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a Puckered gastroesophageal junction on endoscopy suggestive of hypertonic lower esophageal sphincter; (b) manometry showing esophagogastric junction outflow obstruction (high lower esophageal sphincter pressure with incomplete relaxation and normal esophageal body peristalsis) in a patient on morphine pump and (c) type III achalasia (high lower esophageal sphincter pressure with incomplete relaxation and esophageal body with high amplitude simultaneous contraction) in a patient on oxycodone.
Source publication
Adverse effects of opioids on the gastrointestinal tract are well known. However, with the rising epidemic of opioids, its detrimental effects on esophageal physiology are now being increasingly recognized. In this commentary, we briefly review the current evidence behind opioid-induced esophageal dysfunction with potential pathophysiology and trea...
Citations
... Opioids are commonly prescribed for postoperative pain control, acute or chronic pain management and/or opioid maintenance therapy [17][18][19]. Opioids can depress the gastrointestinal and immune systems [17,20,21], cough and airway protective reflexes and have been linked to esophageal dysfunction and aspiration [12,[22][23][24][25]. Buprenorphine is a commonly prescribed opioid often advertised as safe [26]. ...
... Pharyngeal distension prior to swallow initiation increased in the non-surgical group, and cervical esophageal distension prior to primary peristalsis increased in the postoperative group. This suggests that opioids decrease the sensitivity of pharyngeal and esophageal distension reflexes, consistent with reports that esophageal circuitry is enriched with mu-opioid receptors, and human studies demonstrating disordered peristalsis and achalasia following opioid administration [22,23,68,[76][77][78]. We speculate that increased filling of the pharynx and cervical esophagus increases the likelihood of airway invasion and laryngopharyngeal reflux. ...
Purpose
Postoperative pneumonia remains a common complication of surgery, despite increased attention. The purpose of our study was to determine the effects of routine surgery and post-surgical opioid administration on airway protection risk.
Methods
Eight healthy adult cats were evaluated to determine changes in airway protection status and for evidence of dysphagia in two experiments. (1) In four female cats, airway protection status was tracked following routine abdominal surgery (spay surgery) plus low-dose opioid administration (buprenorphine 0.015 mg/kg, IM, q8-12 h; n = 5). (2) Using a cross-over design, four naive cats (2 male, 2 female) were treated with moderate-dose (0.02 mg/kg) or high-dose (0.04 mg/kg) buprenorphine (IM, q8-12 h; n = 5).
Results
Airway protection was significantly affected in both experiments, but the most severe deficits occurred post-surgically as 75% of the animals exhibited silent aspiration.
Conclusion
Oropharyngeal swallow is impaired by the partial mu-opioid receptor agonist buprenorphine, most remarkably in the postoperative setting. These findings have implications for the prevention and management of aspiration pneumonia in vulnerable populations.
... In addition to well-known respiratory-depressant effects, opioids also depress the immune system, gastrointestinal system, and airway defense mechanisms (e.g., cough) (24,31,32). Clinical trials have reported esophageal dysfunction and aspiration following opioid administration, and several reports have identified aspiration pneumonia as a serious complication of opioid use following both overdose and chronic use (33)(34)(35)(36)(37)(38)(39). Postmortem studies have established a link between opioid overdose and pulmonary aspiration, with evidence of aspiration in up to 66% of overdose fatalities (40,41). ...
Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, effects of opioids on swallow excitability and motor pattern are unknown. We tested the effects of the clinically-relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated the utility of 5-HT 1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing. We evaluated the hypotheses that swallow varies by stimulus, opioids depress swallow and breathing, and that 5-HT 1A agonists improve these depressions. Our results largely confirmed the hypotheses: 1) Swallow-related EMG activity was larger during swallows elicited by esophageal distension plus oral water infusion than by either stimulus alone. 2) Buprenorphine depressed swallow in both sexes, but females were more susceptible to total swallow suppression. 3) Female animals were also more vulnerable to opioid-induced respiratory depression. 4) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pre-treatment with the partial 5-HT 1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5) 8-OH-DPAT enhanced mylohyoid and thyropharyngeus EMG amplitude during swallow but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide pre-clinical evidence of a 5HT 1A agonist for the treatment of respiratory depression and dysphagia.
... Opioids are commonly prescribed for post-operative pain control, acute or chronic pain management, and/or opioid maintenance therapy [17][18][19] . Opioids can depress the gastrointestinal and immune systems 17,20,21 , cough and airway protective reflexes, and have been linked to esophageal dysfunction and aspiration 12,[22][23][24][25] . Buprenorphine is a commonly prescribed opioid often advertised as safe 26 . ...
... Pharyngeal distension prior to swallow initiation increased in the non-surgical group, and esophageal distension prior to primary peristalsis increased in the post-operative group. This suggests that opioids decrease the sensitivity of pharyngeal and esophageal distension reflexes, consistent with reports that esophageal circuitry is enriched with mu-opioid receptors, and human studies demonstrating disordered peristalsis and achalasia following opioid administration 22,23,[70][71][72][73] . We speculate that increased filling of the pharynx and esophagus increases the likelihood of airway invasion and laryngopharyngeal reflux. ...
Objective
Postoperative pneumonia remains a common complication of surgery, despite increased attention. The purpose of our study was to determine the effects of routine surgery and post-surgical opioid administration on airway protection risk.
Methods
Eight healthy adult cats were evaluated for dysphagia in 2 experiments. 1) In 4 female cats airway protection status was tracked following routine abdominal surgery (spay surgery) plus low-dose opioid administration (buprenorphine 0.015mg/kg, IM, q8-12h; n =5). 2) Using a cross-over design (2 male, 2 female) cats were treated with moderate (0.02mg/kg) or high (0.04mg/kg) dose buprenorphine (IM, q8-12h; n =5) to determine changes in airway protection status or evidence of dysphagia.
Results
Airway protection was significantly affected in both experiments, but most severely post-surgically where 75% of the animals exhibited silent aspiration.
Conclusion
Oropharyngeal swallow is impaired by the partial mu-opioid receptor agonist buprenorphine, most remarkably in the post-operative setting. These findings have implications for the prevention and management of aspiration pneumonia in vulnerable populations.
... With type III achalasia, premature spastic contractions (i.e., distal latency < 4.5 s) occur with at least 20% of swallows [16]. Further studies show that HRM in the opioid patient subset frequently demonstrates impaired lower esophageal sphincter (LES) relaxation, high integrated relaxation pressure, and low distal latency, consistent with the manometry pattern seen in patients with primary achalasia [11,17,18]. Additionally, opioid-induced esophageal dysfunction has been shown to be more likely in patients taking a higher median 24-h opioid dose [19]. ...
... Current standard of care for diagnosis of primary esophageal motility disorders and opioid-induced esophageal dysfunction entails a thorough work-up including high-resolution manometry, upper endoscopy, and barium swallow study [18,20]. Despite the use of these diagnostic modalities, difficulty in differentiating these two diagnoses persists [30]. ...
Background
Opioid use in the U.S. has increased dramatically over the last 15 years, recently being declared a public health emergency. Opioid use is associated with esophageal dysmotility lending to a confusing clinical picture compared to true achalasia. Patients exhibit symptoms and elicit diagnostic results consistent with esophageal motility disorders, in particular type III achalasia. Modified therapeutic strategies and outcomes become challenging. Differentiating true achalasia from opioid-induced achalasia is critical. Conventional surgical interventions, i.e., myotomy, are ineffective in the absence of true achalasia. We assess the utility of esophageal muscle layer mapping with endoscopic ultrasound (EUS) in distinguishing primary from opioid-induced achalasia.Methods
From 2016 to 2019, patients with abnormal manometry and suspected achalasia underwent esophagogastroduodenoscopy and EUS mapping of esophageal round muscle layer thickness. Maximum round layer thickness and length of round muscle layer thickness > 1.8 mm were collected and compared between opioid users and non-opioid users using Wilcoxon Rank sum test.Results45 patients were included: 12 opioid users, 33 non-opioid users. Mean age 56.8 years (range 24–93), 53.3% male patients. Mean BMI in the opioid-induced achalasia group was 30.2 kg/m2, mean BMI in the primary achalasia group 26.8 kg/m2 (p = 0.11). In comparing endoscopic maximum round layer thickness between groups, non-opioid patients had a thicker round muscle layer (2.7 mm vs 1.8 mm, p = 0.05). Length of abnormally thickened esophageal muscle (greater than 1.8 mm) also differed between the two groups; patients on opioids had a shorter length of thickening (4.0 cm vs 0.0 cm, p = 0.04). Intervention rate was higher in the non-opioid group (p = 0.79). Of the patients that underwent therapeutic intervention, symptom resolution was higher in the non-opioid group (p = 0.002), while re-intervention post-procedure for persistent symptomatology was elevated in the opioid subset (p = 0.06). Patients in the opioid group were less likely to undergo invasive treatment (Heller). As of 2017 all interventions in the opioid group have been endoscopic.Conclusion
Endoscopic ultrasound is an essential tool that has improved our treatment algorithm for suspected achalasia in patients with chronic opioid usage. Incorporation of EUS findings into treatment approach may prevent unnecessary surgery in opioid users.
Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We sought to test the effects of the clinically-relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated utility of serotonin 5-HT1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing outcomes following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing behaviors. We evaluated the hypotheses that swallow varies by stimulus, opioids depress swallow and breathing, and that 5-HT1A agonists improve these depressions. Our results largely confirmed the hypotheses: 1) Swallow-related muscle activity was larger during swallows elicited by oral water infusion plus esophageal distension than by either stimulus alone. 2) Buprenorphine depressed swallow in both sexes, but most significantly in females. 3) Female animals were more susceptible to buprenorphine-induced respiratory arrest. 4) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pre-treatment with the partial 5-HT1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5) 8-OH-DPAT enhanced swallow-related mylohyoid drive, but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide pre-clinical evidence of a 5HT1A agonist for the treatment of respiratory depression and dysphagia.
The objective of our study was to determine the role of 5-HT 1A receptors in modulating breathing and swallowing following opioid administration. Our previous experiments in anesthetized male and female Sprague Dawley rats demonstrated that swallow is suppressed by the opioid buprenorphine, and that female rats are more susceptible to buprenorphine-induced respiratory arrest (71% mortality at 0.3 mg/kg) than male rats (100% survival at 0.3 mg/kg). We hypothesized that following buprenorphine administration, intravenous administration of the 5-HT 1A agonist 8-OH-DPAT would restore breathing and swallowing. Experiments were performed in spontaneously breathing female Sprague Dawley rats anesthetized with sodium pentobarbital ( n = 7). Bipolar electromyography (EMG) wires were inserted into various muscles to measure breathing and airway protective behaviors. Swallow was stimulated by oral water infusion. Intravenous buprenorphine was administered in doses that yield respiratory arrest in female rats. Sustained apnea occurred in 86% of animals following buprenorphine administration (one animal resisted respiratory depression). 8-OH-DPAT was then administered to effect (100, 300, or 1,000 μg/kg i.v.). 8-OH-DPAT did not restore swallow, but breathing was recovered in 100% of animals (33% at 100 μg/kg, 50% at 300 μg/kg, and 17% at 1,000 μg/kg). This effect of 8-OH-DPAT was reversed by the 5-HT 1A antagonist WAY 100635 (1 mg/kg i.v.), which abolished breathing in all animals. These results indicate that 5-HT 1A agonists may be utilized to restore breathing following respiratory arrest, and that opioid-induced depression of breathing and swallowing are mediated by potentially separate mechanisms.
This work was supported by NIH grants HL 111215, HL 103415 and OT20D001983, the Craig H. Neilsen Foundation Pilot Research Grant 546714, Kentucky Spinal Cord and Head Injury Research Trust, and the Commonwealth of Kentucky Challenge for Excellence.
This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Background Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. Aims To investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist. Methods Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study. Study participants received target-controlled remifentanil infusions and placebo infusions in a randomized order. Methylnaltrexone was administered by intravenous injection of doses of 0.3 mg/kg. Recordings of pressure and impedance data were acquired using a combined manometry and impedance solid state catheter. Data was analyzed from three series of bolus swallows, baseline, during remifentanil exposure, and 15 min after methylnaltrexone. Results Remifentanil induced significant effects on multiple pharyngeal and esophageal function parameters. No significant differences in remifentanil-induced swallowing dysfunction related to different bolus volumes were found. Pharyngeal effects of remifentanil were not significantly counteracted by methylnaltrexone, whereas on the distal esophageal level, effects on distension pressures were counteracted. Conclusions Changes in pharyngeal and esophageal pressure flow variables were consistent with previous results on remifentanil-induced swallowing dysfunction, and uniform across all bolus volumes. The effects of remifentanil on the pharyngeal level and on the proximal esophagus appear to be predominantly centrally mediated, whereas the effects of remifentanil on the distal esophagus may be mediated by both central and peripheral mechanisms.
The literal definition of dysphagia is “disturbed eating”. However, it is more accurately described in clinical practice as a sensation of food or liquid being stuck in the esophagus or chest. If this sensation is associated with pain, it is labeled odynophagia, and if it is associated with persistent obstruction and bolus retention, it is categorized as a food impaction. Through research and technological advances, we continue to expand our understanding of the etiologies and underlying pathophysiology relating to this complaint. However, for now, our clinical algorithms focus on endoscopy and manometry to break down dysphagia into three categories: obstructive dysphagia, esophageal motility disorders, and functional dysphagia. Here, we review some critical pitfalls in our current clinical diagnoses, new proposed underlying mechanisms of esophageal motor disorders, and developing technologies to aid in diagnosis and treatment.
The impact of opioid use on the lower gastrointestinal tract is well described, but recent opioid crisis has caused increased awareness of the detrimental effects of these drugs on esophageal and gastroduodenal motility. Opioid use has been associated with increased incidence of spastic esophageal motility disorders and gastroduodenal dysfunction. Opioid receptors are present with high abundance in the myenteric and submucosal plexus of the enteric nervous system. Activation of these receptors leads to suppressed excitability of the inhibitory musculomotor neurons and unchecked tonic contraction of the autogenic musculature (such as the lower esophageal sphincter and the pylorus).
With the advances in technology and medical knowledge, new diseases are being identified and investigated. Esophageal motility disorders have been re-defined using high-resolution manometry and their pathogenesis are being better understood. The use of opioid analgesics is increasing worldwide, particularly in the United States, but their chronic use can cause opioid-induced esophageal dysfunction, which mimics spastic motor disorders, including achalasia type 3 or 2 and esophagogastric junction outflow obstruction. Eosinophilic esophagitis is identified by eosinophilic infiltration confirmed on a pathological examination. The condition is often associated with esophageal motility abnormalities. On the other hand, recent studies have suggested that muscle-predominant eosinophilic infiltration, eosinophilic esophageal myositis, might manifest as spastic motor disorders, including achalasia or jackhammer esophagus. Lymphocytic esophagitis is an unusual esophageal condition, which is confirmed by the increased number of lymphocytes
in the esophageal epithelium. Although several reports have supported the existence of lymphocytic esophagitis, it is still unclear whether lymphocytic esophagitis is a distinct disease entity or another spectrum of other esophageal diseases, such as gastroesophageal reflux disease or eosinophilic esophagitis. This review presents evidence and reports on the emerging issues in esophageal motility disorders, including opioid-induced esophageal dysfunction, eosinophilic esophagitis with eosinophilic esophageal myositis, and lymphocytic esophagitis.
