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


CONCLUSIONS
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.
Department of Neurology, Mount Sinai Beth Israel, New York, New York. Electronic address: bnatelson@bethisraelny.org.
Benjamin H
BH
Natelson
Department of Neurology, Mount Sinai Beth Israel, New York, New York.
Diana
D
Vu
Department of Radiology, Weill Medical College of Cornell University, New York, New York.
Xiangling
X
Mao
Department of Radiology, Weill Medical College of Cornell University, New York, New York.
Nora
N
Weiduschat
Educational Physiology Laboratory, Graduate School of Education, The University of Tokyo, Tokyo, Japan.
Fumiharu
F
Togo
Department of Neurology, Mount Sinai Beth Israel, New York, New York.
Gudrun
G
Lange
Department of Neurology, Mount Sinai Beth Israel, New York, New York.
Michelle
M
Blate
Department of Radiology, Weill Medical College of Cornell University, New York, New York.
Guoxin
G
Kang
Department of Psychiatry & Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, New York.
Jeremy D
JD
Coplan
Department of Radiology, Weill Medical College of Cornell University, New York, New York.
Dikoma C
DC
Shungu
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001288:Attention / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002552:Cerebral Ventricles / Q000187:drug effects* / Q000378:metabolism; D003521:Cyclopropanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D056344:Executive Function / Q000187:drug effects; D005260:Female; D005356:Fibromyalgia / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008875:Middle Aged; D000078764:Milnacipran; D017711:Nonlinear Dynamics; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement; D066244:Proton Magnetic Resonance Spectroscopy; D011581:Psychological Tests; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
D018759:Adrenergic Uptake Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D003521:Cyclopropanes; D019344:Lactic Acid; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors
Widespread pain; brain function; magnetic resonance spectroscopy; serotonin-norepinephrine reuptake inhibitor