Background/Purpose:  Knee osteoarthritis (OA) is a degenerative joint disease causing symptoms in 12% of people over the age of 65 . A variety of treatments have been tested to alleviate knee OA symptoms, most being focused on reducing pain through analgesic or anti-inflammatory actions. Clinical studies have reported a beneficial effect of pharmaceutical-grade chondroitin sulfate (CS) on knee pain, and a parallel  reduction in the rate of decline in joint space width. Nevertheless, not all clinical trials have been successful  and reports exist suggesting that CS is not equally effective in all clinical situations (Clegg 2006) . Inherent problems with efficacy assessment of pain medication are the lack of objective pain measurements and the large variability of subjective pain ratings. The aim of the present fMRI study was to objectively identify the effects of CS treatment on the brain response to pressure painful stimulation in patients with symptomatic knee osteoarthritis.

Methods: Phase IV, randomized, double-blind clinical trial in which patients received CS (pharmaceutical-grade manufactured by Bioibérica) 800 mg/day or placebo for a 4-month treatment course. Patients were assessed at baseline and after four-month of treatment. Two fMRI tests were conducted in each session by applying painful pressure on the knee medial interline (pain sensitive maneuver) and on the patella surface (cartilage selective targeting). The main outcome measurement was attenuation of the response evoked by knee painful stimulation in the pain-processing brain system.

Results: Twenty-two evaluable patients received CS and 27 placebo. No  effects of CS were detected using the knee interline pressure test. Patients receiving CS showed a tendency to report reduced subjective pain after treatment during patella pressure test (p=0.077), but no significant group by session interaction was demonstrated. fMRI of patella pain, showed a larger activation reduction in the CS group than in placebo in a posterior mesencephalon region including the periaqueductal gray (PAG). The entire PAG cluster (238 voxels) with significant interaction showed a pre>post-treatment difference at p<0.05 (peak difference at x=-10, y=-34, z=-16; t= 2.4, p= 0.007). In this paired analysis, the CS group showed significant activation reduction in the primary somatosensory cortex (including the cortical representation of the leg) and extending to the primary motor cortex and posterior supplementary motor area. Group by session interaction consistently revealed a tendency for this cortical change to be larger in the CS than in placebo (peak interaction x=2, y=-6, z=72; t=2.96, p= 0.002 and 43 voxels -subthreshold- with p<0.01).

Conclusion:  fMRI was sensitive to objectify CS effects on brain response to knee painful stimulation. The current work yields further support to the utility of fMRI to objectify treatment effects on OA pain. The positive treatment effect of CS on brain was identified on pain elicited by pressure on patellofemoral cartilage, where the cartilage component of pain is a relevant factor. This result  is consistent with the known CS mechanisms of action and the results obtained in previous clinical trials.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-chondroitin-sulfate-on-brain-response-to-painful-stimulation-in-knee-osteoarthritis-patients-a-randomized-double-blind-placebo-controlled-clinical-trial/