The Role of Opioids and Alcohol in the Development of Achalasia Type III and Esophagogastric Junction Outflow Obstruction

The chronic use of opioids has been an issue in the United States with an increasing rate of use, and even non-cancer patients are on opioid medications, amounting to up to 4% of adults.¹ Side effects of opioid-induced bowel dysfunction have been described in most gastrointestinal luminal organs and include delayed gastric emptying as well as prolonged small and large bowel transit.¹ Symptomatically, these manifest as nausea, vomiting, distension, and constipation.¹

It has been shown that the acute administration of opiates, such as morphine, in both humans and animals may result in the increased tone of the circular muscle of the intestine. It also increased non-propagating contractions in the colon and small intestine.^2,3 Endogenously released endorphins interact with opioid receptors to affect sensation, secretion, and motility.⁴ These receptors have complex effects that are both inhibitory and excitatory, mediated by both presynaptic and postsynaptic receptors.^2,5 These may be presynaptic effects that are especially important for blocking or downregulating cholinergic excitatory pathways.^2,5 The blockade of these inhibitory neural inputs can occur due to decreased receptor expression due to chronic opiate stimulation and the impaired release of nitric oxide from inhibitory motor neurons, the disinhibition of gastrointestinal muscle activity, the elevation of resting muscle tone, and nonpropulsive motility patterns.^4–7

The effects of chronic opioid use on esophageal function have been reported recently.^1,8–12 There are 3 different subtypes of opioid receptors (δ, μ, and κ), and the mu-type opioid receptor is associated with dysphagia or gastroesophageal reflux disease.¹ In earlier experimental reports, injected morphine increased lower esophageal sphincter (LES) tone in humans.¹³ Moreover, morphine decreased transient LES relaxation in gastroesophageal reflux disease patients.¹³ Moreover, other mu-type opioid agonists, including loperamide, were attempted in gastroesophageal reflux disease patients.¹⁴ However, recent papers have reported the effects of long-term opioids on esophageal motility in a case series of patients with what appeared to be esophageal dysmotility in patients on chronic opioids.^8–10,12 Various manometric abnormalities have been reported in dysphagia patients, including impaired LES relaxation, simultaneous distal esophageal contractions, esophagogastric junction outflow obstruction (EGJOO), and elevated integrated relaxation pressure.^9,10 These findings can mimic spastic esophageal dysmotility, such as achalasia type II, III, or EGJOO.¹⁰ Therefore, a detailed previous medication history should be taken before the initiation of treatment because stopping opioid medication can restore spastic esophageal dysmotility to nearly normal peristalsis.^8,10

In the retrospective study of Schindler et al. in this issue,¹⁵ chronic opioid use was associated with EGJOO disorders, like in previous studies. Because of the limitations of retrospective analysis, they could not show the reversal of spastic contractility after the cessation of opioid medication. Interestingly, this study also showed a significant correlation with chronic alcohol abuse. In a limited study based on a human or animal model, excessive alcohol use could mimic EGJOO by interfering with nitric oxide-mediated LES relaxation.^16,17 This nitric oxide mechanism was also postulated to be a factor in opioid-related esophageal dysmotility disorders.¹⁷

In conclusion, a detailed medication history should be taken in patients with spastic esophageal dysmotility disorders including alcohol or opioid medications before the initiation of treatment. After the widespread use of invasive treatment including per-oral endoscopic myotomy (POEM), POEM became the optimal treatment of choice even in EGJOO or other spastic esophageal motility disorders,^18–20 because the cessation of those medications or alcohol could reverse their esophageal dysmotility.