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Current Perspectives on the Diagnosis and Treatment of Functional Esophageal Disorders Roy Dekel, MD and Ronnie Fass, MD

Address Section of Gastroenterology, Southern Arizona VA Health Care System, 1-111G-1, Tucson, AZ 85723, USA. E-mail: [email protected] Current Gastroenterology Reports 2003, 5:314–322 Current Science Inc. ISSN 1522-8037 Copyright © 2003 by Current Science Inc.

Among the functional gastrointestinal disorders, functional disorders of the esophagus are second in prevalence only to irritable bowel syndrome. Progress has been made in recent years in our understanding of the pathophysiology of functional esophageal disorders. In this review we focus on recent advances in their diagnosis and treatment. Additionally, we critically appraise the current understanding of the various clinical aspects of each esophageal disorder. Finally, we highlight unanswered questions and areas of controversy.

Introduction Functional gastrointestinal disorders can affect any level of the gastrointestinal tract, from the esophagus (eg, functional dysphagia and globus sensation) to the colon and rectum (eg, functional constipation and rectal pain). Patients with these disorders are frequently seen in primary care settings as well as in tertiary referral centers. In a US householder survey for functional gastrointestinal disorders using the Rome I diagnostic criteria, the national prevalence for one or more functional gastrointestinal disorders was estimated to be as high as 70% [1]. Forty-two percent of the responders reported at least one symptom that was attributed to the esophagus. For comparison, a similar proportion of responders (44%) reported symptoms that were related to the large bowel. The Rome II criteria, formulated in 1999, were recently used in a Canadian householder survey. At least one functional gastrointestinal disorder was detected in 61.7% of the 1149 responders to a mailed questionnaire. Functional disorders of the bowel were the most prevalent, diagnosed in 41.6% of the responders, whereas functional esophageal disorders were diagnosed in 28.9% [2]. The most prevalent functional esophageal disorder, detected in 22.3% of the responders, was functional heartburn. Although the

symptoms of functional gastrointestinal disorders in this population-based study were significantly more prevalent in female subjects, no gender predilection was demonstrated in esophageal-related functional symptoms [2]. As a group, functional esophageal disorders are characterized by the presence of chronic symptoms attributed to the esophagus without evidence of structural or biochemical abnormality (Table 1). According to the Rome II criteria, patients should experience functional esophageal disorders for at least 3 months, which need not be consecutive, within the previous year [3]. Gastroesophageal reflux disease (GERD) and various esophageal motility disorders may be responsible for the spectrum of functional esophageal-related symptoms. Hence, it is imperative that these conditions be ruled out before a diagnosis of a functional esophageal disorder is established (Table 1). Although benign in nature, functional gastrointestinal disorders cause considerable impairment in quality of life and result in a significant economic burden on the healthcare system [4–7]. Additionally, the obscure pathophysiologic basis of these conditions commonly results in frustration for both patients and physicians. Moreover, therapies are mainly empiric in nature and in many cases of limited value.

Functional Dysphagia Functional dysphagia (also called nonobstructive dysphagia) is defined as the presence of dysphagia to solids, liquids, or both in the absence of an obstructive lesion, GERD, or a motility disorder with a recognized pathologic basis [3]. The epidemiology of functional dysphagia has never been rigorously studied. Various population-based studies have estimated the prevalence of functional dysphagia to be between 2.6% and 7% [1,2]. In a study that evaluated the prevalence of swallowing complaints in the general population, 3% of the participants reported experiencing an “obstruction of the bolus” while eating. This symptom was the most likely cause for patients to seek medical attention [8]. Unfortunately, very little progress has been made in our understanding of the pathophysiology of functional dysphagia. Esophageal motility abnormalities (eg, simultaneous contractions and ineffective peristalsis) and impaired

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Table 1. Rome II diagnostic criteria for functional esophageal disorders Esophageal disorder *

Diagnostic criteria

Globus sensation

The chronic or intermittent sensation of a lump or foreign body in the throat, appearing between meals and in the absence of dysphagia or odynophagia Persistent or recurrent regurgitation of food into the mouth with subsequent remastication and swallowing or spitting it out Absence of nausea and vomiting and cessation of the process with acidic regurgitated material Midline chest pain or discomfort that is not of burning quality Burning retrosternal discomfort or pain Sense of solid and/or liquid foods sticking, lodging, or passing abnormally through the esophagus Unexplained symptoms attributed to the esophagus that do not fit into previously described categories

Rumination syndrome

Functional chest pain Functional heartburn Functional dysphagia Unspecified functional esophageal disorder

*Establishing a diagnosis of any of these functional esophageal disorders additionally requires duration of at least 3 months within the preceding year, which need not be consecutive; and absence of pathologic gastroesophageal reflux, achalasia, or other motility disorder with a recognized pathologic basis.

visceral sensitivity to chemical or mechanical stimuli have been suggested as underlying mechanisms [3]. Functional dysphagia remains a diagnosis of exclusion. Figure 1 summarizes the evaluation of a patient presenting with dysphagia. A negative workup for a structural esophageal abnormality or an esophageal motor disorder leads to the diagnosis of functional dysphagia. Empiric esophageal dilation has been suggested as a therapeutic option in functional dysphagia. However, this recommendation is based on very limited data from studies that are afflicted with multiple shortcomings. Recently, two prospective, randomized studies evaluated the use of empiric esophageal dilation in functional dysphagia and reached conflicting conclusions. The first study randomly assigned 23 patients to undergo esophageal dilation using either a 50-F or a 26-F Maloney dilator. Patients who failed to improve after dilation were crossed over to the alternate dilator and restudied [9]. Response to the dilation was determined 2 weeks after the procedure and again after 2 years. Decreased severity (ie, types of foods causing dysphagia) or frequency of dysphagia was considered a positive outcome. An overall difference of borderline statistical significance in response rate was noted in favor of the 50-F dilator (73.3% vs 33.3% response, P=0.059). Three of the six nonresponders in the 26-F group improved after they were crossed over to the 50-F dilator. Dysphagia severity scores improved significantly in patients who were treated with the 50-F dilator compared with baseline. Two years after dilation, 80% and 75% of the patients in the 50-F and 26-F groups, respectively, maintained their favorable response. The authors concluded that empiric esophageal dilation is a safe and effective therapy for patients with functional dysphagia. Subtle structural lesions not detected during the pretreatment endoscopic evaluation were suggested as an explanation for the significant success rate. Several flaws in the study’s design make interpretation of the results relatively difficult. The addition of a sham dilation arm would have strengthened

the results and helped to define the extent of placebo response in these patients. Additionally, under the definition of positive response to dilation, patients could still have up to six dysphagic episodes per week. Lastly, the study included only male subjects, which may have affected the generalizability of the results. However, at least one anecdotal report suggests that dilators with a larger diameter (60-F) are likely to improve response rate [10]. A second study of empiric dilation in functional dysphagia reached an opposite conclusion. Eighty-three patients who were referred for an upper endoscopy because of solid food dysphagia were randomly assigned to undergo 18-mm balloon dilation or a sham procedure [11•]. Esophageal manometry was not performed before enrolling patients in the study although those with pre-existing esophageal motility abnormalities were excluded. No difference in dysphagia scores after dilation was documented between the two groups in the course of a 6-month followup. Improvement rates on day one after dilation were 66% and 67% for the balloon and sham interventions, respectively. After a 6-month follow-up, success rates increased to 84% and 73% in the two groups, respectively. This study highlights two important findings: the high placebo response rate that has been observed in functional bowel disorders and the benign, intermittent course of the disorder. The follow-up period in this study was relatively short, and 10% of the participants were found to have GERD that required antireflux treatment. The role of empiric dilation remains unclear. However, because of the limited therapeutic options in this challenging group of patients, this practice is commonly used by gastroenterologists. Other common therapeutic modalities such as smooth-muscle relaxants and psychotropic compounds were never systematically studied. The possibility that smooth-muscle relaxants modulate nonspecific esophageal motility abnormalities that may impede bolus transit has been suggested. Tricyclic anti-

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Functional Gastrointestinal Disorders

Figure 1. A negative esophageal workup for structural or motor abnormality in patients with dysphagia results in the diagnosis of functional dysphagia. ENT—ear, nose, and throat.

depressants (TCAs) and anxiolytics, used to treat underlying psychological disorders, may also be useful in modulating visceral sensitivity. In patients with abnormal esophageal acid exposure, an empiric trial of acid-suppressive therapy is a reasonable approach.

Functional Heartburn Classic GERD symptoms (eg, heartburn and acid regurgitation) in the presence of a normal esophageal mucosa have been used to define nonerosive reflux disease (NERD) [12]. Recently, Fass et al. [13] suggested an alternative definition offering a more pathophysiologic perspective. NERD is defined as classic GERD symptoms caused by gastroesophageal reflux in the absence of visible esophageal mucosal injury. This definition strengthens the relationship between gastroesophageal reflux (acid and nonacid) and classic GERD symptoms. Additionally, it excludes those patients with heartburn from non–reflux-related stimuli (eg, motor event). Early studies originating from tertiary referral centers suggested that approximately half of the patients presenting with typical reflux symptoms had erosive esophagitis on upper endoscopy. However, recent studies carried out in the community revealed that up to 70% of GERD patients have NERD [13]. Studies have demonstrated that patients with NERD are a heterogeneous group. Subcategorization of NERD relies primarily on the results of 24-hour esophageal pH monitoring. A recent study by Martinez et al. [14] evaluated symp-

tom and acid reflux patterns in patients with NERD. The investigators found that approximately half of the study patients had normal esophageal acid exposure during 24hour esophageal pH monitoring and hence were classified as having “functional heartburn.” The Rome II committee for functional esophageal disorders defined functional heartburn as an episodic retrosternal burning in the absence of pathologic gastroesophageal reflux or pathology-based motility disorders [3]. Thus, patients with functional heartburn demonstrate normal esophageal mucosa on endoscopy as well as esophageal acid exposure within the normal range. However, the Rome committee emphasized that, in a subset of patients with functional heartburn symptoms, these symptoms may still be attributed to acid reflux even in the presence of normal acid exposure. Given that NERD probably accounts for up to 70% of GERD patients in the community, functional heartburn appears to be a very common phenomenon. In approximately 40% of patients with functional heartburn, a close relationship can be demonstrated between their symptoms and acid reflux events. Symptoms in this subgroup of patients are related to acid reflux events. These patients are said to have a “hypersensitive esophagus.” Others have demonstrated that patients with a hypersensitive esophagus have lower perception thresholds for such painful stimuli as intra-esophageal balloon distention and acid perfusion, compared with patients with abnormal esophageal acid exposure or healthy control subjects. These findings suggest a spectrum of visceral hypersensitivity in these patients, which includes both altered


esophageal chemoreceptor and mechanoreceptor sensitivity [15]. The remaining 60% of patients with functional heartburn lack any temporal relationship between their symptoms and esophageal acid reflux events. Symptom generation in these patients is likely not related to acid and may be the consequence of nonacid reflux, various motor events, or other unidentified intraesophageal stimuli. Additionally, some patients with functional heartburn have minute pH changes in the distal esophagus that do not reach the arbitrarily defined acid reflux event (pH < 4) but are sufficient to trigger classic GERD symptoms. Patients with functional heartburn appear to have no unique clinical characteristics that would allow us to differentiate them from other GERD patients [16••]. Thus, establishing the diagnosis of functional heartburn requires two invasive procedures: upper endoscopy and 24-hour esophageal pH monitoring. The yield of random distal esophageal biopsies in improving diagnosis of GERD in patients with functional heartburn is very low. Histologic evidence of acidrelated mucosal injury can be found in less than 10% of the patients [17]. Consequently, the role of upper endoscopy is limited to exclusion of esophageal mucosal involvement. Twenty-four–hour esophageal pH monitoring allows identification of patients with either normal or abnormal distal esophageal acid exposure and determination of the temporal relationship between their symptoms and acid reflux events. The latter enables us to stratify functional heartburn patients into those with acid-related versus those with non– acid-related symptoms. The recent introduction of the Bravo pH monitoring system (Medtronic, North Shoreview, MN), a catheter-free approach for ambulatory esophageal pH monitoring, may provide further information about the reflux pattern of patients with functional heartburn. Using this system, a small pH-sensitive capsule is inserted into the esophagus either transnasally or during upper endoscopy. Subsequently, the capsule is attached to the esophageal wall and provides pH recordings over a 48-hour period. The longer duration of pH recording may enable us to identify more patients with GERD. Up to 35% of the patients who undergo pH monitoring using the Bravo capsule demonstrate a normal esophageal acid exposure on one day and an abnormal result on the other day [18]. Additionally, patients receiving the Bravo capsule are more likely to maintain their regular reflux-provoking diet and activities. Lastly, measurements of esophageal acid exposure lower than the traditional location (5 cm > lower esophageal sphincter [LES]) are more feasible with the Bravo capsule. These pH measurements may reveal very distal acid reflux in patients who were diagnosed with functional heartburn. Another novel technique that may expand our knowledge about the role of nonacid reflux in functional heartburn is multichannel intraesophageal impedance. Impedance measurements in conjunction with pH monitoring may clarify the extent of nonacid reflux in functional heartburn patients and its relationship with heartburn symptoms. As a group, patients with functional heartburn respond less favorably to acid-suppressive therapy than do NERD

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patients with abnormal esophageal acid exposure or patients with erosive esophagitis. In general, it appears that the higher the distal esophageal acid exposure, the greater the symptom response rate to a standard dose of proton pump inhibitor (PPI) in patients with NERD [19]. Approximately 50% of patients with functional heartburn failed treatment with a standard dose of PPI [19]. Several studies of patients with functional heartburn treated with a PPI have demonstrated that a double or even triple dose is needed to improve symptom response (37%–60%) [20–22]. Patients with a hypersensitive esophagus are more likely to respond to PPI treatment. How high one can raise the PPI dose and still improve symptoms or increase the number of responders is still to be elucidated. Nevertheless, PPIs remain the best initial treatment, albeit a limited one, for patients with functional heartburn. Patients with functional heartburn who do not respond to PPI treatment are likely to experience heartburn as a result of various non–acid-related stimuli. Successful therapeutic strategies for this group of patients must address the underlying mechanism that is responsible for their symptoms. For example, motor events such as sustained contractions of the esophageal longitudinal muscle have been suggested as the motor corollary of heartburn [23]. These underlying mechanisms have led some experts to suggest that smooth-muscle relaxants (eg, calcium channel blockers and nitrates) may have a role in the treatment of functional heartburn patients with non–acid-related stimuli [24]. No data are available to support this hypothesis. Other investigators have suggested pain modulators for treatment of patients with functional heartburn who have failed PPI therapy. TCAs, trazodone, and selective serotonin reuptake inhibitors (SSRI) have shown efficacy in other functional esophageal disorders, including noncardiac chest pain [25,26]. Although the use of pain modulators is highly attractive, studies demonstrating their efficacy in functional heartburn patients are still lacking. In summary, the diagnosis of functional heartburn is dependent on upper endoscopy and pH testing. PPIs should be the first line of therapy because they are beneficial for patients with a hypersensitive esophagus. However, for most patients with functional heartburn, pain modulators, and possibly muscle relaxants, may provide symptom relief [16••].

Globus Sensation Globus is defined as a chronic sensation of a lump or foreign body in the throat that is not associated with eating or swallowing difficulties [3]. In a recent Canadian householder survey based on the Rome II criteria, globus sensation was reported by 2.5% of the responders regardless of gender. Moreover, with the Rome I criteria, the prevalence of globus sensation reached 7.3%, whereas the Rome II criteria (excluding patients with concomitant heartburn and dysphagia) reduced the prevalence to 2.5% [2]. In

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another study, globus sensation was the reason for referral to an otolaryngology clinic in 4% of 4330 consecutive new patients [27]. Although several studies have demonstrated an association between various clinical conditions and globus sensation, all failed to establish a definite causal relationship. For example, one study found a high incidence of nonpalpable thyroid nodules in globus patients, whereas another detected hyperviscoelasticity of the epipharyngeal mucus [28,29]. However, most of the clinical research on the underlying mechanisms of globus sensation has concentrated on GERD, esophageal dysmotility, and psychological abnormalities. An association between globus sensation and GERD has been suggested. A recent international study evaluated the current attitudes and practices of otolaryngologists in relation to laryngopharyngeal reflux [30]. One hundred fiftyeight physicians responded to a mailed questionnaire. Of the responding physicians, 85% perceived globus sensation to be associated with laryngopharyngeal reflux. After a fiberoptic laryngeal examination, dual sensor 24-hour esophageal pH monitoring was the most commonly ordered test for patients with suspected laryngopharyngeal reflux. The pH test was also perceived to be the most sensitive and specific adjunctive diagnostic test in patients with globus sensation. Population-based studies support the association between globus sensation and GERD. Heartburn was reported by as many as 30% to 50% of globus patients in different studies [3]. Some studies even found evidence of abnormal esophageal acid exposure as well as a positive temporal relationship between reflux episodes and globus sensation in 30% to 40% of patients [3]. These studies suggest that GERD must be excluded in patients with globus sensation, especially if concomitant symptoms of GERD are present. The dual-sensor pH test is commonly used for evaluation of patients with globus sensation. However, the yield of the test in this challenging group of patients has not been elucidated. Recently, the role of PPI treatment in patients with globus sensation was evaluated [31]. Twenty-five globus patients with concomitant GERD-related laryngeal anatomic findings were treated with lansoprazole, 30 mg/d, for 8 weeks. Physical findings considered to be related to GERD included pooling of saliva in the piriform sinus, erythema of the posterior larynx, interarytenoid hypertrophy, and vocal process granulomas. Heartburn and acid regurgitation were reported by 68% and 76% of the patients, respectively. Fifty-two percent of the patients had evidence of erosive esophagitis on upper endoscopy. Patients were asked to grade the severity of their symptoms at the end of the treatment period. Upon completion of the study, 17 (68%) patients reported that their globus sensation had resolved or was somewhat improved. However, this was an open-label study, the number of participants was relatively small, and GERD was documented only by upper endoscopy. Additionally, the use of a once-daily standard dose of PPI may be insufficient for control of extraesophageal manifestations of GERD, such as globus sensa-

tion. These limitations prevent us from drawing any therapeutic conclusions form this study. However, this study should be the impetus for future PPI studies in globus sensation. Unfortunately, this is the only study that evaluated the specific role of PPI treatment in patients with globus. Future studies should also focus on the required PPI dose as well as duration of administration. It is reasonable to assume that a higher dose of a PPI for at least 3 months would probably be needed for patients with GERD-related globus sensation. Esophageal motility disorders, particularly abnormal upper esophageal sphincter (UES) function, have also been suggested as the cause for globus sensation. Early studies demonstrated conflicting results, with some documenting elevated basal UES pressure and others reporting normal basal UES pressure [32–34]. A recent study by Corso et al. [35] found a strong association between high UES basal pressure and reports of globus sensation. Twenty-eight percent of the patients with high UES basal pressure reported globus sensation, compared with only 3% of those with normal basal UES pressure. The authors concluded that high UES pressure is associated with reports of globus sensation. These findings were challenged recently by those from another study that used state-of-the-art esophageal manometry equipment. The latter study found no differences in UES basal pressures between 32 patients with globus sensation and 24 healthy volunteers [36]. Consequently, the association between globus sensation and elevated basal UES pressure remains unknown. More studies are needed using advanced esophageal manometry probes, which allow more accurate measurement of the UES. Until such a study is undertaken, any intervention aimed at disturbing the basal UES pressure has very little merit. A variety of nonspecific esophageal body motility abnormalities have been reported in patients with globus sensation, but these nonspecific manometry findings almost certainly cannot offer a pathophysiologic explanation for globus [3]. A possible association between globus sensation and achalasia has been suggested by one study, which evaluated the psychological profile and physiologic aspects of 88 patients with globus sensation who were referred to a clinic for psychosomatic disorders [37]. Esophageal manometry studies were consistent with achalasia in 24 of the patients. The unusually high prevalence of achalasia is likely due to the definition of achalasia used by the investigators: incomplete LES relaxation with predominantly synchronous swallow-initiated contractions in at least the lower two thirds of the esophageal body. These criteria differ from the currently used manometric definition of achalasia, which requires the presence of aperistalsis after all swallows [38].

Rumination Syndrome Rumination is defined as an effortless regurgitation of recently ingested food followed by remastication, reswallowing, or spitting. Symptoms usually occur shortly after meals and are absent during sleep [2]. Rumination is a rel-


atively rare disorder and is twice as prevalent in males as in females. Approximately 1.1% of males and 0.5% of females in the general population experience rumination [2]. Populations with an especially high prevalence of rumination include infants, the mentally retarded, and people with eating disorders. The pathophysiology of rumination is yet to be elucidated. Some studies have demonstrated postprandial abnormal gastric and small bowel spikes on antroduodenal manometry, representing abdominal wall contractions that coincide with the regurgitation of food [39]. However, in a more recent and relatively large study, these spikes appeared in only a third of the 38 participants [40]. Other studies suggest that increased gastric sensitivity accompanied by LES relaxation during gastric distention is the underlying pathophysiologic event [41]. Psychological assessment of patients with rumination syndrome suggests that it is a learned habit influenced by a poor mother-infant relationship. Alternatively, rumination may originate from the child’s search for parental attention or simply from indulgence of the process itself. Most of the studies evaluating treatment of this disorder have focused on psychological modalities, including punishment techniques, biofeedback, psychotherapy, and regulation of eating habits. Because this is a rare disorder, the studies were usually very small, making it difficult to draw definite conclusions and create an evidence-based therapeutic approach. Furthermore, psychotherapy, which is used to treat rumination in adults, is limited because of the need for an intelligent and highly motivated candidate, whereas many of the patients affected by rumination are mentally retarded or young children. A recent small study offered a novel therapeutic approach. Five adult patients with rumination underwent Nissen fundoplication, based on the hypothesis that some of the known postoperative effects of fundoplication would benefit these patients [42]. These effects include elevation of LES basal pressure, reduction in the frequency of transient lower esophageal sphincter relaxation (TLESR), and the occasional postoperative impairment of vomiting and belching. Three patients had concomitant GERD and three had low LES basal pressure on presurgical esophageal manometry. All five patients reported complete resolution of symptoms after 1 year. One patient experienced obstruction-related symptoms after surgery that resolved after revised fundoplication. This small study provides a new physiologic perspective on the treatment of rumination in adults. However, it is the first report of a surgical solution to a disorder that is traditionally treated with psychological techniques. Further studies are needed to determine the long-term value of Nissen fundoplication in patients with rumination.

Functional Chest Pain of Presumed Esophageal Origin The Rome II committee uses the term “functional chest pain of presumed esophageal origin” to describe recurrent episodes of substernal chest pain of visceral quality with no

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apparent explanation. As with all other functional esophageal disorders, GERD and esophageal dysmotility should be ruled out before the diagnosis is established [3]. The prevalence of functional chest pain of presumed esophageal origin remains to be determined. However, noncardiac chest pain (NCCP) affects up to 26% of the general population and has no gender predilection [43]. An algorithm for the evaluation and treatment of NCCP patients is presented in Figure 2. GERD is the most common cause for NCCP, accounting for up to 60% of these patients. Thus, ruling out GERDrelated NCCP should be the first goal of any diagnostic evaluation. A short course of high-dose PPI (the PPI test) is a simple, readily available, and cost-effective initial step. The high sensitivity and specificity of the PPI test enables clinicians to identify NCCP patients who are the most likely to benefit from long-term PPI treatment [44••]. A pH test can be used to identify GERD patients who fail to improve during the PPI test or on empiric therapy. The pH test offers a unique opportunity to identify GERD patients by demonstrating a close temporal relationship between symptoms of chest pain and acid reflux events. Some authors suggest that this positive association is sufficient to warrant treatment with a higher dose of PPI even without other evidence of GERD. The symptom index is the most widely used parameter to assess clinically significant association between GERD symptoms and acid reflux events. A recent study evaluated the use of the symptom index in identifying GERD in patients with NCCP and normal esophageal acid exposure [45]. Of the 47 NCCP patients with a normal upper endoscopy and pH test, only five (10.6%) had a positive symptom index, suggesting the diagnosis of GERD-related NCCP. Lack of chest pain in many patients during the pH test was the primary reason why the symptom index was of limited value. After GERD has been excluded, esophageal manometry is suggested. This test may help to identify NCCP patients with an underlying motility disorder, which may or may not be related to their symptoms. In a large study, “nutcracker esophagus” was identified in approximately half of a group of NCCP patients with an abnormal esophageal motility test. However, this study, along with previous reports, represents the experience of a single tertiary referral center with a special interest in esophageal motility [46]. Different results were recently demonstrated in a study with a much more diverse database [47]. In this study, which analyzed esophageal manometry results from university medical centers, private gastroenterology practices, and the Veterans Administration, hypotensive LES was the most common esophageal motility abnormality to be diagnosed in patients with NCCP (61%). Low LES basal pressure is commonly associated with gastroesophageal reflux. Consequently, many NCCP patients who underwent esophageal manometry had undiagnosed GERD. Nutcracker esophagus and other spastic esophageal motility disorders were documented in only 10% of the NCCP patients. Smooth-muscle relaxants, particularly calcium channel blockers, are widely used in NCCP patients with such welldefined spastic motility disorders as nutcracker esophagus or

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Functional Gastrointestinal Disorders Figure 2. Diagnostic and treatment algorithm for patients with noncardiac chest pain. GERD—gastroesophageal reflux disease. PPI—proton pump inhibitor; SSRI—selective serotonin reuptake inhibitor.

diffuse esophageal spasm. Although these drugs are known to reduce esophageal contraction amplitude, a similar reduction in symptoms was not conclusively demonstrated. Data regarding the efficacy of calcium channel blockers in NCCP patients with esophageal dysmotility are conflicting. In general, response to calcium channel blockers is transient and may take several weeks to be noticed by the patients themselves [48,49]. A more invasive approach to NCCP in patients with documented spastic motility disorder was recently proposed [50]. Twenty-nine patients with nonachalasia spastic esophageal motility disorders were treated with botulinum toxin injection into the LES. Seventy-two percent of the patients responded with at least a 50% reduction in their chest pain score. In those who responded to treatment, a 79% post-injection reduction was established in the mean chest pain score after 1 month of follow-up. The mean duration of response was 7.3 months. Regardless of whether NCCP patients demonstrate esophageal motility abnormalities, pain modulators remain the cornerstone of therapy. This is a particularly attractive approach in patients with functional chest pain of presumed esophageal origin. These agents include TCAs, trazodone, SSRIs, and potentially the partial 5HT4 agonist, tegaserod.

Both trazodone and imipramine were found to reduce symptom burden after short-term treatment in patients with NCCP [25,26]. These findings were independent of the presence of depression or other psychiatric abnormalities. More recently, the long-term outcome of 21 NCCP patients treated with imipramine was evaluated [51]. This study included patients who had failed conventional treatment with antireflux medications and smooth-muscle relaxants. After a median follow-up of 2.7 years, 81% of the patients reported marked improvement in symptoms. Early positive response to treatment was predictive of long-term symptom relief. As with the shortterm trials, the long-term effect of imipramine was independent of the presence of a psychiatric disorder. The exact mechanism of action of imipramine or other TCAs remains to be elucidated. The efficacy of these agents in somatic pain syndromes may be related to their ability to inhibit synaptic reuptake of such neurotransmitters as norepinephrine and serotonin. This effect has not yet been demonstrated in unmyelinated visceral nerves. Increasing esophageal perception thresholds for pain to various visceral stimuli has been suggested as the effect of TCAs. To date, studies evaluating this attractive hypothesis have generated conflicting results. Whereas some investigators found a significant increase in


esophageal pain thresholds during balloon distention in healthy subjects treated with imipramine, others failed to demonstrate a similar outcome [52,53]. The potential of a serotonin-mediated effect of imipramine was the impetus for a more recent study evaluating the effect of SSRIs on functional chest pain of presumed esophageal origin. Varia et al. [54•] conducted a doubleblind, placebo-controlled trial in 30 patients with functional chest pain of presumed esophageal origin using the SSRI sertraline. After 8 weeks of treatment, patients who received sertraline reported a significant reduction in chest pain compared with those who received placebo. Larger studies are needed to confirm this interesting initial observation. In patients with panic disorder who presented with chest pain, barbiturates were suggested to have clinical value [55,56]. Unfortunately, these observations were made in a small number of subjects. Recently, Rao et al. [57] evaluated the efficacy of theophylline in patients with functional chest pain of presumed esophageal origin. Sixteen patients with a hypersensitive esophagus (typical chest pain was reproduced at ≤ 55 cm of H2O during balloon distention) were studied before and after administration of intravenous theophylline. Twelve patients demonstrated a significant reduction in chest pain or normalization of sensory thresholds during balloon distention after treatment. These 12 patients were then given oral theophylline for 3 months (6 mg/kg in two divided doses). Of the eight patients who completed the 3-month treatment, one had total resolution of symptoms, six demonstrated a 50% reduction in chest pain frequency and intensity, and one patient did not respond. Other compounds with visceral analgesic properties, especially 5HT3 antagonists, kappa agonists, and N-methylD-aspartate antagonists, may be beneficial and could have a future role in treatment of patients with functional chest pain of presumed esophageal origin. A behavioral approach or other psychological interventions may also be helpful for these patients. Behavioral techniques such as controlled diaphragmatic breathing, muscle relaxation, or transcendental meditation have resulted in decreased frequency and severity of chest pain episodes. These benefits were maintained during long-term follow-up of 3 to 46 months in several studies [58–60].

Conclusions Among the functional gastrointestinal disorders, functional esophageal disorders are second in prevalence only to irritable bowel syndrome. In recent years, some progress has been made in our understanding of the pathophysiologic basis of functional esophageal disorders. However, the diagnostic process still relies primarily on exclusion of GERD and esophageal motility disorders. Treatment is mostly empiric and based on studies with a relatively small

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number of patients. Future studies that assess symptom generation in patients with functional esophageal disorders will pave the way for new treatment modalities.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Drossman DA, Li Z, Andruzzi E, et al.: U.S. householder survey of functional gastrointestinal disorders: prevalence, sociodemography, and health impact. Dig Dis Sci 1993, 38:1569–1580. 2. Thompson WG, Irvine EJ, Pare P, et al.: Functional gastrointestinal disorders in Canada: first population-based survey using Rome II criteria with suggestions for improving the questionnaire. Dig Dis Sci 2002, 47:225–235. 3. Rome II: The Functional Gastrointestinal Disorders. Lawrence, KS: Allen Press; 2000. 4. Akehurst RL, Brazier JE, Mathers N, et al.: Health-related quality of life and cost impact of irritable bowel syndrome in a UK primary care setting. Pharmacoeconomics 2002, 20:455–462. 5. Koloski NA, Talley NJ, Boyce PM: The impact of functional gastrointestinal disorders on quality of life. Am J Gastroenterol 2000, 95:67–71. 6. Badia X, Mearin F, Balboa A, et al.: Burden of illness in irritable bowel syndrome comparing Rome I and Rome II criteria. Pharmacoeconomics 2002, 20:749–758. 7. El-Serag HB, Olden K, Bjorkman D: Health-related quality of life among persons with irritable bowel syndrome: a systematic review. Aliment Pharmacol Ther 2002, 16:1171–1185. 8. Lindgren S, Janzon L: Prevalence of swallowing complaints and clinical findings among 50-79-year-old men and women in an urban population. Dysphagia 1991, 6:187–192. 9. Colon VJ, Young MA, Ramirez FC. The short- and long-term efficacy of empirical esophageal dilation in patients with nonobstructive dysphagia: a prospective, randomized study. Am J Gastroenterol 2000, 95:910–913. 10. Langdon DE: Dysphagia and Maloney dilations. Am J Gastroenterol 2001, 96:3045–3046. 11.• Scolapio JS, Gostout CJ, Schroeder KW, et al.: Dysphagia without endoscopically evident disease: to dilate or not? Am J Gastroenterol 2001, 96:327–330. This is the first study to assess the value of empiric esophageal dilation in functional dysphagia, compared with a sham procedure. 12. Dent J, Brun J, Fendrick AM, et al.: An evidence-based appraisal of reflux disease management: The Genval Workshop Report. Gut 1999, 44(Suppl 2):S1–S16. 13. Fass R, Fennerty MB, Vakil N: Nonerosive reflux disease: current concepts and dilemmas. Am J Gastroenterol 2001, 96:303–314. 14. Martinez SD, Malagon IB, Garewal HS, et al.: Non-erosive reflux disease (NERD): acid reflux and symptom patterns. Aliment Pharmacol Ther 2003, 17:537–545. 15. Trimble KS, Pryde A, Heading RC: Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut 1995, 37:7–12. 16.•• Fass R, Tougas G: Functional heartburn: the stimulus, the pain and the brain. Gut 2002, 51:885–892. An excellent up-to-date review of the topic. 17. Schindlbeck NE, Wiebecke B, Klauser AG, et al.: Diagnostic value of histology in non-erosive gastro-oesophageal reflux disease. Gut 1996, 39:151–154. 18. Pandolfino JE, Kahrilas PJ, Cisler J, et al.: Esophageal pH monitoring using a catheter-free pH-system (Bravo pH System) [abstract 152]. Gastroenterology 2002, 122:A-192.

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