To determine whether pharmacologic exposure is associated with differences in fibromyalgia neurobehavioral phenotypes and whether medication burden explains symptom variability within phenotypes.

We analyzed a multisite cohort of 695 adults meeting fibromyalgia criteria, stratified into low- and high-impact phenotypes using a disability-based classification. Medication burden was quantified as total, centrally acting, and noncentrally acting medication counts. Between-phenotype differences and within-phenotype associations between medication burden and symptom severity were evaluated using nonparametric tests, Spearman correlation analyses, and multivariable linear regression models. Phenotypes were interpreted within the framework of centrally mediated neurobehavioral dysfunction.

Participants classified within the high-impact neurobehavioral phenotype (n = 175) demonstrated substantially greater symptom burden across fibromyalgia impact, central sensitization, depressive symptoms, pain severity, and vitality compared with low-impact participants (n = 520). Centrally acting medication burden increased stepwise with phenotype severity, whereas noncentrally acting medication use did not differ between phenotypes. Within phenotypes, centrally acting medication burden showed weak and nonsignificant associations with symptom severity after adjustment for demographic covariates, explaining minimal variance in fibromyalgia impact (R2 < 0.05).

Fibromyalgia symptom phenotypes remained distinct across varying levels of pharmacologic exposure, and medication burden explained little within-phenotype symptom variability. Medication burden primarily reflects downstream clinical response to symptom severity rather than a determinant of phenotype organization. These findings support the use of stable multidimensional phenotypes for mechanistic, neurobiological, and stratified intervention studies in chronic pain and related central nervous system disorders.