Esophageal hypercontractility is abolished by cholinergic blockade.

BACKGROUND: Esophageal hypercontractility (EHC) is considered a major esophageal motor disorder of unclear etiology. Different mechanisms have been proposed, including an imbalance in inhibitory and excitatory esophageal innervation. We hypothesized that patients with EHC suffer from cholinergic hyperactivity. AIM: To interrogate the excitatory and inhibitory neurotransmission in EHC by assessing the esophageal motor response to atropine (ATR) and cholecystokinin (CCK), respectively, in EHC patients. METHOD: We retrospectively reviewed patients who underwent high-resolution manometry (HRM) with pharmacologic challenge in a tertiary referral center between 2007 and 2017. We identified 49 EHC patients who were categorized based on frequency of hypercontractile peristaltic sequence into "frequent" and "infrequent" and motility diagnosis groups. Deglutitive pressure metrics and esophageal motor responses to ATR (12 mcg/kg iv) and CCK (40 ng/kg iv) were analyzed across groups. RESULTS: Atropine abolished hypercontractility across all groups studied, converting nearly half of patients to a motor pattern of ineffective esophageal motility. Abnormal CCK responses primarily occurred in the patient groups with concomitant outflow obstruction. CONCLUSIONS: Hypercontractility is cholinergically mediated in all esophageal motor disorders. Most patients with isolated EHC appear to have excessive cholinergic drive, rather than loss of inhibitory innervation, and might be candidates for treatment with anticholinergic agents.

Diagnostic differences in the pharmacologic response to cholecystokinin and amyl nitrite in patients with absent contractility vs type I Achalasia.

BACKGROUND: Absent esophageal contractility (AC) is distinguished from type 1 achalasia (ACH1) during high-resolution manometry (HRM) on the basis of normal or elevated deglutitive integrated relaxation pressure (IRP) values. However, IRP measurements are subject to pressure recording error. We hypothesized that distinctive responses to pharmacologic provocation using amyl nitrite (AN) and cholecystokinin (CCK) could reliably distinguish AC patients from those with ACH1. AIM: To compare esophageal response with AN and CCK in a well-defined cohort of ACH1 and AC patients. METHOD: All available clinical, radiographic, endoscopic, and manometric information in 34 patients with aperistalsis was reviewed to determine the final diagnosis of ACH1 and AC. The differences in response to provocative challenges with the rapid drink challenge (RDC) test and administration of AN and CCK were compared between these two groups. RESULTS: Eighteen patients were diagnosed with ACH1 and sixteen with AC. While IRP values were significantly higher in ACH1, the standard criterion value misclassified four AC patients as having ACH1 and five ACH1 patients as having AC. IRP values on the RDC did not accurately segregate AC from ACH1, but we were able to identify AN and CCK esophageal motor response criteria that allowed correct classification of ACH1 and AC patients. CONCLUSIONS: Nearly a quarter of AC and ACH1 patients may be misdiagnosed based on manometric IRP criteria alone. Differences in the esophageal motor responses to AN and CCK have the potential to facilitate the correct diagnosis in these challenging patients.

Motility Patterns Following Esophageal Pharmacologic Provocation With Amyl Nitrite or Cholecystokinin During High-Resolution Manometry Distinguish Idiopathic vs Opioid-Induced Type 3 Achalasia.

BACKGROUND & AIMS: In some patients, the type 3 achalasia (A3) motor pattern may be an effect of chronic use of high-dose opioids. No motor findings have been identified to differentiate opioid-induced A3 (OA3) from idiopathic A3 (IA3). We investigated whether OA3 could be distinguished from IA3 on the basis of differences in esophageal motor responses to amyl nitrite, cholecystokinin, or atropine. METHODS: We performed a retrospective study of patients who received pharmacologic provocation during esophageal high-resolution manometry from 2007 through 2017 at a tertiary referral center. We identified 26 patients with IA3 (9 women; mean age, 68 ± 13 years) and 24 patients with OA3 (15 women; mean age, 59 ± 10 years). We compared pressure topography metrics during deglutition and after administration of amyl nitrite, cholecystokinin, or atropine between patients with OA3 vs IA3. RESULTS: Amyl nitrite induced a similar relaxation response in both groups, but the rebound contraction of the lower esophageal sphincter during amyl nitrite recovery, and the paradoxical esophageal contraction during the first phase of cholecystokinin response, were both significantly attenuated in patients with OA3. The second phase of cholecystokinin response in patients with OA3 was 100% relaxation, when present, in contrast to only 26% of patients with IA3. There was no significant difference between groups in inhibition of lower esophageal sphincter tone or esophageal body contractility by cholinergic receptor blockade. CONCLUSIONS: Nearly half of patients with an A3 pattern of dysmotility are chronic, daily users of opioids with manometry patterns indistinguishable from those of patients with IA3. Patients with OA3 differ from patients with IA3 in responses to amyl nitrite and cholecystokinin. These findings might be used to identify patients with dysmotility resulting from opioid use.

Pharmacologic interrogation of patients with esophagogastric junction outflow obstruction using amyl nitrite.

BACKGROUND: The Chicago Classification of esophageal motility includes a group of patients who show evidence of esophagogastric junction outflow obstruction (EGJOO) as demonstrated by elevated integrated relaxation pressure (IRP) and preserved peristalsis. Our aim is to classify EGJOO patients based on response to amyl nitrite (AN) during high-resolution manometry. METHODS: Patients were considered to have true EGJOO if elevated IRP during supine swallow persisted in the upright position and was associated with high intrabolus pressure. The EGJ response to AN was compared between patients with achalasia type 2 (A2) and normal esophageal motility. Based on the relaxation gain (deglutitive IRP-AN IRP) value that best discriminated these two groups (10 mm Hg), patients with true EGJOO were categorized as being in either the AN-responsive (AN-R) or AN-unresponsive (AN-U) subgroups. KEY RESULTS: In the group of 49 patients with true EGJOO, the AN response classified 27 patients (IRP = 25 ± 10 mm Hg) with AN-R and 22 patients (IRP = 20 ± 5 mm Hg) with AN-U (P = 0.2). In AN-R, AN produced a relaxation gain and rebound after-contraction response at the EGJ comparable to A2 patients. AN-U patients had an elevated IRP after AN and a relaxation gain similar to normal esophageal motility patients. AN-U patients were obese and had higher prevalence of sleep apnea (P < 0.05). CONCLUSIONS: Among patients with true EGJOO, only half have pharmacologic evidence of impaired LES relaxation. Pharmacologic interrogation of the EGJ is thus necessary to identify the subgroup of EGJOO patients who could be expected to benefit from LES ablative therapies.

Chronic daily opioid exposure is associated with dysphagia, esophageal outflow obstruction, and disordered peristalsis.

BACKGROUND: Opioid receptors are present in the esophagus, and chronic opioid therapy may be associated with esophageal dysfunction. Given the current opioid epidemic in the United States, the potential contribution of opioids to esophageal dysmotility is important from both public health and patient care perspectives. Therefore our aim is to investigate the potential contribution of opioids to dysphagia and the prevalence of major motor disorders in patients undergoing manometric evaluation. METHODS: The anonymized electronic medical records of patients linked to their de-identified high-resolution manometry (HRM) studies were reviewed. The patients were grouped based on their opioid exposure history at the time of HRM: opioid-naïve and chronic daily users. The oral morphine milligram equivalent daily dose (MMED) of opioids was computed. KEY RESULTS: 10% of patients referred for esophageal HRM were taking opioid analgesics on a chronic daily basis, and they had a significantly higher prevalence of dysphagia than their opioid-naïve counterparts. The chronic daily opioid users displayed a significantly higher prevalence of achalasia type 3 (ACH3) and esophagogastric junction outflow obstruction (EGJOO) motility phenotypes. The MMED of opioids was a significant predictor of esophageal pressure metrics and motility diagnoses (P < 0.0001). CONCLUSIONS: Chronic daily opioid intake is associated with impaired deglutitive LES relaxation and disorganized peristaltic sequence. While a minority of patients on chronic daily opioid therapy present with major esophageal motor disorders, they comprise nearly half of ACH3 and a third of EGJOO motility phenotypes.