Background/Purpose: Fibromyalgia (FM) is a chronic widespread pain disorder characterized by muscle tenderness, fatigue, poor sleep, and mood disturbance.  Milnacipran is a dual serotonin-norepinephrine reuptake inhibitor FDA-approved for the treatment of this condition; however its clinical mechanism of action remains unknown.  We used functional connectivity magnetic resonance imaging (fcMRI) to examine the effect of milnacipran on brain connectivity during evoked pressure pain.

Methods: 13 patients with FM completed a randomized double-blind two-period cross-over study of milnacipran versus placebo. Each 7-week period (drug or placebo) was followed by a 14 day taper and washout.  Prior to and following each period, all subjects underwent fcMRI during which pressure was applied to their thumbnail. Two pressure intensities were delivered in a pseudo-random sequence: an individually calibrated pressure evoking moderate pain (50 on a 100 point Numerical Rating Scale [NRS]) and an equal pressure across all subjects. All fcMRI data were preprocessed and analyzed using Statistical Parametric Mapping 5 and the CONN toolbox.  Seed based functional connectivity analyses included three anterior cingulate cortex (ACC) and bilateral periaqueductal gray (PAG) regions.  Paired t-test image comparisons were deemed significant at p<0.05 cluster level corrected. Pearson’s r values for connectivity were extracted and correlated with clinical pain from the Brief Pain Inventory (BPI) and “average evoked pain” acquired immediately after the fcMRI run (NRS) for placebo and drug treatments using SPSS 19. 

Results: Milnacipran treatment was associated with increased connectivity between multiple cortical regions and brain stem areas involved with descending analgesia: the perigenual ACC (seed region) showed greater connectivity to the pons and PAG (both p<0.05 corrected), and the PAG (seed region) showed greater connectivity with the bilateral mid insula cortex and the supplementary motor area/mid cingulate cortex (midCC; all p<0.05 corrected).  Milnacipran also significantly decreased inter-cortical connectivity between the ACC seed regions and the inferior parietal lobule and midCC (p<0.05 corrected).  These effects were not detected during the placebo period (all p>0.05).  Interestingly increases in ACC to PAG connectivity following milnacipran were associated with the decreases in clinical pain (BPI interference: r = -0.672, p = 0.012) while decreases in connectivity between the ACC and midCC were associated with reduced levels of average evoked pain (r = 0.648, p = 0.017). 

Conclusion:

Here we provide the first evidence that milnacipran alters brain connectivity during evoked pain in patients with FM.  The increased connectivity between the ACC and the PAG suggests that the analgesic action of milnacipran involves, at least in part, enhanced cortical modulation of brainstem sites implicated in descending antinociception. Conversely, the brain regions that show decreased connectivity during milnacipran therapy are regions where functional connectivity is increased in chronic pain states, and is associated with clinical pain report.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/milnacipran-increases-cortical-to-brainstem-connectivity-during-pain-in-fibromyalgia/