Sometimes you just guess right. Natelson and Shungu and company made two big guesses in this oh so interesting clinical trial.


The Shungu – Natelson team guessed right on two important questions in fibromyalgia

First, they guessed that people with fibromyalgia would have the same increased brain lactate levels that they’ve found that  people with chronic fatigue syndrome do.  Then they  guessed that an “antidepressant” drug (Milnacipran; e.g. Savella) would be able to reduce that brain lactate.

They guessed right on both counts.

Natelson BH, Vu D, Mao X, Weiduschat N, Togo F, Lange G, Blate M, KangG, Coplan JD, Shungu DC, Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia : A Randomized, Double-blind, Placebo-controlled Trial, Journal of Pain (2015), doi: 10.1016/ j.jpain.2015.08.004.

The fibromyalgia patients in this study either took 8 weeks of Savella (n=17) or a placebo (n=17). Their brain lactate levels were measured before and after the treatment.

The study found that FM patients brain lactate levels  were indeed elevated at rest – and not by a small amount (P<.0001). Relatively speaking the FM patient’s brains were loaded with lactate, relative to the healthy controls.

High Lactate – Low Energy

High lactate levels are usually associated with reduced oxygen levels in the tissues. When the cells don’t get enough oxygen to power the aerobic energy production process they turn to anaerobic energy production to produce energy.

During anaerobic energy production pyruvate is broken down into lactate, which then fuels the energy production process. This kind of energy production only works for short periods – two to three minutes in fit people – before fatigue and pain set in.

Lactate, therefore, is a natural outcome of anaerobic energy production. High blood lactate occurs when some lactate spills over into the blood.

High lactate levels are usually associated with strenuous exercise, however, not a “resting” brain. (Whether the brains or bodies of ME/CFS and FM patients can be described as ever being in a “resting state”, of course, is open to interpretation… :))

fibromyalgia brains high lactate

The study suggested that fibromyalgia patients brains – even at rest – were a bit low on the energy scale

The authors reported that the brain lactate levels found were similar to those found in people with chronic fatigue syndrome. In three studies over the past six years Shungu and Natelson have validated high levels of lactate in the ventricular regions of the brains of people with ME/CFS.

These findings suggest that aerobic energy production – the kind of energy production we rely on for most of our energy – is not exactly going gangbusters in ME/CFS and FM patients brains.  That would fit in well with the cognitive issues (fibro-fog, brain-fog) so well known in these disorders.

Lower Lactate = Lower Pain

Savella lowered  brain lactate levels significantly, and as it did so, it significantly reduced the FM patients pain. The lactate levels in the FM patients brains were still significantly higher than in the healthy controls brains but probability factors indicated they were remarkably reduced (p  <0001 vs p <.01).

As noted, Savella didn’t lower the FM brain lactate levels to normal. Nor did it leave the FM patients pain-free. The significant reductions in both lactate and pain levels suggested, however, that further reductions in brain lactate levels could reduce pain levels further. It suggests that if researchers can figure out how to reduce brain lactate levels to normal the pain in FM might even disappear.

The reduced brain lactate did not significantly improve cognition, however. The authors, suspected that a larger study would find significantly improved levels of cognition.

Potential Biomarker

The authors noted that these high lactate levels could function as a biomarker for both ME/CFS and FM. This is one potential biomarker, it should be noted, that does not require exertion to produce it; the high lactate levels are found during rest. This could suggest that lactate accumulations in the brain – and the processes behind them – could constitute a fundamental part of ME/CFS and FM pathophysiology.

(Shungu’s finding of similarly increased lactate levels in depression (but not anxiety) as well as ME/CFS, however, has complicated the biomarker scenario. Shungu is currently engaged in a larger study which he believes will show that significantly higher lactate levels are found in ME/CFS than depressed patients. If he’s correct, high brain lactate levels may be a biomarker for ME/CFS – and fibromyalgia.)


Intriguingly, the authors suggested that the increased lactate levels may result from neuroinflammation; i.e. by over-activated glial cells pumping out pro-inflammatory factors that are increasing oxidative stress and generally producing havoc. (The “usual suspects” regarding inflammation in the brain basically end at the glial cells – the only immune cell found in the brain.)

neuroinflammation fibromyalgia

Is neuroinflammation behind the pain in fibromyalgia?

The authors noted that activated glial cells have been tied to central sensitization – a key finding in fibromyalgia.  Glial activation could also be behind a recent finding of “large increases” of IL-8 in the cerebrospinal fluid of FM patients.

If increased brain lactate levels are linked to glial cell activation in FM and ME/CFS, then evidence of significant neuroinflammation has been present for chronic fatigue syndrome since 2009. (Who knew?)

Savella – Antidepressant, Anti-Pain and Anti-inflammatory Agent?

But why would Savella – a serotonin and norepinephrine reuptake inhibitor – otherwise known as an antidepressant, be able to affect inflammation and glial functioning? Antidepressants were developed to effect neurotransmitter levels – not the immune system in the brain.

Research dating back at least to 2008 suggests, however, that antidepressants can also be potent anti-inflammatory agents. A 2012 study, in fact, found that all the SSRI”s tested (fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram) “potently” inhibited the microglia from pumping out pro-inflammatory factors (TNF-a, NO).

Of course, this brings up the question just what Savella is doing in the brains of the ME/CFS and/or FM subjects that are benefitting from it.  If it’s helping with pain, this study suggests it’s probably reducing inflammation. (Since about a third of depression is associated with inflammation – the same may be true if it’s helping with depression.)

Since preliminary results from the Hornig/Lipkin microbiome studies suggest some people with ME/CFS may have problems with serotonin as well, it’s possible it’s working as a serotonin enhancer as well.

The Inflammation – Low Blood Flow Hypothesis

What’s happening here? Earlier Shungu proposed that high levels of oxidative stress were producing elevated levels of free radicals called isoprostanes in the brains of ME/CFS patients.

This oxidative stress could result from glial cell activation, low antioxidant levels, or perhaps most likely – both. Those isoprostanes then reduce blood flows and oxygen delivery to the brain by constricting the blood vessels in the brain. The low oxygen levels then reduce aerobic energy production and increase anaerobic energy production leading to high lactate levels.

Another hypothesis by Newton suggests that pH handling problems in the muscles could prompt  blood vessel constriction and the restriction of blood flows in the brain.

(Low blood flows (ischemia) can also set up the blood vessels for a free radical explosion when more normal blood flows return. Could an ischemic environment contribute to the PEM that occurs when some people with ME/CFS try to concentrate – and thus send more blood flows to their brain?)


In this study Natelson and company provided evidence suggesting that a) FM is a neuroinflammatory disorder, b) Savella reduces pain levels by reducing inflammation in the brain and c) that FM and ME/CFS share a central brain factor.  The study also suggested that focusing future treatments on reducing neuroinflammation might be a very good idea indeed.


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