Opioid-induced Esophageal Dysfunction

Diana L. Snyder; Marcelo F. Vela

Disclosures

Curr Opin Gastroenterol. 2020;36(4):344-350. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: Chronic opioid use is common and can cause opioid-induced esophageal dysfunction (OIED). We will discuss the pathophysiology, diagnosis, and management of OIED.

Recent findings: OIED is diagnosed based on symptoms, opioid use, and manometric evidence of distal esophageal spasm, esophagogastric junction outflow obstruction, achalasia type III, or jackhammer esophagus. Chronic opioid use appears to interfere with inhibitory signals involved in control of esophageal motility, allowing for unchecked excitatory stimuli, and leading to spastic contractility and impaired esophagogastric junction relaxation. Patients may present with dysphagia and chest pain. OIED is significantly more prevalent in patients taking the stronger opioids oxycodone and hydrocodone compared with the weaker opioid tramadol. Based on 24-h morphine equivalent doses, patients with OIED take higher opioid doses than those without OIED. Impaired inhibitory signaling was recently demonstrated in a study showing reduced deglutitive inhibition during multiple rapid swallows in patients taking opioids.

Summary: OIED is frequent in chronic opioid users undergoing manometry for esophageal symptoms, especially at higher doses or with stronger opioids. OIED appears to be due to impaired inhibitory signals in the esophagus. Opioid cessation or dose reduction is recommended, but studies examining management of OIED are lacking.

Introduction

An estimated 11% of adults in the United States suffer from chronic pain. Long-term opioids are prescribed to 3–4% of the US population.[1] More than 165 000 people in the United States died from opioid pain medication overdose between 1999 and 2014, and roughly 1.9 million people were abusing or dependent on prescription opioids in 2013.[1] This opioid public health crisis is being addressed through state and national action.[1] In 2016, the centers for disease control released guidelines for prescribing opioid medications in the setting of chronic pain to educate medical practitioners on safe opioid practices.[1] State agencies are also regulating opioid prescriptions to reduce potential adverse events.[2]

In addition to the risk of abuse, overdose, and dependency associated with prescription opioid medications, numerous adverse effects are well established with these medications. Opioid-induced bowel dysfunction is a well studied side effect in patients taking opioids.[3,4] The most common bowel-related adverse effect reported is constipation; however, a number of upper gastrointestinal symptoms (e.g., nausea, vomiting, dyspepsia, dysphagia, and reflux) are common in patients who use opioids.[5,6] Data remain limited on how opioids may affect esophageal function. In this review, we evaluate the existing literature on opioid-induced esophageal dysfunction (OIED), and discuss the pathophysiologic mechanisms, diagnosis, and recommendations for management.

Opioid Receptors and Effects on the Enteric Nervous System

In the early 20th century, Paul Trendelenburg, a German pharmacologist, was the first to elucidate that morphine inhibits the gut's peristaltic reflex.[7] By the 1970s, Kosterlitz et al.[8] had isolated enkephalins from brain tissue and defined them as endogenous opioid receptor agonists. Subsequent studies determined that enkephalins interact with receptors in the enteric nervous system to regulate gastrointestinal motility and secretion.[9,10] Ultimately, three opioid receptors were identified in the enteric nervous system: μ, κ, and δ. Opioids used clinically for pain management preferentially act on the μ receptor. Peripheral opioid receptors are located in the submucosal and myenteric plexus neurons of the human stomach, small bowel, and colon;[11–13] their precise location in the esophagus remains unknown. These are G-protein coupled receptors that act in the central nervous system to regulate pain sensation, respiration, and dependence as well as in the peripheral nervous system regulating gut motility and secretion.[14]

In 1980, mammalian animals were found to have enkephalin-like immunoreactivity in the muscularis mucosae and external smooth muscle layer nerve plexus of the esophagus. Enkephalin inhibited contractions in the esophagus induced by electrical stimulation and this effect was blocked by naloxone, suggesting that enkephalin nerves are part of esophageal motility regulation.[15] A French study in 1988 found that administration of acetorphan (an agent that prevents enzyme degradation of endogenous enkephalins) to 10 healthy volunteers significantly inhibited lower esophageal sphincter (LES) relaxation on conventional manometry, indicating that endogenous enkephalins are part of the physiology of LES relaxation in humans.[16]

Pathophysiology of Opioid-induced Esophageal Dysfunction

To understand how opioids alter esophageal motor function, it is important to summarize normal esophageal function. Numerous studies have helped elucidate the mechanisms that organize esophageal peristalsis and govern the behavior of the LES. The striated muscle of the cervical esophagus and the smooth muscle of the thoracic esophagus receive different neural innervation. Primary peristalsis of the short segment of striated esophagus is centrally controlled through lower motor neurons in the nucleus ambiguus of the brainstem; in contrast, primary peristalsis in the longer smooth muscle portion of the esophagus is controlled through both central mediation and peripheral innervation. The excitatory pathway for smooth muscle includes vagal preganglionic neurons stimulating post ganglionic neurons that release acetylcholine and Substance P. The inhibitory pathway includes vagal stimulation of postganglionic inhibitory neurons releasing nitric oxide and vasoactive intestinal peptide.[17,18] Primary peristalsis is characterized by a sequence of esophageal contractions that proceed aborally in an organized fashion, requiring a contraction latency that increases gradually from the proximal to distal esophagus. This increasing latency is determined by the pattern of activation and regional gradients of inhibitory and excitatory signals in the esophagus.[17] The LES is a high-pressure zone that is tonically closed at rest. During swallowing, to allow ingested material to pass into the stomach, the LES has to relax and open, and this is also mediated by inhibitory and excitatory signals similar to those involved in primary peristalsis.[19]

Data remain limited on the pathophysiologic mechanisms of how opioids alter esophageal motility to cause OIED. The proposed mechanism for OIED is that chronic opioid use interferes with the inhibitory signals involved in control of esophageal motility, allowing for unchecked excitatory stimuli. This in turn leads to abnormal esophageal motor function that may include vigorous, rapid or simultaneous contractions in the esophageal body, and impaired relaxation of the LES. These abnormalities are manifested in esophageal manometry studies as distal esophageal spasm (DES), achalasia type III, esophagogastric junction outflow obstruction (EGJOO), and possibly jackhammer esophagus (a form of hyper-contractile peristalsis) (Figure 1). As summarized in the next section, currently available data show that these esophageal motility disorders are common in opioid users, and lend support to interference with inhibitory signals as a mechanism of action.

Figure 1.

High resolution manometry examples of esophageal motility disorders seen in opioid-induced esophageal dysfunction. (a) Esophagogastric junction outflow obstruction characterized by impaired esophagogastric junction relaxation with preserved peristalsis; (b) distal esophageal spasm with premature contractions but normal esophagogastric junction relaxation; (c) achalasia type III defined by impaired esophagogastric junction relaxation and spastic contractility in the esophageal body; and (d) jackhammer esophagus characterized by peristalsis with increased contractile vigor. Adapted from [27]

Human Clinical Studies

The earliest human studies were completed to determine whether the physiologic effects of opioids in the human esophagus were similar to those found in animal models (Table 1). The first studies evaluating effects of clinical opioids on esophageal motility are conflicting. In 1985, Dowlatshahi et al. measured basal pressure and relaxation of the LES as well as distal esophageal body peristalsis in 10 healthy adults given subcutaneous morphine sulphate compared with five adults given normal saline. Morphine slightly increased LES pressure, and significantly decreased LES relaxation with the maximum effect 30 min after injection. There was also an increase in amplitude of peristaltic waves that was not statistically significant.[20] In contrast, a 1986 study from Mittal et al.[21] found a decrease in LES sphincter pressure with administration of an intravenous morphine bolus to 10 healthy individuals. These disparate results may be due to the complexity of central and peripheral control of esophageal function in addition to endogenous and exogenous opioid effects on receptors in the esophagus. Morphine predominantly acts on μ opioid receptors whereas endogenous opioids including enkephalins have a stronger effect on δ opioid receptors.[22]

Further studies were done to understand opioid pathways by evaluating the effects of opioid antagonists in the esophagus. A double blind cross over study in 1987 assessed the effects of naloxone (an opioid antagonist acting predominantly at the μ receptor) on endogenous opioid production and esophageal motility. Twelve asymptomatic healthy volunteers received a naloxone bolus followed by a continuous naloxone infusion, and the equivalent volumes in normal saline, in random order. Using conventional esophageal manometry, this study showed that naloxone increased LES pressure, but swallow-induced LES relaxation was complete and there was no alteration in the amplitude of esophageal body contractions.[22] In another study, Penagini et al. studied eight healthy adults with conventional manometry given morphine intravenously (100 μg/kg) followed by naloxone intravenously (80 μg/kg). Morphine significantly impaired LES relaxation after single swallows, and naloxone reversed the effect.[23] A more recent double-blinded, randomized, crossover trial from 2015 treated 14 healthy volunteers with naloxone followed by remifentanil (an opioid) or saline followed by remifentanil. Remifentanil decreased swallow-evoked LES relaxation and decreased distal contractile latency; however, naloxone did not reverse these effects, which was hypothesized to be due to an inadequate dose of naloxone.[24]

All of the studies summarized above provide insight into how esophageal motor function may be affected by acute opioid administration. Kraichely et al. were the first to document the effects of chronic opioid use on esophageal motility using conventional manometry. Their 2010 publication is a retrospective review of 15 patients with dysphagia taking chronic opioids. Twelve of the 15 patients had abnormal motility defined by at least 30% nonperistaltic contractions. Among the abnormalities they documented were high amplitude contractions and incomplete LES relaxation. Follow-up manometry off opioids completed in three patients showed normalization of LES relaxation.[25]

In a larger study published in 2015, our group evaluated chronic opioid users with high-resolution manometry (HRM). We found that esophagogastric junction outflow obstruction (EGJOO, a newer term used to describe impaired LES relaxation in patients who have some peristaltic activity in the esophageal body), achalasia type III, and DES were significantly more common in 121 chronic opioid users (on opioids for ≥3 months) compared with 100 nonusers. A trend toward greater frequency of jackhammer esophagus among opioid users was also observed. Furthermore, among the chronic opioid users, EGJOO and achalasia type III were significantly more common in those who had taken opioids within 24 h of performing HRM, compared with those who were off opioids for at least 24 h.[26] This large study adds weight to the notion that opioids lead to spastic contractions in the esophageal body and impaired relaxation of the EGJ.

We subsequently described the effect of opioid dose and type on OIED. OIED was found to be significantly more prevalent in patients taking the stronger opioids oxycodone and hydrocodone compared with the weaker opioid tramadol (31 vs. 28 vs. 12%). Furthermore, based on total 24-h morphine equivalent doses, patients with OIED were taking a significantly higher median 24-h opioid dose than those without OIED (45 vs. 30 mg).[27] The demonstration of a dose effect further supports the effect of opioids on esophageal motor function.

More recently, to further explore the hypothesis that opioids interfere with inhibitory signals in the esophagus, we evaluated the impact of these medications on deglutitive inhibition during multiple rapid swallows (MRS). The normal response to MRS involves contractile inhibition of the esophageal body during the MRS sequence, followed by a post-MRS peristaltic contraction. Indeed, impaired inhibition during MRS was significantly more frequent in 72 chronic opioid users compared with 100 patients not taking opioids and 24 healthy asymptomatic controls who underwent HRM (54 vs. 14 vs. 0%).[28] These findings provide additional support for impaired inhibitory signaling as a mechanism of action in OIED (Figure 2).

Figure 2.

Examples of normal and impaired inhibition during multiple rapid swallows in subjects undergoing high-resolution esophageal manometry. The normal response is characterized by absent esophageal body contractility during the multiple rapid swallows sequence, followed by a strong peristaltic contraction after the multiple rapid swallows. When there is impaired inhibition, esophageal body contractility is seen during the multiple rapid swallows.

Clinical Presentation

In a study that included 55 patients with OIED, dysphagia was the most common esophageal symptom, present in 60.0%.[27] Other commonly reported complaints included gastroesophageal reflux symptoms (23.6%) and chest pain (9.0%).[27] Another recent study evaluated patients taking chronic opioids and those naïve to opioids who presented for esophageal manometry. They found that dysphagia was significantly more common in patients taking chronic daily opioids compared with opioid naïve patients (62 and 43%, respectively).[29] The true prevalence of dysphagia and other esophageal symptoms in patients taking chronic opioids is currently unknown, as the available studies are generally based on patients who have been referred for esophageal manometry. Studies evaluating the prevalence of esophageal symptoms in a wider sample of chronic opioid users are needed.

Diagnosis

OIED is a clinical diagnosis based on patient symptoms, opioid use, and manometric evidence of DES, EGJOO, achalasia type III, or jackhammer esophagus. However, as these esophageal motility abnormalities are also seen in patients not taking opioids, the best way to discern between opioid-induced vs. idiopathic dysmotility, is to repeat esophageal manometry after opioid cessation. To date, there are no studies documenting the effect of opioid cessation on motility disorders consistent with OIED as diagnosed by HRM. A recent study evaluated the use of pharmacologic provocation with inhaled amyl nitrite (AN) and intravenous cholecystokinin (CCK) during HRM to distinguish between opioid-induced achalasia type III and idiopathic achalasia type III.[30] Rebound contraction of the LES after AN-induced relaxation was seen in patients with idiopathic achalasia type III, but not in those with opioid-induced achalasia type III. Furthermore, the paradoxical esophageal contraction seen in idiopathic achalasia type II during the first phase of CCK response, was attenuated in patients with opioid-induced achalasia typed III.[30] The response to AN and CCK has not been studied in EGJOO, DES, and jackhammer esophagus with idiopathic vs. opioid-induced dysmotility.

Finally, it is important to note that the prevalence of OIED in patients taking chronic opioids (>3 months) is approximately 25% based on the largest and most recent studies.[27] The prevalence of disorders that would qualify as OIED in patients not taking opioids is much lower at 5–10%.[27,29] In the 2019 study by Snyder et al.[27] among patients with OIED, the most common Chicago Classification diagnoses were DES (49%), EGJOO (43%), jackhammer esophagus (24%), and achalasia type III (2%).

Management of Opioid-induced Esophageal Dysfunction

Opioid use should be determined in all patients undergoing HRM. If a patient is a chronic opioid user, HRM should be performed while on the opioid medication to obtain an accurate assessment. For patients taking acute courses of opioids, deferring HRM until after the patient completes the opioid course is recommended since they will be off the medication in the near future. There are no clinical trials evaluating management strategies for OIED. Needless to say, opioid cessation with symptom assessment and repeat manometry after discontinuation of these medications is the preferred approach. However, stopping opioids is challenging and not always feasible, and may be best accomplished through a structured opioid cessation clinic. For patients in whom opioid cessation is not possible, reducing the opioid dose or changing the medication to a weaker opioid such as tramadol may be of help based upon available data supporting a dose effect in OIED.[27] Whether OIED responds to opioid antagonists in chronic opioid users has not been studied in the clinical setting, but an early study in eight healthy subjects showed that intravenous naloxone reversed the impaired LES relaxation caused by acute intravenous morphine administration.[23] The role of testing with AN and CCK to guide management needs to be further studied. Finally, patients who are unable to discontinue opioids, or in whom the motility abnormality does not resolve after opioid cessation or dose reduction, may be treated in the same manner as patients with idiopathic EGJOO, achalasia type III, DES, and jackhammer esophagus. Importantly, while data are very limited, a retrospective study showed that persistent symptoms after treatment of achalasia were more common in opioid users vs. nonusers (22 vs. 3%).[31] Clearly, we are very much in need of prospective studies clarifying how to treat OIED.

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