Journal of Rehabilitation Medicine 51-10 | Page 64

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A. Jablochkova et al.
DISCUSSION
This study produced 4 major findings:
• The level of circulating NGF was significantly de-
creased in FM compared with HC.
• The BDNF level in plasma was significantly in-
creased in FM.
• In a multivariate context, no significant correlations
existed between BDNF or NGF plasma levels and
cytokines and chemokines, clinical aspects (e.g.
age, BMI, pain severity, health, pain aspects, such
as intensity, tender point count, and FM duration),
fatigue, depressive and anxiety symptoms, and cata-
strophizing, and pain sensitivity (algometry).
• In the FM group, neither NGF nor BDNF changed
significantly after the interventions.
To the best of our knowledge, this is the first study
to report circulating levels of NGF in FM; it found sig-
nificantly decreased levels. Based on previous sparse
studies of human conditions associated with chronic
pain, one might expect higher levels of NGF in FM.
Patients with chronic migraine had higher levels of
plasma and saliva NGF than controls (35). In intersti-
tial cystitis/bladder pain, significantly increased serum
levels of NGF were found (36, 37). Increased NGF
levels in the synovial fluid in patients with rheumatoid
arthritis and in herniated discs of patients receiving
surgery have been reported (24, 38). In contrast to
these studies, the current study found the opposite;
i.e. significantly lower levels of plasma NGF in FM.
This study does not exclude that NGF levels may
have been increased in the subacute and early chronic
stage of FM. The fact that both IL-1β and NGF were
significantly lower in FM may be due to the fact that
NGF induces IL-1β release via TrkA (24), although
we did not find any multivariate correlations between
NGF and cytokines/chemokines.
A possible explanation for the lower levels of NGF
might be related to the emotional situation of the pa-
tients with FM. Reduced levels of serum NGF were
found in patients with major depression disorder (39)
as well as in depressed elderly patients (40). However,
against such an interpretation no significant asso-
ciations with depressive symptoms were found in the
present study. A highly conservative interpretation of
our results could be that the lower levels of NGF are
just random results and no peripheral alterations exist
in FM. However, the study found increased levels of
BDNF, and other studies of FM and of chronic wides-
pread pain (mainly FM) have found altered levels of
metabolites, cytokines, and anti-inflammatory lipids,
and proteomic studies have reported prominent alte-
rations both in muscle tissue and circulating proteins
(28, 30, 41–43).
www.medicaljournals.se/jrm
Our results of significantly lower levels of NGF may
be consistent with other findings in the literature regar-
ding patients with FM. NGF is a key molecule involved
in the sensitization of primary afferent nociceptors
associated with tissue inflammation and is increased
in inflamed tissue (8). NGF may also be involved in
sprouting of nociceptive fibres in peripheral tissues and
promote pain (44). Several studies report a reduction
in distal intraepidermal nerve fibre density (IENNFD)
in the skin of prominent subgroups of FM, as well as
a more prominent reduction in IENNFD with ageing
in FM (3). Moreover, reduced nerve regeneration and
growth factors were found in skin nerves of patients
with FM (3). In addition, C-fibres with smaller dia-
meters have been found in FM (3). These reports of
small nerve fibre impairment may speculatively be due
to lower levels of NGF in FM affecting development
and regeneration of NGF-dependent neurones (45).
According to preclinical data, neutralization of endo-
genous NGF prevents inflammatory hyperalgesia (8),
and the potential of anti-NGF antibodies have recently
been the focus of intensive research, including several
clinical trials in different chronic pain conditions. A
review of low back pain with radiculopathy found po-
sitive evidence for small effects of anti-NGF treatment
on pain relief and functional improvements (46). Our
results with low NGF levels do not indicate a role of
anti-NGF treatment in FM. The present results, with
significantly lower levels of circulating NGF in FM,
need to be confirmed before a definite conclusion can
be drawn about the role of anti-NGF treatment in FM.
There are few studies of circulating BDNF in pa-
tients with FM and they are not in agreement. This, and
a previous study, found higher plasma levels of BDNF
in FM, but another study found no difference (17,
18). In addition, the results concerning serum levels
of BDNF in FM are conflicting (19, 47). Conflicting
results also exist for other pain conditions. Plasma le-
vels of BDNF were higher in rheumatoid arthritis (RA)
and in patients with osteoarthritis than in controls (48,
49). In contrast, a large study found no differences in
serum levels of BDNF between patients with chronic
pain (n = 764) and controls (n = 882) (50).
The significantly increased levels of BDNF cannot
be explained by psychological factors according to the
existing literature. As recently summarized, BDNF
in serum was significantly decreased in depressed
patients, whereas the results from plasma studies were
inconclusive (51). In fact, several studies, including
this study, have not been able to establish significant
correlations between blood levels of BDNF and depres-
sive symptomatology (17, 20, 47). Serum BDNF levels
were significantly lower in subjects with insomnia
compared with non-sleep disturbed control, and the