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A subgroup analysis from the meta-analysis, however, found that the Leu allele was significantly associated with risk in African Americans, using either an additive (odds ratio = 1.91, 95% confidence interval [CI]: 1.02–3.58) or recessive (odds ratio = 2.09, 95% CI: 1.16–3.76) model, suggesting the need for additional studies, as the numbers of cases in this subgroup were small (173)

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Higher doses or additional medications Repeated injections without sustained improvement Increasing side effects with diminishing therapeutic return At this stage, pain is no longer simply a symptom—it reflects underlying regulatory imbalance