Background/Purpose:  Brain imaging techniques including functional magnetic resonance imaging (fMRI) may be useful in probing the mechanisms of action of centrally acting analgesics. Previously we have used brain resting state functional connectivity (fcMRI) outcomes to predict clinical pain response in fibromyalgia (FM) for the two efficacious compounds pregabalin (PG), preclinically shown to reduce presynaptic cell calcium thereby reducing the concentration of glutmate, an excitatory neurotransmitter, into the synapse, and milnacipran (MLN), preclinically shown to inhibit the reuptake of serotonin and norepinephrine, improving descending modulation. Here we extend our analyses to determine if these compounds have a differential effect on brain connectivity patterns in human patients with fibromyalgia.

Methods:  28 female FM patients were included in this study. 13 completed a double-blind placebo-controlled crossover study with PG, and 15 completed a similar study with MLN. All patients underwent a 6 minute fcMRI scan pre- and post-treatment for both the drug and placebo (PBO). Patients reported clinical pain pre- and post-treatment using a 0-10 rating scale. fcMRI data were analyzed with a priori regions of interest approach using the Conn toolbox running in SPM8 and Matlab. Regions previously identified as independently predictive for PG and MLN were cross-utilized in both data sets. Changes in fcMRI were analyzed in SPM8 with paired t-tests (within treatment) and a flexible factorial interaction (PG vs MLN) that included seed-to-whole brain correlation maps. Finally, PG and MLN were directly contrasted with a two-sample t-test.

Results were significant on the cluster level with a false discovery rate p value < 0.05 derived from an uncorrected voxel level p value < 0.001. Significant results were correlated with changes in clinical pain in SPSS v22 Results: PG significantly decreased fcMRI between the anterior and posterior insula seeds to the dorsolateral prefrontal cortex (DLPFC, p = 0.003 and p = 0.05). Decreases in PG anterior insula – DLPFC fcMRI were associated with reduced clinical pain (rho = 0.830, p < 0.001). MLN significantly increased fcMRI between the subgenual anterior cingulate (sgACC) seed and the inferior parietal lobule (IPL, p = 0.040). Increased sgACC – IPL fcMRI was associated with reduced clinical pain (rho = -0.515, p = 0.049). When directly compared MLN significantly increased and PG significantly decreased fcMRI between the right DLPFC seed and the precuneus (p = 0.007). PG DLPFC – precuneus fcMRI, decreases were associated with reductions in clinical pain (rho = 0.808, p = 0.001). No PG seeds produced significant fcMRI relationships in the MLN data and no MLN seeds displayed significant fcMRI relationships in PG data.

Conclusion:  These data demonstrate differential effects of PG and MLN on resting brain activity, thus providing further evidence that these compounds may have different mechanisms of action. PG was found to act more so on pro-nociceptive brain regions, whereas MLN acted more so on an anti-nociceptive brain region. These results suggest that a combination of both PG and MLN in the same patient may be more effective due to the medications working on separate yet complementary brain processes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-analgesic-pharmacological-effects-on-brain-connectivity-in-fibromyalgia-fm/