is also thought to impact the upper esophageal sphincter (UES) [139]. Under normal circumstances, the UES relaxes with esophageal distention allowing for gas to escape through the mouth in the form of a belch. In patients with achalasia, air in the esophagus frequently causes a paradoxical increase in UES pressures without a belch. This further causes esophageal distention and resultant chest pain. It is estimated that up to 85% of patients have difficulty belching and that nearly 60% of patients complain of substernal CP [140]. In fact, the frequency of CP in patients with achalasia is so common that CP is one of the four components of the commonly used Eckardt score used to assess and monitor the severity of achalasia, with the other three being recent weight loss, dysphagia, and regurgitation [141].
Distal esophageal spasm
Distal (or diffuse) esophageal spasm (DES) is a rare motility disorder with an annual incidence of 1 per 100,000 and a prevalence of nearly 2% [142, 143]. The characteristic findings on HRM are premature contractions in ≥20% of swallows in conjunction with normal relaxation of the LES [124]. On HRM, a premature contraction is defined as a swallow with a distal latency of less than 4.5 seconds. More focused and expansive discussion can be found in Chapter 15.
Pathophysiology
Distal esophageal spasm occurs due to impaired inhibitory innervation resulting in premature contractions that may cause symptoms of dysphagia and retrosternal pain [124]. The underlying pathophysiology of DES remains poorly understood. One proposed theory is that patients with DES suffer from malfunctioning endogenous nitric oxide synthesis and/or its degradation [124]. Nitric oxide (NO) and cholinergic neurons mediate smooth muscle contraction. A pilot study by Konteurek et al. treated five patients with esophageal spasm using glyceryl trinitrate (prodrug of nitrous oxide) in increasing doses of L‐arginine (amino acid necessary for nitrous oxide synthesis) on two separate occasions with repeated manometric measurements [144]. Patients treated with glyceryl trinitrate had a notable reduction in the duration of contraction (from 11.2 +/‐ 4.8 sec to 4.4 +/‐ 0.8 sec), while the administration of L‐arginine did not cause any significant alterations in manometric findings. Further supporting this hypothesis, Murray et al. evaluated the role of nitric oxide in asymptomatic, fasting male volunteers randomly assigned to receive intravenous human serum albumin or recombinant human hemoglobin (which inactivates nitrous oxide) [145]. A majority of those who received recombinant human hemoglobin demonstrated increased velocities of peristaltic contractions (p < 0.01), increased amplitude and duration of contractile waves (p < 0.05), and impaired LES relaxations, suggesting that NO mediates the timing of smooth muscle esophageal peristalsis and LES relaxations [145]. Additionally, retrosternal chest pain during swallowing was also seen in four of nine subjects, further supporting a role for DES and NO production in the etiology of ECP. Some experts believe DES to be a precursor to achalasia and thus may share mechanisms by which noncardiac chest pain develops [146, 147]
Hypercontractile (jackhammer) esophagus
Hypercontractility (i.e. jackhammer esophagus) is found in approximately 4% of patients who undergo manometric evaluation, as estimated by recent retrospective reviews of both healthy volunteers and consecutive patients undergoing manometry [148, 149]. Some isolated episodes of hypercontractility can be seen in healthy controls; however, among controls, no distal contractile integral (which measures the vigor of peristalsis) values were > 8,000 mmHg/cm/s [149]. Therefore, HRM diagnostic criteria necessary for jackhammer esophagus are a distal contractile integral of > 8,000 mmHg/cm/s on ≥20% of swallows [124].
Pathophysiology
Esophageal hypercontractility is thought to be a result of excess cholinergic secretion and/or muscular asynchrony of the esophageal wall contractions. Supporting the role of impaired cholinergic secretion, Loo et al. evaluated esophageal function in 14 patients with insulin‐dependent diabetes and peripheral and autonomic neuropathy in the absence of esophageal symptoms [150]. Diabetics with autonomic neuropathy had a higher frequency of multipeaked waves (of normal amplitude) when compared to diabetics without neuropathy or controls. Following injection of atropine, these multipeaked contractions were converted to a single‐peaked contraction [150]. Jung et al. evaluated the synchrony between muscles in the circular and longitudinal muscle layers in patients with a hypercontractile esophagus compared to healthy controls [151]. Pressure measurements were gathered from a manometry catheter, as well as imaging using high‐frequency intraluminal ultrasound at 2 and 10 cm above the LES during wet swallows. Images obtained were analyzed for the cross‐sectional area of the circular and longitudinal muscle layers. Patients with hypercontractility had temporal asynchrony between the contractions of circular and longitudinal muscle layers. [151].
Available treatment options for esophageal chest pain
Pharmacotherapy
Since the underlying pathophysiology for primary achalasia, DES, and esophageal hypercontractility (i.e. jackhammer esophagus) remains poorly understood, the evidence‐based best practice pharmacologic recommendations are weak. The primary goal of available therapy aims to improve peristalsis and smooth muscle relaxation at the level of the LES. Ideally, this approach will translate into improved patient symptoms. Calcium channel blockers (CCBs) and nitrates remain the most commonly used drugs for the treatment of esophageal chest pain, but evidence to support this is limited.
The CCBs act by inhibiting calcium‐dependent myocyte contraction, leading to smooth muscle relaxation, although much of the data surrounding their use is both mixed and relatively dated. In these studies, nifedipine 10–30 mg three times daily was the most commonly used CCB, and in a small randomized crossover study of 16 patients it was shown to improve the chest pain index (severity × frequency) but not the chest pain frequency or intensity alone [152]. Diltiazem, another CCB, was used in a small trial of 14 patients and shown to decrease the chest pain score in patients with nutcracker esophagus (hypercontractile esophagus) [153]. The studies in this area, however, have significant methodological issues and small sampling sizes, precluding clear clinical benefit [152–156].
Nitrates are another pharmacologic agent used in the treatment of ECP related to motility disorders. As previously discussed, NO is thought to play a key role in the development of achalasia and DES. Small‐scale studies have suggested nitrates may improve manometric findings and chest pain in DES [157, 158]; however, data supporting its use in achalasia [159] and hypercontractile states [160] has been equivocal or lacking. More recently, phosphodiesterase‐5 inhibitors have recently emerged as a potential therapeutic option by acting to inhibit the degradation of NO, thus regulating smooth muscle relaxation. Bortolotti et al. evaluated in a double‐blind study the effect of sildenafil 50 mg/d vs. placebo on the esophageal musculature in 14 patients with achalasia [161]. Sildenafil inhibited contractile activity, decreased LES tone, residual pressure, and contraction amplitude as measured by a low‐compliance manometric system [161]. Eherer et al. investigated the effect of sildenafil on esophageal motility among six healthy male volunteers in a double‐blind study in which the participants underwent 12‐hour manometry on two separate days, once with sildenafil 50 mg and once with placebo [162]. The other arm was an open study on the effects of sildenafil 50 mg on manometric features and clinical responses in 11 patients with hypercontractility [162]. Results showed sildenafil lowered LES pressures and pressure amplitudes in the distal esophagus on esophageal manometry in all the healthy subjects, with a sustained effect for at least eight hours in three of the four patients who underwent prolonged manometric study. Among the patients with hypercontractility, they found manometric improvement in 9 of the 11 patients, however only 4 had symptomatic improvement, and 2 of those patients had to discontinue treatment due to side effects [162].
Finally, another potential therapy is the use of peppermint oil, which is postulated to have effects as a smooth relaxant. One group of investigators demonstrated that peppermint oil improved manometric findings in DES; however, repeat studies to date have failed to replicate this data [163]. More recent evidence has shown that its use improves difficulty swallowing and noncardiac chest pain,