Pregabalin reduces insula grey matter density in fibromyalgia (FM)

Pregabalin has been shown to reduce fibromyalgia (FM) pain; however, its clinical mechanism of action is unknown. Preclinical studies indicate that pregabalin may potentially down regulate glutamate release while also inhibiting astrocyte induction of glutamatergic synapse formation.We used Voxel-based Morphometry (VBM) to quantify grey matter (GM) density in FM patients before and after pregabalin treatment. We hypothesized that pregabalin treatment would be associated with changes in local brain morphology in regions involved in pain perception. 16 female FM patients completed a randomized double-blind two-period cross-over study of pregabalin versus placebo. Each 14-day period was followed by taper and washout. Before and after each period, patients underwent magnetic resonance imaging (MRI). Anatomical scans were acquired using a high-resolution T1-weighted protocol. Differences in GM density pre- and post-treatment at every voxel were obtained using a general linear model within the program SPM5. Regions of interest showing significant change were extracted and analyzed using SPSS v19. Patients also rated maximum evoked pressure pain at the thumbnail bed using the Gracely Box scale (GBS). GM density was significantly reduced following pregabalin treatment (p<0.05, corrected) within the right posterior insula and left posterior insula. Changes in GM density were non-significant following placebo (both p$0.05). Following pregabalin treatment, greater reductions in GBS pressure pain ratings were associated with greater GM density reductions within the right posterior insula (r=0.55, p=0.028). Pregabalin reduces GM density in the posterior insula bilaterally in individuals with FM. This may reflect pregabalin's ability to alter synaptic plasticity. Pregabalin's effects on GM density in the first period were largely reversible following placebo treatment. While structural MRI cannot specifically identify neural changes such as GM loss, and interpretation should be considered carefully, our data may suggest a short-term structural effect of pregabalin on the insula.