Impact of Opioid Exposure on the Coronary Microvasculature in ANOCA: A Coronary Microvascular Disease Registry Analysis

BACKGROUND: Angina with non-obstructive coronary arteries (ANOCA) accounts for up to 50% of patients undergoing angiography for chest pain, with many cases due to coronary microvascular dysfunction (CMD). Opioids are often prescribed to patients for multiple indications, and their effects on coronary microcirculation are unclear. AIMS: To investigate the association between opioid exposure and coronary microvascular dysfunction in patients with ANOCA, focusing on differences in CMD prevalence, CFR, IMR, and MRR between opioid users and non-users, and whether opioid exposure independently predicts impaired microvascular vasodilatory function. METHODS: A total of 367 ANOCA patients from the Coronary Microvascular Disease Registry (NCT05960474) who underwent invasive coronary function testing (August 2021 to March 2025) were analyzed. CMD was defined by coronary flow reserve (CFR) < 2.5 and index of microcirculatory resistance (IMR) ≥ 25; microvascular resistance reserve (MRR) < 3.0 indicated impaired vasodilatory capacity. All indices were measured by bolus thermodilution. Opioid exposure during the 12 months preceding testing was obtained from the electronic health record and Surescripts database. Patients were categorized as opioid users (≥ 1 prescription > 3 days) or non-users, and stratified as short-term (< 90 days) or long-term (≥ 90 days). The primary outcome was the comparison of CMD prevalence and physiologic parameters (CFR, IMR, MRR) between exposure groups. Because groups differed at baseline, unadjusted comparisons were descriptive; the primary interpretation used a multivariable model of log-transformed MRR adjusted for hypertension, hemoglobin, and chronic kidney disease. RESULTS: Opioid users had more hypertension, chronic kidney disease, and CCS class IV angina, and lower hemoglobin (12.38 ± 1.60 vs. 13.32 ± 1.58 g/dL; all p < 0.05). CMD prevalence was numerically higher among opioid users (19/55; 34.5%) versus non-users (85/312; 27.2%), but not significantly (p = 0.27). Mean CFR was lower in opioid users (2.84 ± 1.65 vs. 3.32 ± 1.80; p = 0.06), suggesting a trend toward impaired coronary flow. In unadjusted analysis, mean MRR was lower in opioid users (3.27 ± 1.78 vs. 4.02 ± 2.32; p = 0.01). Mean of IMR was similar between groups (18.51 ± 10.58 vs. 18.60 ± 12.24; p = 0.96). After adjustment, the MRR difference was no longer significant (β = -0.11 on the log scale, an estimated 10.5% lower MRR; 95% CI -0.30 to 0.08; p = 0.25); hemoglobin was the only independent correlate (p = 0.011). CONCLUSIONS: In ANOCA, opioid users represented a distinct clinical phenotype with greater comorbidity, lower hemoglobin, and more severe angina. Their lower unadjusted MRR did not persist after adjustment, and CMD prevalence, CFR, and IMR were similar between groups, suggesting that opioid exposure marks a more complex clinical state rather than independently impairing microvascular vasodilatory function. Residual confounding cannot be excluded, and these exploratory findings require confirmation in larger studies. TRIAL REGISTRATION: Coronary Microvascular Disease Registry, clinicaltrials.gov, NCT05960474.