[Etiology and pathophysiology of fibromyalgia syndrome].

Article (PDF Available)inDer Schmerz 26(3):259-67 · June 2012with288 Reads
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The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. Current data do not identify distinct etiologic or pathophysiological factors mediating development of FMS. The development of FMS is associated with inflammatory rheumatic diseases (EL2b), with gene polymorphisms of the 5-hydroxytryptamine (HT)(2) receptor (EL3a), lifestyle factors (smoking, obesity, lack of physical activity; EL2b), physical and sexual abuse in childhood and adulthood (EL3a). FMS is most likely the result of various pathogenetic factors and pathophysiological mechanisms. The English full-text version of this article is available at SpringerLink (under "Supplemental").
English Version of "Ätiologie und
Pathophysiologie des Fibromyalgiesyndroms".
DOI 10.1007/s00482-012-1174-0
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag -
all rights reserved 2012
C. Sommer
 · W. Häuser
 · M. Burgmer
 · R. Engelhardt
 · K. Gerhold
 · F. Petzke
T. Schmidt-Wilcke
 · M. Späth
 · T. Tölle
 · N. Üçeyler
 · H. Wang
 · A. Winkelmann
K. Thieme
Neurologische Klinik, Universitätsklinikum Würzburg
Innere Medizin 1, Klinikum Saarbrücken gGmbH, Saarbrücken
Klinik für Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Münster
Zentralinstitut für die kassenärztliche Versorgung in Deutschland, Berlin
Klinik für Pädiatrie mit Schwerpunkt Pneumologie/Immunologie und
Berlin School of Public Health, Charité – Universitätsmedizin Berlin
Schmerz-Tagesklinik und -Ambulanz, Universität Göttingen
Department of Anesthesiology, Chronic Pain and Fatigue Research
Center, University of Michigan, Ann Arbor (Michigan)
Rheumatologische Praxis, München-Gräfelfing
Klinik für Neurologie, Technische Universität München, Munich
Department für Orthopädie und Unfallchirurgie, Stiftung Orthopädische Universitätsklinik Heidelberg
Klinik und Poliklinik für Physikalische Medizin und Rehabilitation,
Klinikum der Universität München, Munich
Institut für Medizinische Psychologie, Philipps-Universität Marburg
Etiology and 
pathophysiology of 
fibromyalgia syndrome
Background and goals
There is extensive scientific literature on
the etiology and pathophysiology of fibro-
myalgia syndrome (FMS) which makes it
difficult for the individual practitioner to
stay up-to-date. Recent review articles fo-
cus either on biological or psychological
aspects. The classification of FMS (phys-
ical illness vs. mental disorder), contents
of patient education, and the preferred
treatment methods are closely related to
the identified etiologic and pathophysi-
ologic factors. Therefore, we decided to
perform a literature review and a formal
consensus process on the pathogenesis
and pathophysiology of FMS and chronic
widespread pain (CWP). We aimed to an-
alyze the content and quality of published
studies on these topics in order to iden-
tify possible risk factors for the develop-
ment of FMS and CWP and also to iden-
tify factors that are unrelated to the two
The methodology of the literature search
and analysis, and preparation of recom-
mendations are presented in the article
“Methodological fundamentals used in
developing the guideline.
Preliminary note
The following findings apply to adults. For
the etiology and pathophysiology of FMS
and CWP in children and adolescents
please refer to the chapter “Definition,
diagnosis and therapy of chronic wide-
spread pain and so-called fibromyalgia
syndrome in children and adolescents.
Risk indicators and factors
Evidence-based observation
Current evidence does not allow definite 
conclusions to be drawn about the eti-
ology of CWP/FMS. It is unclear wheth-
er the risk indicators of CWP and FMS de-
scribed in the following observations are 
risk factors. Strong consensus
Comment. Risk indicators are character-
istics whose presence indicates a great-
er risk of illness without playing a caus-
ative role. Risk factors (etiologic factors)
are characteristics that are causally associ-
ated with an increased risk of disease. Risk
indicators and risk factors for disease are
identified by retrospective and prospec-
tive cohort studies. The design of these
studies, however, do not allow proof of a
causal relationship. The following crite-
ria increase the likelihood of a causal rela-
tionship: dose–effect relationship and ex-
perimental evidence, i.e., randomized-
1DerSchmerz3 ·2012
controlled trials that demonstrate elimi-
nation of risk when the risk factor is elim-
The literature search yielded 3,107 hits.
There were 6 prospective cohort studies
with a follow-up duration ranging from
15 months to 45 years on biopsychoso-
cial risk indicators for the development
of CWP. There were 2 prospective cohort
studies with a follow-up duration ranging
from 11–24 years on biopsychosocial risk
indicators for the development of FMS
and 2 systematic reviews of case–control
studies. There were no studies on dose–
effect relationships. Experimental stud-
ies on risk factors for CWP and FMS were
not found.
Risk indicators of CWP
Evidence-based observation
The following biologic, mechanical, and 
psychosocial factors are associated with 
the development of CWP (risk indica-
F biological factors: gene polymor-
phisms (β
-adrenergic receptors, 
ACTH precursor receptor, corticoste-
roid binding globulin), dysfunction of 
the hypothalamic–pituitary–adrenal 
(HPA) axis (EL 2b);
F mechanical factors: uncomfortable 
postures at work (crouching, repet-
itive movements of wrist), monoto-
nous work (EL 2b);
F psychological factors: increased phys-
ical complaints and illness behavior; 
low physical health-related quality of 
life; sleep disorders (EL 2b); perma-
nent threat to life (EL 2c);
F childhood: hospitalization after traffic 
accident; institutionalization; mater-
nal death; financial need (EL 2b).
Strong consensus
Comment. The results of prospec-
tive cohort studies are summarized in
. Tab. 1. A study from Israel [1] com-
pared 1,024 people from a town (Sder-
ot) that was repeatedly attacked by rocket
fire with 1,006 people who lived in anoth-
er town (Okafim) with a similar socioeco-
nomic and demographic profile, but who
were not exposed to rocket fire. Trau-
ma-related symptoms and physical com-
plaints were more frequent and the point
prevalence of CWP was higher in Sder-
ot (11.1%) than in Ofakim [8.3%; odds ra-
tio (OR) 1.37].
Tab. 1 Predictors of chronic widespread pain (CWP) in prospective population-based cohort studies
Study design Risk indicator (statistical predictor) Risk (95% CI) Reference
Prospective population-based cohort study of
1,658 adults between 25–65 years of age; follow-up
after 36 months
Repetitive movements of wrists OR 1.8 (1.2–2.7) [25, 26, 27]
Increased illness behavior OR 9.0 (3.7–22.2)
Regional pain at baseline measurement OR 2.1 (1.3–3.3)
Increased physical symptoms OR 3.3 (1.5–7.4)
Prospective cohort study of 1,081 newly employed
individuals at 12 different work places; follow-up after
24 months
Crouching activity >15 min OR 2.0 (1.1–3.6) [16]
Monotonous work OR 1.9 (1.1–3.2)
Prospective population-based cohort study;
3,171 adults without CWP between 25–65 years of
age; follow-up after 15 months
Increased physical symptoms OR 1.8(1.1–3.1) [14]
Increased illness behavior OR 3.3(2.3–4.8)
Sleep disorder OR 2.7(1.6–3.2)
Prospective cohort study of 768 individuals without
CWP but with a profile indicating increased risk for
CWP, out of a population-based sample of 11,000 in-
dividuals; follow-up after 15 months
HPA axis dysfunction OR 8.5 (1.5–47.9) [28]
EPIFUND: 2,509 patients from three British general
practitioners between 25–65 years of age; follow-up
after 15 months
Gene polymorphisms affecting the HPA axis OR 1.61 (1.0–2.6) [19]
ACTH-precursor-receptor OR 1.2 (1.0–1.3)
SERPINA6, rs941601, genotype CT OR 2.2 (1.1–4.4)
Genotype TT
Corticosteroid-binding globulin MC2R rs11661134, genotype
AG and AA
OR 2.2 (1.2–4.4)
Decreased health-related quality of life RR 4.0 (2.6–6.2) [33]
1958 British Cohort Study: 18,558 individuals; follow-
up after 45 years
Teacher reports of persistent behavioral abnormalities at ages
7, 11 and 16 years of age
RR 2.1 (1.4–3.2) [34]
-adrenergic receptor (ADRB2) combinations, e.g. H2-H2 RR 1.8 (1.1–2.9) [18]
Hospitalization after traffic accident RR 1.5 (1.1–2.1) [30, 31]
Institutionalization RR 1.7 (1.3–2.4)
Maternal death RR 2.0 (1.1–3.7)
Financial need RR 1.6 (1.3–1.9)
Multiple physical symptoms at the age of 7 years RR 1.5 (1.0–2.3)
ACTH adrenocorticotropic hormone; CI confidence interval; CWP chronic widespread pain; HPA hypothalamic–pituitary–adrenal; OR odds ratio; RR relative risk.
Der Schmerz 3· 2012
Risk indicators for FMS
Evidence-based observation
The following biological and psychoso-
cial factors are associated with the devel-
opment of FMS:
F biological factors: inflammatory–
rheumatic diseases (EL 2b),
F gene polymorphisms of the 5HT2-re-
ceptor (EL 3a),
F life style: smoking, overweight, lack 
of physical activity (EL 2b)
F psychological factors: physical abuse 
in childhood and adulthood, sex-
ual abuse in childhood and adult-
hood (EL 3a), stress at the work place 
(EL 3b).
Strong consensus
Comment. See . Tab. 2. Genetic factors
are likely present since FMS tends to clus-
ter in families [38]. Candidate genes in the
serotonergic, dopaminergic, and catechol-
aminergic systems may play a role. How-
ever, this is also the case in other chronic
pain syndromes and therefore these find-
ings are not specific for FMS [3, 4].
In a retrospective cohort study of 62,000
members of a U.S. health insurance an as-
sociation with FMS was found for rheu-
matoid arthritis [RR (relative risk) for
women 4.5 (95% CI 3.6–5.5), RR for men
6.1 (95% CI 4.2–8.8)] and with systemic
lupus erythematosus [RR for women, 5.8
(95% CI 4.2–8.0); RR for men not signif-
icant; [46]).
Out of 9,739 patients with rheumatoid
arthritis without FMS (U.S. National Da-
ta Bank for Rheumatic Diseases) on aver-
age 19.8% met the criteria for FMS at least
once during 4.4 years of observation; 7.4%
met the criteria at the end of the obser-
vation period. Poverty [HR (hazard ratio)
1.64 (95% CI 1.47–1.82)], overweight [HR
1.60 (95% CI 1.43–1.79)], depressive symp-
toms [HR 2.28 (95% CI 1.97–2.64)], nu-
merous physical comorbidities [HR 2.53
(95% CI 2.36–2.71)], and low physical ac-
tivity [HR 2.53 (95% CI 2.36–2.71)] pre-
dicted FMS [47].
In a 2-year prospective observation-
al study of 4,791 hospital employees
(4,250 women, 541 men), increased bully-
ing in the workplace, low freedom of ac-
tion, and high workload increased the risk
of physician-diagnosed FMS [22]. Due to
problems with the study design (no detec-
tion of pain using validated instruments at
the beginning and end of the study), the
level of evidence was downgraded for this
Abstract · Zusammenfassung
Schmerz 2012 · DOI 10.1007/s00482-012-1174-0
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
C. Sommer ·W. Häuser · M. Burgmer · R. Engelhardt · K. Gerhold · F. Petzke · 
T. Schmidt-Wilcke · M. Späth · T. Tölle · N. Üçeyler · H.Wang · A. Winkelmann · K. Thieme
Etiology and pathophysiology of fibromyalgia syndrome
Background. The scheduled update to the
German S3 guidelines on fibromyalgia syn-
drome (FMS) by the Association of the Scien-
tific Medical Societies (“Arbeitsgemeinschaft
der Wissenschaftlichen Medizinischen Fach-
gesellschaften, AWMF; registration number
041/004) was planned starting in March 2011.
Materials and methods. The development
of the guidelines was coordinated by the
German Interdisciplinary Association for Pain
Therapy (“Deutsche Interdisziplinäre Vereini-
gung für Schmerztherapie, DIVS), 9 scientif-
ic medical societies and 2 patient self-help or-
ganizations. Eight working groups with a to-
tal of 50 members were evenly balanced in
terms of gender, medical field, potential con-
flicts of interest and hierarchical position in
the medical and scientific fields.Literature
searches were performed using the Medline,
PsycInfo, Scopus and Cochrane Library da-
tabases (until December 2010). The grading
of the strength of the evidence followed the
scheme of the Oxford Centre for Evidence-
Based Medicine.
Results. Current data do not identify distinct
etiologic or pathophysiological factors medi-
ating development of FMS. The development
of FMS is associated with inflammatory rheu-
matic diseases (EL2b), with gene polymor-
phisms of the 5-hydroxytryptamine (HT)
ceptor (EL3a), lifestyle factors (smoking, obe-
sity, lack of physical activity; EL2b), physi-
cal and sexual abuse in childhood and adult-
hood (EL3a).
Conclusion. FMS is most likely the result of
various pathogenetic factors and pathophys-
iological mechanisms.The English full-text
version of this article is available at Springer-
Link (under “Supplemental”).
Fibromyalgia syndrome · Guideline ·
Systematic review · Etiology ·
Ätiologie und Pathophysiologie des Fibromyalgiesyndroms
Hintergrund. Die planmäßige Aktual-
isierung der S3-Leitlinie zum Fibromyal-
giesyndrom (FMS; AWMF-Registernummer
041/004) wurde ab März 2011 vorgenom-
Material und Methoden. Die Leitlinie
wurde unter Koordination der Deutschen In-
terdisziplinären Vereinigung für Schmerzther-
apie (DIVS) von 9 wissenschaftlichen Fachge-
sellschaften und 2 Patientenselbsthilfeorgan-
isationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausge-
wogen in Bezug auf Geschlecht, medizinisch-
en Versorgungsbereich, potenzielle Interes-
senkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen Sys-
tem besetzt.Die Literaturrecherche erfolg-
te über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke er-
folgte nach dem Schema des Oxford Center
for Evidence Based Medicine.
Ergebnisse. Die aktuelle Studienlage erlaubt
keine eindeutigen Aussagen zur Ätiologie
und Pathophysiologie des FMS. Die Entwick-
lung eines FMS ist mit entzündlich-rheuma-
tischen Erkrankungen (EL2b), Genpolymor-
phismen des 5-Hydroxytryptamin(HT)
eptors (EL3a), Lebensstilfaktoren (Rauchen,
Übergewicht, mangelnde körperliche Aktiv-
ität; EL2b), körperlicher Misshandlung und
sexuellem Missbrauch in Kindheit und Erwa-
chsenenalter (EL3a) assoziiert.
Schlussfolgerung. Das FMS ist wahrschein-
lich die Endstrecke verschiedener ätiopatho-
genetischer Faktoren und pathophysiolo-
gischer Mechanismen.
Fibromyalgiesyndrom · Leitlinie ·
Systematische Übersicht · Ätiologie ·
DerSchmerz3 ·2012
Vitamin D deficiency, infectious 
diseases, and accidents
Evidence-based observation
Data on the association between FMS 
and vitamin D deficiency, infectious dis-
eases, and accidents are inconsistent. 
EL 3b. Strong consensus
Vitamin D deficiency: In population-based
studies [29] and in case–control stud-
ies [17], an association of CWP with de-
creased vitamin D levels has been report-
ed. However, in case–control studies no
difference in vitamin D levels were found
between patients with FMS and healthy
controls [10, 42].
Infections: Prospective studies are not
available. In case–control studies, the as-
sociation of chronic hepatitis C and FMS
is contradictory. The results of two case–
control studies showing an increased
prevalence of FMS in patients with chron-
ic hepatitis B and HTLV-1 infection, re-
spectively, have not been replicated [38,
39]. Case–control studies investigating
the association of Lyme disease with FMS
are not available. In a large single-cen-
ter observational study of 287 patients,
22 patients (8%) developed FMS. Fifteen
patients diagnosed with FMS participat-
ed in the 4.5-year observational study.
Symptoms of Lyme disease improved in
14 of 15 patients following antibiotic ther-
apy but FMS symptoms persisted in all pa-
tients [11]. Following Lyme disease, 5% of
patients report persistent musculoskeletal
pain, fatigue, and difficulties in concen-
trating [6].
Accidents: Data are contradictory. A
total of 154 patients who were hospital-
ized after a whiplash injury were exam-
ined after 1.5 and 3 years for the presence
of FMS; 53 patients with fractures served
as a control group. After 3 years of follow-
up, 3 of 126 patients with whiplash inju-
ry and 1 of 53 patients with fracture were
diagnosed with FMS [43]. A prospective
cohort study of 957 members of a health
insurance who had recently suffered an
automobile accident examined the oc-
currence of widespread pain (WP) after
12 months of follow-up; 7.8% of patients
had WP. Physical symptoms after the ac-
cident (RR 2.5, 95% CI 1.2–5.1), high utili-
zation of health care services prior to the
accident (RR 3.6, 95% CI 1.6–7.9), soma-
tization prior to the accident (RR 1.7, 95%
CI 0.99–2.8), and older age (RR 3.3, 95%
CI 1.5–7.1) predicted WP [48].
In a prospective cohort study of
7,462 members of a health insurance com-
pany with whiplash injuries of the cervical
spine, 266 individuals had localized pain
after the accident and were followed-up at
4, 6, and 12 months. The cumulative inci-
dence of CWP was 21%. CWP was report-
ed most commonly in the early time peri-
od after the accident. The risk of develop-
ing CWP was greater in individuals with
depressive symptoms at baseline measure-
ment (OR 3.2, 95% CI 1.6–6.3) [20]. CWP
at 12 months was rare (49).
The examination of 53 of 153 survi-
vors 3.5 years after a major train accident
demonstrated that 15% fulfilled FMS cri-
teria [5].
Altered central pain processing, 
dysfunction of the HPA axis, 
peripheral pain generators
Evidence-based observation
It is possible that the following patho-
physiological mechanisms play a patho-
genic role in FMS:
F altered central pain processing 
(EL 3b),
F dysfunction of the HPA axis (EL 2b), 
F peripheral pain generators (EL 3b).
Strong consensus
Comment. The literature search yielded
763 hits. These included a systematic re-
view of biomarkers [9], no other system-
atic reviews of other pathophysiological
mechanisms, and numerous narrative re-
view articles (e.g., [2, 3, 13, 35, 37, 38, 40]).
Systematic reviews completed by mem-
bers of the working group regarding cyto-
kines [44] and central nervous system im-
Tab. 2 Predictors of fibromyalgia syndrome (FMS) in prospective population-based cohort
studies and systematic reviews, respectively
Study design Risk indicator (predictor) Risk (95% CI) Refer-
Adventist Health Study 1
and 2: cohort study of
3,136 women; follow-up
after 25 years
Number of allergies OR 4.0 (2.3–6.9) [8]
Tobacco smoking OR 2.4 (1.3–4.2)
Nord-Trøndelag Health
Study. Population-based
cohort study of 15,990 in-
dividuals; follow-up after
11 years
Overweight (BMI 25–29.9) RR 1.7 (1.4–2.1) [32]
Obesity (BMI >30) RR 1.6 (1.2–2.3)
Overweight and lack of physical
RR 2.1 (1.4–3.2)
Population-based cohort
study of 214 women; follow-
up after 5 years
Increased physical symptoms RR 4,6 (1,7–12,2) [12]
Depression RR 2,3 (1,3–4,0)
Regional pain for >6 years RR 2,8 (1,2–6,7)
Cohort study of 4,791 hos-
pital employees; follow-up
after 2 years (outcome: phy-
sician-diagnosed FMS)
Mobbing at the workplace OR 4.1 (2.0–9.6) [22]
High workload OR 2.1 (1.2–3.9)
Decreased discretion in making
OR 2.1 (1.1–4.0)
Meta-analysis of 21 case–
control studies regarding
genetic variants
C-allele of the 5HT
receptor 102T OR 1.3 (1.1–1.7) [24]
CC-allele of the 5HT
OR (1.5, 1.0–2.3)
CT-allele of the 5HT
OR 1.8 (1.2–3.9)
Meta-analysis of 18 studies
with 13,095 individuals
Physical abuse in childhood OR 2.5 (1.8–3.4) [15]
Physical abuse in adulthood OR 3.1 (1.0–9.4)
Sexual abuse in childhood OR 1.9 (1.4–2.8)
Sexual abuse in adulthood OR 2.2 (1.1–4.7)
BMI body mass index; CI confidence interval; FMS fibromyalgia syndrome; OR odds ratio; RR relative risk.
Der Schmerz 3· 2012
aging (Burgmer and Petzke, 2011, person-
al communication) revealed the following
substantial problems that limit the signifi-
cance of the available studies:
1. Lack of longitudinal studies: due to the
cross-sectional design of most studies,
statements regarding causation are not
possible. It is unclear whether the de-
scribed pathophysiological changes are
epiphenomena of other processes or
whether they are confounded by other
variables (e.g., changes in cytokine pat-
terns because of depression).
2. Confounding of the results due to co-
morbidities: due to the frequent co-
morbidity of FMS with other psychiat-
ric disorders and functional disorders,
it is difficult to define a “pure FMS”
group [36]. The potential influence of
these comorbidities has not been suffi-
ciently controlled in these studies. One
study that controlled for comorbid de-
pressive disorder found no consistent
differences in the gray matter between
FMS patients and healthy controls [21].
3. Lack of specificity of findings: in most
studies on pathophysiology, the healthy
control subjects were healthy individu-
als of the same age and sex as the affect-
ed individuals, but not patients with
other chronic pain syndromes and
mental disorders. It is unclear wheth-
er the described pathophysiological ab-
normalities are specific for FMS.
4. Methodological problems: the hetero-
geneity of analysis makes a comparison
of study results difficult [35]. The sam-
ple sizes of most studies are small (<25
individuals per group). In addition, the
quality of these studies is mostly low.
5. Ignoring the probable heterogeneity of
the FMS population.
Because of the problems mentioned, we
chose not to summarize the numerous
studies presented—neither in a narrative
fashion nor in the form of a meta-analysis.
Instead a few pathophysiological mecha-
nisms for which the data are largely con-
sistent are discussed.
HPA axis: Dysfunction of the HPA axis
as a pathophysiological factor is discussed
in many review articles (e.g., [3]). Data on
cortisol secretion and individual tests of
the HPA axis are inconsistent and the role
of comorbid depression is unclear [9].
The best evidence for the role of a
disturbed HPA axis derives from a pro-
spective population-based study. Out of
11,000 individuals, 768 were chosen be-
cause their psychosocial profile indicated
an increased risk for the development of
CWP. Then, 463 subjects were randomly
selected and 267 (58%) eventually agreed
to participate in the study, of whom
241 completed the study. After 15 months,
12% of these individuals had newly de-
veloped CWP. A lack of suppression in
the dexamethasone suppression test (OR
3.53, 95% CI 1.17–10.65), low morning se-
rum cortisol levels, and high evening sali-
va cortisol levels were associated with the
development of CWP [28].
Autonomic nervous system: A number
of differences in the function of the au-
tonomic nervous system among patients
with FMS and healthy subjects have been
described (e.g., decreased heart rate vari-
ance, a tendency for syncope, altered cuta-
neous capillary responsiveness). Howev-
er, a causal relationship could not be prov-
en [38].
Immune system: Many studies ad-
dressed the issue of immune dysfunction
in FMS. Some groups detected autoanti-
bodies whose significance is still unclear
[9]. Among the cytokines, interleukin-6
is increased in the plasma or serum of pa-
tients with FMS [44]. In one longitudinal
study, elevated cytokine levels normalized
after multimodal therapy [45].
Neurotransmitter: The neurotrans-
mitter substance P is increased in the ce-
rebrospinal fluid (CSF) of patients with
FMS, but also in other chronic pain syn-
dromes, so that substance P is more of a
marker for chronic pain than for FMS spe-
cifically. Serotonin levels in CSF and se-
rum are decreased. The CSF levels of the
neurotrophic factors nerve growth factor
(NGF) and brain-derived neurotrophic
factor (BDNF) are increased, but the sig-
nificance of these findings is unclear. Data
for other neuropeptides and neurotrans-
mitters are inconsistent [39].
Peripheral nervous system and muscle:
It was hypothesized that peripheral pain
generators contribute significantly to the
initiation or maintenance of FMS [41]. In
a subgroup of patients with FMS, poly-
neuropathy was present [7]. Modulation
of muscle afferent fibers may play a role
Altered central pain processing: The
studies on central pain processing in FMS
cannot be reliably interpreted due to the
use of different methods (e.g., PET, fMRI,
EEG), different study designs (e.g., mea-
surement while resting or during stimula-
tion), the lack of longitudinal studies, and
the low quality of the methods used and of
data analysis. Augmentation of pain pro-
cessing and a tendency for altered struc-
ture and functions of brain areas that are
important for the cognitive–emotional
processing of pain and descending pain
inhibition have been reported. Howev-
er, due to the general lack of patients with
other chronic pain syndromes in the con-
trol groups, these findings cannot be in-
terpreted as being FMS specific [35].
Disorders of the thyroid hormone 
system, disorders of the female 
sex hormones, disorders of the 
system, structural muscle changes, 
cosmetic breast implants
Evidence-based observation
The following statements from the first 
version of the guidelines still apply: there 
is no evidence of a link between FMS and
F disorders of the thyroid hormone sys-
F disorders of the female sex hormones,
F disorders of the renin–angiotensin–
aldosterone system,
F structural muscle changes, and
F cosmetic breast implants.
EL 2c, strong consensus
Comment. See [39]
Mechanisms of learning
Evidence-based observation
The following statements from the 
first version of the guidelines still ap-
ply: learning mechanisms such as oper-
ant conditioning, and sensitization play a 
role in the chronicity of FMS.
EL 2b, strong consensus
Comment. See [39]
DerSchmerz3 ·2012
Biopsychosocial model
Evidence-based observation
A biopsychosocial model with respect to 
predisposition, initiation, and chronic-
ity of FMS is postulated. Physical and/
or biological and/or psychosocial stress-
ors in the context of an appropriate ge-
netic predisposition and learning history 
produce autonomic, endocrine, and cen-
tral nervous system reactions that result 
in the symptoms of FMS, such as pain, 
fatigue, and sleep disorders, autonom-
ic and psychological symptoms.There is 
heterogeneity in the genetic predispo-
sition, learning history, and in the auto-
nomic, endocrine, and central nervous 
system reactions. FMS is a final path-
way of various pathogenetic factors and 
pathophysiological mechanisms. Strong 
Comment. See [39]
It is difficult to summarize the evidence
on the etiology and pathophysiology of
CWP and FMS due to several factors.
There is an extensive literature on indi-
vidual factors that are related to CWP or
FMS and which may play a role in the eti-
ology or pathophysiology of these con-
ditions. Since the publication of the first
version of these guidelines, multiple oth-
er factors have been examined, includ-
ing gene polymorphisms, smoking, over-
weight and nutrition, vitamins, neuroen-
docrine factors, immunologic factors, mi-
tochondrial function, different infections,
central pain processing, and individual bi-
ographical aspects.
Unfortunately, for the majority of these
studies, due to limitations in methodolo-
gy and design, it remains unclear whether
the findings indicate random associations,
factors inherent to the conditions studied,
consequences of disease, or if they indeed
represent relevant factors in etiology or
As was mentioned in the first version
of these guidelines, there are some fac-
tors for which there is definitely no rela-
tionship with FMS. These conclusions are
still accurate and apply to the thyroid hor-
mone system, the renin–angiotensin–al-
dosterone system, female sex hormones,
structural muscle changes, Lyme disease,
and cosmetic breast implants.
The best evidence for positive correla-
tions of causative factors with the develop-
ment of CWP or FMS has been obtained
from prospective cohort studies. Sever-
al biologic factors could be identified, in-
cluding the presence of inflammatory
rheumatic diseases, genetic factors, life-
style factors such as smoking, overweight,
and decreased physical activity, and psy-
chological factors, such as physical abuse
or sexual abuse. Additional prospective,
population-based studies with an anal-
ysis of dose–effect relationships, and in-
teractions of presumed risk factors are re-
Conclusion for clinical practice
Several factors reduce the meaningful-
ness of many studies on pathophysiol-
ogy, such as their sectional design, the 
lack of consideration of confounding co-
morbidities, the small number of study 
subjects, and the use of very heteroge-
neous methods. The pathophysiologi-
cal factors that are probably associated 
with FMS have been listed above. How-
ever, because of the aforementioned lim-
itations, it is difficult to assess a causal re-
lationship. There is an urgent need for 
further research. Future research should 
employ standardized methods, con-
trol for current medication use and psy-
chological comorbidities, and include 
adequate control groups consisting of 
healthy individuals and individuals with 
other chronic pain syndromes. In addi-
tion, studies with larger sample sizes are 
required to simultaneously examine dif-
ferent potential neuroimmunological 
and neurobiological factors, and their re-
ciprocal relationships.
Corresponding address
C. Sommer
Neurologische Klinik,
Universitätsklinikum rzburg
Josef-Schneider-Str. 11, 97080 Würzburg
Conflict of interest. See Tab. 5in “Methodological
fundamentals used in developing the guideline by W.
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DerSchmerz3 ·2012
    • "Muscle pain and fatigue are common symptoms, even at rest. Patients often develop fibromyalgia, a related neuroimmune disorder distinguished by chronic widespread pain and allodynia (a heightened and painful response to pressure) [11]. Abnormalities are evident within the immune [12] and central nervous [13] systems that likely stem from defective oxidative and nitrosative pathways and a lower antioxidant status [14,15]. "
    [Show abstract] [Hide abstract] ABSTRACT: Fatigue is a common symptom of numerous acute and chronic diseases, including myalgic encephalomyelitis/chronic fatigue syndrome, multiple sclerosis, heart failure, cancer, and many others. In these multi-system diseases the physiological determinants of enhanced fatigue encompass a combination of metabolic, neurological, and myofibrillar adaptations. Previous research studies have focused on adaptations specific to skeletal muscle and their role in fatigue. However, most have neglected the contribution of physical inactivity in assessing disease syndromes, which, through deconditioning, likely contributes to symptomatic fatigue. In this commentary, we briefly review disease-related muscle phenotypes in the context of whether they relate to the primary disease or whether they develop secondary to reduced physical activity. Knowledge of the etiology of the skeletal muscle adaptations in these conditions and their contribution to fatigue symptoms is important for understanding the utility of exercise rehabilitation as an intervention to alleviate the physiological precipitants of fatigue.
    Full-text · Article · Sep 2014
    • "The exact cause is unknown but has been attributed to neurochemical imbalances, including activation of inflammatory pathways in the brain leading to abnormal processing of pain. Psychological, genetic, neurobiological and environmental factors are thought to be involved in its etiology789. The incidence is estimated to be 2-4% of the population with a 9:1 female to male preponderance. "
    [Show abstract] [Hide abstract] ABSTRACT: Methotrexate is a Disease Modifying Anti Rheumatic Drug (DMARD) we used in the treatment of patients with severe fibromyalgia symptoms. We present two case discussions of low dose methotrexate treatment resulting in dramatic relief of widespread body pain in patients diagnosed with fibromyalgia. These patients had been refractory to prior treatment with opioids, NSAIDs, anti-seizure medications, anti-depressant medications, pregabalin and corticosteroids. Our case reports endorse Sota Omoigui’s theory of pain which states that the origin of all pain is inflammation and the inflammatory response. Low dose methotrexate has unique broad spectrum anti-inflammatory activity that is not found in any other medication. The drug may significantly decrease or resolve generalized body pain associated with fibromyalgia. The use of low dose Methotrexate co-administered with folic acid should be considered as an adjunct to pain medication to help decrease and sometimes eliminate pain and improve other symptoms such as fatigue and disability in fibromyalgia. Limiting factors include the ability of patients to tolerate the medication.
    Full-text · Article · Jan 2014
    • "FMS opinion leaders reported two guidelines. Three of these met our inclusion criteria: the 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome [10], the guidelines of the Association of the Scientific Medical Societies in Germany (AWMF) on the definition, pathophysiology, diagnosis, and treatment of fibromyalgia syndrome [11] [12] [13] [14] [15] [16] [17] [18] [19], and the Israeli guidelines for the diagnosis and treatment of fibromyalgia syndrome [20]. The reasons for excluding other hits were as follows: duplications (í µí±› = 19), not commissioned by a scientific society (í µí±› = 2) [21] [22]. "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives. Fibromyalgia syndrome (FMS), characterized by subjective complaints without physical or biomarker abnormality, courts controversy. Recommendations in recent guidelines addressing classification and diagnosis were examined for consistencies or differences. Methods. Systematic searches from January 2008 to February 2013 of the US-American National Guideline Clearing House, the Scottish Intercollegiate Guidelines Network, Guidelines International Network, and Medline for evidence-based guidelines for the management of FMS were conducted. Results. Three evidence-based interdisciplinary guidelines, independently developed in Canada, Germany, and Israel, recommended that FMS can be clinically diagnosed by a typical cluster of symptoms following a defined evaluation including history, physical examination, and selected laboratory tests, to exclude another somatic disease. Specialist referral is only recommended when some other physical or mental illness is reasonably suspected. The diagnosis can be based on the (modified) preliminary American College of Rheumatology (ACR) 2010 diagnostic criteria. Discussion. Guidelines from three continents showed remarkable consistency regarding the clinical concept of FMS, acknowledging that FMS is neither a distinct rheumatic nor mental disorder, but rather a cluster of symptoms, not explained by another somatic disease. While FMS remains an integral part of rheumatology, it is not an exclusive rheumatic condition and spans a broad range of medical disciplines.
    Full-text · Article · Nov 2013
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