INTRODUCTION

There has been a significant increase in opioid prescriptions over the past 20 years, with multiple reported gastrointestinal side effects and dysmotility (1). Prior studies have consistently shown increased abnormal esophageal manometry patterns among patients taking opioids, including an elevated integrated relaxation pressure (IRP), distal esophageal spasm (DES), hypercontractile esophagus (HE), and type III achalasia (2–5). Despite these manometric changes, the correlation between opioid use and symptomatic dysphagia has not been directly established because prior studies have mainly focused on patients clinically referred for high-resolution manometry (HRM) due to esophageal complaints. However, the overall burden of dysphagia that may be attributable to opioid use in the US population remains unclear. We aimed to investigate whether opioid use was associated with increased outpatient visits for dysphagia in a large nationally representative US sample.

METHODS

Data were extracted from the prospectively collected National Ambulatory Medical Care Survey (NAMCS) between 2008 and 2018 (6). All patients older than 15 years were included. Variables collected included age, sex, race/ethnicity, body mass index, reason for visit, physician diagnosis, diabetes, and medication list. The primary outcome was outpatient visit for dysphagia, which was defined by the patient listing dysphagia as the reason for visit. This reason for visit is generally more inclusive than a visit diagnosis and is based on the patient's directly stated complaint, which in this case represented complaints such as “trouble swallowing” or “difficulty swallowing.” Patients were considered opioid users if they reported any opioid agent, including partial opioid agonists, on their active medication list for the visit. All analyses were performed using SAS 9.4 with survey procedures to account for the complex sampling design. The NAMCS provides data on physician visits rather than specific patients and its sampling methods were previously validated to provide population-level estimates from the collected sample of visits (5). Univariate analyses were performed using the Student t test and χ2 tests. Multivariable logistic regression was performed to adjust for potential confounders.

RESULTS

A total of 288,617 outpatient visits were included in the sample, which is accurately representative of 792 million visits between 2008 and 2018 when using the NAMCS population-level estimates. Overall, 29,823 (10.3%) visits included patients taking opioids (representing 81 million visits) and 791 (0.27%) visits were for dysphagia (representing 2.1 million visits). Baseline characteristics are summarized in Table 1. Of the 791 dysphagia visits, 76 (9.7%) involved patients reporting opioid use.

Table 1. - Baseline characteristics of sample by opioid use status Characteristics Opioid nonuse (n = 258,794) Opioid use (n = 29,823) P value Age (mean, SD) 53.8 (0.2) 55.5 (0.3) <0.0001 Male sex—n (%) 106,696 (39.3) 12,455 (41.8) <0.0001 Race—n (%) <0.0001  White 225,383 (84.2) 25,654 (84.6)  Black 22,745 (10.1) 2,966 (11.6)  Other 11,733 (5.7) 927 (3.8) Ethnicity—n (%) 0.0002  Hispanic 23,166 (11.6) 2,279 (9.5)  Non-Hispanic 236,695 (88.4) 27,268 (90.5) Diabetes—n (%) 33,466 (14.2) 4,692 (17.0) <0.0001 BMI (kg/m2)—n (%) <0.0001  <18.5 15,095 (7.7) 1,927 (7.2)  18.5–24.9 37,906 (27.0) 4,585 (23.2)  25.0–29.9 42,862 (30.9) 5,619 (29.3)  30.0–39.9 38,547 (27.7) 6,038 (31.0)  >40 9,562 (6.7) 1,869 (9.3) Connective tissue disease—n (%) 136 (0.1) 17 (0.1) 0.2345 GERD (%) 4,911 (2.3) 612 (2.6) 0.1579

BMI, body mass index; GERD, gastroesophageal reflux disease.

Among visits for opioid users, dysphagia was reported only in 76 (0.3%), which was similar in proportion to visits for nonopioid users (715 of 258,794, 0.3%). After adjusting for potential confounders including age, sex, race/ethnicity, diabetes, and body mass index, there remained no significant association between opioid use and visits for dysphagia (adjusted odds ratio [aOR] = 0.98, 95% confidence interval [CI]: 0.59–1.65). Of note, independent predictors for reporting dysphagia as a reason for visit in the multivariable model included age (aOR = 1.01, 95% CI: 1.00–1.03), female sex (aOR = 1.73, 95%: CI 1.18–2.52), and Hispanic patients (aOR 3.00, 95% CI: 1.61–5.62) (Figure 1).

Figure 1.:

Forest plot of odds ratios for covariates in the multivariable logistic regression model for dysphagia. Reference groups for class variables (race and BMI groups) were white race (race) and BMI 18.5–24.9 kg/m2 (the BMI group). BMI, body mass index.

DISCUSSION

Opioid-induced esophageal dysfunction (OIED) has been described with characteristic HRM features including elevated IRP, DES, HE, and type III achalasia. Prevalence of OIED also seems to increase with more potent and higher doses of opioid (3–5,7). However, prior studies of OIED primarily included only patients with esophageal symptoms referred for HRM. The overall symptom burden of dysphagia attributable to opioid use, therefore, remains unclear. Using a nationally representative ambulatory database, we found that opioid use was not associated with a significant increase in outpatient visits for dysphagia. To our knowledge, this is the first nationwide study examining the relationship between opioid use and dysphagia complaints. Our findings seem to suggest that opioid-related HRM changes previously described may often be subclinical and induce relevant symptoms only in a small proportion of patients, such as those with type III achalasia. This may be supported by reports of OIED changes in some patients undergoing HRM for primary complaints other than dysphagia, such as heartburn or reflux (3).

Several key modifications were introduced to the Chicago classification, version 4.0, to improve the clinical relevance of HRM findings. A conclusive esophagogastric junction outflow obstruction diagnosis now necessitates elevated IRP in >1 position, evidence of impaired clearance, and nonmanometric evaluations such as abnormal timed barium esophagram or impedance planimetry (8,9). Moreover, esophagogastric junction outflow obstruction, DES, and HE require associated obstructive symptoms (dysphagia) or noncardiac chest pain to be considered clinically relevant (8,10,11). These changes highlighted the inconsistent connections observed between abnormal HRM patterns and relevant clinical symptoms, their frequent presence in individuals without esophageal complaints, and the variable outcomes of treatment targeting these findings. Given the increased prevalence of abnormal HRM findings among opioid users persistently reported in prior studies (3–5), our findings seem to offer further evidence that certain abnormal HRM findings alone (e.g., elevated IRP) may not correlate with or sufficiently account for dysphagia complaints, and additional testing or supportive evidence are needed.

Opioid has been postulated to interfere with inhibitory neural signaling in OIED, with evidence of reduced deglutitive inhibition, including increased IRP, spastic swallows, and hypercontractility, and impaired inhibition during multiple rapid swallows. However, our study suggests that the population burden of dysphagia symptoms attributable to opioid use likely remains small because patients may experience little to no swallowing symptoms despite altered HRM patterns. These results may have important clinical implications, especially given the current lack of studies evaluating the management of OIED. Withdrawal of opioid may often be difficult or not feasible, depending on the underlying causes necessitating its use. Other primary or secondary causes of dysphagia, including a neurosensory or functional cause, should be considered before attributing symptoms to opioid use alone.

Our study had some limitations. The nature of the NAMCS did not allow further characterization of specific opioid type and dosage. Details on dysphagia symptom severity were also not available in this nationwide data set. Certain comorbid conditions, such as head and neck cancers, could not be included in the analysis because the NAMCS database did not provide this level of detail, although such potential confounding would have likely biased the results toward increased association between opioid use and dysphagia. Despite these limitations, this study offers a large and generalizable population-wide sample that is representative of the entire US population.

In conclusion, despite the increased HRM abnormalities observed in prior studies, we found a low frequency of ambulatory visits for dysphagia among opioid users in a nationwide sample over 10 years, with no difference compared with that among nonusers. This suggests that opioid-related HRM changes may only be clinically relevant in a small proportion of patients. Opioid users who present with dysphagia symptoms should undergo a complete esophageal evaluation to determine the underlying cause and appropriate treatment. Further studies are also needed for strategies of OIED management.

CONFLICTS OF INTEREST

Guarantor of the article: Walter W. Chan, MD, MPH.

Specific author contributions: R.F. was involved in planning/conducting the study, collecting and analyzing the data, and drafting the manuscript. E. L., J.G.B., and M.T. were involved with planning/conducting the study, data collection, and data analysis. W.C. was involved in planning/conducting the study, data analysis, and drafting the manuscript. All authors contributed to critical revision of the manuscript for important intellectual content.

Financial support: None to report.

Potential competing interests: None to report.

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