Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing. At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation.

Perspective: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

Trial registration: ClinicalTrials.gov NCT01108731.

Keywords: Widespread pain; brain function; magnetic resonance spectroscopy; serotonin-norepinephrine reuptake inhibitor.

Figure 1

Consort Statement.

Figure 2

[A] T₁-weighted human brain MR images showing (top) a grid of lateral ventricular voxels of interest, and (middle and bottom) the location and angulation of the MRSI slices for optimal sampling of the lateral ventricular lactate (highlighted structure). The presented ventricular cerebrospinal fluid lactate data are the mean value obtained for all the voxels in ventricular space represented by the grid on the top MR image. [B] Sample ¹H MR spectra from a voxel in the right posterior horn of the lateral ventricle (filled box on top image in [A]) (a) in a subject without a visible lactate (Lac) peak and (b) in a patient with FM who showed a clear lactate doublet peak at 1.33 ppm. The other identified resonances are for N-acetylaspartate (NAA), total creatine (tCr) and total choline (tCho), which appear with greatly decreased intensity in ventricular spectra because they arise from partial volume-averaging with surrounding brain tissue.

Figure 3

Individual subject’s ventricular lactate values in institutional units (unadjusted means ± SEM) before and after placebo or drug treatment; the outlier was not plotted. Using BMI and baseline lactate as covariates, analysis revealed a significant effect of treatment group with the change in drug-treated ventricular lactate values decreased compared to those of placebo as well as compared to levels found prior to active drug treatment.

Figure 4

Change in ventricular lactate versus change in VAS Pain from the start to end of the study for patients in milnacipran and placebo groups. The overall correlation was significant (ρ = 0.54; p < 0.05) – an effect which was due to a different pattern of response between the groups with more drug-treated patients showing decreases in both variables in contrast to placebo-treated patients (compare number of Xs to Os in stippled area).