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Background: Studies have found that diffuse pain, indicative of central sensitization, portends poor interventional outcomes. Multiple chemical sensitivities are associated with signs of central sensitization. We sought to prospectively determine whether hypersensitivity reactions (HR) were associated with epidural steroid injection (ESI) outcomes.Methods: HR were classified as immune-related or non-immune-related and categorized by number (0=low, 1 or 2=intermediate, ≥3=high). The primary outcome measure was mean reduction in average leg pain score 1 month post-procedure. A positive outcome was defined as a two-point or greater decrease in average leg pain accompanied by satisfaction 1 month post-procedure.Results: The mean number of immune-mediated and non-immune-mediated HR were 0.6±1.2 and 0.8±1.4, respectively. Individuals in the high (n=24) total HR group had a mean reduction in average leg pain of 0.1±2.7, compared with those in the low (n=61; 1.8±2.1, p=0.025) and intermediate groups (n=52; 1.6±3.1, p=0.060). For back pain and categorical successful outcome, those with fewer HR experienced greater benefit. There were no differences in outcomes when patients were stratified by immune-related HR. Among participants in the low, intermediate and high non-immune-mediated HR groups, the mean reductions in average leg pain scores were 1.7±2.5, 1.6±3.0, and -0.2±2.3, respectively (p = 0.002). 51%, 35%, and 12% of people with low, intermediate and high numbers of non-immune-mediated HR experienced a positive categorical outcome, respectively (p=0.007).Conclusions: Non-immune-related HR were inversely correlated with some ESI outcome measures. [ABSTRACT FROM AUTHOR]