Background In recent years, the prescription of
serotonin-noradrenalin reuptake inhibitors (
SNRIs) for treatment of
fibromyalgia (FM) has increased with reports of their efficacy. The
SNRI milnacipran is approved by the U.S. Food and Drug Administration (FDA) for treatment of FM, yet, the mechanisms by which
milnacipran reduces FM symptoms are unknown. A large number of neuroimaging studies have demonstrated altered brain function in patients with FM but the effect of
milnacipran on central
pain processing has not been investigated. The primary objective of this study was to assess the effect of
milnacipran on sensitivity to pressure-evoked
pain in FM. Secondary objectives were to assess the effect of
milnacipran on cerebral processing of pressure-evoked
pain using fMRI and the tolerability and safety of
milnacipran 200 mg/day in FM. Methods 92 patients were randomized to either 13-weeks
milnacipran treatment (200 mg/day) or placebo in this double-blind, placebo-controlled multicenter clinical trial. Psychophysical measures and functional MRI (fMRI) assessments were performed before and
after treatment using a computer-controlled pressure-
pain stimulator. Here, we present the results of several a priori defined statistical analyses. Results
Milnacipran-treated patients displayed a trend toward lower pressure-
pain sensitivity
after treatment, compared to placebo, and the difference was greater at higher
pain intensities. A single group fMRI analysis of
milnacipran-treated patients indicated increased
pain-evoked brain activity in the caudatus nucleus, anterior insula and amygdala
after treatment, compared to before treatment; regions implicated in
pain inhibitory processes. A 2 × 2 repeated measures fMRI analysis, comparing
milnacipran and placebo, before and
after treatment, showed that
milnacipran-treated patients had greater
pain-evoked activity in the precuneus/posterior cingulate cortex
after treatment; a region previously implicated in intrinsic brain function and FM pathology. This finding was only significant when uncorrected for multiple comparisons. The safety analysis revealed that patients from both treatment groups had treatment-emergent adverse events where
nausea was the most common complaint, reported by 43.5% of placebo patients and 71.7% of
milnacipran-treated patients. Patients on
milnacipran were more likely to discontinue treatment because of side effects. Conclusions Our results provide preliminary indications of increased
pain inhibitory responses in
milnacipran-treated FM patients, compared to placebo. The psychophysical assessments did not reach statistical significance but reveal a trend toward higher pressure-
pain tolerance
after treatment with
milnacipran, compared to placebo, especially for higher
pain intensities. Our fMRI analyses point toward increased activation of the precuneus/posterior cingulum in patients treated with
milnacipran, however results were not corrected for multiple comparisons. The precuneus/posterior cingulum is a key region of the default mode network and has previously been associated with abnormal function in FM. Future studies may further explore activity within the default mode network as a potential
biomarker for abnormal central
pain processing. Implications The present study provides novel insights for future studies where functional neuroimaging may be used to elucidate the central mechanisms of common pharmacological treatments for
chronic pain. Furthermore, our results point toward a potential mechanism for
pain normalization in response to
milnacipran, involving regions of the default mode network although this finding needs to be replicated in future studies.