Dual Reuptake Inhibitor Milnacipran and Spinal
Pain Pathways in Fibromyalgia Patients: A
Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Desmeules Jules A. 
Published: March 2021

Background: Investigations based on quantitative sensory testing have consistently shown evidence
of allodynia in fibromyalgia syndrome (FMS) patients involving both the spinal and supraspinal pain
regulatory systems. Functional imaging studies have demonstrated enhanced neural activities in painrelated brain areas as well as impairment of pain inhibition in the descending nociceptive regulatory
system. A higher state of excitability of spinal nociceptive neurons as evidenced by lowered nociceptive
flexion reflex R-III (NFR) threshold was reported for FMS patients. The NFR procedure has been shown
to be a valuable tool to evaluate pharmacologically active therapeutic agents at the spinal level.
Objective: Serotonin-noradrenaline reuptake inhibitors have been shown to reduce pain in FMS
patients possibly through descending monoaminergic pain pathways modulation. This randomized
double-blind placebo-controlled trial assessed the pharmacodynamic activity of the dual-reuptake
inhibitor milnacipran (MLN) at the spinal level by means of the objective spinal NFR.
Study Design: Randomized, double-blind, placebo-controlled trial
Setting: A single academic medical center, outpatient setting
Methods: Seven-week exposure (100, 150, 200mg/day) in women fibromyalgia patients. Evaluation
consisted of extensive quantitative sensory testing including determination of the NFR threshold, selfreported standard questionnaires investigating pain, visual analog scales, fibromyalgia impact, healthrelated quality of life, depression and anxiety questionnaires, as well as the Patient’s Global Impression
of Change (PGIC). Analysis of covariance adjusted for baseline value was used for all endpoints.
Results: Seventy-seven (39 placebo, 38 milnacipran all doses) out of 80 randomized patients were
available for analysis. The absence of influence of MLN (any dose) on the NFR surprisingly contrasted with
the dose-dependent analgesic effect observed in MLN-treated patients with an adjusted change difference
of -18.4mm (-30.9; -5.8) in pain reduction between placebo and the maximum dosage (200 mg) MLN
groups (P = 0.02). Unchanged depression and anxiety scores confirmed the predominant selectivity
of the analgesic effect of MLN on nociceptive pain pathway. Self-reported questionnaires consistently
reflected the positive effects of MLN on quality of life and psychological well-being. Odds ratio 5.1 for PGIC
responders (i.e. much/very much improved) was significantly in favor of MLN (P = 0.04).
Conclusion: Milnacipran has a predominantly supraspinal analgesic effect as evidenced by the
significant clinical benefits and the absence of changes in the nociceptive spinal reflex threshold.
Higher dose was associated with higher pain reduction. Reported analgesia was independent of
patients’ emotional status.
Key words: Fibromyalgia; chronic pain, spinal nociceptive flexion reflex, milnacipran, dual- reuptake
inhibitor, 5-HT noradrenaline re-uptake inhibitor, descending noxious inhibitory controls, quantitative
sensory testing, Patient Global Impression of Change, Fibromyalgia Impact Questionnaires