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The Esophagus


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(p = 0.02) and post‐treatment (p = 0.01) evaluations [94]. No significant improvement was seen for paroxetine compared to placebo [94].

       Tricyclic antidepressants

      Imipramine, a tricyclic antidepressant, represents one of the earliest pharmacologic options for NCCP. This was demonstrated in a randomized, double‐blind, placebo‐controlled three‐week trial of 60 patients assigned to clonidine 0.05–0.1 mg twice daily (included in the study as it had previously been used to treat chronic pain syndromes), imipramine 25–50 mg nightly, or placebo. Only patients in the imipramine group had a significant improvement in their pain (p = 0.03) [95]. More robust data regarding the use of tricyclic antidepressants is lacking; however, there was one retrospective long‐term follow up of 21 outpatients over 2.7 years treated with tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine; doses ranging from 20–75 mg daily with median 50 mg) after incomplete response to anti‐reflux medications, which found 7 patients (41.2%) were successfully treated continuously or for symptom relapses and 5 patients (29.4%) discontinued therapy after 6 months with sustained benefits [96].

       Trazadone

      Trazodone is another early pharmacologic agent that was previously investigated in a six‐week double‐blind, randomized placebo‐controlled trial in 29 patients with esophageal symptoms and contraction abnormalities. In this trial, 15 patients treated with trazodone 100–150 mg daily showed a significantly greater global improvement (p = 0.02) with less residual distress over their esophageal symptoms (p = 0.03) [97].

       Theophylline

      Outside of antidepressant medications, another potential treatment option for ECP is theophylline, which is an older medication that has been used in asthma for over 70 years. Theophylline functions by inhibiting phosphodiesterases (PDEs), antagonizing adenosine receptors, as well as affecting inflammatory gene expression [98]. Rao et al. administered intravenous theophylline [loading dose = (0.5 L/kg body weight) × (average body weight) × (15 mg/L)] to 21 consecutive patients with functional CP, showing this increased the pain threshold in 76% of patients whose symptoms were reproduced by esophageal balloon distension, as well as improved median threshold pressures for pain and discomfort (p < 0.01) [99]. Eight patients with response to IV theophylline were then treated with oral theophylline (maintenance dose oral 6 mg/kg/day in two divided doses) for three months, seven of whom reported a symptomatic benefit. The results of this study were then followed up with a double‐blind, randomized, placebo‐controlled study that assessed sensory and biomechanical responses to IV theophylline [loading dose = (0.5 L/kg body weight) × (average body weight) × (15 mg/L)] and symptomatic patient responses to oral theophylline 200 mg twice daily after meals [100]. With IV theophylline (n = 16), chest pain thresholds increased (p = 0.027), as did esophageal balloon distensibility thresholds (p = 0.04) [100]. With oral theophylline, reduction in painful days (p = 0.03), chest pain episodes (p = 0.025), pain duration (p = 0.002) and pain severity (p = 0.031) all decreased, with an overall improvement in symptoms in 58% vs. 6% on placebo (p < 0.02) [100].

       Emerging therapies

      QX‐314 is a novel lidocaine formulation that inhibits hypersensitivity by acting on the vagal afferent C fiber [101]. These fibers express a capsaicin‐responsive channel TRPV1, which is also activated by non‐selective cations such as protons. Under normal conditions, the cell membrane is impermeable; however, activation of this TRPV1 channel opens pores for QX‐314 delivery; this subsequently causes inhibition of somatosensory transmission, and therefore pain, without impairing motor function [102–105]. Hu et al. demonstrated that reflux lowers the pH sufficiently to activate the TRPV1 channel and enable QX‐314 inhibition. They also demonstrated that this effect is activated only when acid reflux occurs in the esophagus and is localized to the nociceptive afferent C type fibers. While any effect on neurogenic inflammatory response has not been well studied, the preliminary results highlight a novel pathway focus for treatment of esophageal chest pain [101].

      Non‐pharmacologic

      In addition to pharmacologic therapy, ECP shows excellent responsiveness to a variety of non‐pharmacologic treatment modalities. The emphasis on non‐pharmacologic treatments of GI disorders continues to increase as our understanding of the brain‐gut axis expands. The American Gastroenterological Association now has clinical practice updates on the use of incorporating psycho‐gastroenterology into the management of digestive disorders [106]. This section will discuss the role of cognitive behavioral therapy (CBT), biofeedback therapy, coping skills training, hypnotherapy, and other non‐pharmacologic options available for the treatment of NCCP.

       Cognitive behavioral therapy

      CBT in NCCP has been studied in a variety of settings over the past three decades. One of the earliest studies enrolled 31 patients with NCCP despite negative workup and assigned them to receive CBT focused on teaching patients how to anticipate and control their symptoms or a control group with the assessment of symptoms only. Patients undergoing CBT had significant reductions in chest pain, limitations and disruption in daily life, autonomic symptoms, distress, and psychological morbidity, which were maintained for four to six months of follow‐up [107].

      In a similar follow‐up study, consecutive patients presenting to a cardiology clinic with NCCP despite normal evaluation were given the option to participate in CBT. A total of 37 patients agreed to participate. Improvement in symptoms, mood, and activity was noted at three months (p < 0.05 for each). At six months, however, there were only significant advantages in limitation of activities (p < 0.05)and worry about physical symptoms (p < 0.05) [108].

      In 60 patients with NCCP, group psychological treatment was also shown to significantly reduce the number of chest pain episodes (p < 0.01), improve depression and anxiety scores (p < 0.05), and improve disability rating (p < 0.0001) at six months of follow‐up [109]. Similar findings, but with more durability of response, have also been reported. Van Peski‐Oosterbaan et al. randomized 72 patients with NCCP to undergo CBT vs. usual medical care and found CBT resulted in a significant improvement in the frequency and intensity of chest pain (48% vs. 13%) (p = 0.002) at 12 months of follow‐up [110]. Jonsbu et al. randomized 40 patients with NCCP to receive three sessions of CBT and one physical activity session vs. usual care from a practitioner and found CBT resulted in an improvement in fear of bodily sensations (p = 0.008), avoidance of physical activity (p = 0.007), depression (p = 0.02), and various domains of health‐related quality of life (HRQOL) at 3 and 12 months of follow‐up (p = 0.03) [111].

      For patients with NCCP and coexistent panic or depressive disorder, randomization to 12 sessions of CBT was superior to treatment as usual in reducing disease severity with the clinical global improvement scale (p < 0.001) [112]. Furthermore, patients with NCCP and heart‐focused anxiety were found to respond to CBT (p = 0.023) but not pharmacologic treatment (p > .05) in a randomized control trial by Spinhoven et al [94].

       Coping skills training

      Keefe et al. suggested a potential synergist effect between non‐pharmacologic and pharmacologic treatments through coping skills training (CST) among patients with NCCP randomized into four groups: CST plus sertraline 50–200 mg daily, CST plus placebo, sertraline alone, or placebo alone [93]. Compared to placebo, CST plus sertraline, CST plus placebo, and sertraline alone all resulted in reductions of reported pain intensity and unpleasantness (p < 0.001); however, only those randomized to CST plus sertraline had a reduction in reported pain catastrophizing (p = 0.02) [93].

       Biofeedback therapy

      Biofeedback therapy is another potential option for the treatment of NCCP; however, the data is sparse. In a small