of a heterogeneous group of disorders only some of which are related to gastroesophageal reflux disease (GERD). Although commonly invoked, erosive reflux disease (defined as esophageal mucosal ulceration or erosion on endoscopy) is actually present in only a minority of patients presenting with heartburn ( Figure 1 ). Non-erosive reflux disease (NERD) is characterized by reflux symptoms in the absence of esophageal mucosal breaks, with objective evidence of pathological levels of gastroesophageal reflux on ph or ph-impedance monitoring. In contrast, patients with esophageal hypersensitivity demonstrate normal esophageal acid exposures but a positive correlation between reflux events and symptoms, as documented by a symptom index >50%, and/or a symptom association probability of >95%. Finally in functional heartburn (FH), heartburn occurs in the setting of normal endoscopic findings with no correlation of symptoms with objective testing. The Rome III criteria define FH as burning retrosternal discomfort or pain without evidence of GERD for at least 3 of the last 6 months ( 3 ). Further confusing the literature is the inconsistent use of the above terms. Investigators sometimes describe endoscopy-negative reflux disease (ENRD), a catchall term for any patient with reflux symptoms investigated with endoscopy and found to be without endoscopic stigmata of reflux. Additionally, the symptom(s) necessary for inclusion in one of the above endoscopically normal subgroups varies from study to study. For instance, some investigators require the presence of heartburn for inclusion in ENRD studies, whereas others may include subjects with solely symptoms of regurgitation and other symptoms. Despite the somewhat confusing nature of this literature, precise definition of the patients disease categorization is essential to understand and apply the findings of studies to patient care. Importantly, the differentiation of these conditions must occur in the absence of potent acid suppressive therapy, given that PPI therapy will convert the majority of patients with erosive esophagitis to a normal endoscopic appearance and lead to misclassification of these patients. EPIDEMIOLOGY Some series have suggested FH affects adults of all ages but more commonly after age 40 and women disproportionately ( 4,5 ). This 1 Division of Gastroenterology, St Louis University, St Louis, Missouri, USA ; 2 Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Correspondence: Christine Hachem, MD, Division of Gastroenterology, St Louis University, 3635 Vista Avenue, Firmin Desloge Tower, St Louis, Missouri 63110, USA. chachem@slu.edu Received 9 June 2015 ; accepted 14 October by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

2 54 Hachem and Shaheen Heartburn NERD 40% Normal EGD 65% Hypersensitive esophagus 35% Functional heartburn 25% No dysplasia 83% Barrett s esophagus 3 5% Low-grade dysplasia 7% High-grade dysplasia/eac 10% Erosive esophagitis 20 30% Figure 1. Distribution of fi ndings in patients with heartburn undergoing endoscopy ( ). EGD, esophagogastroduodenoscopy; NERD, non-erosive reflux disease. LA class A/B 81% LA class C/D 19% may be more a reflection of healthcare seeking behaviors than true demographic distribution. The majority of patients complaining of heartburn have normal endoscopic exams ( 6 ). One recent study reported 91% of patients with suspected GERD had a normal endoscopy and approximately one-third of these patients had a diagnosis of FH when ph testing was used ( 7 ). Multiple studies have demonstrated that those with objective evidence of reflux tend to be older, male, and smokers in comparison to patients with FH ( 5,7,8 ). Anatomically, patients with objective reflux or complications of reflux disease have increased prevalence of hiatal hernia and decreased lower esophageal sphincter tone ( 9 ). Increased body mass index (>25 kg/m 2 ) is also associated with PPI failure in patients with acid reflux compared with those patients with hypersensitive esophagus or FH ( 10 ). These findings highlight the divergent pathophysiology of patients with heartburn symptoms; as FH patients do not have symptoms that are acid-mediated, demographic and anatomic factors associated with acid reflux are less commonly found in these patients. However, demographics do not reliably distinguish subgroups of patients suffering from heartburn. Understanding the epidemiology and pathogenesis of patients with FH may allow early recognition of these patients and help anticipate and avert therapeutic failure. PATHOPHYSIOLOGY Visceral hypersensitivity Abnormally elevated esophageal acid exposure, by definition, does not have a role in symptoms of FH. As reflux events are not temporally associated with the generation of symptoms, it is unclear the extent to which FH is truly an esophageal phenomenon, as opposed to a neuropathic or psychosomatic issue. Although we differentiate esophageal hypersensitivity from FH, some symptoms in FH patients may still be related to visceral hypersensitivity of esophageal pain receptors to normal stimuli. Abnormal responses to balloon distention and intra-esophageal acid perfusion with abnormally high levels of pain are seen in patients with FH ( 11 ). In fact, hypersensitivity in these patients may not be site specific, as patients with functional gastrointestinal (GI) disease often demonstrate heightened visceral hypersensitivity outside the main organ of symptoms ( 12 ). However, others have suggested that symptoms may be a result of heightened sensitivity of mechano-receptors and chemoreceptors in only some patients, as not all FH patients demonstrate a similar increase in chemoreceptor sensitivity ( 8 ). Central neural mechanisms have also been postulated to have a role in FH ( 11,13 ). Patterns of cortical evoked potentials in FH patients have been identified, which may provide further evidence of central visceral afferent sensitization ( 11 ). Esophageal dysmotility In addition, motility testing in patients with FH identifies nonspecific manometric findings in up to 2/3 of patients ( 4 ). The most common finding is either weak or frequent failed peristalsis leading some authors to suggest that an underlying motility disorder could have a role in the pathophysiology of FH. The extent to which these findings are truly pathogenic, as opposed to epiphenomena, is not clear. Regardless of the utility of motility studies to discern discrete patterns indicative of FH, these studies are useful in ruling out motility disorders, which may cause refractory heartburn symptoms, such as achalasia. FH as a possible manifestation of psychiatric disease The importance of psychiatric issues in the generation of FH symptoms may be considerable. Patients with FH demonstrate high rates of anxiety with fewer social support structures, compared with patients with good symptom correlation between reflux events and symptoms ( 14 ). Shared traits with other functional bowel disorders, such as somatization and altered autonomic function, have also been noted ( 8 ). Although concurrent psychiatric disease is not likely to be the primary factor in most patients with FH, these associated factors certainly, if not recognized and controlled, may aggravate symptoms of FH and serve as a potential therapeutic target for improving the quality of life of patients with FH. CLINICAL PRESENTATION AND DIAGNOSIS FH is often suspected by lack of response to aggressive acid suppressive therapy, usually defined as twice daily dosing. In addition to absence of pathologic reflux, motility disorders and structural abnormalities must be excluded as a prerequisite for a diagnosis of FH (15 ). The frequency and severity of the heartburn symptoms appear to be stable over time, and the low quality of life scores seen in patients with FH are similar to patients with end-stage renal disease ( 4,16 ). Approximately 40 80% of patients with ENRD report problems in eating/drinking, sleeping, energy, and anxiety ( 17 ). Unfortunately, demographics and symptoms cannot distinguish between patients with FH and true refractory The American Journal of GASTROENTEROLOGY VOLUME 111 JANUARY

3 Diagnosis and Management of FH 55 heartburn ( 7 ) or those patients with functional dyspepsia ( 18 ) with sufficient accuracy to allow for clinical decision-making solely in these factors. Also, up to 2/3 of patients with FH endorse other gastrointestinal (GI) symptoms, most commonly, belching, bloating, and postprandial fullness. Some studies note significantly increased prevalence of dyspeptic symptoms (postprandial fullness, bloating, early satiety, and nausea) in patients with FH as compared with NERD or hypersensitive esophagus ( 19 ). In fact, patients with FH on average report >6 upper GI symptoms. In addition, a higher prevalence of irritable bowel syndrome and somatization has been seen in FH patients compared with NERD patients ( 20 ). Patients often undergo extensive testing to evaluate heartburn if there is inadequate response to optimal acid suppressive therapy, as testing differentiates FH from refractory acid reflux. Optimal acid therapy is not well-defined in the literature. In the setting of objective acid testing, optimal therapy may be considered adequate control of acid by reflux testing. However, a simple and more often used definition for optimal acid suppression is lack of symptoms in response to acid suppression (defined as twice a day proton pump inhibition) ( 21,22 ). Two commonly performed tests in evaluating heartburn are upper endoscopy and reflux testing. Endoscopy helps to assess for complications of acid reflux such as esophagitis, Barrett s esophagus, or esophageal cancer. It should be noted that while endoscopy for refractory reflux symptoms is commonly performed, endoscopy for patients with solely dyspeptic symptoms can be delayed if alarm symptoms are absent and patients are below 55-years-old, according to national guidelines ( 23 ). Endoscopy is often performed on acid suppressive therapy or after a course of acid suppression, with most patients undergoing a therapeutic trial of PPI therapy of 2 months duration before testing. Endoscopic mucosal biopsies may help distinguish patients with NERD from FH, as dilated intercellular spaces in patients on acid suppressive medications can be a microscopic marker of reflux and esophageal damage associated with NERD which is less commonly found in patients with FH ( 24 ). The presence of dilated intercellular spaces may predict lack of response to acid suppression ( 25 ). However, these findings are not adequately sensitive or specific to use in the diagnostic algorithm, and routine esophageal biopsy as a means of making a diagnosis of FH is not recommended. On the other hand, biopsies to rule out eosinophilic esophagitis, especially in those who endorse dysphagia and heartburn, are important, as eosinophilic esophagitis may mimic symptoms of refractory heartburn. A diagnosis of FH relies on assessment of acid exposures but endoscopy alone is inadequate for assessing acid exposure. ph testing is an integral component to evaluating patients with refractory heartburn. ph testing should be performed off acid suppression, as acid suppression can convert acidic refluxate into neutral refluxate, and the majority of patients on acid suppression will have a normal ph test ( 26,27 ). Sensitivity and specificity of ph testing for the diagnosis of GERD have been reported to be 77 and 92%, respectively, with poor negative predictive values ( 28 ). Also, the reliability of ph testing has been questioned with variability in repeat tests in the same individual ( 29 ). In addition to acid exposure data, measures of symptom association such as the symptom index, the symptom association probability, and the symptom sensitivity index are fraught with misinterpretation. Significant controversy exists in the value of these tests and they are poorly validated tools for identifying reflux ( 30 ). In fact, a true diagnostic gold standard for FH may depend on the outcomes of multiple tests, as even an endoscopy negative, ph-negative patient may still have reflux disease due to inadequacies of available tests. Few studies have assessed the added utility of ph-impedance parameters in distinguishing refractory NERD patients from FH patients. ph-impedance also introduces a new category of patient the patient who has normal acid exposures, normal total numbers of reflux events, and no correlation between acidic reflux events and symptoms, but a positive correlation between non-acidic reflux events and symptoms. The most appropriate classification of such patients is unclear. Some have classified such patients as having true reflux-mediated disease rather than FH ( 31 ). Specifically, a large study in endoscopy-negative heartburn patients found 12% of patients could be re-classified as NERD patients due to positive symptom association to nonacid reflux when both acid and nonacid reflux were assessed ( 32 ). A better understanding of the prognostic value of ph-neutral reflux, and the response of such patients to therapy, is essential to optimizing treatment approaches. The assessment of both acid and non-acid reflux correlation with symptoms may allow us to select patients who would benefit from anti-reflux surgery or an endoscopic anti-reflux procedure ( 33 ). At present, the data available are insufficient to answer this question. There may be other uses of data from esophageal impedance studies as well. For instance, baseline impedance levels may help to distinguish FH and hypersensitive esophagus, in that subjects with hypersensitive esophagus generally have lower impedance values (34 ). This differentiation might impact treatment approaches, as the diagnosis of a hypersensitive esophagus demonstrates a more favorable response to acid suppression than FH. However, there is no consensus on the diagnostic criteria for ph-impedance testing in FH patients. The value of esophageal motility testing is similarly unclear in this patient population, however, it should be considered following a negative upper endoscopy to rule out a motility disorder as the cause of symptoms. Some data suggest that a substantial minority of subjects with PPI-refractory reflux symptoms have motility disorders ( 35 ). Because patients with FH often endorse a variety of other GI symptoms, this test may be especially useful in those who also complain of dysphagia or non-reflux-like chest pain. In addition, other causes of heartburn not responding to acid suppression should be considered such as cardiac, biliary or pulmonary etiologies, and be worked up as appropriate. Table 1 highlights a variety of potential explanations for refractory heartburn symptoms. In summary, the sensitivity and specificity of heartburn symptoms for GERD is far from ideal ( 36,37 ). Testing to discern FH from other causes of heartburn includes esophagogastroduodenoscopy (EGD), ph or ph-impedance studies, and motility testing. The limitations of these studies, and their operating characteristics, must be taken into account when evaluating patients in whom FH is a consideration. A diagnostic algorithm is suggested for evaluating patients with refractory heartburn in Figure by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

4 56 Hachem and Shaheen TREATMENT Lifestyle changes By definition, FH is not associated with pathologic levels of esophageal acid exposure. Despite a lack of association with reflux, an anti-reflux diet is often recommended to patients with FH, including avoidance of meals high in fat, acid, or spice. There are no randomized controlled studies to support these recommendations and the few studies from which these recommendations are adopted are largely based on cohort/retrospective studies in GERD patients ( 38 ). Other lifestyle changes, such as elevation of the head of the bed, avoidance of late day meals, and weight loss are similarly poorly supported in this patient population. Despite this lack of evidence, identifying triggers may be key to treating symptoms and improving quality of life in some patients. Evaluating for concomitant functional bowel diseases is an important aspect of care as FH is rarely found in isolation. In addition, recognition and treatment of co-existing psychological features such as anxiety, emotional lability, and poor social support are fruitful targets for therapy ( 14 ). Stress has been demonstrated Table 1. Differential diagnosis for heartburn not responding to acid suppression Ongoing acid refl ux due to insuffi cient acid suppression Esophageal hypersensitivity FH Non-acidic or weakly acidic refl ux Eosinophilic esophagitis Gastroparesis FH, functional heartburn. Peptic ulcer disease Esophageal motility disorders Esophagitis of any etiology Esophageal cancer Cardiac etiologies Biliary pathology Pulmonary pathology to alter esophageal sensitivity and it may be a natural trigger in patients with FH. In one study, FH patients (defined by poor correlation of acid reflux and symptoms) displayed significantly higher levels of trait anxiety and hysteria; improvement in psychosocial status may improve therapeutic responses ( 14 ). Acid suppression Although neither abnormal esophageal acid exposures, nor temporal association with reflux events is present in FH, clinicians often use acid suppression as the first pharmacological intervention in FH patients. This is usually done empirically, before ph testing documenting lack of association between reflux and symptoms. Although ph testing suggests that this maneuver should be largely unsuccessful after a diagnosis of FH has been made, response rates of ~50% in FH patients have been reported ( 7 ). Why such patients respond to acid suppression is unclear. Certainly, ph-impedance testing is associated with a false negative rate with reported sensitivities of 66% ( 39 ) and some responders may be true NERD patients in whom ph-impedance testing inappropriately failed to detect pathologic reflux. Another reason for response to PPI therapy in FH patients may be misclassification of visceral hypersensitivity patients as FH patients. Patients may not be diligent in recording events during ph studies ( 40,41 ). Therefore, some patients classified as FH may truly have an association between symptoms and reflux which was not detected by the study. It would not be surprising for such patients to respond to acid suppression. In addition, the standardization of acid exposure is based on studies of healthy controls and patients with erosive esophagitis. We do not know the minimum acid exposure necessary to cause symptoms and it likely varies from person to person. Therefore, a normal ph profile and a negative symptom index may not rule out pathology in all patients. Finally, some subgroup of patients with FH who do respond to acid suppression likely have this response as a placebo effect. We know from Refractory heartburn (unresponsive to 2-month trial of PPI) EGD Abnormal Treat underlying condition Normal ph-impedance + Reflux ± Symptom correlation Reflux + Symptom correlation Reflux Symptom correlation GERD/NERD Esophageal hypersensitivity Motility testing Normal Functional heartburn Abnormal Motility disorder Figure 2. Diagnostic algorithm for refractory heartburn. EGD, esophagogastroduodenoscopy; GERD, gastroesophageal refl ux disease; NERD, non-erosive reflux disease; PPI, proton pump inhibitor. The American Journal of GASTROENTEROLOGY VOLUME 111 JANUARY

5 Diagnosis and Management of FH 57 Table 2. Controlled studies evaluating interventions in refractory heartburn patients Patients enrolled Intervention Comparator Study design ( n ) Duration Primary outcome variable Outcome Rome II criteria a for FH ( 43 ) Ranitidine 150 mg b.i.d. Placebo RPCT cross-over (18) 7 days Time to sensation and/or pain with acid infusion or balloon distention, and/or severity of pain after ranitidine therapy on a mm VAS b and 5-point Likert scale (0 4) Ranitidine increased time to pain with acid perfusion by 29% compared with placebo; ranitidine positively altered sensory parameters; ranitidine did not change barostat balloon distention sensory parameters Rome III c criteria for FH ( 45 ) Nortriptyline 25 mg (PamelorTM; Patheon, Whitby, Ontario, Canada), or overthe-counter melatonin 6 mg at bedtime for 3 months (and omeprazole 20 mg daily and lifestyle modifi cations) Placebo (omeprazole 20 mg daily and lifestyle modifi cations) RPCT parallel (60) 3 months GERD symptoms (GERD-HRQOL scores on 10 questions with a 0 5 score) Melatonin resulted in improvement in GERD-HRQOL: % improvement in heartburn symptoms: 75% (melatonin) vs. 45% (placebo) vs. 20% (nortryptyline; P =0.015) Heartburn and normal endoscopy who failed once daily PPIs ( 47 ) Fluoxetine or omeprazole Placebo RPCT parallel (144) 6 weeks GERD symptoms (daily diary on a 0 5 point scale), effi cacy (The patient assessment of upper gastrointestinal disorders-symptom severity index-20 items covering six subscales with 0 5 point score) Fluoxetine superior to omeprazole and placebo in heartburn-free days 35.7 (fl uoxetine) vs (omeprazole) vs (placebo) P <0.001 FH defi ned by Rome II criteria a with symptoms 12 weeks in the last 12 months ( 48 ) 5HT-4 partial agonist tegaserod 6 mg b.i.d. Placebo RPCT cross-over trial (42) 2 weeks Pain severity for balloon distention on a 100-mm VAS b and Bernstein sensory test on a 5-point Likert scale Tegaserod reduced esophageal symptoms through increased balloon pressure to pain by 9% ( P =0.04), no change on pain with acid infusion NERD with a partial response to PPI (GERD symptoms, negative endoscopy) ( 50 ) AZD mg oral 1 dose Placebo RPCT (12) Single dose (1) Effect (as measured on a 0 10 VAS b ) on pain response to esophageal heat stimulation; (2) distension and electrical current; (3) somatic pain tolerance to heat and deep pressure; and (4) safety and tolerability profi le (adverse events during treatment up to 8 h after dose) AZD 1386 had (1) no analgesic effect on esophageal heat pain, (2) no analgesic effect on esophageal pain evoked by distension or electrical current, (3) a heat-specifi c analgesic effect in response to somatic pain, and (4) an acceptable safety and tolerability profi le Refractory heartburn d : 3-month history of GERD-related symptoms at least 2 days per week while taking standard-dose PPI (omeprazole 20 mg once daily) and normal EGD ( 55 ) Acupuncture and omeprazole 20 mg daily Omeprazole 20 mg b.i.d. Randomized parallel group trial (30) 4 weeks GERD symptoms (GERD Symptom Checklist-duration, frequency severity, and intensity), Quality of life (SF-36) Acupuncture +PPI resulted in improvement in mean heartburn scores (day time ( P <0.001), night time ( P <0.001) and regurgitation ( P <0.001)), no change with PPI only group in clinical end points EGD, esophagogastroduodenoscopy; FH, functional heartburn; GERD, gastroesophageal refl ux disease; HRQOL, health-related quality of life; NERD, Non-erosive refl ux disease; PPI, proton pump inhibitor; RPCT, randomized placebo-controlled trial. a Rome II criteria: 12 weeks of burning retrosternal discomfort or pain, absence of pathological refl ux, or motility disorder. b Visual analog scale. c Rome III criteria: with negative 24 h ph testing, motility testing, and endoscopy. d Refractory heartburn: 3-month history of GERD symptoms at least 2 days per week while taking omeprazole 20 mg daily. No evidence of erosive esophagitis, Barrett s esophagus on EGD by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

6 58 Hachem and Shaheen placebo-controlled trials in other functional bowel disorders that the placebo effect can be substantial in these patients ( 42 ). One compelling additional explanation for the use of acid suppressive therapies in patients with FH is that they may provide benefit beyond acid suppression. A randomized controlled study demonstrated benefit of a single dose of ranitidine in decreasing esophageal hypersensitivity in FH ( 43 ). Eighteen patients with FH were given oral ranitidine 150 mg b.i.d. or placebo for 7 days. Barostat balloon distention and acid infusion testing was compared between day 1 and 7. Patients who received ranitidine had increased time to pain with acid infusion and positive alterations in sensory parameters. The authors suggested that the underlying mechanism was not acid suppression but instead secondary to the ability of H2RA receptors in the esophagus to modulate pain thresholds. Whether this postulated mechanism accounts for a substantial proportion of the observed benefit of these medications is currently unclear. Other pharmacological interventions Despite the common nature of the disorder, there are limited controlled studies of pharmacological therapies for FH patients. FH patients are often excluded in trials of medications for GERD therapy because the mechanism of symptom generation is poorly understood. Also, most GERD therapies target either acid suppression or motility enhancement, neither of which may be mediators of symptom generation in FH. However, several trials have assessed interventions for either FH patients, or the larger category of ENRD. The quality of evidence by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria is low or moderate quality for these studies ( 44 ). Table 2 highlights controlled studies performed to evaluate refractory heartburn. Modulation of pain perception Several studies have attempted to improve symptoms in patients with FH. Because of the overlap of symptoms and shared pathophysiology, much of the treatment of FH is derived from studies assessing related functional disorders and has focused on improving visceral hypersensitivity. Physicians often rely on neuromodulating therapies. Common neuromodulating agents include tricyclic antidepressants and selective serotonin uptake inhibitors. Melatonin is another drug that has potential anti-nociceptive properties through interaction with dopaminergic, adrenergic, and serotonergic receptors ( 45 ). In one study, patients with FH as defined by Rome III were randomized to placebo, nortryptyline (25 mg), or melatonin (6 mg) for 3 months. Patients who received melatonin had a significant improvement in heartburn symptoms as compared with patients with nortryptyline or placebo and fewer adverse events. Little other objective evidence exists; a recent systematic review demonstrated no randomized controlled studies or case reports evaluating other antidepressants in FH ( 46 ). Data from larger subgroups of patients which contain FH subjects are available. Ostovaneh et al. (47 ) demonstrated benefit of fluoxetine in ENRD (with heartburn who failed daily PPI), measured as an increase in heartburn-free days. In this study, 144 adult patients with heartburn for at least 6 months but incomplete response to PPIs were randomized to fluoxetine (20 mg), omeprazole (20 mg), or placebo once daily for 6 weeks. The primary end point was the percentage of 24 h heartburn-free days in the last 14 days of the trial compared with 1 week before randomization. The primary end point of heartburn-free days was significantly greater in fluoxetine compared with omeprazole and placebo groups. In subgroup analysis, there was a significant increase in percentage of 24 h heartburn-free days for fluoxetine compared with both omeprazole and placebo in the ph-negative subgroup but no significant difference between treatments in the ph-positive subgroup. Because of the differential response based on ph testing the authors suggest that this response might be also seen in FH patients. This may be related to fluoxetine s ability to treat concomitant psychological triggers which may be at play in FH. Another randomized controlled study revealed a benefit of tegaserod (6 mg b.i.d.) in the management of FH thought to be mediated by the drug s inhibition of visceral sensitivity ( 48 ). This was a double-blind, placebo-controlled cross-over study where 42 FH patients, identified by Rome II criteria and with baseline hypersensitivity to mechanical stimuli, underwent a 2-week treatment period (tegaserod or placebo) followed by cross-over 2-week alternate treatment period. The primary aim was to evaluate tegaserod on pain/discomfort thresholds to esophageal mechanical distention as measured by esophageal balloon distention at the end of each 2-week treatment period. Increased pain thresholds and improved symptoms were noted over placebo. However, this drug is no longer commercially available. Modulation of esophageal pain receptors is another therapeutic target. Transient receptor potential vanilloid 1 is a nociceptor that is responsive to noxious heat and acid and may be upregulated in esophageal pain ( 49 ). Two randomized studies evaluated singledose oral AZD1386 effects on esophageal pain through its role as a transient receptor potential vanilloid 1 antagonist ( 50,51 ). The first study evaluated single-dose oral AZD1386 (30 and 95 mg) vs. placebo in 22 healthy men ( 51 ). Patients underwent a single oral dose of treatment before undergoing mechanical, electrical and acid stimulation. Stimulation consisted of a probe with a bag placed into the lower esophagus which was then heated, distended, or electrically stimulated to provoke moderate pain to test visceral pain ( 51 ). Tolerance to acid stimulation, measured as the volume of acid tolerated, and assessments of heat, mechanical and electrical stimulation were also performed before and after acid infusion. Between treatment periods, a 10 day wash out period was administered. The primary outcome of increased esophageal heat pain thresholds in response to acid-induced hyperalgesia of the esophagus was demonstrated with both doses of AZD1386, but secondary outcomes of effect on esophageal pain in response to acid, distention, or electrical current were not demonstrated. This finding supports the hypothesis that AZD1386 has a receptor specific analgesic effect rather than a generalized analgesic effect (51 ). A second study evaluated single-dose AZD1386 (95 mg) in NERD patients who had a partial response to PPI despite >6 weeks of PPI therapy ( 50 ). Fourteen patients were randomized to AZD1386 (95 mg) vs. placebo and each patient s esophagus underwent stimulation with heat, distention, and electrical current on treatment The American Journal of GASTROENTEROLOGY VOLUME 111 JANUARY

7 Diagnosis and Management of FH 59 Functional heartburn Lifestyle modifications (trigger avoidance, identify psychosocial features) Acid suppression Neuromodulation (melatonin vs. TCA vs SSRI) Alternative therapies (biofeedback or acupuncture or hypnotherapy) Figure 3. Therapeutic algorithm for functional heartburn (FH) after diagnosis of FH made. days. In this study, no effect of AZD1386 was seen 1.5 h after drug administration in response to heat stimulation of the esophagus and no effect in response to distention and current in the esophagus. A heat-specific analgesic effect in response to somatic pain was the only effect seen in this population. Unfortunately, many of these drugs are not clinically available. The studies above are also limited by patient numbers as well as the short-term nature of the work. In addition, many studies do not differentiate between FH, GERD, and dyspepsia. in heartburn catastrophizing ( P =0.06) was reported. The authors concluded that esophageal directed hypnotherapy is a feasible and acceptable therapeutic option for patients with FH. In another study, 10 acupuncture sessions over 4 weeks were administered to patients with refractory heartburn (symptoms despite daily omeprazole) ( 55 ). Comparison was made to doubling the PPI dose vs. single daily PPI and acupuncture. Acupuncture resulted in significant improvement in heartburn symptoms as compared with doubling the PPI dose. The authors hypothesized that this effect may be related to the effect of acupuncture on visceral hypersensitivity. Figure 3 identifies a suggested therapeutic algorithm for patients diagnosed with FH. Outcomes Reassurance is key, as the diagnosis of FH is associated with a benign course clinically. By definition, these patients do not have pathologic reflux, and are therefore unlikely to develop complications of acid reflux disease. However, patients do need to be aware of the chronic persistent nature of FH ( 4 ). Although long-term data are limited in the FH population, 1 year follow-up data suggest that the majority of patients will continue to have heartburn as a main symptom without significant change over time ( 4 ). Although significant decreased quality of life may be encountered ( 4 ), there is no evidence that mortality is influenced by a diagnosis of FH. However, the proportion of patients seeking medical care is likely to be high, given the increased utilization seen in other functional bowel disorders. Long-term studies of functional dyspepsia patients document >6 visits a year and higher consultation rates if present with co-existing functional GI disorders ( 56 ). Although identical data specific to FH do not exist, it might be reasonable to assume that similar high rates of utilization occur. Alternative medicine Because of the few available conventional therapies, many patients turn to alternative therapies. Psychological therapies have been documented to have success in functional bowel disease ( 52 ). However, the role of biofeedback may be limited in FH. In one study, biofeedback seemed more effective and durable in functional chest pain patients as compared with FH patients, when measuring global assessment of complaints at the end of treatment and mean time of 2.8 years after treatment ( 53 ). In this study, patients underwent 8 10 weekly sessions of biofeedback using the galvanic skin resistance feedback which teaches control of sympathetic systemic activity. Interestingly, in this study functional chest pain patients had twice the acid exposure time of FH patients (although both groups had normal ph testing) suggesting a possible different pathophysiology in the two groups. Another behavioral intervention, esophageal directed hypnotherapy, has recently been studied in FH patients ( 54 ). In this open-label controlled trial, 9 patients with FH (Rome III criteria) underwent 7 weekly sessions of hypnotherapy with a trained clinical health psychologist. Six of nine patients completed the entire seven-session protocol. A significant decrease in visceral anxiety ( P =0.01), an increase in emotional quality of life ( P =0.05), a decrease in symptom severity ( P =0.01), and a trend for reduction CONCLUSION Understanding that heartburn is a symptom common to multiple subgroups of patients is key to identifying FH patients. FH patients are a subgroup that respond poorly to PPI therapy, have normal esophageal acid exposure, and no correlation between symptoms and reflux events. The pathophysiology of FH is unknown but it is often associated with visceral hypersensitivity, nonspecific esophageal dysmotility patterns and shared traits with other functional bowel disorders. Endoscopy, motility, and ph testing help objectively assess patients with heartburn, identify potential complications of heartburn, and differentiate FH from other diseases. Making the diagnosis of FH may be the most difficult challenge. Owing to the overlap of disease processes and variable definitions for FH, it has been difficult to identify effective treatments specifically targeting FH. Lifestyle changes and acid suppression are often recommended therapies for FH patients with limited supporting data. Unfortunately, data from well-designed clinical trials are also lacking for pharmaceutical treatment options. Modulation of pain perception and alternative therapies may be potential therapeutic options in this population. Because of the chronic nature of this disease, reassurance of its benign clinical course is key by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

8 60 Hachem and Shaheen CONFLICT OF INTEREST Guarantor of the article: Christine Hachem, MD. Specific author contributions : Analysis and interpretation of evidence, drafting of the manuscript, and critical revision of the manuscript for important intellectual content: Christine Hachem and Nicholas J. Shaheen. Financial support: Shaheen receives research funding from Covidien, CSA Medical, NeoGenomics, GI Dynamics, Takeda Pharmaceuticals, and CDx Diagnostics. Potential competing interests: None. REFERENCES 1. D e an BB, Gano AD Jr., Knig ht K et al. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol 2004 ;2 : Fass R, Sifrim. D. Management of heartburn not responding to proton pump inhibitors. Gut 2009 ;58 : Galmiche JP, Clouse RE, Balint A et al. Functional esophageal disorders. Gastroenterology 2006 ;130 : Surdea Blaga T, Dumitrascu D, Galmiche JP et al. Functional heartburn: clinical characteristics and outcome. 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