to four years, there was a significant improvement in reported symptoms (p = 0.048) among the 5 patients with functional chest pain compared to the 3 not receiving biofeedback [113]. No significant differences were seen in the patients with functional heartburn receiving biofeedback [113].
Hypnotherapy
Hypnotherapy is another therapy that is also listed as one of the two major brain‐gut psychotherapies in the AGA practice update [106]. In 28 patients with NCCP randomized to hypnotherapy vs. placebo for 17 weeks, Jones et al. found that hypnotherapy had greater global improvement in pain (p = 0.008) and a reduction in pain intensity (p = 0.046), although not frequency [114].
Other non‐pharmacologic treatments
Emerging areas of non‐pharmacologic treatment focus on the role of mindfulness‐based interventions such as Johrei, which is described as a process of “transmitting healing energy” [115]. One trial that enrolled 21 patients into a Johrei group and compared their reported symptoms of functional chest pain to 18 patients on the waitlist for Johrei treatment found no significant reduction in symptom intensity between the treatment and waitlist group but did find improvement in their reported symptom intensity after treatment (p = 0.0023) [116].
Non‐pharmacologic summary
Overall, it is clear that the studies on non‐pharmacologic treatment modalities for NCCP are relatively weak and exceptionally varied. Attempting to integrate this information, a 2015 Cochrane review on psychological interventions for nonspecific cardiac chest pain found 17 trials, including a total of 1006 patients [117]. Results from this systematic review suggested that there may be a modest to moderate benefit for psychological interventions, in particular those using CBT, but this benefit was restricted to the first three months after intervention [117]. Additionally, all studies included had a high risk of performance bias, as well as high heterogeneity among studies and wide variability in secondary outcomes, all of which largely limit the interpretation of these outcomes [117].
Conclusion
In summary, there are a number of pharmacologic and nonpharmacological agents for the treatment of ECP. Current recommendations vary depending on expert opinion and prior experience, as the evidence‐based data for many therapeutic modalities is overall weak. Furthermore, emerging evidence highlights a complex pathogenesis of esophageal hypersensitivity involving pain signaling and neurogenic feedback loops, which may overlap with mental health disorders, in particular anxiety and hypervigilance. As a result, we recommend an approach that takes into consideration the frequency of patient comorbidities, in particular mental health, as well as the cost and availability of the different drug options (Figure 2.1).
Given the low cost, ease of accessibility, options for in‐class switching, frequency of mental health overlap, and general tolerability as well as cardiac safety, we recommend a SSRI/SNRI as an initial treatment option for patients with esophageal chest pain due to esophageal hypersensitivity. At the current time, four of the SSRIs/SNRIs (citalopram, sertraline, paroxetine, and venlafaxine) are available on the $4 Walmart prescription list [118]. For patients failing to respond to these classes of medications, we recommend in‐class or between‐class switching as an initial second choice. For patients still unresponsive, a reasonable next drug class would be the tricyclic antidepressants. Whereas imipramine has been the TCA studying in clinical trials, it does run a higher cost than amitriptyline, and either could be considered a starting drug based on clinical scenario and patient selection [118, 119].
Finally, theophylline has been shown to have little risk of serious toxicity when administered properly [120]. However, it does present a number of risks: narrow therapeutic range, large pharmacokinetic variability, need for dose titration, and recommendations for steady‐state concentration assessment along with the possibility of inadvertent overdose [121]. Furthermore, since clinical data comes from only one randomized‐control trial of 24 patients on oral theophylline, the data supporting use is weak.
Evidence‐based data for the non‐pharmacologic treatment of NCCP is also weak. While there are a number of studies, they are significantly varied in the study design, are of small size, and incorporate a wide variety of therapies. Additionally, these studies include patients with NCCP rather than ECP specifically. This limits comparison to more recent studies using more advanced methods of diagnosis, which can characterize the type of NCCP. In general, the strongest evidence is likely for cognitive behavioral‐based therapy. The efficacy of these non‐pharmacologic therapies is likely greatest when used in combination with pharmacologic therapy but may be limited to the first three months of therapy [117].
Dysmotility
Achalasia
Achalasia is a rare neurodegenerative motility disorder of the esophagus with an annual incidence and prevalence of approximately 1.6 cases per 100,000 and 10 cases per 100,000 individuals, respectively [122]. Recent data with the use of high‐resolution manometry (HRM) suggests that the prevalence may be higher, as HRM has a greater diagnostic yield and may lead to an earlier diagnosis compared to conventional manometry [123]. Achalasia affects males and females equally without racial predilection. It can occur at any age, albeit rare in childhood, with a peak incidence between the ages of 25 to 60 years old. Expanded focused discussion on achalasia can be found in Chapter 13.
Pathophysiology
Primary achalasia is subdivided into three subtypes based on HRM findings with treatment implications depending on the specific subtype. While the manometric details of subclassifications are beyond the scope of this chapter, it is worth noting that achalasia Type II typically has the best response to therapy, whereas Type III usually has the worst response, in particular, for resolution of ECP [124].
The hallmark loss of ganglion cells in the myenteric plexus, albeit the underlying pathogenesis of primary achalasia, remains uncertain. Available data, however, strongly suggests an immune‐mediated response (both cell‐ and antibody‐mediated). This is supported by analysis of tissue samples taken after Heller myotomy for achalasia, which demonstrated an abundance of T‐lymphocytes, some eosinophils, plasma cells and B cells, along with occasional mast cells and macrophages surrounding ganglia and neurons in the myenteric plexus [125–127]. Notably, the T‐cells found in the myenteric infiltrate stained positive for TNF‐α, demonstrated IgM antibodies, and also evidence of complement activation, which taken together are thought to promote apoptosis of myenteric neurons [128, 129]. Additionally, impaired endogenous nitric oxide synthesis and degradation are thought to play a role in achalasia. The role of nitric oxide will be discussed later in detail in relation to distal esophageal spasm, which is also potentially considered a precursor to achalasia [124].
Antibodies specific to myenteric neurons have been seen in patients with primary achalasia, most notably in patients with HLA‐DQA1*0103 and HLADQB1*0603 alleles [130, 131]. These human leukocyte antigen (HLA) proteins play a pivotal role in antigen recognition, suggesting an anomalous immunity to a specific antigen. Several proposed theories have included herpes simplex (namely HSV‐1), human papillomavirus, and the measles virus, but available data to date has been inconclusive [132–136].
Pertinent to ECP, achalasia can have several symptoms, with dysphagia being the most common, followed by regurgitation, chest pain, and heartburn [137]. Typically, the symptoms experienced by patients depend on the degree and location of neural cell loss. In the distal esophagus, the inability for lower esophageal sphincter (LES) relaxation and impaired peristalsis results in dysphagia. As a consequence, the esophagus spasms and the esophageal lumen dilates. This produces sensations similar to heartburn, and thus patients are often misdiagnosed as having gastroesophageal reflux rather than underlying achalasia [138].