Fibromyalgia, Excessive Nitric Oxide/Peroxynitrite and Excessive
One of the barriers to our understanding of the mechanisms
involved in fibromyalgia (FM) is the lack of any animal models
of FM. So whereas proposed animal models for chronic fatigue
syndrome (CFS),multiple chemical sensitivity (MCS) and
posttraumatic stress disorder (PTSD) are available which suggest
a role for excessive nitric oxide in each of these conditions,
there is no similar animal model to study for FM. Consequently,
we a left with studies of human FM patients to suggest a
possible mechanism. The human data suggests a mechanism centered
on excessive levels of nitric oxide and its oxidant product,
peroxynitrite, as well as excessive activity of a
neurotransmitter system called the NMDA system. It is known that
when NMDA receptors are hyperactive they produce excessive
nitric oxide and peroxynitrite (1). This is consistent with the
mechanism I have proposed for CFS, MCS and PTSD, centered on
excessive nitric oxide and peroxynitrite (1) and may explain the
overlaps among these conditions and FM.
Excessive NMDA activity is implicated in FM by three different
types of studies. The most recent of these was recently reported
by Smith et al (2), reporting that a subgroup of FM patients had
a complete resolution of their symptoms by removing both
monosodium glutamate (MSG) and aspartame from their diets. MSG
and aspartame are both described as excitotoxins (2), because
both glutamate from MSG and aspartate from aspartame, activate
the NMDA receptors in the nervous system and may lead to neural
damage as a consequence of excessive activation. A major
mechanism of such NMDA-mediated damage is produced by the
excessive nitric oxide and peroxynitrite produced by such
activation. There are two other types of studies that provide
support for excessive NMDA activity in FM. Several research
groups have reported that NMDA antagonists, drugs that lower
NMDA receptor activity, improve the symptoms of FM patients
(3-6), strongly suggesting the such activity is excessive in FM
and that the excessive activity is responsible for producing FM
symptoms. A. A. Larson's group at the University of Minnesota
has reported studies of the cerebrospinal fluid of FM patients,
strongly suggesting that NMDA activity is elevated and that
nitric oxide synthesis is also elevated (7). So we have three
different types of studies that provide support for the
inference that NMDA activity is elevated in FM, one of which
also provides evidence for a consequent elevated level of nitric
How does this fit into the symptoms of FM? The most
characteristic symptom of FM is multiorgan pain and it is known
that both excessive NMDA activity and excessive nitric oxide
levels can generate pain. Nitric oxide is known to stimulate
some but not all of the nociceptors, the neurons that generate
the sensation of pain, providing an explanation for the pain
generation (reviewed in 1). Peroxynitrite is implicated in
generating pain responses, as well (8). Other symptoms are
similar to those in CFS and may be generated by mechanisms
consistent with a nitric oxide/peroxynitrite etiology (9).
Peroxynitrite is a potent oxidant and if its levels are
elevated, as proposed, than levels of oxidative damage should
also be elevated in FM. Two studies have reported such oxidative
damage in FM, consistent with this prediction (10,11). However
one of these studies also suggests that nitric oxide levels are
low (11), not high as reported in a previously cited study (7).
So there is some confusion in the literature on this important
point. In the study inferring low nitric oxide, the parameter
measured was nitrosothiol level in the blood and nitrosothiols
react with peroxynitrite (12), suggesting that the pattern
reported may be due to high peroxynitrite levels, rather than
low nitric oxide levels.
FM as well as CFS and MCS is commonly treated with vitamin B12
injections, using B12 in the form of hydroxocobalamin or
cyanocobalamin at doses of 1 to 10 mg (13). Hydroxocobalamin is
a potent nitric oxide scavenger and I have proposed that this is
the way such B12 injections may work to alleviate symptoms of
these conditions (13). There is an enzyme in human cells that
converts cyanocobalamin into hydroxocobalamin so cyanocobalamin
injections may work by this same mechanism. The symptoms of FM,
CFS and MCS are quite distinctive from those of B12 deficiency,
so it seems unlikely that the B12 injections act in these
conditions by alleviating such a deficiency.
Many cases of FM are reported to be preceded by physical trauma,
such as caused by a car accident, fall or operation (reviewed in
1). How might this initiate FM events? A study of physical
trauma in humans reports that they are associated with elevated
nitric oxide levels (14) and specifically traumatic head injury
is widely reported to produce elevated nitric oxide levels (A
Pubmed search on traumatic head injury and nitric oxide will
generate many references on this :
At least some of this nitric oxide generation is through the
action of excessive NMDA activity. An essential component of the
elevated nitric oxide/peroxynitrite theory of these several
conditions is that once peroxynitrite levels are elevated, they
may act to raise the levels of both nitric oxide and its other
precursor, superoxide, thus possibly leading to a chronic
elevation of peroxynitrite. This may explain how a chronic
condition like FM may be initiated by a short term traumatic
1. Pall M. L. Common etiology of posttraumatic stress disorder,
fibromyalgia, chronic fatigue syndrome and multiple chemical
sensitivity via elevated nitric oxide/peroxynitrite. Med Hypoth
2. Smith J. D., Terpening C. M., Schmidt S. O. F., Gums J. G.
Relief of fibromyalgia symptoms following discontinuation of
dietary excitotoxins. Ann Pharmacotherapy 2001;35:702-706.
3. Sörensen J., Bengtsson A., Bäckman E., Henriksson K. G.,
Bengtsson M. Pain analysis in patients with fibromyalgia.
Effects of intravenous morphine, lidocaine, and
ketamine. Scand J Rheumatol 1995;24:360-365.
4. Nicolodi M., Volpe A. R., Sicuteri F. Fibromyalgia and
headache. Failure of serotonergic analgesia and N-methyl-D-aspartate-mediated
neuronal plasticity: their common clues. Cephalalgia, 1998;18:
5. Graven Nielsen T., Aspegren Kendall S., Henriksson K. G. et
al. Ketamine reduces muscle pain, temporal summation, and
referred pain in fibromyalgia patients. Pain 2000:85:483-91.
6. Buskila D. Fibromyalgia, chronic fatigue syndrome and
myofascial pain syndrome. Curr Opin Rheumatol 2001;13:117-127.
7. . Larson A. A., Giovengo S. L., Russell I. J., Michalek J. E.
Changes in the concentrations of amino acids in the
cerebrospinal fluid that correlate with pain in patients with
fibromyalgia: implications for nitric oxide pathways. Pain
8. Liu T., Knight K. R., Tracey D. J. Hyperalgesia due to nerve
injury role of peroxynitirte. Neuroscience 2000;97:125-131.
9. Pall M. L. Elevated peroxynitrite as the cause of chronic
fatigue syndrome: Other inducers and mechanisms of symptom
generation. J Chronic Fatigue Syndr 2000:7(4):45-58.
10. Eisinger J., Zakarian H., Pouly F., Plantamura A., Ayavou T.
Protein peroxidation, magnesium deficiency and fibromyalgia.
Magnes Res 1994;7:285-288.
11. Eisinger J., Gandolfo C., Zakarian H., Ayavou T. Reactive
oxygen species, antioxidant status and fibromyalgia. J
Musculoskeletal Pain 1997;5(4);5-16.
12. Rauhala P., Chiueh C. C. Neuroprotection by S-nitrosoglutathione
of brain dopamine neurons from oxidative stress. FASEB J
13. Pall M. L. Cobalamin used in chronic fatigue syndrome
therapy is a nitric oxide scavenger. J Chronic Fatigue Syndr
14. Gebhard F., Nüssler A. K., Rösch M., Pfetsch H., Kinzl L.,
Brückner U. B. Early posttraumatic increase in production of
nitric oxide in humans. Shock 1998;10:237-242.