Are Oxygen Starved Tissues Causing Pain and Fatigue in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)?
The Pain of Exercise
Chronic fatigue syndrome is not the only disorder featuring post-exertional malaise. Widespread pain may be fibromyalgia’s main symptom but exercise problems, while not as severe as found in ME/CFS, are common.
Most studies suggest that ‘exercise’ is generally helpful for FM but a CFS-like scenario still prevails; vigorous exercise such as running, biking, etc, will throw an FM patient into bed and really vigorous exercise is almost unheard of. Just as in chronic fatigue syndrome, most fibromyalgia exercise prescriptions focus on mild exercises such as walking, aquatic strengthening exercise, qigong, tai chi, etc.
Fibromyalgia is four times as numerous as ME/CFS, is associated more with pain – a much more active field of study than fatigue – and has three FDA approved drugs. Chronic fatigue syndrome is the exertion inhibited disorder par excellence – but FM with its painful muscles has gotten more muscle studies.
Something strange is going on in fibromyalgia to cause the exercise intolerance there and researchers are zeroing in on the same area in both FM and chronic fatigue syndrome – blood flows and the muscles.
In this study researchers used an hybrid Near Infrared Spectroscopy ( NIRS) technique to measure three important features of producing energy; how much blood was flowing to the muscles, how much oxygen was present, and how much oxygen was actually taken up by the muscles.
Large blood flows flood the muscles (or should flood the muscles) during exercise to deliver oxygen for aerobic energy production and wash away toxic byproducts ( such as lactic acid).
This study found FM patients muscles were getting the blood they needed but for some reason they weren’t taking up the oxygen very quickly and it took longer for the oxygen levels of their cells to get back to normal after exercise. Two things could explain this strange scenario..
The mitochondria use oxygen to produce energy; since damaged mitochondria don’t use as much oxygen, damage to the mitochondria could explain the low oxygen uptake in FM. Damaged mitochondria also often pump out large numbers of cell damaging free radicals which could interfere with muscle metabolism and cause pain.
Or A Debt Too High?
During exercise enormous amounts of oxygen are needed to neutralize the lactate and other toxic by products created during exercise. This is called ‘repaying the oxygen debt’; it took much longer for FM patients to repay that debt than expected.
The normal muscle blood flows suggested there was more than enough blood flow to ‘clean up’ the lactate the muscles produced. If the muscles were producing more lactate and other toxic by-products than normal, however, then the oxygen present might be going to clean up that rather than getting used up by the mitochondria.
So we have the possibility of mitochondrial and muscle metabolism problems.
Reduced Blood and Oxygen Flows a Critical Element in FM and Chronic Fatigue Syndrome?
More FM studies than not have found reduced blood flows to the muscle and several ME/CFS studies have as well. These researchers didn’t find reduced blood flows but they did find reduced oxygen uptake which suggested the cells were in an ischemic state – and that could be the key to the whole shebang.
‘Ischemia’ occurs when blood flows to a tissue are low enough to reduce the levels of oxygen and glucose needed for cellular energy production. The problem is actually not the ischemia per se but what comes after it; in what must be one of nature’s weirdest tricks, re-infusing tissues that have been deprived of oxygen with oxygen again can cause a serious problem called ‘reperfusion injury’.
It turns out that the absence of oxygen – which means the switching on of anerobic metabolism and the production of toxic-by products – creates an environment packed for inflammation. Oxygen is a mild free radical and throwing it back into an oxygen deprived environment can result in an explosion of stronger free radicals such a nitric oxide, superoxide and finally peroxynitrite (eg. Dr. Pall’s). Bizarrely, as that’s going on white blood cells may also bind to the endothelial cells lining the small blood capillaries, once again blocking the flow of the blood….Depriving your cells of oxygen is not something you want to do, even temporarily.
(Hibernating animals get around reperfusion injury by limiting, get this, their level of anerobic production; an interesting fact given that people with ME/CFS enter into anerobic production very early while exercising or, for some of them, simply walking. VO2 max defined exercise prescriptions are designed to stop ME/CFS patients from entering anerobic energy production as much as possible. Could people with ME/CFS/FM be creating ischemic zones simply by regularly entering into anerobic energy production?)
The big question here is how significant the reperfusion injury is in ME/CFS. It’s very clear that reperfusion injury in heart attack where the blood flow has been almost completely cut off, is very damaging but it hasn’t been clear how much of a problem lesser amounts of ischemia might cause.
The Sympathetic Nervous System and Fibromyalgia Again
Several researchers, however, believe that ischemia induced pain plays a key role in the reduced activity and ‘deconditioning’ sometimes found in FM. Elvin concluded that muscle ischemia induced pain played a key role in FM patients activity limitations. He felt that the reduced muscle blood flows following exercise he found in FM could be explained by deconditioning and sympathetic nervous system issues and/or ischemia induced pain.
Kulshreshtha suggested that sympathetic nervous system caused vasoconstriction of the blood vessels produced a low oxygen (hypoxic) state that results in pain. Light proposed that a similar vasoconstriction caused pain in FM by decreasing blood flows to multiple parts of the body and causing the buildup of metabolites and inflammatory agents. Indeed, the Light’s finding of a huge buildup of muscle injury sensing receptors in ME/CFS/FM could conceivably be due to the need to constantly monitor the muscles for signs of reperfusion induced injury.
Martinez-Lavin’s finding that intramuscular norepinephrine injections increased pain in most FM patients but not in healthy controls suggests FM is indeed a ‘sympathetically maintained syndrome’. One study found that increased vasodilation of the blood (increased parasympathetic nervous system functioning) is associated with decreased pain in FM.
Blood Vessel Issues
Reduced capillary density in FM could further limit blood flows. Increased thickening of the endothelial walls of the blood vessels is found in FM, and increased arterial stiffness is found in ME/CFS; both can effect blood flows and ischemia/reperfusion injury and sympathetic nervous system activation could cause both. Damaged blood vessel walls often result in more vasoconstriction. Interestingly, stress and chronic pain appear to be enough to cause blood vessel wall problems.
Once the process gets started it tends to feed on itself; hypoxia and pain trigger more sympathetic nervous system activity presumably causing more constricted blood vessels and further reductions in blood flow.
Note that this process is probably working ‘system-wide’ and Vermoulen proposed that the increased brain lactate levels in ME/CFS derive from the same processes that create them in the muscles. Indeed, Shungu found decreased blood flows and increased lactate levels (300% higher!) in his ME/CFS patients brains. Lactate levels are a function of anerobic metabolism; the high lactate levels suggest that a hypoxic (low oxygen) state is present. Shungu recently received a large grant to continue and expand his work.
Muscle Issues and Metabolic Problems
The muscles themselves may be affected in ME/CFS/FM. Increased levels of pyruvate and lactate in the interstitial spaces of back muscles (trapezius, again) pointed to an anerobic state and suggested metabolic problems were present as well in FM patients. The same pattern, interestingly enough, was found in the trapezius muscles of people with trapezius myalgia but not in people with whiplash (and sore trapezius muscles) suggesting different metabolic problems exist in different pain conditions. The authors suggested increased pyruvate/lactate may be synonymous with central sensitization syndromes such as FM, CFS, IBS, etc.).
Reduced small blood vessel development (capillarization), degraded type II muscle fibers and evidence of mitochondrial disturbances in Type I muscle fibers suggested significant muscle issues were present in FM. Gerdle proposed that alterations in intramuscular ATP, phosphoreatinine (PCr) and muscle fat content probably were probably caused by activity limitations due to pain and problems with muscle mitochondria.
Note the theme here – researchers proposing that inactivity caused by muscle pain in FM may result in deconditioning which exacerbates the initial problems. Reduced capillary production, increased heart rate low blood volume, poor blood vessel functioning, etc. can all be consequences of, or be worsened by, deconditioning.
Chronic Fatigue Syndrome (ME/CFS)
Significantly lowered blood volume is endemic in ME/CFS and blood volume enhancers such as salt, saline, NUUN and electrolyte enhancing drinks are commonly used. Interestingly a recent study suggested, fibromyalgia patients take note, low blood volume – a very common problem in ME/CFS – is present in FM as well.
ME/CFS studies have suggested low blood flows (low oxygen states) are important. Vermeulen et. al concluded that the reduced aerobic metabolism found in ME/CFS was probably due to low blood flows (read oxygen flow) to the mitochondria. Natelson concluded that the 20% reduction in aerobic capacity he found in people with ME/CFS was probably due to low blood flows caused by autonomic nervous system problems.
ME/CFS doctors agree. Dr. Bell’s book “Cellular Hypoxia and Neuro-immune Fatigue’ is focused entirely on the idea that hypoxic (low oxygen states) cause ME/CFS/FM. Dr DeMeirleir believes the large blood vessels are overly opened in ME/CFS while the small blood vessels are too tightly constricted to let enough blood to get to the tissues. Dr. Cheney believes low blood flows are hampering gut and other functioning in ME/CFS. Some evidence suggest anerobic bacteria are commonly found in ME/CFS patients guts.
The strangest thing about the sympathetic nervous system activation in FM and ME/CFS is that it appears to be activated during rest and sleep and blunted during exercise; just the opposite of the way it should be. Essentially the fight/flight system is turned on during rest and then folds when presented with a challenge. To put this into blood vessel terms; the SNS shuts down the blood vessels when you’re at rest and then fails to open them sufficiently when you exercise or become otherwise active. That’s a nice recipe for someone who can’t sleep well and then falls apart when asked to take on activities during the day.
The fact that several popular drugs used in ME/CFS/FM effect sympathetic nervous system functioning and the blood vessels suggests they may be alleviating low oxygen states.
Kulshreshtha proposed amytripyline’s efficacy in FM is due, at least in part, to its ability to open blood vessels (by whacking adrenoreceptors) thus increasing blood flows to the muscles. In a twist, Light et al found that low doses of a sympathetic nervous system enhancing drug called propanolol reduced pain, , assisted with standing, and moderately increased cortisol levels in FM patients. (They believe low dose propanolol turns off overactive sensory receptors in the muscles (reducing SNS activation) while normal dose propanolol turns on the SNS, thus constricting the blood vessels, causing more low oxygen states and pain.
- Amytriptyline in ME/CFS/FM
Other drugs that reduce SNS activity such as tricyclic antidepressants, duloxetine, pregbalin (lyrica), venlafaxine and pindolol have been helpful in FM and other pain disorders.
If low oxygen states are causing body-wide pain in ME/CFS and fibromyalgia then pushing patients with low aerobic capacity would be a recipe for more pain. The correct exercise prescription for Fibromyalgia is being debated but it’s clear that high doses of aerobic exercise result in more pain while lower levels of exercise can be helpful. Some evidence suggests that short bouts of resistance exercise training, presumably non-anerobic, can reduce pain and increase parasympathetic nervous functioning and heart rate variability.
It appears that exercises that enhance oxygen delivery and don’t stress the aerobic system such as Tai Chia, yoga and qiGong are recommended and aerobic exercise regimes need to be entered into so ever carefully in both fibromyalgia and ME/CFS. So long as exercise does not require ongoingly increased blood flows to the muscles it’s better tolerated at least in ME/CFS.
A recent FM study indicated problems with oxygen delivery to the tissues may be present. Significant evidence suggests low oxygen states caused by low blood volume, overly constricted blood vessels and perhaps mitochondrial dysfunction could be causing pain and other problems in FM and ME/CFS. Oddly, reperfusing these areas with oxygen can increase inflammation and oxidative stress. Similar findings in the brains of ME/CFS patients suggests the low oxygen state may be body-wide. Most researchers point to a sympathetic nervous system which appears to be over activated during rest but then poops out during activity and mitochondrial issues may come into play as well.
Teaser - Stayed tuned for more on this from the ME/CFS researchers in the not too distant future.
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