Background & Aims
Chronic pain (CP) affects over 50 million adults in the United States alone (1). Current treatments vary highly in efficacy, demonstrating a need to identify pathophysiological differences between patients with low-impact versus high-impact CP. Studies suggest a link between inflammatory mechanisms and pain severity (2). However, research is needed to fully understand the factors related to pain severity phenotypes.
The development and persistence of CP is mediated by inflammatory processes in the central and peripheral nervous systems (3). Cytokines, intracellular regulatory proteins secreted by immune cells, have been implicated in various CP conditions including fibromyalgia, rheumatoid arthritis, and migraines (4-6). Therefore, we hypothesize cytokine profiles may be associated with the severity and extent of chronic orofacial pain. The identification of biological markers associated with CP phenotypes may enable us to develop successful, personalized treatment approaches.
Methods
Patients with temporomandibular disorder (TMD, n=273; F:211) and healthy controls (HC, n=210; F:129) were recruited to study orofacial pain phenotypes. Pain severity was calculated using the Graded Chronic Pain Scale (GCPS), and TMD patients were classified into “Low-Impact” (n=163) and “High-Impact” (n=110) groups (7). Plasma samples were taken from each participant, and levels of five cytokines were quantified using Mesoscale Discovery’s chemiluminescence-based multiplexed ELISA. Shapiro-Wilk tests were performed on cytokine distributions. Due to lack of normality, Whitney-Mann U-tests were used to identify differences in cytokine levels between HC and TMD groups and between High-Impact and Low-Impact GCPS pain groups. A Bonferroni correction was applied for an adjusted significance threshold (p=0.01). Based on univariate analyses, multivariate logistic regression analyses were run to confirm cytokines as a predictor of pain severity, with age, sex, and pain duration as covariates.
Results
TMD participants had significantly elevated protein levels of anti-inflammatory Interleukin-1 Receptor Antagonist (IL-1RA) and proinflammatory cytokines Interleukin-6 (IL-6), Interleukin-8 (IL-8) and monocyte chemotactic protein (MCP-1) as compared to HC participants (p < 0.001). GCPS-related pain severity was positively correlated with levels of IL-1RA and IL-6, such that participants with High-Impact pain had elevated protein levels compared to those with Low-Impact pain (p < 0.01). Linear modeling confirmed IL-1RA as a significant predictor of pain severity independent of any covariates. Increased age was associated with higher cytokine levels and pain severity. Moreover, we found a sex effect, where females had significantly higher levels of IL-1RA than males in the total sample and within the TMD sample (p < 0.01). Within female TMD participants, levels of IL-1RA and IL-6 remained significantly higher in those with High-Impact pain.
Conclusions
Our findings indicate a relationship between the severity of pain and circulating levels of cytokines. We build on the existing understanding of age and sex as important variables in cytokine levels (8). Future research will seek to examine additional cytokines, as well as their relationship to duration of pain and the existence of Complex Overlapping Pain Conditions (9). In addition, we will investigate cytokine-associated structural and functional brain differences. This research will enhance our understanding of individual neuroimmunological bases that contribute to distinct pain outcomes. These findings may help advance future treatments based on local or systemic delivery of cytokines or cytokine antagonists as an avenue to relieve CP.
References
1. Rikard SM, Strahan AE, Schmit KM, Guy GP Jr. (2023). Chronic Pain Among Adults — United States, 2019–2021. MMWR Morb Mortal Wkly Rep, 72:379–385.
2. Wu N, Kong H, Han L, Chen Y, Bai J, Liu Y. (2024). An Analysis of Biopsychosocial Factors Associated With Chronic Pain Severity Among Hospitalized People Living With HIV in Shenzhen, China: A Cross-Sectional Study. Journal of the Association of Nurses in AIDS Care, 35(1): 51-59.
3. Zhang JM, An J. Cytokines, inflammation, and pain. (2007). Int Anesthesiol Clin., 45(2):27-37.
4. Wang H, Moser M, Schiltenwolf M, Buchner M. (2008). Circulating cytokine levels compared to pain in patients with fibromyalgia—a prospective longitudinal study over 6 months. The Journal of Rheumatology, 35(7): 1366-1370.
5. Burska A, Boissinot M, Ponchel F. (2014). Cytokines as Biomarkers in Rheumatoid Arthritis. Mediators of Inflammation, 2014.
6. Musubire AK, Cheema S, Ray JC, Hutton EJ, Matharu M. (2023). Cytokines in primary headache disorders: a systematic review and meta-analysis. J Headache Pain, 24(1):36.
7. Miller V.E., Poole C., Golightly Y., et al. (2019). Characteristics Associated With High-Impact Pain in People With Temporomandibular Disorder: A Cross-Sectional Study. J Pain, 20(3): 288-300.
8. Larsson A, Carlsson L, Gordh T, Lind AL, Thulin M, Kamali-Moghaddam M. (2015). The effects of age and gender on plasma levels of 63 cytokines. Journal of Immunological Methods, 425: 58-61.
9. Maixner W, Fillingim RB, Williams DA, Smith SB, Slade GD. (2016). Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification. J Pain, 17(9): T93-T107.
Presenting Author
Rebecca Aitken
Poster Authors
Topics
- Specific Pain Conditions/Pain in Specific Populations: Orofacial Pain