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Peer-reviewedCC BY 4.0CNS Spectrums

Fibromyalgia neurobehavioral phenotypes remain distinct across varying levels of pharmacologic exposure: evidence from a multisite cohort (n = 695)

  • Kevin V. Hackshaw1
  • Michelle M. Osuna-Diaz2
  • Katherine R. Sebastian2
  • Shreya Madhav Nuguri2
  • Silvia deLamo Castellvi3
  • Lianbo Yu4
  • M. Monica Giusti3
  • Zhanna Mikulik5
  • Luis Rodriguez-Saona3
5 affiliations
  1. 1Division of Rheumatology, Department of Medicine, The University of Texas at Austin Dell Medical School, Austin, USA
  2. 2Department of Medicine, The University of Texas at Austin Dell Medical School, USA
  3. 3Food Sciences and Technology, The Ohio State University, USA
  4. 4Bioinformatics, The Ohio State University Wexner Medical Center, USA
  5. 5Division of Immunology and Rheumatology, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, USA
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Abstract

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

Methods: 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.

Results: 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 (R 2 < 0.05).

Conclusions: 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.

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Cite

BibTeXRIS
BibTeX
@article{hackshaw2026fibromyalgia,
  title = {{Fibromyalgia neurobehavioral phenotypes remain distinct across varying levels of pharmacologic exposure: evidence from a multisite cohort (n = 695)}},
  author = {Kevin V. Hackshaw and Michelle M. Osuna-Diaz and Katherine R. Sebastian and Shreya Madhav Nuguri and Silvia deLamo Castellvi and Lianbo Yu and M. Monica Giusti and Zhanna Mikulik and Luis Rodriguez-Saona},
  journal = {CNS Spectrums},
  year = {2026},
  month = sep,
  doi = {10.1017/s1092852926101199},
  url = {https://doi.org/10.1017/s1092852926101199},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Fibromyalgia neurobehavioral phenotypes remain distinct across varying levels of pharmacologic exposure: evidence from a multisite cohort (n = 695)
AU  - Kevin V. Hackshaw
AU  - Michelle M. Osuna-Diaz
AU  - Katherine R. Sebastian
AU  - Shreya Madhav Nuguri
AU  - Silvia deLamo Castellvi
AU  - Lianbo Yu
AU  - M. Monica Giusti
AU  - Zhanna Mikulik
AU  - Luis Rodriguez-Saona
PY  - 2026
DA  - 2026/09/22
JO  - CNS Spectrums
DO  - 10.1017/s1092852926101199
UR  - https://doi.org/10.1017/s1092852926101199
AB  - Objective: To determine whether pharmacologic exposure is associated with differences in fibromyalgia neurobehavioral phenotypes and whether medication burden explains symptom variability within phenotypes.  Methods: 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.  Results: 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 (R 2 < 0.05).  Conclusions: 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.
SN  - 1092-8529
SN  - 2165-6509
ER  -