Relation of adipokines to pain sensitization and pain patterns in patients with knee osteoarthritis
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Abstract
INTRODUCTION: Pain sensitization, a process whereby nociceptive processing pathways are altered, leading to enhanced pain perception, is associated with pain severity in knee osteoarthritis (OA) and the progression in patterns of pain symptoms from being presently only intermittently to eventually becoming constant. What contributes to pain sensitization in knee OA is not clear. Obesity and low-grade inflammation, both of which are common in knee OA, play a role in the pain experience in knee OA. Whether pain sensitization in knee OA is induced by nociceptive input from systemic pro-inflammatory cytokines produced and released by adipose tissue is not known. Heightened pain as a result of systemic cytokines could be one mechanism by which obesity contributes to pain in knee OA. Characterizing the relation of systemic inflammatory cytokines to pain sensitization and pain pattern progression could help identify potential targets for the development of disease-modifying therapies and may provide additional rationale for weight-related interventions among patients with knee OA.
OBJECTIVES: The goal of this study was to examine the contributions of leptin and TNF-α, two systemic pro-inflammatory proteins produced by adipocytes, to pain sensitization and pain pattern progression in people with knee OA.
METHODS: Data were obtained from the Multicenter Osteoarthritis (MOST) Study, a longitudinal cohort of older adults with or at risk of knee OA. Leptin and TNF-α levels were measured at baseline. Sensitization measures, pressure pain threshold (PPTs) and temporal summation (TS), were completed at baseline and 24 months later. Pain patterns were assessed as frequency and severity of intermittent pain and the severity of constant pain using the Intermittent and Constant OA Pain (ICOAP) questionnaire. We examined the relation of cytokine levels, analyzed as sex-specific tertiles, to PPT and TS at baseline and to changes in PPT and TS over two years. We also evaluated the relation of cytokines to the following pain patterns, assessed by the ICOAP instrument: (1) no pain; (2) intermittent pain only; (3) constant +/- intermittent pain. Finally, to test our hypothesis that higher cytokine levels increase the risk of pain pattern progression, we defined a binary outcome as the development of more frequent intermittent or constant pain.
RESULTS: Among 739 participants (1478 knees) that met the inclusion criteria, the mean age was 61, mean BMI 30, and 58% were female. At baseline, higher leptin levels were associated with lower PPT (greater sensitivity or lower threshold for pain) at the knee (adjusted ß = -0.44 [95% confidence interval (CI) -0.86, -0.02]) while higher TNF-α levels were associated with lower PPT at the wrist (adjusted ß = -0.28 [95% CI -0.54, -0.01]). There were no significant associations with temporal summation at baseline, nor with change in PPT or temporal summation over two years. There was no significant difference in the odds of having intermittent pain (odds ratio (OR) 0.53 [95% CI 0.11, 2.63]) nor in the odds of having constant pain +/- intermittent pain (OR 0.40 [95% CI 0.06, 2.46] compared with no pain between those in highest versus lowest tertiles of leptin. Similarly higher baseline levels of TNF-α were not significantly associated with the odds of having intermittent pain (OR 0.1.72 [95% CI 0.40, 7.36]) nor in the odds of having constant pain +/- intermittent pain (OR 3.21 [95% CI 0.68, 15.00] compared with no pain. Lastly, belonging to the highest tertile of leptin (OR 0.70 [95% CI 0.37, 1.33]) or TNF-α (OR 1.14 [95% CI 0.71, 1.85]) did not significantly increase the odds of developing more frequent pain when compared to their lowest tertile counterparts.
CONCLUSION: PPT had a small association with both leptin and TNF-α after adjusting for pertinent confounders. A lack of an association with change in PPT or TS over two years suggests these cytokines may only have a transient effect on nociceptive neurons. Similarly, leptin and TNF-α were not associated with pain patterns or with the likelihood of developing more frequent pain, which has been linked to sensitization. Given this study did not track longitudinal changes to cytokine levels, it provides an incomplete assessment of the potential role leptin and TNF-α may have in generating and maintaining chronic pain states. Nonetheless, in this sizable cohort, these pro-inflammatory cytokines did not appear to have an appreciable contribution to pain sensitization or pain patterns in knee OA.
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