Evidence supporting the role of GERD in NCCP comes from several sources. NCCP is more common in patients who experience heartburn weekly as opposed to those having heartburn less than once a week. Ambulatory pH testing in large numbers of patients with NCCP reveals that approximately 50 % have abnormal reflux. More convincingly, therapeutic trials aimed at acid inhibition have shown approximately an 80 % response to proton pump inhibitors (PPIs).

Esophageal motility disorders were previously considered the most common cause of NCCP. With the advent of ambulatory pH testing in the 1980s, it became apparent that GERD is a more common cause of NCCP than abnormal esophageal motility. Indeed, only about 30 % of patients with non-GERD-related NCCP have esophageal dysmotility. Furthermore, in those patients with abnormal esophageal motility, a spectrum of esophageal motility disorders can be observed including esophageal spasm (now termed “distal” esophageal spasm to emphasize the distal location of abnormal motility findings), nutcracker esophagus, hypertensive lower esophageal sphincter (LES), nonspecific motility disorders (now described mostly as “ineffective motility”), and, rarely, achalasia. The recent introduction of high-resolution esophageal manometry has uncovered other motility disorders such as “jackhammer esophagus” that may be seen in patients with NCCP. Despite the recognition that some patients with NCCP have abnormal esophageal motility, it has been difficult to prove that these disorders cause NCCP. Many patients have abnormal motility, yet, at the time of testing, they do not experience chest pain. In addition, therapeutic trials aimed at reducing or normalizing the spastic motility have not resulted in consistent improvement of chest pain. These observations have led investigators to consider that these motility abnormalities represent a “marker” associated with NCCP, but not the cause.

Using high-frequency intraluminal ultrasonography (a research tool that allows for evaluation of smooth muscle esophageal contractions), investigators have identified a unique pattern of esophageal muscle contractions in patients with NCCP termed “sustained esophageal contractions.” These esophageal muscle contractions appear to arise from the longitudinal muscle layer. As such, they are not detectable by conventional esophageal motility which measures circular esophageal muscle contraction primarily. These contractions occur either spontaneously or can be induced by edrophonium and generally precede episodes of chest pain. Interestingly, while the duration of swallow-induced contractions lasts about 6.4 s, those associated with chest pain last 68 s. Shorter duration of contractions is also more commonly linked to heartburn. Further studies, particularly therapeutic trials, are needed to determine whether the correction of this contractile pattern results in symptom improvement.

Visceral hypersensitivity has been repeatedly demonstrated using various techniques in NCCP. Using intra-esophageal balloon distension, NCCP patients perceive chest pain at lower volumes of esophageal balloon distension compared to healthy controls. Perceptual responses to intraluminal esophageal balloon distension using an electronic barostat showed that, when compared with saline, acid perfusion reduces the perception threshold (innocuous sensation) and tended to reduce the pain threshold (aversive sensation). This study demonstrated short-term sensitization of mechanosensitive afferent pathways by transient exposure to acid and led the investigators to suggest that in NCCP, acid reflux induces sensitization of the esophagus, which may subsequently alter the way the esophagus perceives otherwise normal esophageal distention. Patients with NCCP also experience visceral hypersensitivity to an innocuous stimulus in normal tissue proximal to a site of injury (allodynia) as well as in the somatic area (chest wall). These findings suggest that in NCCP there are both visceral hypersensitivity and amplified secondary allodynia. Recent studies have shown that in patients with GERD-related NCCP, there is a lower esophageal threshold for chest pain than controls and that PPI therapy reduces this hypersensitivity. It is likely that the visceral (esophageal) hypersensitivity noted in patients with NCCP may be triggered by noxious stimulus, such as acid, bile, or the release of local irritants or neuropeptides. These agents in turn stimulate afferent sensory visceral nerves whose impulses travel to the spinal cord via sensory neurons into the sensory cerebral cortex. A better understanding of the origin of esophageal pain, putative neurotransmitters, neurosensory transmission, and perception will lead to more selective pharmacologic intervention in the management of NCCP.

Other investigations have identified a number of differences in central nervous processing of esophageal stimuli between NCCP patients and controls suggesting that the perception of chest pain in patients is unique and may be modulated at the central level. Again, these observations open new avenues for future treatment interventions capable of altering central perception of pain.

Psychological disorders have been reported in 17–43 %, and as high as 75 % of patients, in some studies of NCCP. The most common disorders observed in NCCP include anxiety, panic disorders, depression, neuroticism, and hypochondriac behavior. When NCCP patients are compared to coronary artery disease controls, the prevalence of psychological disorders is not uniformly higher in NCCP. The high association between psychological disorders and NCCP raises several questions: which came first, the psychological problem or chest pain, and how does the psychological disorder influence NCCP and vice versa?

An important priority in the initial approach to the patient with chest pain is to ensure that life-threatening conditions such as coronary artery disease and other cardiac causes of chest pain are excluded. This typically requires cardiac consultation and objective testing. Once this has been done, it is also important that other non-esophageal sources of pain are excluded. The differential diagnosis of chest pain is broad (see Table 3.2). Thus, a careful history and physical exam are imperative to secure an accurate diagnosis. Once cardiac, pericardial, vascular, pulmonary, gastrointestinal, and musculoskeletal sources of chest pain have been excluded, esophageal sources must be considered.