Opioid-induced bowel dysfunction is a well-established side effect in patients taking opioids (1). The most common adverse effect reported is constipation; however, a number of upper gastrointestinal complaints (e.g., nausea, vomiting, dyspepsia, dysphagia, and reflux) are also common in patients who use opioids (2,3).
Opioids act on 3 receptors in the brain and peripheral nervous system—μ, κ, and δ. Activation of peripheral opioid receptors affects gastrointestinal motility, secretion, and sensation (4). Peripheral opioid receptors are located in the submucosal and myenteric plexus neurons of the human stomach, small bowel, and colon (5,6). Activation of these receptors slows intestinal transit, decreases intestinal secretion, and alters visceral sensation, potentially leading to symptoms of constipation, bloating, dyspepsia, nausea, and vomiting. Data remain limited on how opioids may affect esophageal motility and function. Opioid receptors have been localized to the esophageal body and lower esophageal sphincter in animal models, and activation elicits both excitatory and inhibitory effects on esophageal contraction (7,8). The precise location of these receptors in the human esophagus remains unknown.
A few small studies (all with sample sizes of 15 patients or less) have reported the effects of opioids on esophageal motility in humans, suggesting that these medications can impair esophagogastric junction (EGJ) relaxation (9–14). More recently, our group demonstrated that esophagogastric junction outflow obstruction (EGJOO), achalasia type III, and distal esophageal spasm (DES) were significantly more common in 121 chronic opioid users compared with 100 nonusers; a trend toward greater frequency of jackhammer esophagus (JE) among opioid users was also seen. Furthermore, among the chronic opioid users, EGJOO and achalasia type III were significantly more common for those who had taken opioids within 24 hours of performing high-resolution manometry (HRM), compared with those who were off opioids for at least 24 hours (15). However, we did not evaluate the effect of opioid dose or opioid type on opioid-induced esophageal dysfunction (OIED), and we hypothesize that these factors may affect the strength of association with OIED. Therefore, the aim of this study was to evaluate the association between opiate type and dosing, and OIED in patients undergoing HRM.
We performed a retrospective study of opioid users who underwent HRM at our motility laboratory between January 2012 and January 2018. Study subjects were identified from a query of a prospectively maintained esophageal manometry database. Patients with esophageal botulinum toxin injection within 6 months before HRM, previous gastroesophageal surgery or pneumatic dilation, esophageal stricture, and achalasia types I and II were excluded. Those with incomplete clinical or manometric data were also excluded. Demographic, endoscopic, clinical, and manometric data were obtained from the manometry database along with chart review. All study subjects were chronic opioid users taking opioids for at least 3 months. Based on the timing of opioid use, patients were classified into 2 groups: (i) patients who underwent HRM while on opioids (last dose within 24 hours of HRM) and (ii) patients who were studied off opioids (last dose taken over 24 hours before HRM). The opioid dose for each patient was obtained from patient chart review, and it was converted to a 24-hour morphine equivalent dose (16,17). The study was approved by the Mayo Clinic Institutional Review Board.
HRM was performed using a catheter with 36 solid-state sensors spaced at 1-cm intervals (Medtronic, Minneapolis, MN). Patients were studied in recumbent, left lateral position after an overnight fast. The HRM included a 5- to 10-minute baseline recording, and ten 5-mL diluted saline swallows at 30-second intervals. HRM tracings were analyzed using ManoView analysis software (Medtronic). Esophagogastric junction (EJG) resting pressure, EGJ integrated relaxation pressure, distal contractile integral, and distal latency were calculated, and Chicago classification version 3.0 algorithms were applied to make a diagnosis of normal or an esophageal motility disorder (18). HRM studies were interpreted by an expert, with confirmation of HRM diagnosis by a second expert. OIED was defined by the presence of EGJOO, DES, achalasia type III, or JE. Representative examples of esophageal pressure topography plots for these disorders are provided in (Figure 1).
Data were entered manually and statistically assessed using JMP, Version 14.0 (SAS Institute, Cary, NC). Frequency distributions were evaluated for all categorical variables (e.g., sex). Student t tests were performed to evaluate differences in continuous measures (e.g., age and body mass index). Tests for proportionality between groups were made using Fisher exact tests. Summary statistics included point estimates and SDs or number and proportions. All significance levels are set to P < 0.05.
A total of 274 patients who were using opioids for at least 3 months before undergoing HRM were identified. Of these, 49 patients taking fentanyl, morphine, codeine, codeine with acetaminophen, hydromorphone, meperidine, and methadone were excluded due to low patient numbers. As a result, a total of 225 patients taking opioids for ≥3 months before HRM were included in the study: 68 on oxycodone, 97 on hydrocodone, and 60 on tramadol (Figure 2). Six of the 225 patients (2.7%) were taking a second opioid medication concurrently with oxycodone, hydrocodone, or tramadol: fentanyl (2), tramadol (2), oxycodone with acetaminophen (1), and methadone (1). OIED was present in 24% (55 of 225) of opioid users. There were no significant differences in age, body mass index, or sex for patients with vs without OIED (Table 1). Among patients with OIED, the most common Chicago Classification diagnoses were DES in 49%, EGJOO in 43%, JE in 24%, and achalasia type III in 2% (Figure 3). The breakdown of OIED disorders was no different between oxycodone, hydrocodone, and tramadol (Table 2).
The most common indications for performing HRM in all study patients were dysphagia (33.8%), gastroesophageal reflux (22.2%), and chest pain (12.4%). For patients with OIED, the most common HRM indications were dysphagia (60.0%), gastroesophageal reflux (23.6%), and chest pain (9.0%). Patients without OIED most commonly completed HRM due to gastroesophageal reflux (39.4%), dysphagia (29.4%), and chest pain (18.2%). The symptom indications for patients with and without OIED were different (P = 0.001). Esophagogastroduodenoscopy was performed at our institution in 69% (155) of the patients. Of these patients, 26% (41) had normal endoscopic appearance of the esophagus, and the remainder of the patients had the following findings: hiatal hernia 25% (38), esophagitis 12% (18), Barrett's esophagus 7% (10), tortuous esophagus 3% (4), and nonocclusive Schatzki's ring 4% (6). Data regarding indication for opioid use were available in 185/225 patients. The most common indications for opioid use were back pain (32.9%), joint pain (22.7%), and abdominal pain (5.9%).
There was a significant increase in OIED for chronic opioid users who were studied on opioids (last dose within 24 hours of HRM), compared with chronic users studied off opioids (last dose ≥24 hours from HRM) (33% vs 15%, P = 0.004). OIED was significantly more prevalent with oxycodone or hydrocodone compared with tramadol (31% vs 28% vs 12%, P = 0.016) (Figure 4). OIED was more prevalent for oxycodone alone compared to oxycodone with acetaminophen (43% vs 21%, P = 0.048). The median 24-hour morphine equivalent dosing for the oxycodone group was 90 mg compared with 45 mg for the oxycodone with acetaminophen group (P = 0.188). There was no difference in OIED for patients taking hydrocodone alone vs hydrocodone with acetaminophen (29.4% vs 26.9%, P = 0.799). The median 24-hour morphine equivalent dosing for the hydrocodone group was 25 mg compared with 20 mg for the hydrocodone with acetaminophen group (P = 0.246). The dose of oxycodone, hydrocodone, or tramadol was converted to a 24-hour morphine equivalent dose. Patients with OIED were taking a higher median 24-hour morphine equivalent dose of opioids than those without OIED (45 vs 30 mg/d; P = 0.058) (Figure 5).
Although this article focuses on the effects of opioid dose and type on OIED, we felt it was important to assess the prevalence of spastic esophageal motor abnormalities that would qualify as OIED in patients who were not taking opioids during the same study period as the 225 on opioids who were used to evaluate the effect of opioid type and dose on OIED. The prevalence of disorders that would qualify as OIED was lower in 1706 patients not on opioids compared with the 225 patients on opioids (9.5% vs 24% P < 0.0001). The prevalence of these esophageal motor abnormalities in the 1706 patients not on opioids was as follows: EGJOO 3.3%, JE 1.8%, achalasia type III 1.3%, and DES 3%.
Opioids are the most prescribed pain medications in the United States and Western world for acute and chronic pain disorders. A wide variety of opioid adverse effects on the gastrointestinal tract have been described. Opioid-induced bowel dysfunction (OIBD) is a well-recognized complication of opioid use, with constipation being the most common symptom (1). Adverse opioid effects on gastric, small intestine, and colonic motility are well established; however, less is known regarding the effects of opioids on the esophagus. The term OIED has emerged only recently as a way to describe esophageal motor abnormalities associated with opioid use. The mechanisms underlying the effects of opioids on esophageal motility have not been clearly elucidated. The esophageal motor abnormalities found in patients with OIED are characterized by impaired inhibition and hypercontractility. These disorders may be due to an imbalance between neurotransmitters that relax the esophagus such as nitric oxide and those that help the esophagus contract including acetylcholine. Opioids were found to elicit tonic spasm in smooth muscle by inhibiting release of nitric oxide (19,20). We hypothesize that opioids may inhibit nitric oxide releasing neurons in the esophagus allowing for unopposed excitatory input from cholinergic neurons leading to the impaired EGJ relaxation, and spastic, vigorous esophageal body contractions that are seen in OIED (15).
Previously published data evaluating OIED using conventional manometry have produced conflicting results. Only one of these studies evaluated patients taking chronic oral opioids similar to our study while the other studies evaluated patients after a single dose of intravenous morphine administered immediately before manometry. Kraichely et al. (14) found that 15 patients taking chronic oral opioids had impaired LES relaxation similar to our previous study. Although Mittal et al. and Penagini et al. found acute administration of intravenous morphine resulted in decreased LES tone, more recent studies including our own from 2015, assessing the effects of chronic opioid use, have suggested it results in increased LES pressure and is associated with hypercontractility (9–15).
Our previous study (15) in 2015 was the first to report the effect of opioids on esophageal motility using HRM and the Chicago classification of esophageal motility disorders v3.0. This study compared the prevalence of esophageal motor abnormalities in 100 consecutive patients who were not on opioids, during the same period of the study, with a cohort of 121 patients on opioids, and found that patients not on opioids had lower prevalence of spastic esophageal motor abnormalities as follows: achalasia (5% vs 12%), JE (0% vs 9%), and EGJ outflow obstruction (2% vs 18%). During our current study, we confirmed this lower prevalence of spastic esophageal motor abnormalities in patients not taking opioids of only 9.5% compared with 24% in patients on opioids. Interestingly, our current study showed that although OIED is less of a problem with tramadol compared with oxycodone and hydrocodone, some of these esophageal motor abnormalities are still overall more frequent in tramadol (JE 2%, EGJOO 7%) than in nonusers. Of note, there were no cases of achalasia type III for patients on tramadol in our sample.
Our current study is not only larger than our previous study, but we have also evaluated opioid type and dosing effects on OIED, which may be important for clinical decision-making when managing patients with OIED. Our current study with 225 patients supports the findings from our initial study of 121 patients, confirming that OIED is more common in patients using opiates within 24 hours of HRM compared with those who took the last opioid dose >24 hours before HRM (15). However, it is important to note that these disorders are overall more common in all chronic opioid users taken together (a combined group including those studied off vs on medication), compared with patients not taking opioids, as shown in our 2015 study. This suggests that chronic opioid use is important, and that the abnormalities are more likely to be found if HRM is performed within 24 hours of the last opioid dose.
Among patients with OIED, the most common Chicago Classification diagnosis was DES in 49%, followed by EGJOO in 43%, JE in 24%, and achalasia type III in 2% (Figure 3). This supports the findings of our earlier study where the most common OIED diagnoses were DES and EGJOO (15). To the best of our knowledge, only 1 publication has evaluated OIED since our initial report in 121 patients. This 2016 study from Ravi et al. (21) reviewed 56 patients with a new diagnosis of achalasia to assess which patients were taking opiates. They identified that 25% of the new achalasia patients were on opiates. Of those patients on opiates, 36% had type III achalasia compared with only 10% of those not on opiates. These findings highlight the importance of keeping the possibility of OIED in mind when HRM reveals EGJOO, DES, achalasia type III, or JE. In fact, we recommend that opioid use should be routinely ascertained before HRM as part of the preprocedure intake assessment.
Our study is the first to show the effects of opioid dose and type on esophageal dysfunction. We found a significantly greater association for oxycodone and hydrocodone with OIED compared with tramadol (Figure 4). This finding was expected since tramadol is a weaker opioid. We also showed that opioid doses are higher in opioid users with vs without OIED, although this did not reach statistical significance (Figure 5). Furthermore, OIED was more frequent in patients taking oxycodone alone vs oxycodone with acetaminophen, and this appeared to be due to a lower opioid dose in patients concurrently taking acetaminophen.
We recognize limitations to our study. Owing to the retrospective design, there may be effects from confounding factors, but there were no significant differences in baseline demographics between patients with or without OIED. This is the largest retrospective study to date evaluating OIED, and currently, there are no prospective studies examining the effects of opioids on esophageal motor function. Another limitation was the need to exclude a substantial group of patients taking chronic opioids with esophageal surgeries or procedures to avoid confounders affecting the results of our analysis. Of course, our findings can only suggest an association between opioids and OIED, and a causal relationship cannot be proven based on our data. There are no studies to date that have evaluated the effects of opioid cessation on symptoms and HRM findings in patients with OIED.
Based on the findings our study, we believe that opioid use should be determined in all patients undergoing HRM. If a patient is a chronic opioid user, manometry should be performed while on the opioid medication. For patients taking an acute course of opioids, we recommend waiting to perform HRM until the patient is completely off the opioids, or holding the medication for at least 24 hours before the test to get an accurate assessment of their esophageal motility since they will be off the medication in the near future. How to treat patients with OIED is not entirely clear, and multiple questions remain including whether these patients have a similar clinical course and response to treatment as those with esophageal dysfunction not taking chronic opioids. Although opioid cessation would be the most logical and desirable management strategy to reduce OIED, this is not always possible in patients with chronic pain. Clearly, additional studies are needed to examine the effects of changing opioid type or stopping opioids altogether, on symptoms and manometric findings. Based on our results, we would recommend opioid cessation as the first management strategy to consider when treating OIED. If this is not feasible, the next approach would be to reduce the opioid to the least effective dose or change to a less potent type such as tramadol.
CONFLICTS OF INTEREST
Guarantor of the article: Marcelo F. Vela, MD.
Specific author contributions: D.L.S. contributed to the study design and coordination, acquisition and interpretation of data, analysis, and drafted the manuscript. The author has approved the final draft submitted. M.D.C. contributed to the design and coordination of the study; acquisition, analysis, and interpretation of data; and revision of manuscript for intellectual content. The author has approved the final draft submitted. J.H.-S. contributed to the design and coordination of the study and revision of the manuscript for intellectual content. The author has approved the final draft submitted. K.R. contributed to critical revision of the manuscript for important intellectual content. The author has approved the final draft submitted. B.E.L. contributed to critical revision of the manuscript for important intellectual content. The author has approved the final draft submitted. M.F.V. contributed to the design and coordination of the study, interpretation and analysis of data, and revision of manuscript for intellectual content. The author has approved the final draft submitted.
Financial support: None.
Potential competing interests: M.F.V.: Medtronic consultant and Sandhill research support.
WHAT IS KNOWN
- ✓ There is an association between chronic opioid use and esophageal motor dysfunction (OIED).
WHAT IS NEW HERE
- ✓ OIED is more prevalent in patients taking oxycodone or hydrocodone than tramadol.
- ✓ There is a higher likelihood of OIED in patients on higher doses of opioids.
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