Natelson, Benjamin H, Vu, Diana, Mao, Xiangling et al. · The journal of pain · 2015 · DOI
This study tested whether a medication called milnacipran could reduce brain inflammation and pain in fibromyalgia patients. Researchers measured a chemical called lactate in the brain using a special MRI scan and found that fibromyalgia patients had higher levels than healthy people. After 8 weeks of treatment, patients taking milnacipran showed lower lactate levels and less pain compared to those taking placebo, suggesting the medication may work by reducing brain inflammation.
This study is significant because it identifies a potential biological marker (ventricular lactate) for central inflammation in chronic pain conditions and demonstrates that a currently-approved medication can reduce both this marker and symptoms. For ME/CFS patients and researchers, it supports the hypothesis that elevated lactate may indicate neuroinflammation in post-exertional malaise and other central nervous system symptoms, opening possibilities for targeting similar pathways.
This study does not prove that milnacipran is effective for ME/CFS, as it examined only fibromyalgia patients—a different diagnosis with overlapping but distinct pathophysiology. It also does not establish that lactate reduction directly causes pain improvement (correlation does not prove causation), and the fact that lactate remained elevated after treatment raises questions about whether this biomarker fully explains therapeutic response. The lack of cognitive improvement despite lactate reduction suggests the mechanism may be more complex than initially hypothesized.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
The first block is for the primary paper and is the citation you should use in research work. The atlas-snapshot line only applies if you are specifically referring to this atlas’s reading of the paper on the date shown.
Primary citation
Natelson, Benjamin H, Vu, Diana, Mao, Xiangling, Weiduschat, Nora, Togo, Fumiharu, Lange, Gudrun, et al. (2015). Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial.. The journal of pain. https://doi.org/10.1016/j.jpain.2015.08.004
BibTeX
@article{mecfsatlas-natelson-2015-effect-milnacipran,
author = {Natelson, Benjamin H and Vu, Diana and Mao, Xiangling and Weiduschat, Nora and Togo, Fumiharu and Lange, Gudrun and Blate, Michelle and Kang, Guoxin and Coplan, Jeremy D and Shungu, Dikoma C},
title = {Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial.},
journal = {The journal of pain},
year = {2015},
doi = {10.1016/j.jpain.2015.08.004},
note = {PubMed: 26335989},
url = {https://www.mecfsatlas.com/evidence/natelson-2015-effect-milnacipran},
}Atlas snapshot reference
ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-05-28. https://www.mecfsatlas.com/evidence/natelson-2015-effect-milnacipran
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