within the brain (Figure 2.2).
Another overlap with functional disorders is the phenomenon known as viserco‐somatic convergence, whereby esophageal pain can be referred to distinct somatic structures if there is any synapse at the same level of the spinal cord [79,80]. In a similar fashion, visceral pain syndromes from organs sharing part of the same spinal cord level innervation can lead to intensification of pain from the esophagus in what is known as viscero‐visceral hyperalgesia [80, 81]. These mechanisms highlight the complexity not only of pain signaling but also of the means by which esophageal chest pain closely overlaps with other somatic or functional disorders. There is data to support a strong influence of stress on the perception and signaling of esophageal hypersensitivity [48]. Fass et al. demonstrated that acute auditory stress resulted in a reduction in time to initial symptom perception, increased pain intensity score, and increased acid sensitivity store in GERD patients [82]. Additionally, psychological stressors can exacerbate symptoms of heartburn. This has been shown experimentally in patients with heartburn and acid reflux who are exposed to an acute psychological stressor while undergoing 24‐hour esophageal pH monitoring [83]. These patients showed a significant increase in cortisol and anxiety levels, in addition to a dissociation between the objectively measured reflux and reported symptom severity [83]. Similarly, Naliboff et al. found patients with stressful life events in the previous six months had a significant increase in heartburn symptoms during the following four months. However, most importantly, the stress ratings were not significantly associated with heartburn score; rather, anxiety showed the strongest relationship to impaired quality of life, depression, and heartburn medication use [84].
Figure 2.2 Mechanisms of esophageal injury and peripheral and central sensitization in esophageal hypersensitivity.
Neuro‐psychologic assessment of patients with NCCP compared to healthy controls also suggests subgroups of patients with NCCP and hypersensitivity. One subset of patients are those with normal esophageal evoked potential latencies but enhanced afferent transmission, with a consequent increased esophageal afferent pathway sensitivity [51]. Another group of patients are those with increased esophageal evoked potential latencies with reduced pain threshold, implying a heightened secondary cortical processing likely due to psychological factors such as hypervigilance [51]. Hypervigilance is becoming increasingly recognized as a factor contributing to patient symptoms. Guadagnoli et al. studied 117 patients with GERD undergoing four days of pH monitoring and completing questionnaires on reflux severity and esophageal hypervigilance and anxiety scale (EHAS) [85]. The EHAS scores and the number of days with positive acid exposure time (p = 0.378) or the number of days with positive symptom‐reflux association did not significantly differ (p = 0.125), suggesting that patients may be at risk for developing hypervigilance and anxiety over their symptoms even in the absence of acid exposure [85]. Although evidence suggests that stress impacts the perception of esophageal hypersensitivity, the mechanisms are not as well understood. The key mediator is likely related to the master hypothalamic stress control mediated by the release of corticotropin‐releasing hormone (CRH). In healthy subjects, the administration of CRH can lead to increased esophageal hypersensitivity to mechanical stimulation [86]. More specific to some of the previously discussed mechanisms, psychological stress may induce the systemic and peripheral release of CRH, resulting in increased mucosal permeability. This occurs due to the expression of CRH receptors by many of the cells within the lamina propria and the subsequent recruitment and activation of mast cells, eosinophils, and macrophages, which may worsen the underlying inflammation and increase the activation of the nociceptive receptors [87,88].
In summary, esophageal hypersensitivity represents a critical facet of esophageal chest pain. Most importantly, there are a number of mechanisms through which hypersensitivity can impact the perception of esophageal pain, including mechanical, chemical, and nociceptive pain receptors. At present, the full impact of inflammation and intestinal permeability on these signaling pathways is not well understood. Clearly, the role of stress in esophageal hypersensitivity strongly supports that psychological disorders play a significant role in esophageal hypersensitivity and overlap closely with other functional gastrointestinal disorders.
Treatment
The current literature suggests a number of potential treatment options for esophageal hypersensitivity. The efficacy of these therapies varies greatly, and there is not any robust data from large randomized controlled trials to support a single best practice strategy. Available pharmacologic options at present are antidepressants, theophylline, and novel inhibitors of esophageal pain channels. Additionally, the large overlap with functional gastrointestinal and psychiatric disorders presents a wide array of non‐pharmacologic approaches for the treatment of esophageal hypersensitivity.
Pharmacologic
The best‐studied class of pharmacologic therapies for esophageal hypersensitivity are the antidepressants: including selective‐serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), trazadone, and tricyclic antidepressants (TCAs).
Selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors
As a class, the SSRIs and SNRIs have the largest number of studies for the treatment of esophageal hypersensitivity. Among these, Lee et al. randomized 43 patients with functional chest pain to four weeks of venlafaxine 75 mg extended‐release daily or placebo and found a positive response in 52% vs. 4% (p < 0.001) in addition to greater improvement in body pain and emotional role (p = 0.002) [89]. Similarly, Doraiswamy et al. enrolled 50 patients with NCCP for a randomized, double‐blind, placebo‐controlled eight‐week trial of paroxetine 10–50 mg daily, showing paroxetine‐treated patients had a significant improvement in the Clinical Global Impressions scale (p < 0.05) [90].
Looking more closely at the effect of SSRIs on motility, Broekaert et al. administered intravenous citalopram 20 mg to 10 patients with established esophageal hypersensitivity undergoing esophageal manometry with mechanical and chemical stimulation via balloon distension and acid infusion. [91]. These authors found that citalopram did not significantly alter esophageal motility; however, it increased the threshold for the first perception (p < 0.005) and discomfort (p < 0.01) of balloon distension as well as prolonged the time for perception (p < 0.005) and discomfort (p < 0.001) of heartburn with acid infusion [91]. These results suggest that administration of citalopram, even in the acute setting, may reduce esophageal hypersensitivity without affecting esophageal motility.
Other studies have looked at the role of SSRIs as monotherapy or in combination with nonpharmacological treatment. Varia et al. conducted a double‐blind, placebo‐controlled study of sertraline 50–200 mg daily in 30 patients with noncardiac chest pain. These patients used subjective reporting with the Beck Depression Inventory and daily pain diaries during the nine‐week trial period. Overall, patients in the sertraline group demonstrated a clinically significant reduction in the reporting of daily pain (p = 0.02) [92]. In addition, the role of sertraline in noncardiac chest pain was evaluated by Keefe et al., who randomized 115 patients to receive coping skills training (CST) and sertraline 50–200 mg daily, alone or in combination, vs. placebo [93]. These authors found that sertraline alone was able to decrease reported pain intensity and unpleasantness, but not anxiety or pain catastrophizing, whereas CST was the only means effective for pain catastrophizing; therefore, these authors suggest that the combination of CST and sertraline rather than either alone may result in the greatest benefit [93].
Finally, Spinhoven et al. randomized 69 patients with NCCP to 16 weeks of cognitive‐behavioral therapy (CBT), paroxetine 10–40 mg daily, or placebo. Daily pain diaries and anxiety questionnaires were used to monitor patient outcomes [94]. Overall, CBT was more effective than placebo,