Chest pain that is not explained by reflux disease or cardiac, musculoskeletal, mucosal, or motor esophageal abnormalities is classified as functional chest pain (FCP). Although several mechanisms are involved, esophageal hypersensitivity plays a major role and it could be considered a biomarker for FCP. Psychologic comorbidity such as anxiety, neuroticism, depression, and somatization is common. When the diagnosis of FCP is suspected, patients should undergo evaluation with esophageal motility testing, endoscopy, 24-h esophageal pH monitoring, and in some cases, sensory tests. Once the diagnosis of FCP has been established, treatment options rely on controlling patients’ symptoms. Medical treatment has focused predominantly on medications that target pain, such as antidepressants and other pain neuromodulators. Non-pharmacologic interventions with complementary behavioral treatments, such as cognitive behavioral therapy, biofeedback, and hypnosis, have recently been recognized as useful in FCP patients. The latest findings on the evaluation and treatment of FCP are outlined herein.
Chest pain is usually perceived as a life-threating symptom, and the initial approach can be costly. In the United States, there are over six million hospital admissions for patients presenting with chest pain per year, representing an approximate expense of eight billion USD . However, up to 40 % of patients admitted to emergency departments (ED) with chest pain do not have acute coronary disease and receive a non-cardiac diagnosis (non-cardiac chest pain [NCCP]) . For example, a recent study analyzing national data in the U.S. reported that out of 10,907 patients seen for chest pain, the most common diagnosis was non-specific chest pain (51.7 %) . It has been estimated that the pooled prevalence of NCCP in the community is 13 % (a 2-32.5 % range) [1, 4, 5], appearing to be similar across different geographic regions and unaffected by sex or age.
NCCP may be the manifestation of extra-esophageal (i.e. anxiety, musculoskeletal, pulmonary, and/or pericardial disorders) or esophageal conditions. Fifty to sixty percent of NCCP patients present with gastroesophageal reflux disease (GERD), making it the most common contributing factor. In a meta-analysis regarding the epidemiology of NCCP, Ford et al.  found a significant association between GERD and NCCP. The patients that had symptoms consistent with GERD had an almost fivefold increase in the odds of presenting with NCCP.
However, it is important to recognize that symptoms in 30-40 % of NCCP patients are not related to GERD and other esophageal conditions, resulting in the ruling out of motility disorders (i.e. achalasia, spastic disorders) and eosinophilic esophagitis (EoE) [6•]. Thus, if NCCP is not explained by reflux disease or other mucosal or motor esophageal abnormalities, it can then be classified as functional chest pain (FCP) . Patients with FCP have good prognoses in terms of cardiac adverse events and mortality, but they tend to have poor outcomes in terms of psychologic morbidity and impairment of quality of life (QoL) [8–10].
According to the new Rome IV criteria [11••], diagnostic criteria for FCP must include all of the following:
Retrosternal chest pain or discomfort. Cardiac causes should be ruled out.
Absence of associated esophageal symptoms, such as heartburn and dysphagia.
No evidence that GERD or EoE is the cause of the symptom.
Absence of major esophageal motor disorders (achalasia/esophagogastric junction [EGJ] outflow obstruction, diffuse esophageal spasm ([DES], jackhammer esophagus, no peristalsis).
These criteria must be fulfilled during the last 3 months, with symptom onset at least 6 months before diagnosis and a frequency of at least once a week. Given that the Rome IV criteria for FCP are very recent and the fact that most studies have evaluated patients under the term NCCP, the terms FCP and NCCP will be used synonymously in this review.
Although several mechanisms are involved, esophageal hypersensitivity plays a major pathophysiologic role and may be considered a biomarker for FCP [12, 13]. Several studies have confirmed the importance of esophageal hypersensitivity in symptom generation in patients with FCP, through the use of different esophageal sensory tests, such as esophageal balloon distension (EDB) , impedance planimetry, electrical stimulation, and acid perfusion [15–17]. For example, in a large cohort of 189 subjects with FCP that underwent EBD using impedance planimetry, Nasr et al.  found that 75 % had esophageal hypersensitivity.
Numerous pathophysiologicmechanisms have been associated with esophageal hypersensitivity. These include abnormally enhanced peripheral responses to sensory inputs and abnormal central managing of such inputs. Evidence suggesting that esophageal hypersensitivity is a peripheral, rather than a central, phenomenon is based on studies that show lower sensory thresholds after differential responses to stretch, chemical, and electrical stimuli in patients with FCP and functional heartburn (FH) [15–18]. In addition, increased expression and stimulation of several receptors located in the esophageal mucosa (transient receptor potential cation channels [TRP channels], acid-sensing ion channels [e.g. capsaicin or vanilloid receptor TRVP1], and adenosine receptors) suggest that peripheral mechanisms are mainly responsible for enhanced sensitivity [19–21].
Developments in neuroimaging have revealed central sensitization and processing mechanisms in FCP patients. Limbic and paralimbic structures, such as the anterior cingulate, prefrontal cortex, and insula, have been described as visceral pain foci . The induction of cortical evoke potentials (CEPs) through the performance of different studies suggests that some patients with chest pain and visceral hypersensitivity have sensitized esophageal afferents, whereas a central perturbation of pain regulation is implied by the fact that other patients are hypervigilant in relation to esophageal sensations .
Dysmotility has also been associated with esophageal hypersensitivity. Rao et al.  found that patients with NCCP have a hyper-reactive and poorly compliant esophagus when compared with controls. Some authors have postulated that chest pain in NCCP patients with esophageal dysmotility is caused by esophageal spasm, as a result of distension of the proximal segment of the esophagus (mechanoreceptor activation) or myoischemia (chemoreceptor activation) .
Using endoluminal ultrasonography in 10 FCP patients, Balaban et al.  described the presence of sustained longitudinal muscle contractions during episodes of spontaneous chest pain and hypothesized that ischemia is involved in the pathogenesis. However, this activity solely occurred in a subset of patients and only during some of the pain episodes. The results of a subsequent study demonstrated that sustained esophageal contractions (SECs) correlated with heartburn and acid reflux .
Likewise, in other functional gastrointestinal disorders, psychologic comorbidity most likely influences symptom perception in FCP. Anxiety, neuroticism, depression, and somatization are more common in subjects with FCP [27, 28]. Psychologic disturbances may interact with environmental stress to produce increased perceptions of symptoms through neurohormonal interactions .
The medical history and physical examination of the patient do not reliably segregate esophageal pain from cardiac chest pain, stressing the need for an initial cardiac evaluation in appropriate clinical settings. Thus, esophageal evaluation should proceed only after those symptoms are confirmed to be unrelated to concurrent cardiovascular diseases. Table 1 shows a list of the tests used in the evaluation of FCP.
a) PPI Test: GERD should first be excluded in all patients with FCP [30•]. Therefore, when there are no alarm signs, empiric therapy for GERD should be recommended as initial management strategy. For GERD diagnosis, the PPI test involves the administration of high doses of PPI for a short period of time. Compared with other diagnostic tests, it has a significantly lower cost [30•]. The results of two meta-analyses demonstrated an 80 % sensitivity and a 73-74 % specificity for the PPI test, suggesting its use in the initial approach for detecting GERD in the NCCP patient [31, 32]. However, more recent studies have shown a specificity that does not exceed 36.3 % .
b) Upper endoscopy: This study is justified in the FCP evaluation for ruling out mucosal abnormalities that include benign or malignant tumors, esophageal stenosis, or peptic stricture in the patient that presents with any alarm symptom, such as decreased appetite, weight loss, dysphagia, odynophagia, hematemesis, and/or anemia. The diagnostic yield of upper endoscopy for the detection of GERD has been reported to vary between 10 and 70 % among subjects with NCCP [34, 35]. Dickman et al.  evaluated the clinical usefulness of endoscopy in NCCP and found that 56 % of the patients had an abnormal endoscopy. The most common findings were hiatal hernia (29 %), erosive esophagitis (19 %), Barrett’s esophagus (4 %), and esophageal stricture or stenosis (4 %).
Endoscopy is also recommended in patients with dysphagia or a history of food impaction. In the absence of visible mucosal abnormalities, esophageal biopsies must be taken to rule out EoE . In a retrospective study of 171 consecutive NCCP patients referred for EGD, Achem et al. reported that 14 % of patients had findings suggestive of EoE .
c) Esophageal manometry: The aim of this test is to exclude esophageal motor disorders as the underlying cause of FCP. Conventional esophageal manometry has revealed a motor dysfunction in 25 % of NCCP patients . More recently, in a large cohort of 332 FCP subjects, only 28 % were found to have esophageal dysmotility during esophageal manometry . Nutcracker esophagus was the most common motility disorder (48 %), followed by non-specific esophageal motility disorder (36 %), DES (10 %), hypertensive lower esophageal sphincter (LES) (4 %), and achalasia (2 %). High-resolution esophageal manometry (HRM) is currently considered the gold standard for identifying motility disorders. The major motor disorders (according to version 3.0 of the Chicago Classification) that should be ruled out before establishing FCP diagnosis include: achalasia, EGJ outflow obstruction, DES, jackhammer (hypercontractile) esophagus, and absent contractility [40••]. In a recent study, Barret et al.  performed ambulatory 24-h HRM and pH-impedance on 59 NCCP patients and abnormalities in the former test explained the symptoms in 7 % of the patients (n = 4), whereas anomalies in the latter clarified the symptoms in 37 %. Fifty-two percent of the patients were diagnosed with functional chest pain. According to the criteria of the version 3.0 Chicago Classification alone, conventional HRM did not identify esophageal spasm in any of the four patients that presented with it upon ambulatory manometry. Nevertheless, when simultaneous (rapid) or repetitive contractions were considered, HRM showed a 75 % sensitivity and 98.2 % specificity for diagnosing DES.
d) Ambulatory 24-h esophageal pH monitoring and wireless pH system: Approximately 50-60 % of NCCP patients have abnormal esophageal acid exposure or a positive symptom association . Richter et al.  in 100 patients with NCCP found abnormal acid exposure in 48 %. Of the 83 patients that had spontaneous chest pain during the study, 37 (46 %) had abnormal reflux parameters, and 50 (60 %) had a normal study, but a positive symptom index. The authors concluded that 24-h esophageal pH testing with symptom index is the single best test for evaluating patients with NCCP. In the study performed by Nasr et al. , the pH test was abnormal in 28 % of subjects with FCP, indicating that excessive acid reflux was a likely source of their chest pain. In contrast, Dekel et al.  demonstrated that asymptomatic correlation with abnormal esophageal acid exposure was a relatively uncommon phenomenon in NCCP patients, because most did not experience chest pain during the pH study. This suggests that excessive acid reflux on a pH test is associated with chest pain, but is not inevitably its cause. Invasiveness, high cost, lack of validation, and limited availability are all limitations of the pH test.
There is a supposed greater sensitivity in the evaluation of patients presenting with typical or atypical GERD symptoms when impedance recording is added to the 24-h pH test, but no studies have been conducted specifically on FCP patients.In the only available study addressing the impact of the 24-h multichannel intraluminal impedance (MII)-pH test, Kim et al.  demonstrated that, from a total of 75 FCP patients, 16 (21.3 %) had pathologicacid exposure and 40 (53.3 %) had pathologic bolus exposure. The authors concluded that impedance-pH monitoring improved the detection and characterization of FCP. However, the role of non-acidic reflux in causing chest pain has yet to be explained.
Two studies have also evaluated the impact of extended pH testing (48 h) on patients with NCCP. Prakash et al.  found that extending pH testing to 48 h provided meaningful information in 20 % of the NCCP patients. In a more recent study, Karamanolis et al.  found that 48-h pH measurement identified GERD as the cause of FCP with an increased yield of almost 12 %, compared with the 24-h pH test. They concluded that a modest, but relevant and likely GERD-related advantage was obtained with extended wireless pH testing in regard to FCP patient evaluation.
d) Esophageal sensory tests: Provocative tests, such as the acid perfusion test (Bernstein), edrophonium test, EBD tests, and more recently, electrical and thermal stimulation, are all tests for examining esophageal hypersensitivity [12, 47]. A generally accepted useful method for evaluating esophageal sensory properties is balloon distension. Several such methods and techniques have been tested, including: balloon inflation with air or water, intermittent phasic or ramp distensions with a hand-held syringe, computerized balloon distensions (barostat), and dynamic balloon distensions using impedance planimetry. The definition of esophageal hypersensitivity varies greatly and depends on the technique used . Even though the EBD test can be a useful diagnostic test in patients with FCP, more studies are needed to confirm and evaluate its usefulness in clinical practice, especially since it is usually performed in specialized centers .
Multiple sensory assessment (thermal, mechanical, acid, and electrical stimulation) of esophageal sensory function can be carried out using the novel multimodal probe [12, 49]. Receptors in the superficial (thermal), deep (mechanical), or combined (electrical) layers of the esophagusare likely to be activated by the stimuli this probe induces. Hence, the probability of activating a range of relevantly involved nervous mechanisms increases through the use of a test battery that utilizes different stimuli. Recently, a new technique based on high-resolution impedance planimetry, the functional lumen-imaging probe (FLIP), has been used to assess the distensibility of the EGJ in reflux disease, achalasia, eosinophilic esophagitis, and post-fundoplication patients [50–52]. This tool could be used in the future to study the mechanical properties of the esophagus in FCP .
Figure 1 shows an algorithm for the diagnosis and management of FCP.
The treatment goal for FCP patients is to control the frequency and intensity of episodes of pain, as well as to improve quality of life. Table 2 shows the therapeutic options used in FCP.
These drugs can modulate central hyperalgesia and, to some degree, peripheral hyperalgesia . In addition, antidepressants can treat co-existing anxiety or depression. It is also worth noting that the analgesic effect ofantidepressants is not related to their effect on mood. In a recent systematic review, Weijenborg et al. [55•] found benefits of antidepressants in five out of eight studies, when compared with placebo. Treatment with imipramine [56, 57], sertraline , and venlafaxine  all had significant beneficial effects on chest pain severity or frequency compared with placebo, reducing symptoms by more than 50 %. Contrastingly, in two studies evaluating treatment with paroxetine, the reduction in chest pain duration or intensity was similar in the paroxetine and placebo groups [60, 61]. Comparable results were also obtained with trazodone, reducing chest pain, but not leading to a significant advantage over placebo .
Tricyclic antidepressants (TCAs): This class of drugs has been successfully used in patients with FCP. Visceral analgesic effects of TCAs might be related to their 5-HT reuptake inhibitory properties, due to the fact that the descending serotonergic systems, in both the supraspinally and spinally projecting pathways, are involved in antinociception mechanisms.
For pain modulation, TCAs are commonly given in low doses. Different trials have reported ranges in an initial therapeutic dose from 10-50 mg/day and in a maximum therapeutic dose from 25-150 mg/day. TCAs are commonly administered at low doses (10 mg once a day), usually at bedtime, due to their anticholinergic and sedative side effects. Increments in dosing should be based on symptom improvement and the development of side effects. Table 2 shows the side effects of TCAs and other antidepressants. Because of their greater receptor affinity, tertiary amines (such as amitriptyline and imipramine) are more commonly associated with side effects than secondary amines (such as nortriptyline and desipramine). In the event of side effects, the dose can be decreased or the patient can be switched to a different TCA, given their different receptor activity.
Trazodone: This drug is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs) . Trazodone inhibits the serotonin transporter (SERT) and blocks serotonin type 2 (5-HT2) receptor antagonism (both the 5-HT2A and 5-HT2C receptors) .
As with TCAs, the visceral analgesic effect of the drug has been evaluated in FCP patients . Trazodone (100-500 mg, four times a day, orally) for 6 weeks significantly improved the symptoms of patients with NCCP and esophageal dysmotility, compared with placebo. However, esophageal motility abnormalities remained unchanged. A small, open-label study reported symptom control and improved esophageal motility in patients with NCCP and DES following treatment with both trazodone and clomipramine .
Selective serotonin reuptake inhibitors (SSRIs): SSRIs have a relatively safe side-effect profile compared with other antidepressant medications. Recently, Atluri et al.  conducted a meta-analysis of randomized controlled trials (RCTs) comparing SSRIs with placebo in patients with FCP. It included four studies, and a reduction in chest pain was observed in patients taking SSRIs. There were no significant differences in depression score changes or treatment discontinuation between the two groups. The authors concluded that SSRIs were not superior to placebo in improving chest pain or depression symptoms in patients with FCP. In order to assess the benefits and drawbacks of SSRIs in FCP treatment, larger trials with longer follow-up periods are needed.
Citalopram (20 mg once a day) was evaluated in a double blind, placebo-controlled study as treatment for hypersensitive esophagus in 75 patients (including FCP patients) . At the end of the follow-up period, 38.5 % of patients that received citalopram and 66.7 % of patients with placebo continued to report reflux symptoms (p = 0.021).
Serotonin-norepinephrine reuptake inhibitors (SNRIs). Only venlafaxine has been studied in FCP . A 4-week randomized placebo-controlled study was conducted on 43 patients. Fifty-two percent of the patients who received 75 mg venlafaxine showed a therapeutic response, compared with 4 % on placebo. The venlafaxine group also showed improvements in body pain and emotional role (p < 0.002).
The side effects of SNRIs resemble those of SSRIs.
Non-antidepressant pain modulators
Other drugs that have been used in FCP include dronabinol , tegaserod , and theophylline [70, 71]. Cannabinoid receptors 1 (CB1) and 2 (CB2) modulate the release of neurotransmitters. CB1 is located in the esophageal epithelium. It reduces excitatory enteric transmission and could potentially reduce esophageal hypersensitivity. With this rationale, Malik et al.  conducted a small (n = 13) prospective pilot study to evaluate the effects of dronabinol (5 mg, twice daily) or placebo on pain threshold, frequency, and intensity in FCP. Dronabinol significantly increased pain thresholds (assessed by the EBD test) and reduced pain intensity, compared with placebo (p = 0.04). No significant adverse effects were observed.
In another placebo-controlled study, the 5HT-4 partial agonist, tegaserod (6 mg bid for 14 days), improved esophageal pain thresholds to mechanical distension, but not to chemically induced pain in patients with functional heartburn and esophageal hypersensitivity .
Theophylline, as an adenosine antagonist, has been shown to be effective in the treatment of patients with FCP [76, 77]. Two hundred milligrams bid of theophylline for 4 weeks was more effective than placebo in decreasing the mean number of days with pain and the intensity and duration of pain episodes. Overall, 58 % of patients reported that their symptoms had improved on theophylline, compared with only 6 % on placebo. The analgesic effect of theophylline has no relation to its effect on smooth muscle relaxation.
Pregabalin and gabapentin have been used in other functional esophageal disorders, such as globus, and may have a potential use in FCP . However, further studies are required.
Psychologic intervention, through the use of cognitive behavioral therapy (CBT), coping skills, and hypnosis has been shown to be effective for FCP. The goal of treatment is to correct the misattributions that physical symptoms (e.g. chest pain) are harmful. Patients must adopt the belief that psychologic factors cause chest pain and attribute the chest pain to panic attacks, anxiety, and/or other psychologic factors [73, 74].
Four single blinded RCTs [74–76] have evaluated the benefits of CBT, and according to a recent systematic review, the evidence is fair (Level II) . Kuipers et al.  reported that a previous cardiac history was not associated with a psychiatric diagnosisin NCCP patients seeking medical attention at EDs. In contrast, a Type D personality (tendency to experience emotional distress) was independently associated with the presence of psychopathology in this population. CBT interventions are effective in this group of patients, but ED settings are not adequate environments for their performance. Taking the acceptability and relevance of self-help interventions into account is an important first step in acknowledging the needfor such therapies. Webster et al.  evaluated the acceptability and relevance of an evidence-based self-help intervention for patients admitted to the ED with persistent NCCP and anxiety. Intervention acceptability and feasibility were evaluated from the perspective of patients and nurses specializing in chest pain. Both patients and nurses reported that the intervention was relevant, acceptable, and potentially useful.
Hypnotherapy has also been evaluated in the treatment of FCP patients. While the precise mechanisms of hypnotherapy in the esophagus are unknown, esophageal hypersensitivity and esophageal hypervigilance are amenable to treatment with this intervention . Riehl et al reported an 80 % improvement with hypnotherapy . In addition to its analgesic effect, hypnotherapy improves quality of life and the perception of well-being, and decreases medication usage.
Neuromuscular reconditioning with biofeedback has been successfully used for more than 30 years in functional anorectal disorders. In a recent pilot study with a small sample size, esophageal biofeedback using diaphragmatic exercises and breathing techniques was applied to patients with functional esophageal disorders (six with FCP and six with functional heartburn) . There was significant symptom improvement after relatively long-term treatment (up to 4 years) in patients with FCP, but not in patients with functional heartburn, compared with untreated subjects.
The effects of the Johrei treatment (a form of energy healing) were evaluated in 39 patients with FCP in a randomized trial . When compared with the baseline, there was a significant reduction in the chest pain symptom intensity score (p < 0.0002) in patients that received 20-min Johrei sessions for 6 weeks, compared with the control group. The mechanism of action for this alternative therapy is unclear.
Functional chest pain represents a challenge for clinicians. The currently available tests used in FCP are performed to rule out GERD, esophageal mucosal abnormalities, and motor disorders. Esophageal hypersensitivity is a hallmark of FCP, but unfortunately, esophageal sensory tests are still only considered for use in research. Psychologic comorbidity is common in FCP and present-day treatment options include pain modulators and non-pharmacologic interventions, such as CBT, hypnotherapy, and biofeedback.
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Conflict of Interest
José Maria Remes-Troche has served as a member of the advisory board for Commonwealth, Allergan and Carnot; has received grant support for research from Sanfer and Asofarma; and also has served as speaker for Takeda, Allergan, Carnot, Menarini and Sanfer.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Motility
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Remes-Troche, J.M. How to Diagnose and Treat Functional Chest Pain. Curr Treat Options Gastro 14, 429–443 (2016). https://doi.org/10.1007/s11938-016-0106-y
- Functional chest pain
- Pain modulators