Study Of The Effect Of Chondroitin Sulfate On Pain In Knee Osteoarthritis Patients Assessed By Functional Mri: A Randomized, Double Blind, Placebo-Controlled Clinical Trial

Purpose: The aim of the present fMRI study was to objectively identify the effects of Chondroitin Sulfate (CS) treatment on the brain response to pressure painful stimulation in patients with radiological and clinical knee osteoarthritis. Material and methods: The current study was developed in the Rheumatology Department and the MRI Research Unit of the Hospital del Mar in Barcelona, from December 2010 to January 2013. This is a phase IV, randomized, double-blind clinical trial in which patients received CS (Condrosan®, Bioibérica S.A.) 800 mg/day or placebo for a 4-month treatment course. 64 patients were randomized (32 to placebo and 32 to CS), and finally 51 patients were evaluable by ITT (27 in the placebo group and 24 in the CS group). Patients were assessed at baseline and post-treatment. Two tests were conducted in each session by applying painful pressure on the patella surface and on the knee medial interline, using a MRI-compatible algometer, during the acquisition of two 6-min fMRI sequences. Stimulus intensity to be applied in both fMRI sessions was individually adjusted prior to baseline fMRI. Each subject was asked to rate the subjective pain perceived during the whole fMRI sequence immediately after fMRI acquisition using NRS. All fMRI data were processed using the Statistical Parametric Mapping (SPM8) package, Wellcome Department of Imaging Neuroscience, running in Matlab 7.1. One-sample t-statistic maps were calculated to describe task-related activations, and ANOVA (SPM Full Factorial repeated measurements within groups and independent between groups) was used to identify group by session treatment interaction effects and to compare groups and sessions. The main outcome measurement was attenuation of the response evoked by knee painful stimulation in the pain-processing brain system. Results: 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=-4, y=-40, z=-16; t=2.4, p=0.01). 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) (Figure 1). No effects of CS were detected using the knee interline pressure test. Conclusions: The study succeeded in the primary objective as a significant effect was demonstrated showing attenuation of brain response to painful pressure in key regions of the pain-processing network using the patella test. Despite knee medial interline is one of the most tenders points in patients with knee osteoarthritis, pressure on this site may generate pain from damage or sensitization in a variety of structures. The pain generated by pressing down the patella surface, in contrast, is probably less complex, and may be more selectively related to sensitization processes in the bone and the junction between the bone and cartilage as a result of erosion in the patella and femoral cartilages. The observed positive treatment effect of CS is consistent with the known CS action on cartilage protection due to chondrocyte regeneration. fMRI was able to objectify CS effects on brain response to knee pressure painful stimulation, yielding further support to the utility of fMRI to objectify treatment effects on OA pain.