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English Version of "Das Fibromyalgiesyndrom.
Definition, Klassifikation, klinische Diagnose
und Prognose".
DOI 10.1007/s00482-012-1169-x
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
AWMF-Register Nr. 041/004
W. Eich1 · W. Häuser2 · B. Arnold3 · W. Jäckel4 · M. Offenbächer5 · F. Petzke6 ·
M. Schiltenwolf7 · M. Settan8 · C. Sommer9 · T. Tölle10 · N. Üçeyler9 · P. Henningsen11
1 Department of Internal Medicine II (General Internal and Psychosomatic Medicine),
Heidelberg University Hospital, Heidelberg
2 Internal Medicine 1, Saarbrücken Hospital, Saarbrücken
3 Pain Therapy Department, Dachau Hospital, Dachau
4 Quality Management and Social Medicine Department, Freiburg University Hospital, Freiburg im Breisgau
5 GRP - Generation Research Program, Human Science Center, LudwigMaximilians-University Munich, Bad Tölz
6 Pain and Outpatient Clinic, Göttingen University Medicine, Göttingen
7 Conservative Orthopedia, Orthopedic University Hospital, Heidelberg
8 German Fibromyalgia Association, Bad Seckach
9 Neurology Hospital, University Hospital Würzburg
10 Neurology Hospital, Technical University Munich
11 Clinic and Policlinic for Psychosomatic Medicine, Psychotherapy and Psychological Medicine,
Klinikum rechts der Isar, Technical University Munich
Fibromyalgia syndrome
Definition, classification, clinical
diagnosis and prognosis
Das Fibromyalgiesyndrom.
Background and questions
The fibromyalgia syndrome (FMS), its
definition, classification and diagnosis
among various medical associations, doctors, psychologists and patients is controversial [61]. The definition, classification and diagnosis of chronic pain in
multiple areas of the body (chronic widespread pain, CWP) has been partially determined by the political claims of professional medical societies and the pension
rights of the patients.
The working group focused on the following key questions:
1.What are the core symptoms of FMS?
2.What differences and overlapping
symptoms exist between FMS and somatoform and depressive disorders?
3.What criteria should be used to diagnose FMS?
4.What exclusion diagnostics are necessary?
5.When are professional psychotherapeutic diagnostics meaningful?
6.Are there different courses and severities of FMS?
7.What is the prognosis (including life
expectancy) of patients with FMS?
Materials and methods
The parameters of the literature search
and analysis and the preparation of the
recommendations are described in the article “Methodological fundamentals used
in developing the guideline”.
Results
Preliminary remarks
The following findings apply to adults. For
the definition, classification, clinical diagnosis and prognosis of chronic pain in
multiple areas of the body in children and
adolescents, see the article titled “Definition, diagnosis and treatment therapy of
chronic widespread pain and so-called fibromyalgia syndrome in children and adolescents”. Key recommendations are italicized.
Definition of chronic pain in
multiple areas of the body
Consensus-based statement
Definition of chronic widespread pain
(CWP): CWP can be defined according to
the American College of Rheumatology
(ACR) 1990 criteria and the modified provisional ACR 2010 criteria. EL 5, strong
consensus
Comment. Pain can be categorized according to clinical criteria into monolocular pain (e.g., in one part of the body),
regional pain (e.g., in one specific area of
the body, such as the shoulder or arm) and
pain in multiple areas of the body. Population-based studies have shown that most
people with musculoskeletal pain have
more than one pain location [18, 45].
The ACR classification criteria from
1990 defines CWP in multiple body regions [58] as pain >3 months of continuous pain in the following areas:
Faxial skeleton (i.e., cervical spine, anterior chest, thoracic or lumbar spine)
and
Fright and left halves of the body and
Fabove and below the waist.
Widespread pain may also be an indication of at least 7–19 of the predefined types
of pain described in the Widespread Pain
Index (WPI; modified preliminary ACR
2010 criteria [20, 64]).
Der Schmerz 3 · 2012 | 1
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Widespread pain can have specific
causes (e.g., inflammatory rheumatic disease and diffuse bone metastases). In most
patients affected with CWP, there are no
specific causes of somatic disease [45].
Definition of FMS
Evidence-based statement
FMS was defined in the ACR 1990 classification criteria by CWP and painful pressure in at least 11 out of 18tender points.
EL 2b, strong consensus
Comment. People with chronic pain,
sleep disorders and fatigue have been described since biblical times. Smythe [51]
provided a historical overview of examples of famous people, such as Florence
Nightingale and Charles Darwin, who
were “lifelong invalids, yet lived to a ripe
old age”. In the rheumatology literature,
the symptom complex is known as soft
tissue rheumatism or fibrositis. According to Smythe [50], fibrositis has an imprecise symptomatology with multilocular pain and stiffness lasting for more
than 3 months with distinctive local hyperalgesia, chronic fatigue and sleep disorders. Additionally, a depressive mood is
often involved. The term fibromyalgia was
first used by Hench (1976) [25]. In 1990,
the ACR defined specific criteria for fibromyalgia that are distinct from inflammatory rheumatic diseases and arthritis.
The ACR classification criteria of FMS
represents a consensus definition based
on clinicians’ descriptions of the clinical picture of the disorder. The combination of the above-mentioned criteria distinguished patients with primary (no organic disease) and secondary (co-morbidity inflammatory rheumatic disease)
fibromyalgia from control patients with
inflammatory rheumatic diseases and regional pain syndromes (e.g., osteoarthritis) with a sensitivity of 88% and a specificity of 81% [58]. These classification criteria were not conceptualized by the ACR
authors as diagnostic criteria [61].
Symptom complex of FMS
Evidence-based statement
People with CWP are described in population-based studies and are present
2 | Der Schmerz 3 · 2012
in facilities that treat all of the stages of
clinical care. Widespread pain is associated with other physical and mental complaints. EL 2b, strong consensus
Comment. Patients with CWP differ from patients with local and regional
pain syndromes that are caused by an increase in the severity of physical and mental symptoms (distress). According to the
ACR 1990 criteria, patients with CWP
and FMS are different from patients with
CWP without FMS because their physical
and mental symptoms are more severe [7,
19, 56], and their tender points are markers of distress [60].
In a representative German population sample of 2,504 individuals in 2009,
an asymptotic distribution of pain locations and physical and mental complaints were described. In a cluster analysis, four groups of individuals were identified: pain-free individuals without physical or mental discomfort (“healthy cluster”), individuals with oligolocular pain
and mild physical or psychological symptoms (“regional pain cluster”), individuals with widespread pain, mild physical
pain symptoms and no mental discomfort (“CWP cluster”) and individuals with
widespread pain and severe physical and
mental symptoms (“FMS cluster”) [19].
On the basis of a continuum representing the severity of physical (including the
number of pain locations) and psychological symptoms, individuals with CWP
were located on the outer region of the
continuum, and people with FMS were at
the end of the continuum [60].
Core symptoms of FMS
Evidence-based statement
In addition to CWP, the other core symptoms of FMS include sleep disorders
(non-restorative sleep) and fatigue or
exhaustion (physical or mental). EL 3b,
strong consensus
Comment. All of the members of a German FMS self-help organization reported numerous physical and mental complaints as a result of a symptom questionnaire developed by the organization. The
primary symptoms (in >97% of those affected) were muscle pain in various loca-
tions, back pain, fatigue, joint pain in various locations, poor sleep quality, morning
stiffness, exhaustion in the morning, weak
concentration, lack of stimulation, reduced performance and forgetfulness [16].
These complaints were also indicated as
the most common by patients with FMS
from various German clinical facilities
who were diagnosed based on the ACR
1990 classification criteria [17], patients
with FMS who were diagnosed based on
the clinical criteria from the United States
(US) database for rheumatic diseases [63]
and patient and expert consensuses on the
“key domains of FMS” [41].
Classification of FMS as a
functional somatic syndrome
Consensus-based statement
FMS can be classified as a functional somatic syndrome. EL 5, majority
Comment. Functional somatic syndromes are defined by a clinical complex
of physical symptoms, a defined time period and the absence of the causative somatic disease factors that explain the
symptoms (e.g., structural tissue damage,
biochemical disorder or specific laboratory findings). The individual medical societies define functional somatic syndromes
associated with their respective symptoms
and do not consider additional physical and mental complaints [40] associated with other disciplines in the definition.
Fibromyalgia is described in the International Classification of Diseases in the
German version of the World Health Organization (WHO) in the chapter titled
“Diseases of the musculoskeletal system
and connective tissue” and the subsection
titled “Other soft tissue diseases not classified elsewhere” (M79.70) [8].
Definition/overlap of FMS with
persistent somatoform pain
disorder (F45.40) and chronic
pain disorder with psychological
and somatic factors (F45.41)
Evidence-based statement
The criteria for FMS (ICD-10 M79.70),
persistent somatoform pain disorder (F45.40) and chronic pain disorder
with psychological and somatic factors
Abstract · Zusammenfassung
(F45.41) overlap and include different
clinical characteristics in individuals with
CWP without specific somatic disease
factors. FMS is not synonymous with a
persistent somatoform pain disorder or a
chronic pain disorder with psychological
and somatic factors. EL 3a, strong consensus
Comment. The International Classification of Diseases published by the WHO
includes the possibility of classifying
chronic physical discomfort without somatic disease factors in the chapters on
somatic diseases and in the chapter titled “Psychological and behavioral disorders” under somatoform disorders (F45).
As a result, patients in Germany with fibromyalgia-like symptoms are not coded as M79.70 but as a persistent somatoform pain disorder (F45.40) or somatization disorder (F45.1) by many doctors and
psychologists.
There is an intensive debate regarding the classification of physical ailments
without somatic disease factors in the latest revision of the International Classification of Diseases [32]. The following are
the opposing positions:
Felimination of the somatoform disorder diagnostic category and classification of physical complaints without
somatic disease factors only for physical diseases [33] and
Fpreservation of the somatoform disorder category in the “Psychological and behavioral disorders” chapter
with clarification of the criteria [37].
Persistent somatoform pain disorders are
not clearly defined by the ICD-10 criteria. The diagnostic criteria of persistent
somatoform pain disorders are not listed
with respect to the primary criteria of a
somatoform disorder that must be met for
accurate classification and how many criteria must be met.
Overall criteria for somatoform disorders:
FMedical findings do not explain the
type and the extent of the symptoms
or the suffering or emotional involvement of the patient (e.g., a discrepancy between how the patient feels and
the medical findings).
Schmerz 2012 · DOI 10.1007/s00482-012-1169-x
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
W. Eich · W. Häuser · B. Arnold · W. Jäckel · M. Offenbächer · F. Petzke · M. Schiltenwolf ·  
M. Settan · C. Sommer · T. Tölle · N. Üçeyler · P. Henningsen
Fibromyalgia syndrome. Definition, classification,
clinical diagnosis and prognosis
Abstract
Background. The updated German S guidelines for managing patients with fibromyalgia syndrome (FMS) published by the Association of the Scientific Medical Societies in Germany (“Arbeitsgemeinschaft der
Wissenschaftlichen Medizinischen Fachgesellschaften”, 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 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 EvidenceBased Medicine. The formulation and grading of recommendations was accomplished
using a multi-step, formal consensus process. The guidelines were reviewed by the
boards of the participating scientific medical societies.
Results and conclusion. The clinical diagnosis of FMS should be based on the 1990
American College of Rheumatology (ACR)
classification criteria (with the examination
of tender points), the modified diagnostic criteria from the ACR 2010 (without the examination of tender points) or the criteria published in the German AWMF guidelines for
FMS.The English full-text version of this article is available at SpringerLink (under “Supplemental”).
Keywords
Fibromyalgia syndrome · Definition ·
Classification · Diagnosis, clinical · Guideline
Das Fibromyalgiesyndrom. Definition, Klassifikation,
klinische Diagnose und Prognose
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer 041/004)
wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie wurde
unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie (DIVS) von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potenzielle Interessenkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolgte über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke erfolgte nach dem Schema des Oxford Center
FRepeated presentation of physical
symptoms in conjunction with persistent requests for medical examina-
for Evidence Based Medicine. Die Formulierung und Graduierung der Empfehlungen erfolgte in einem mehrstufigen, formalisierten
Konsensusverfahren. Die Leitlinie wurde von
den Vorständen der beteiligten Fachgesellschaften begutachtet.
Ergebnisse und Schlussfolgerung. Die
klinische Diagnose des FMS kann sowohl
nach den Klassifikationskriterien des American College of Rheumatology (ACR) von 1990
(mit Untersuchung der „tender points“) als
auch ohne Untersuchung von „tender points“
anhand der modifizierten vorläufigen diagnostischen Kriterien des ACR von 2010 oder
der Kriterien der deutschen AWMF-Leitlinie
zum Fibromyalgiesyndrom erfolgen.
Schlüsselwörter
Fibromyalgiesyndrom · Definition ·
Klassifikation · Klinische Diagnose · Leitlinie
tions despite repeated negative results
(dysfunctional disease behavior).
FPatient resists attempts to discuss the
possibility of a psychological cause,
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even when the beginning and duration of the symptoms are closely related to unpleasant life events, difficulties or conflicts (somatic fixation).
FThe understanding reached regarding
the physical or psychological cause of
the symptoms is often disappointing
to the patients and doctors (dysfunctional relationship behavior).
FThe attention-seeking (histrionic) behavior of patients, as listed in the “Etiology and pathophysiology of fibromyalgia syndrome” chapter [49], is
not sufficiently explained by the physical symptoms of FMS through somatic disease factors. This criterion applies to most FMS patients. No
studies were identified demonstrating
that patients with FMS took the initiative to request another organic diagnosis by exclusion after they had
been diagnosed with FMS.
Case studies from clinical facilities [15]
and cohort studies by FMS self-help organizations [1] report that the majority
of those affected by the question of subjective causes of the disease indicate that
both physical and psychological factors
are involved. A somatic fixation was determined in these samples in only a few
patients with FMS. Studies on dysfunctional patient–physician behavior and attention-seeking relationship behavior in
patients with FMS were not found. A multicenter German study evaluating the utilization of medical services showed that
only a fraction of patients with FMS had
an increased number of medical consultations compared to the entire German population [33].
Criteria for persistent somatoform pain
disorder:
a)severe excruciating pain >6 months,
b)no sufficient evidence obtained from
adequately conducted somatic testing
to explain the symptoms,
c)occurs in conjunction with emotional conflicts or psychosocial problems
that are important causal factors due
to their severity and
d)exclusion of
1psychogenic pain during the course
of a depressive disorder or schizophrenia and
4 | Der Schmerz 3 · 2012
1pain due to known or psychophysiological mechanisms, such as muscle tension pain or migraine.
Criteria a and b apply to patients with
FMS. Criterion c applies to many, but not
all, patients with FMS. Case studies from
clinical facilities have shown that relevant
psychosocial stress was temporally related
to the development of or increase in CWP
in 60–80% of patients with FMS [15]. Psychosocial stressors are associated with an
increased risk of FMS [49]. Regarding criterion d, systematic review articles showed
that co-morbid depressive disorders occur
in 30–80% of patients with FMS [11]. The
psychophysiological mechanisms of pain
in FMS are described in the “Pathophysiology” chapter [49]. Longitudinal studies
from the Swedish twin register have provided evidence of a common factor using
path analysis (determined more by environmental factors than by genetic factors), which can affect both functional somatic disorders (e.g., FMS, irritable bowel
syndrome, headaches and chronic fatigue
syndrome) and psychological disorders
(e.g., depression and generalized anxiety
disorder) [28, 29]. A dimensional analysis of the FMS symptom complex based
on physical and psychological complaints,
psychosocial stressors, availability of medical services and subjective beliefs regarding of the cause of the illness is more appropriate than the categorical classification of FMS as a persistent somatoform
pain disorder [24].
The criteria of a chronic pain disorder
with somatic and psychological factors (F
45.41) are as follows: pain that is present
for at least 6 months in one or more anatomical regions, which originated due to a
physiological process or a physical disorder. Although psychological factors play
an important role in the severity, exacerbation or continuation of the pain, they
are not the direct cause. The pain induces clinically significant distress and impairment in social, occupational or other important functional areas. Pain disorders that are specifically associated with
mood, anxiety, somatization or psychotic disorders should not be considered in
this context [8].
This diagnostic category can be used
for patients with symptoms of CWP that
originated due to inflammatory rheumatic disease or arthritis and because the current extent of their pain symptoms (i.e.,
number of pain sites, impairments) can
be explained by psychosocial processes
instead of inflammatory processes in cases of remission or mild clinical courses of
the inflammatory symptoms.
Definition/overlap of FMS
with depressive disorders
Evidence-based statement
FMS can be associated with depressive
disorders (EL1b). However, FMS is not to
be classified as a depressive disorder. (EL
3a), strong consensus
Comment. Population-based and clinical studies reveal an association between
CWP, FMS and depressive disorders.
However, not every patient with a depressive disorder reports pain, and not every
patient with FMS is depressed [43].
The main symptoms of FMS, including
pain and fatigue, are also possible symptoms of depressive disorders. Among patients with depressive disorders, 30–60%
reported pain [2]. The most common
physical symptom in patients with major
depression disorders in pharmacological
studies was fatigue [53]. Six percent of the
patients in these studies reported ≥6 pain
localizations [54]. The association rates of
multilocular (>2) pain and mood disorders were between 2.8–19.6% in the World
Mental Health Survey [13]. In a clinical
study, 13% of patients with major depression fulfilled the ACR 1990 criteria for
FMS [55]. In a German study, 38% of patients with depressive disorders (F32–34,
F43.2) fulfilled the survey criteria for FMS
(≥7/19 pain sites and fatigue ≥6/10 using
the visual analogue scale) [20]. A subgroup of patients who were diagnosed as
depressed also showed fibromyalgia-like
symptoms.
In a representative sample of the German population in 2009, 12.5% of individuals with FMS met the survey criteria for
major depression and 12.5% met the criteria for another depression syndrome, as
measured using the depression module
of the health questionnaire for patients
[18]. A systematic review of clinical studies showed a prevalence rate of 30–70%
for depressive disorders in patients with
FMS [11]. The symptomatology of a percentage of patients diagnosed with FMS
also meets the criteria for depressive disorders (e.g., major or minor depression or
atypical depression).
Despite a partial overlap in the symptoms and neuroendocrine mechanisms,
one review article concluded that major
depressive disorders and FMS should not
be regarded as variants of the same disease [44].
types (e.g., Down syndrome and Marfan
syndrome) [34].
Fibromyalgia versus
fibromyalgia syndrome
Comment. Because the conditions that
define FMS are distributed in the general
population and clinical populations within a continuum (see statement “Symptom
complex of FMS”), any classification of severity depends on the criteria and thresholds used. There is no generally accepted classification for the degree of severity
of functional disorders in general and for
FMS in particular. The German Guideline “Non-specific, functional and somatoform physical symptoms” differentiates between mild and severe manifestations ([14], . Tab. 1).
In clinical populations of FMS, different clusters of patient groups or severity levels have been distinguished. An increase in physical distress and subjective disturbances were associated with increased drug consumption and physical
and mental health comorbidities [6, 48].
In clinical trials, a severity level classification for FMS can be obtained using the Fibromyalgia Impact Questionnaire (FIQ)
[46].
Consensus-based statement
Because symptomatology is defined by a
symptom complex, the term “fibromyalgia syndrome” is more appropriate than
the term “fibromyalgia”. EL 5, consensus
Comment. Functional somatic syndromes do not exhibit a distinctive clinical picture (such as myocardial infarction). The basis for the definition of functional somatic syndromes is a continuum
of complaints. The definition of a disease
pattern results from the establishment of
a threshold by an expert consensus and/
or by clinical studies. The same approach
is used to describe pronounced continuous biological variables, such as the degree
of constriction of the coronary vessels and
blood sugar levels. The authors are aware
that the term “syndrome” is not used consistently in the medical literature. The concept of a syndrome is understood in these
guidelines as “the aggregation of symptoms, which by themselves are not characteristic of the disease, to form a characteristic disease pattern”. Other functional
somatic syndromes include irritable bowel syndrome or urethra syndrome. FMS is
classified as a first-order syndrome or a
symptom complex with unknown or unclear etiology, heterogeneous pathogenesis and a defined phenotype (see statement “Core symptoms of FMS”). Second-order syndromes (sequences) are defined by unknown etiologies, homogeneous pathogenesis and defined phenotypes (e.g., Cushing’s syndrome). Thirdorder syndromes are defined by homogeneous etiologies, unknown or insignificant pathogenesis and defined pheno-
Progression of FMS
Evidence-based statement
Different forms of FMS progression with
varying severity can be distinguished
based on clinical characteristics. However, a generally accepted classification of
the degree of severity does not exist. EL
5, strong consensus
Case study of a patient with mild FMS:
A 37-year-old female patient reported recurring back pain episodes starting at the
age of 11 without radiation to other areas.
However, the pain began to extend to her
entire back and to all of her extremities
2.5 years ago. Since that time, she reported
experiencing pain almost every day of the
year. However, in the summer months or
during vacations to Mediterranean countries, she experienced little or no pain.
For 2 years, she experienced a constant
pain level, with an average pain intensity
of 6/10, ranging from the lowest pain intensity of 2/10 to the maximum pain intensity of 9/10 on an 11-point numerical
scale (NRS). Additional physical discom-
forts included an increased stiff feeling in
her hands and an increased cold sensitivity with no autonomic symptoms. Carrying heavy loads (such as hot boxes) was
no longer possible, and the patient could
walk but was unable to jog. There were no
restrictions on domestic work. The patient had unobtrusive biographical anamnesis. At the time of the case study, the
patient was married, had a self-employed
husband and did not have any children.
She had no current mental complaints or
emotional disorders, and there were no
reports of psychiatric and psychotherapeutic treatments in her patient history.
Case study of a patient with a severe history of FMS:
A 54-year-old female patient experienced
recurring hip pain as a child and reported recurrent joint and back pain beginning in early adulthood. However, 8 years
prior to the case study, the pain expanded to her entire back and to both of her
arms and legs. At that time, the patient experienced continuous pain with an average pain intensity of 8/10, with the lowest
pain intensity of 7/10 and the maximum
pain intensity of 10/10 on the NRS, with
no pain-free or low-pain intervals. For approximately 5 years, the patient has experienced mostly non-restorative sleep and
increased daytime sleepiness with rapid exhaustion, limited physical or mental
stress, increased feelings of stiffness in the
hands, increased cold sensitivity, recurrent abdominal pain in alternating locations, an increase in the frequency of feces by 3–10 movements, the imperative
and urgent need to urinate and defecate
(gastroenterological and urological clarification without pathological findings) and
arrhythmia (cardiological investigation
without pathological findings and therapy with a β-blocker). She could only do
light household chores, such as cooking
and putting the dishes away; other domestic duties, including cleaning and laundry, were assumed by a housekeeper or
her daughter. She gave up on her painting
hobby 1 year ago due to pain in her arms
and has been unable to work for the past
2 years but receives steady unemployment
benefits. Regarding biographical anamnesis, the patient experienced physical trauma perpetrated by an alcoholic father as a
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Tab. 1 Clinical characteristics of mild and severe manifestations of fibromyalgia syndrome
(transitional, no mandatory criteria) (modified after the AWMF guideline entitled “Non-specific,
functional and somatoform physical symptoms” [14])
Criterion
Physical symptoms
Mild manifestation
Predominant musculoskeletal
discomfort
Duration of physical symptoms
Psychological symptoms
Subjective disease diagnosis
Subjective disturbances (e.g.,
profession, family and free
time)
Use of medical services
Psychosocial stress
Practitioner–patient relationship
Severe manifestation
Numerous complaints, including musculoskeletal and other
organ systems
Relapsing, minor or discomfort- Persistent, none or rare low or
free intervals
discomfort-free intervals
Limited
Pronounced
Appropriate (e.g., dependent
Inappropriate (e.g., persistent
on stress and temperature)
fears of serious disease despite
an exclusion diagnosis)
Missing or minor
High
Minor
Few and mild stressors (family,
profession)
Cooperative
High (doctor-hopping)
Numerous and/or severe
stressors (family, profession)
“Difficult”, frustrating
Tab. 2 Criteria for the clinical diagnosis of FMS
ACR 1990 classification criteria [58]
Obligate core symptom
CWP according to the
ACR 1990 criteria (see
statement “Definition
of chronic pain in
multiple areas of the
body”)
None
Diagnostic exclusions
None
Modified provisional
ACR 2010 diagnostic
criteria [64]
Regional pain index at
≥7/19 pain locations
on the regional pain
scale
AWMF – FMS diagnostic criteria guidelines
[21]
CWP according to the
ACR 1990 criteria (see
statement “Definition of
chronic pain in multiple
areas of the body”)
Symptom intensity
score ≥5a
Fatigue (physical and/or
psychological) and sleep
disorders and/or nonrestorative sleep and
swelling and/or stiffness
in the hands and/or feet
and/or face
Exclusion of a physical
illness that would sufficiently explain the typical pattern of symptoms
Exclusion of a physical illness that would
sufficiently explain
the typical pattern of
symptoms
aSymptom severity score: sum of fatigue, non-restorative sleep and cognitive problems (0: not available to 3:
extremely pronounced); headache, abdominal pain and depression (0: absent, 1: present; range of total scores:
0–12). According to the modified ACR 2010 provisional diagnostic criteria, FMS can be diagnosed in 3–6 pain
locations on the regional pain scale and can have a symptom severity score ≥9 [64]. However, this diagnostic
criterion is incompatible with the primary symptoms of FMS, which include CWP. Regional pain, such as in the
neck, upper arm or forearm, may also occur at three pain locations on the regional pain scale. Therefore, the use
of this diagnostic criterion is not recommended.The rate of agreement between the 1990 ACR criteria and the
diagnostic criteria of the German AWMF guidelines for FMS was 87% [21] in a multicenter study. ACR American
College of Rheumatology; AWMF Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften; CWP chronic widespread pain; FMS fibromyalgia syndrome.
child and a suicide attempt in her youth.
Other stressful life events and psychosocial problems include a drug-addicted
daughter who committed suicide and experiences with conflicts in the workplace.
6 | Der Schmerz 3 · 2012
Prevalence of FMS in Germany
Evidence-based statement
Other obligate
symptoms
able to drive alone for the past 2 years and
can only shop in small stores within the
vicinity of her home. The patient has experienced withdrawal from social contacts for 2 years. For the past 3 years, she
has been depressed most of the time and
has a lack of desire and motivation. She
has received outpatient psychiatric treatment for the past 2 years and has taken
several unsuccessful psychiatric drug regimens.
She has increasing anxiety traceable back
to her childhood, such as a fear of the dark
and abandonment, and experienced panic attacks and an increase in avoidance behavior at the age of 18. She has not been
The prevalence of FMS in Germany is approximately 3.5%. EL 2c, consensus
Comment. In a summary of 10 studies
representing the general adult population
from various countries, the prevalence of
FMS was between 0.7% and 3.3%. The
prevalence was between 1.0% and 4.9%
in women and between 0.0% and 1.6% in
men. The female-to-male ratio was between 2–21:1 [12].
In Germany, the prevalence of FMS
based on the ACR criteria of 1990 in a
population of 35- to 74-year-old women
was 5.5% [46]. In a representative sample
of the population in Germany, the point
prevalence of widespread pain (backache
and pain in all four extremities) was 8.6%.
The point prevalence of FMS (according
to the survey criteria of ≥7/19 pain locations and fatigue of ≥6/10 on the visual analogue scale) was 3.8% [95% confidence
interval (95% CI) 3.6–4.0]. The ratio of
women to men was 1.2:1 [18]. In a European study (including Germany), the point
prevalence of CWP was determined based
on the pain criteria from the London Fibromyalgia Epidemiology Study Screening Questionnaire. The point prevalence
of FMS was estimated based on the frequency of FMS in rheumatology practices using the CWP criterion from the London Fibromyalgia Epidemiology Study
Screening Questionnaire. The point prevalence of CWP in Germany was 11%, and
the point prevalence of FMS was 3.2%
(95% CI 2.1–4.3). The female-to-male ratio for FMS was 1.6:1 [5].
In clinical settings, the female-to-male
ratio is 8–12:1 [21]. The higher prevalence
rates among men in recent epidemiolog-
Tab. 3 Important differential diagnostics of chronic widespread pain in multiple body
regions (modified from [30])
Internal diseases
Chronic inflammatory rheumatic disease
Chronic hepatitis C
Chronic inflammatory bowel disease
Celiac disease
Osteoporosis
Hyper-/hypoparathyroidism
Hyper-/hypothyreosis
Vitamin D deficiency
Neurological diseases
Inflammatory myopathy
Metabolic myopathy
Degenerative myopathy
Endocrinal myopathy
Myotonia
Toxic myalgia
Myalgia in rare diseases (e.g., stiff person syndrome)
Myalgia by alteration to the central and peripheral
nervous system
Tab. 4 Painful myopathy triggered by medications and drugs (modified from [4])
Inflammatory myopathy
Cimetidine
D-Penicillamine
Cocaine
Levodopa
Penicillin
Procainamide
Sulfonamide
Zidovudine
Other myopathies
ACTH
Carbimazole
Clofibrate
Cromoglycate
Cyclosporin
Enalapril
Ezetimibe
HMG-CoA reductase inhibitor
Metoprolol
Minoxidil
Proton pump inhibitor
Salbutamol
ical studies [5, 18] compared to the rates
in clinical institutions can be explained as
follows:
1.Not using the tender point criteria for
the clinical diagnosis of FMS in epidemiological studies leads to a more
frequent diagnosis of FMS in men
with CWP because the average pressure pain intensity is lower in men
than in women. In the general population [58] and clinical samples, men
have fewer pressure-sensitive tender
points than women.
2.It is possible that FMS in men with
CWP is not diagnosed because FMS
is considered a “female sickness” [22].
3.Women with chronic physical discomforts demand more medical services than men with the same discomforts [14].
Clinical diagnosis
Clinical consensus point
The clinical diagnosis of FMS can be determined according to the ACR 1990 classification criteria, the symptom-based
Myopathy and neuropathy
Amiodarone
Colchicine
Heroin
Interferon
L-Tryptophan
Vincristine
criteria of the German FMS S3 guidelines
or the current modified ACR 2010 criteria. The clinical diagnosis is based on the
anamnesis of a typical symptom complex, clinical examination and the exclusion of physical diseases, which could
satisfactorily explain this symptom complex. Strong consensus
Comment. Although the ACR 1990 classification criteria for FMS [58] were designed as classification criteria and not as
diagnostic criteria, they were subsequently used for diagnosis in daily clinical routines and studies. The use of the tender
point examination was criticized due to
the lack of acceptance by non-rheumatologists, lack of objectivity in implementation, missing data on the reliability of the
results outside of rheumatology settings
and the lack of validity [21, 61].
Based on patient surveys, comparisons between patients with arthritis and
rheumatoid arthritis and expert consensus [61], the tentative diagnostic criteria
for FMS were developed by a group of experts from the ACR. In the modified pre-
liminary ACR 2010 criteria, the medical
assessment of the physical symptoms was
replaced by a patient self-assessment using a questionnaire [64]. In the consensus conference of the German S3 guidelines for FMS [10], the AWMF criteria
were developed for the clinical diagnosis
of FMS ([21], . Tab. 2). The historically
described symptom triad of CWP, fatigue
and sleep disorders is a required diagnostic criterion, and these symptoms are considered core symptoms in the diagnosis of
FMS.
Obligatory somatic diagnosis
at the initial evaluation
Clinical consensus point
If the initial assessment indicates possible CWP, the following measures are recommended:
Fcompletion of a sketch of the pain or
the regional pain scale by the patient,
Ftargeted exploration of other core
symptoms, such as fatigue or sleep
disorders,
Fcomplete medical anamnesis, including drug history,
Fcomplete physical examination, including skin, neurological and orthopedic findings
Fbasic laboratory tests:
1erythrocyte sedimentation rate,
C-reactive protein and full blood
count (e.g., polymyalgia rheumatica, rheumatoid arthritis),
1creatine kinase (CK) (e.g., muscular
disorders),
1calcium (e.g., hypercalcemia),
1basal thyroid-stimulating hormone
(e.g., hypothyroidism),
Ffor indications of somatic causes of
the symptoms, further diagnostics
may be necessary depending on the
suspected diagnosis.
Strong consensus
Comment. CWP and fatigue can be
symptoms of several internal and neurological disorders (. Tab. 3, 4). Muscle and
joint pain in multiple body regions without evidence of a neuropathy or myopathy
can be caused by many drugs. Statins are
frequently prescribed, and 10–15% of the
patients receiving statin therapy develop
myalgia of varying degrees with and withDer Schmerz 3 · 2012 | 7
Schwerpunkt
Mortality
How often were you affected by the following complaints in the past 2 weeks?
Not at all
01 Low interest or pleasure in your activities
02 Depression, melancholy or hopelessness
03 Nervousness, anxiety or tension
04 Not being able to stop or control your
worries
On a
single day
On more than
half of the
days
Almost
every
day
0
1
2
3
0
1
2
3
0
1
2
3
0
1
2
3
Fig. 1 8 PHQ-4: patient health questionnaire
out an increase in CK [38]. Arthralgias
and myalgias are side effects of aromatase
inhibitors [57] and interferons [42].
Additional technical diagnostics
Clinical consensus point
In a typical symptom complex and the
absence of clinical references to internal,
orthopedic or neurological diseases (anamnesis and clinical examination without reference to other diseases as causes
of pain and fatigue, including unremarkable basic laboratory test results), additional technical diagnostics, such as follow-up laboratory tests, neurophysiology or imaging are not recommended.
Strong consensus
Comment. A Norwegian longitudinal
study in outpatient primary care indicated that radiological examination had
a low diagnostic value in patients with
CWP [35]. A Canadian study in outpatient primary and secondary care demonstrated that there was no diagnostic value gained from the determination of autoantibodies associated with inflammatory rheumatic diseases in the anamnestic
indication of CWP, fatigue and the lack of
ankle swelling or references to internal organ diseases [52].
Screening for psychological
stress symptoms
Clinical consensus point
In the initial evaluation of CWP, screening
for increased mental workload of symptoms, such as anxiety and depression, is
recommended. Strong consensus
8 | Der Schmerz 3 · 2012
Comment. The most common co-morbid mental disorders in FMS are depressive and anxiety disorders [11]. Screening (via a questionnaire or questions from
the doctor to the patient) is possible using
the German version of the patient health
questionnaire (PHQ)-4 [37] (. Fig. 1).
Values ≥3 are observed as the limit for
possible depressive disorder (questions
1 and 2) or possible generalized anxiety disorder, panic disorder or posttraumatic stress disorder (questions 3 and 4)
and correspond to a percentile rank of
93.4% (depression) and 95.2% (fear) relative to a representative German population sample [37].
Professional psychotherapeutic
investigation
Clinical consensus point
A professional psychotherapeutic investigation by a specialist in psychiatry and
psychotherapy, psychosomatic medicine,
psychotherapy or a medical or psychological psychotherapist is recommended
in the following cases:
a)indications of increased psychological
distress (e.g., anxiety or depression),
b)anamnestic information on current
severe psychosocial stressors,
c)anamnestic information on current or
previous psychiatric treatments,
d)anamnestic information on serious biographical stress factors,
e)maladaptive in coping with disease,
f)subjective attributes of mental illness
Consensus
Evidence-based staement
Mortality is not increased in FMS. EL 2b,
strong consensus
Comment. In a retrospective case control
study of 8,186 patients with FMS treated
in rheumatology practices (US National
Data Bank for Rheumatic Diseases) from
1974–2009, the death rate was not elevated compared to 12,329 patients with osteoarthritis (US National Death Index).
The standardized risk of suicide was increased when compared to the US population [odds ratio (OR) 3.3, 95% CI 2.2–
5.1] [65]. In a retrospective cohort study
in Denmark, 1,361 patients with FMS were
observed from 1984–1999. The mortality
risk was not elevated, although the female
patients had an increased risk of suicide
(OR 10.5, 95% CI 4.5–20.7) [9].
Use of medical services
Evidence-based statement
FMS causes high direct and indirect medical expenses in Germany in terms of utilization of health care and health benefits, respectively. EL 2b, strong consensus
Comment. Only studies from Germany
were considered. In “IMS Mediplus”, a database of 900 general medical practices
in Germany, the use of outpatient services was compared for 4,983 patients with
FMS and 4,983 age- and gender-matched
controls from 2/2006–2/2007. Patients
with FMS reported twice as many visits to
general practitioners, transfers to specialists and sick leave compared to the control
patients during the investigation period.
The medical expenses for patients with
FMS (e.g., doctor visits, medications, inpatient treatments and sick leave) were estimated to be $9,573 compared to $329 for
the controls [3].
In a study of the former Barmer health
insurance (Barmer Ersatzkasse, BEK)
from 1 July 2008 to 30 June 2009 for
19,592 insured individuals (0.3% of the total insured in the population) diagnosed
with FMS, the annual direct medical costs
were calculated to be 3,160 € (outpatient
and inpatient treatment), and the indirect
medical costs were 721 € (sick pay). Data
from the control group were not reported [39].
Conclusion
The validation of the first version of the
German S3 guidelines based on clinical consensus and symptom-based diagnostic criteria [22] and the participation
of guideline group members toward the
development of the modified provisional
2010 ACR diagnostic criteria [64], which
provides a diagnosis of FMS without tender point examination, continues the efforts to facilitate the diagnosis of FMS by
non-rheumatologists.
By comparing the recommendations
of the S3 guidelines to “non-specific/functional/somatoform disorders of the body”
[24] for diagnostic labeling and treatment of the symptom complex, the working group hopes to end the debate of the
classification of CWP without sufficient
explanatory somatic disease factors. We
hope to focus toward filling in the following research gaps:
Fdevelopment of reliable and internationally accepted degrees of severity
for non-specific/functional/somatoform physical disorders in general
and in FMS patients in particular and
Fprospective cohort studies on the importance of secondary disease gain,
social factors, such as unemployment
and pension loss, iatrogenic chronification and diagnostic labels for patients with FMS.
Corresponding address
Prof. Dr. W. Eich
Department of Internal Medicine II (General
Internal and Psychosomatic Medicine),
Heidelberg University Hospital
Im Neuenheimer Feld 10, 69210 Heidelberg
Germany
[email protected]
Conflict of interest. See . Tab. 5 in “Methodological
fundamentals used in developing the guideline” by W.
Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
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Schwerpunkt
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. Sommer1 · W. Häuser2 · M. Burgmer3 · R. Engelhardt4 · K. Gerhold5 · F. Petzke6 ·
T. Schmidt-Wilcke7 · M. Späth8 · T. Tölle9 · N. Üçeyler1 · H. Wang10 · A. Winkelmann11 ·
K. Thieme12
1 Neurologische Klinik, Universitätsklinikum Würzburg
2 Innere Medizin 1, Klinikum Saarbrücken gGmbH, Saarbrücken
3 Klinik für Psychosomatische Medizin und Psychotherapie, Universitätsklinikum Münster
4 Zentralinstitut für die kassenärztliche Versorgung in Deutschland, Berlin
5 Klinik für Pädiatrie mit Schwerpunkt Pneumologie/Immunologie und
Berlin School of Public Health, Charité – Universitätsmedizin Berlin
6 Schmerz-Tagesklinik und -Ambulanz, Universität Göttingen
7 Department of Anesthesiology, Chronic Pain and Fatigue Research
Center, University of Michigan, Ann Arbor (Michigan)
8 Rheumatologische Praxis, München-Gräfelfing
9 Klinik für Neurologie, Technische Universität München, Munich
10 Department für Orthopädie und Unfallchirurgie, Stiftung Orthopädische Universitätsklinik Heidelberg
11 Klinik und Poliklinik für Physikalische Medizin und Rehabilitation,
Klinikum der Universität München, Munich
12 Institut für Medizinische Psychologie, Philipps-Universität Marburg
Etiology and
pathophysiology of
fibromyalgia syndrome
Background and goals
Methods
Etiology
There is extensive scientific literature on
the etiology and pathophysiology of fibromyalgia syndrome (FMS) which makes it
difficult for the individual practitioner to
stay up-to-date. Recent review articles focus either on biological or psychological
aspects. The classification of FMS (physical illness vs. mental disorder), contents
of patient education, and the preferred
treatment methods are closely related to
the identified etiologic and pathophysiologic 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 analyze the content and quality of published
studies on these topics in order to identify possible risk factors for the development of FMS and CWP and also to identify factors that are unrelated to the two
syndromes.
The methodology of the literature search
and analysis, and preparation of recommendations are presented in the article
“Methodological fundamentals used in
developing the guideline”.
Risk indicators and factors
Results
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 widespread pain and so-called fibromyalgia
syndrome in children and adolescents”.
Evidence-based observation
Current evidence does not allow definite
conclusions to be drawn about the etiology of CWP/FMS. It is unclear whether the risk indicators of CWP and FMS described in the following observations are
risk factors. Strong consensus
Comment. Risk indicators are characteristics whose presence indicates a greater risk of illness without playing a causative role. Risk factors (etiologic factors)
are characteristics that are causally associated with an increased risk of disease. Risk
indicators and risk factors for disease are
identified by retrospective and prospective cohort studies. The design of these
studies, however, do not allow proof of a
causal relationship. The following criteria increase the likelihood of a causal relationship: dose–effect relationship and experimental evidence, i.e., randomizedDer Schmerz 3 · 2012 | 1
Schwerpunkt
Tab. 1 Predictors of chronic widespread pain (CWP) in prospective population-based cohort studies
Study design
Prospective population-based cohort study of
1,658 adults between 25–65 years of age; follow-up
after 36 months
Prospective cohort study of 1,081 newly employed
individuals at 12 different work places; follow-up after
24 months
Prospective population-based cohort study;
3,171 adults without CWP between 25–65 years of
age; follow-up after 15 months
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 individuals; follow-up after 15 months
EPIFUND: 2,509 patients from three British general
practitioners between 25–65 years of age; follow-up
after 15 months
1958 British Cohort Study: 18,558 individuals; followup after 45 years
Risk indicator (statistical predictor)
Repetitive movements of wrists
Increased illness behavior
Regional pain at baseline measurement
Increased physical symptoms
Crouching activity >15 min
Monotonous work
Risk (95% CI)
OR 1.8 (1.2–2.7)
OR 9.0 (3.7–22.2)
OR 2.1 (1.3–3.3)
OR 3.3 (1.5–7.4)
OR 2.0 (1.1–3.6)
OR 1.9 (1.1–3.2)
Reference
[25, 26, 27]
Increased physical symptoms
Increased illness behavior
Sleep disorder
HPA axis dysfunction
OR 1.8(1.1–3.1)
OR 3.3(2.3–4.8)
OR 2.7(1.6–3.2)
OR 8.5 (1.5–47.9)
[14]
Gene polymorphisms affecting the HPA axis
ACTH-precursor-receptor
SERPINA6, rs941601, genotype CT
Genotype TT
Corticosteroid-binding globulin MC2R rs11661134, genotype
AG and AA
Decreased health-related quality of life
Teacher reports of persistent behavioral abnormalities at ages
7, 11 and 16 years of age
β2-adrenergic receptor (ADRB2) combinations, e.g. H2-H2
Hospitalization after traffic accident
Institutionalization
Maternal death
Financial need
Multiple physical symptoms at the age of 7 years
OR 1.61 (1.0–2.6)
OR 1.2 (1.0–1.3)
OR 2.2 (1.1–4.4)
OR 2.2 (1.2–4.4)
[19]
RR 4.0 (2.6–6.2)
RR 2.1 (1.4–3.2)
[33]
[34]
RR 1.8 (1.1–2.9)
RR 1.5 (1.1–2.1)
RR 1.7 (1.3–2.4)
RR 2.0 (1.1–3.7)
RR 1.6 (1.3–1.9)
RR 1.5 (1.0–2.3)
[18]
[30, 31]
[16]
[28]
ACTH adrenocorticotropic hormone; CI confidence interval; CWP chronic widespread pain; HPA hypothalamic–pituitary–adrenal; OR odds ratio; RR relative risk.
controlled trials that demonstrate elimination of risk when the risk factor is eliminated.
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 biopsychosocial 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 studies on risk factors for CWP and FMS were
not found.
2 | Der Schmerz 3 · 2012
Risk indicators of CWP
Evidence-based observation
The following biologic, mechanical, and
psychosocial factors are associated with
the development of CWP (risk indicators):
Fbiological factors: gene polymorphisms (β2-adrenergic receptors,
ACTH precursor receptor, corticosteroid binding globulin), dysfunction of
the hypothalamic–pituitary–adrenal
(HPA) axis (EL 2b);
Fmechanical factors: uncomfortable
postures at work (crouching, repetitive movements of wrist), monotonous work (EL 2b);
Fpsychological factors: increased physical complaints and illness behavior;
low physical health-related quality of
life; sleep disorders (EL 2b); permanent threat to life (EL 2c);
Fchildhood: hospitalization after traffic
accident; institutionalization; maternal death; financial need (EL 2b).
Strong consensus
Comment. The results of prospective cohort studies are summarized in
. Tab. 1. A study from Israel [1] compared 1,024 people from a town (Sderot) that was repeatedly attacked by rocket
fire with 1,006 people who lived in another town (Okafim) with a similar socioeconomic and demographic profile, but who
were not exposed to rocket fire. Trauma-related symptoms and physical complaints were more frequent and the point
prevalence of CWP was higher in Sderot (11.1%) than in Ofakim [8.3%; odds ratio (OR) 1.37].
Abstract · Zusammenfassung
Risk indicators for FMS
Evidence-based observation
The following biological and psychosocial factors are associated with the development of FMS:
Fbiological factors: inflammatory–
rheumatic diseases (EL 2b),
Fgene polymorphisms of the 5HT2-receptor (EL 3a),
Flife style: smoking, overweight, lack
of physical activity (EL 2b)
Fpsychological factors: physical abuse
in childhood and adulthood, sexual abuse in childhood and adulthood (EL 3a), stress at the work place
(EL 3b).
Strong consensus
Comment. See . Tab. 2. Genetic factors
are likely present since FMS tends to cluster in families [38]. Candidate genes in the
serotonergic, dopaminergic, and catecholaminergic systems may play a role. However, this is also the case in other chronic
pain syndromes and therefore these findings are not specific for FMS [3, 4].
In a retrospective cohort study of 62,000
members of a U.S. health insurance an association with FMS was found for rheumatoid 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 significant; [46]).
Out of 9,739 patients with rheumatoid
arthritis without FMS (U.S. National Data Bank for Rheumatic Diseases) on average 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 observation period. Poverty [HR (hazard ratio)
1.64 (95% CI 1.47–1.82)], overweight [HR
1.60 (95% CI 1.43–1.79)], depressive symptoms [HR 2.28 (95% CI 1.97–2.64)], numerous physical comorbidities [HR 2.53
(95% CI 2.36–2.71)], and low physical activity [HR 2.53 (95% CI 2.36–2.71)] predicted FMS [47].
In a 2-year prospective observational study of 4,791 hospital employees
(4,250 women, 541 men), increased bullying in the workplace, low freedom of action, and high workload increased the risk
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
Abstract
Background. 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.
Materials and methods. The development
of the guidelines was coordinated by the
German Interdisciplinary Association for Pain
Therapy (“Deutsche Interdisziplinäre 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 EvidenceBased Medicine.
Results. 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).
Conclusion. 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”).
Keywords
Fibromyalgia syndrome · Guideline ·
Systematic review · Etiology ·
Pathophysiology
Ätiologie und Pathophysiologie des Fibromyalgiesyndroms
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer
041/004) wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie
wurde unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie (DIVS) von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potenzielle Interessenkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolgte über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke erfolgte nach dem Schema des Oxford Center
for Evidence Based Medicine.
of physician-diagnosed FMS [22]. Due to
problems with the study design (no detection of pain using validated instruments at
the beginning and end of the study), the
Ergebnisse. Die aktuelle Studienlage erlaubt
keine eindeutigen Aussagen zur Ätiologie
und Pathophysiologie des FMS. Die Entwicklung eines FMS ist mit entzündlich-rheumatischen Erkrankungen (EL2b), Genpolymorphismen des 5-Hydroxytryptamin(HT)2-Rezeptors (EL3a), Lebensstilfaktoren (Rauchen,
Übergewicht, mangelnde körperliche Aktivität; EL2b), körperlicher Misshandlung und
sexuellem Missbrauch in Kindheit und Erwachsenenalter (EL3a) assoziiert.
Schlussfolgerung. Das FMS ist wahrscheinlich die Endstrecke verschiedener ätiopathogenetischer Faktoren und pathophysiologischer Mechanismen.
Schlüsselwörter
Fibromyalgiesyndrom · Leitlinie ·
Systematische Übersicht · Ätiologie ·
Pathophysiologie
level of evidence was downgraded for this
study.
Der Schmerz 3 · 2012 | 3
Schwerpunkt
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)
Adventist Health Study 1
and 2: cohort study of
3,136 women; follow-up
after 25 years
Nord-Trøndelag Health
Study. Population-based
cohort study of 15,990 individuals; follow-up after
11 years
Population-based cohort
study of 214 women; followup after 5 years
Number of allergies
Tobacco smoking
OR 4.0 (2.3–6.9)
OR 2.4 (1.3–4.2)
Overweight (BMI 25–29.9)
Obesity (BMI >30)
Overweight and lack of physical
activity
RR 1.7 (1.4–2.1)
RR 1.6 (1.2–2.3)
RR 2.1 (1.4–3.2)
[32]
Increased physical symptoms
Depression
Regional pain for >6 years
Mobbing at the workplace
High workload
Decreased discretion in making
decisions
C-allele of the 5HT2A receptor 102T
CC-allele of the 5HT2A receptor
102T
CT-allele of the 5HT2A receptor
102T
Physical abuse in childhood
Physical abuse in adulthood
Sexual abuse in childhood
Sexual abuse in adulthood
RR 4,6 (1,7–12,2)
RR 2,3 (1,3–4,0)
RR 2,8 (1,2–6,7)
OR 4.1 (2.0–9.6)
OR 2.1 (1.2–3.9)
OR 2.1 (1.1–4.0)
[12]
OR 1.3 (1.1–1.7)
OR (1.5, 1.0–2.3)
[24]
Cohort study of 4,791 hospital employees; follow-up
after 2 years (outcome: physician-diagnosed FMS)
Meta-analysis of 21 case–
control studies regarding
genetic variants
Meta-analysis of 18 studies
with 13,095 individuals
Reference
[8]
[22]
OR 1.8 (1.2–3.9)
OR 2.5 (1.8–3.4)
OR 3.1 (1.0–9.4)
OR 1.9 (1.4–2.8)
OR 2.2 (1.1–4.7)
[15]
insurance who had recently suffered an
automobile accident examined the occurrence of widespread pain (WP) after
12 months of follow-up; 7.8% of patients
had WP. Physical symptoms after the accident (RR 2.5, 95% CI 1.2–5.1), high utilization of health care services prior to the
accident (RR 3.6, 95% CI 1.6–7.9), somatization 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 company 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 incidence of CWP was 21%. CWP was reported most commonly in the early time period after the accident. The risk of developing CWP was greater in individuals with
depressive symptoms at baseline measurement (OR 3.2, 95% CI 1.6–6.3) [20]. CWP
at 12 months was rare (49).
The examination of 53 of 153 survivors 3.5 years after a major train accident
demonstrated that 15% fulfilled FMS criteria [5].
BMI body mass index; CI confidence interval; FMS fibromyalgia syndrome; OR odds ratio; RR relative risk.
Pathophysiology
Vitamin D deficiency, infectious
diseases, and accidents
Evidence-based observation
Data on the association between FMS
and vitamin D deficiency, infectious diseases, and accidents are inconsistent.
EL 3b. Strong consensus
Comment
Vitamin D deficiency: In population-based
studies [29] and in case–control studies [17], an association of CWP with decreased vitamin D levels has been reported. 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 association of chronic hepatitis C and FMS
is contradictory. The results of two case–
control studies showing an increased
prevalence of FMS in patients with chronic hepatitis B and HTLV-1 infection, re-
4 | Der Schmerz 3 · 2012
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-center observational study of 287 patients,
22 patients (8%) developed FMS. Fifteen
patients diagnosed with FMS participated in the 4.5-year observational study.
Symptoms of Lyme disease improved in
14 of 15 patients following antibiotic therapy but FMS symptoms persisted in all patients [11]. Following Lyme disease, 5% of
patients report persistent musculoskeletal
pain, fatigue, and difficulties in concentrating [6].
Accidents: Data are contradictory. A
total of 154 patients who were hospitalized after a whiplash injury were examined after 1.5 and 3 years for the presence
of FMS; 53 patients with fractures served
as a control group. After 3 years of followup, 3 of 126 patients with whiplash injury and 1 of 53 patients with fracture were
diagnosed with FMS [43]. A prospective
cohort study of 957 members of a health
Altered central pain processing,
dysfunction of the HPA axis,
peripheral pain generators
Evidence-based observation
It is possible that the following pathophysiological mechanisms play a pathogenic role in FMS:
Faltered central pain processing
(EL 3b),
Fdysfunction of the HPA axis (EL 2b),
and
Fperipheral pain generators (EL 3b).
Strong consensus
Comment. The literature search yielded
763 hits. These included a systematic review of biomarkers [9], no other systematic reviews of other pathophysiological
mechanisms, and numerous narrative review articles (e.g., [2, 3, 13, 35, 37, 38, 40]).
Systematic reviews completed by members of the working group regarding cytokines [44] and central nervous system im-
aging (Burgmer and Petzke, 2011, personal communication) revealed the following
substantial problems that limit the significance 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 described pathophysiological changes are
epiphenomena of other processes or
whether they are confounded by other
variables (e.g., changes in cytokine patterns because of depression).
2. Confounding of the results due to comorbidities: due to the frequent comorbidity of FMS with other psychiatric disorders and functional disorders,
it is difficult to define a “pure FMS”
group [36]. The potential influence of
these comorbidities has not been sufficiently controlled in these studies. One
study that controlled for comorbid depressive 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 individuals of the same age and sex as the affected individuals, but not patients with
other chronic pain syndromes and
mental disorders. It is unclear whether the described pathophysiological abnormalities are specific for FMS.
4. Methodological problems: the heterogeneity of analysis makes a comparison
of study results difficult [35]. The sample 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 mechanisms for which the data are largely consistent 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 prospective population-based study. Out of
11,000 individuals, 768 were chosen because 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 developed CWP. A lack of suppression in
the dexamethasone suppression test (OR
3.53, 95% CI 1.17–10.65), low morning serum cortisol levels, and high evening saliva cortisol levels were associated with the
development of CWP [28].
Autonomic nervous system: A number
of differences in the function of the autonomic nervous system among patients
with FMS and healthy subjects have been
described (e.g., decreased heart rate variance, a tendency for syncope, altered cutaneous capillary responsiveness). However, a causal relationship could not be proven [38].
Immune system: Many studies addressed the issue of immune dysfunction
in FMS. Some groups detected autoantibodies whose significance is still unclear
[9]. Among the cytokines, interleukin-6
is increased in the plasma or serum of patients with FMS [44]. In one longitudinal
study, elevated cytokine levels normalized
after multimodal therapy [45].
Neurotransmitter: The neurotransmitter substance P is increased in the cerebrospinal fluid (CSF) of patients with
FMS, but also in other chronic pain syndromes, so that substance P is more of a
marker for chronic pain than for FMS specifically. Serotonin levels in CSF and serum are decreased. The CSF levels of the
neurotrophic factors nerve growth factor
(NGF) and brain-derived neurotrophic
factor (BDNF) are increased, but the significance of these findings is unclear. Data
for other neuropeptides and neurotransmitters 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, polyneuropathy was present [7]. Modulation
of muscle afferent fibers may play a role
[38].
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., measurement while resting or during stimulation), the lack of longitudinal studies, and
the low quality of the methods used and of
data analysis. Augmentation of pain processing and a tendency for altered structure and functions of brain areas that are
important for the cognitive–emotional
processing of pain and descending pain
inhibition have been reported. However, due to the general lack of patients with
other chronic pain syndromes in the control groups, these findings cannot be interpreted as being FMS specific [35].
Disorders of the thyroid hormone
system, disorders of the female
sex hormones, disorders of the
renin–angiotensin–aldosterone
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
Fdisorders of the thyroid hormone system,
Fdisorders of the female sex hormones,
Fdisorders of the renin–angiotensin–
aldosterone system,
Fstructural muscle changes, and
Fcosmetic 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 apply: learning mechanisms such as operant conditioning, and sensitization play a
role in the chronicity of FMS.
EL 2b, strong consensus
Comment. See [39]
Der Schmerz 3 · 2012 | 5
Schwerpunkt
Biopsychosocial model
Evidence-based observation
A biopsychosocial model with respect to
predisposition, initiation, and chronicity of FMS is postulated. Physical and/
or biological and/or psychosocial stressors in the context of an appropriate genetic predisposition and learning history
produce autonomic, endocrine, and central nervous system reactions that result
in the symptoms of FMS, such as pain,
fatigue, and sleep disorders, autonomic and psychological symptoms. There is
heterogeneity in the genetic predisposition, learning history, and in the autonomic, endocrine, and central nervous
system reactions. FMS is a final pathway of various pathogenetic factors and
pathophysiological mechanisms. Strong
consensus
Comment. See [39]
Discussion
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 individual factors that are related to CWP or
FMS and which may play a role in the etiology or pathophysiology of these conditions. Since the publication of the first
version of these guidelines, multiple other factors have been examined, including gene polymorphisms, smoking, overweight and nutrition, vitamins, neuroendocrine factors, immunologic factors, mitochondrial function, different infections,
central pain processing, and individual biographical aspects.
Unfortunately, for the majority of these
studies, due to limitations in methodology 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
pathophysiology.
As was mentioned in the first version
of these guidelines, there are some factors for which there is definitely no relationship with FMS. These conclusions are
still accurate and apply to the thyroid hormone system, the renin–angiotensin–al-
6 | Der Schmerz 3 · 2012
dosterone system, female sex hormones,
structural muscle changes, Lyme disease,
and cosmetic breast implants.
The best evidence for positive correlations of causative factors with the development of CWP or FMS has been obtained
from prospective cohort studies. Several biologic factors could be identified, including the presence of inflammatory–
rheumatic diseases, genetic factors, lifestyle factors such as smoking, overweight,
and decreased physical activity, and psychological factors, such as physical abuse
or sexual abuse. Additional prospective,
population-based studies with an analysis of dose–effect relationships, and interactions of presumed risk factors are required.
Conclusion for clinical practice
Several factors reduce the meaningfulness of many studies on pathophysiology, such as their sectional design, the
lack of consideration of confounding comorbidities, the small number of study
subjects, and the use of very heterogeneous methods. The pathophysiological factors that are probably associated
with FMS have been listed above. However, because of the aforementioned limitations, it is difficult to assess a causal relationship. There is an urgent need for
further research. Future research should
employ standardized methods, control for current medication use and psychological comorbidities, and include
adequate control groups consisting of
healthy individuals and individuals with
other chronic pain syndromes. In addition, studies with larger sample sizes are
required to simultaneously examine different potential neuroimmunological
and neurobiological factors, and their reciprocal relationships.
Corresponding address
C. Sommer
Neurologische Klinik,
Universitätsklinikum Würzburg
Josef-Schneider-Str. 11, 97080 Würzburg
Germany
[email protected]
Conflict of interest. See Tab. 5 in “Methodological
fundamentals used in developing the guideline” by W.
Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
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974
Der Schmerz 3 · 2012 | 7
Schwerpunkt
English Version of "Das Fibromyalgiesyndrom.
Allgemeine Behandlungsgrundsätze,
Versorgungskoordination und
Patientenschulung".
DOI 10.1007/s00482-012-1167-z
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
W. Eich1 · W. Häuser2 · B. Arnold3 · K. Bernardy4 · W. Brückle5 · U. Eidmann6 ·
K. Klimczyk7 · V. Köllner8 · H. Kühn-Becker9 · M. Offenbächer10 · M. Settan11 ·
M. von Wachter12 · F. Petzke13
1 Department of General Internal and Psychosomatic Medicine,
Heidelberg Medical University Hospital, Heidelberg
2 Internal Medicine 1, Saarbrücken Hospital, Saarbrücken
3 Department of Pain Management, Dachau Hospital, Dachau
4 Department of Pain Management, BG University Hospital Bergmannsheil GmbH,
Ruhr University Bochum
5 Fürstenhof Clinic, Bad Pyrmont
6 German Rheumatism Association, Wuppertal
7 Enzensberg Clinic, Hopfen am See
8 Department of Psychosomatic Medicine, Bliestal Clinics, Blieskastel
9 Pain Center, Zweibrücken
10 Human Sciences Center, Ludwig Maximilian University Munich
11 German Fibromyalgia Association, Seckach
12 Department of Psychosomatic Medicine, Ostalb Hospital Aalen
13 Day and Outpatient Clinic for Pain, University Medical Center Göttingen,
George August University Göttingen
Fibromyalgia syndrome
General principles and coordination of
clinical care and patient education
Due to its usually chronic course and the
highly subjective suffering and functional limitations of many patients, fibromyalgia syndrome (FMS) presents physicians
from all fields with complex care and cooperative tasks.
The following key questions were formulated by the supervisory team for the
update of this guidelines chapter:
1.Should the diagnosis of FMS be explicitly communicated to the affected
individual?
2.Which information concerning
symptoms, treatment goals and options should be given at the initial diagnosis?
3.Is patient education worthwhile?
4.Which specialties should coordinate
the treatment of FMS?
5.Does a graded treatment approach
make sense?
6.When is a stationary, multimodal
therapy indicated?
7.How should “therapeutically refractory” courses continue to be treated?
Materials and methods
Initial diagnosis
The methods for the literature research
and analysis, as well as for the preparation of recommendations, are presented
in the article “Methodological fundamentals used in developing the guideline”.
Information at the initial diagnosis
Results
Preliminary note
The following findings and recommendations apply to adults. The general principles of treatment and coordination of care
for children and adolescents are covered
in the article “Definition, diagnosis and
therapy of chronic widespread pain and
so-called fibromyalgia syndrome in children and adolescents”. The key recommendations are italicized.
Evidence-based recommendation
The patients with chronic pain in multiple body regions who meet the criteria of
FMS should be informed of the FMS  
diagnosis. EL 4, strong recommendation,
strong consensus
Comment. In the case of an initial diagnosis of a disease/disorder, releasing the
diagnosis is an ethical medical obligation.
This measure is highly feasible and carries little risk. Therefore, an upgrade of
the recommendation level by two levels
was performed.
No randomized control trials (RCTs)
have been conducted on the issue of
whether an FMS diagnosis positively or
negatively affects the health and functioning of those affected. From the perspective
of those affected, the diagnostic labeling of
a complex complaint, which may have led
to lengthy, frustrating medical diagnostics and therapy, may provide psychologDer Schmerz 3 · 2012 | 1
Schwerpunkt
ical relief and a more adequate basis for
their treatment. A Canadian study showed
greater patient satisfaction with their state
of health and a lower incidence of symptoms 18 months after diagnosis [38]. The
data regarding the impact of an FMS diagnosis on the further use of medical services are inconsistent, and there are no
studies from Germany on this topic. Recent studies from the general medical sector in Great Britain and France indicate a
possible reduction in direct medical costs
as a result of an earlier diagnosis of FMS
[3, 18].
Criteria for recommending
therapeutic procedures
effects) are not determined after 4 weeks,
the medication should be stopped. The assessment of the benefits of exercise therapy and psychotherapeutic procedures is
recommended after 3 months.
Clinical consensus point
Mild forms of FMS
Initial therapy after the
initial diagnosis
For the selection of therapeutic measures, the preferences and comorbidities
of the patient, within the guideline recommendations, should be considered.
Strong consensus
After an initial diagnosis of FMS, the patient should be informed regarding recommended and non-recommended FMS
treatment measures. Strong consensus
Comment. Regarding treatment recommendations, the consideration of patient
preferences (e.g., possible weight gain
under antidepressant therapy) and comorbidities (e.g., aqua jogging instead of
walking with comorbid knee arthritis) is a
medical ethical obligation.
Clinical point of consensus
Comorbidities
Clinical point of consensus
The patient should be advised that their
complaint is not an organic disease (fibromyalgia, in the sense of a rheumatic disease) but is instead based on a functional disorder. The legitimacy of the ailment should be assured. The patient’s
symptoms should be explained in a clear
manner with the aid of a biopsychosocial disease model, which builds on the
subjective disease theory of the patient,
e.g., by means of psychophysiological relationships (stress, vicious circle model).
Information regarding the harmlessness
of the ailment should be given. The possibilities for the patient to alleviate these
symptoms through their own activities
should be emphasized. Strong consensus
Comment. The recommendations of
the FMS guidelines on the basic measures were adapted based on the recommendations for the German (“Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften”, AWMF) S3
guideline recommendations for the management of patients with “non-specific,
functional and somatoform physical complaints” [15].
2 | Der Schmerz 3 · 2012
Clinical point of consensus
Comorbid mental disorders and physical
illnesses should be treated according to
the current guidelines. EL 2a (indirect evidence), strong consensus
Comment. For the treatment of common
comorbid disorders other than FMS (e.g.,
back pain, arthritis and depression), the
evidence and recommendation grades
for individual therapeutic procedures are
found in the relevant guidelines [9, 11, 22].
Therapy evaluation
Clinical point of consensus
The benefits (symptom reduction and
performance improvement versus side
effects and cost) should be regularly evaluated by patients and clinicians.
Therapy should only be continued in the
case of a positive benefit. Strong consensus
Comment. The time frame of the evaluation may be different for drug and nondrug therapies. In the first 2 weeks of drug
therapy, the compatibility (collection of
subjective side effects) of the medication
is especially important. The assessment of
the effectiveness of the treatment is usually possible after 4 weeks [32]. If benefits
(the positive effects that outweigh the side
Clinical point of consensus
For mild forms of FMS, the patient should
be encouraged to perform adequate
physical and psychosocial activity. Strong
consensus
Comment. The distinction between mild
and severe cases can be found in the chapter “Definition, classification and diagnosis of fibromyalgia syndrome” [12]. The
recommendations for the FMS guidelines
on basic measures were adapted based on
the German S3 guideline “Recommendations for the management of patients with
non-specific, functional and somatoform
physical complaints” [15].
Psychosocial activity involves mental
activity and the maintenance of hobbies
and social contact.
Severe cases
Clinical point of consensus
In severe cases, physical therapy, temporary drug therapy and multimodal therapy should be discussed with the patient.
Consensus
Note: “multimodal” — at least one physically activity with at least one psychotherapeutic procedure
Comment. The distinction between mild
and severe cases can be found in the chapter “Definition, classification and diagnosis of fibromyalgia syndrome” [12]. The
recommendation for initial therapy is
based on the recommendation degree of
the therapies mentioned (strong recommendation). The recommendations of the
FMS guidelines on basic measures were
adapted based on the German (AWMF)
S3 guideline “Recommendations for the
management of patients with non-specific, functional and somatoform physical
complaints” [15].
Abstract · Zusammenfassung
Lack of response to multimodal
therapy in severe cases
Schmerz 2012 · DOI 10.1007/s00482-012-1167-z
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
Clinical point of consensus
W. Eich · W. Häuser · B. Arnold · K. Bernardy · W. Brückle · U. Eidmann · K. Klimczyk · V. Köllner ·
H. Kühn-Becker · M. Offenbächer · M. Settan · M. von Wachter · F. Petzke
The patients with severe cases who do
not respond adequately to the above
mentioned measures should be treated
with multimodal programs following the
German Operations and Procedures Code
(“Operationen- und Prozedurenschlüssel”, OPS) and using disorder-specific psychological and/or drug therapy for physical comorbidities. Strong consensus
Comment. According to the German
OPS, multimodal therapy is performed in
the context of multimodal complex treatments, e.g., (semi-)inpatient multimodal pain therapy (OPS paragraphs 8-91c
and 8-918.x), multimodal rheumatologic complex treatment (OPS paragraph
8-983.01/2) or an inpatient psychosomatic–psychotherapeutic hospital treatment
(OPS paragraph 9-60.x to 9-64.x).
Multimodal pain management requires an interdisciplinary diagnosis in at
least two disciplines (compulsory psychiatric, psychosomatic or psychological discipline) and is characterized by the concomitant use of at least three of the following active therapy procedures under
medical supervision: psychotherapy, special physiotherapy, relaxation treatment,
occupational therapy, medical training
therapy, sensorimotor training, workplace training, art or music therapy or
other exercise therapies. Multimodal pain
management also includes a review of the
treatment process through a standardized
therapeutic assessment with interdisciplinary team discussion [4].
The intensity of multimodal pain
therapy for patients with severe cases of
chronic pain syndromes should be >100 h
(>25 h of psychotherapy) [26]. The integration of specific modules for mental disorders (e.g., major depression) in multimodal programs is recommended [17].
Regarding disorder-specific psychological
and/or drug therapy for unipolar depression, refer to the national guidelines [11].
Fibromyalgia syndrome. General principles and
coordination of clinical care and patient education
Abstract
Background. 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.
Materials and methods. The development
of the guidelines was coordinated by the
German Interdisciplinary Association for Pain
Therapy (“Deutsche Interdisziplinäre 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 EvidenceBased Medicine. The formulation and grading of recommendations was accomplished
using a multi-step, formal consensus process. The guidelines were reviewed by the
boards of the participating scientific medical societies.
Results and conclusion. A diagnosis of FMS
should be explicitly communicated with the
afflicted individual. A step-wise treatment,
depending on the severity of FMS and the responses to therapeutic measures, is recommended. Therapy should only be continued
if the positive effects outweigh the side effects.The English full-text version of this article is available at SpringerLink (under “Supplemental”).
Keywords
Fibromyalgia syndrome · Review, systematic ·
Meta-analysis · Guidelines · Coordination of
care · Patient education
Das Fibromyalgiesyndrom. Allgemeine Behandlungsgrundsätze, Versorgungskoordination und Patientenschulung
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer
041/004) wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie
wurde unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie (DIVS) von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potenzielle Interessenkonflikte und hierarchischer Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolgte über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke erfolgte nach dem Schema des Oxford Center
of Evidence Based Medicine. Die Formulierung und Graduierung der Empfehlungen erfolgte in einem mehrstufigen, formalisierten
Konsensusverfahren. Die Leitlinie wurde von
den Vorständen der beteiligten Fachgesellschaften begutachtet.
Ergebnisse und Schlussfolgerung. Die Diagnose eines FMS soll dem Betroffenen explizit mitgeteilt werden. Eine stufenweise Behandlung in Abhängigkeit vom Schweregrad
des FMS und dem Ansprechen auf Therapiemaßnahmen wird empfohlen. Therapien sollen nur fortgeführt werden, wenn die positiven Wirkungen die Nebenwirkungen überwiegen.
Schlüsselwörter
Fibromyalgiesyndrom · Systematische
Übersicht · Metaanalyse · Leitlinie · Versorgungskoordination ·
Patientenschulung
Der Schmerz 3 · 2012 | 3
Schwerpunkt
Duration of drug therapy
Evidence-based recommendation
In the case of a response to drug therapy, after a treatment duration of at least
6 months, a drug cessation trial should
be considered for the patient. EL 2a (indirect evidence), recommendation, consensus
Comment. The maximum duration of
the RCT study with amitriptyline, duloxetine and pregabalin was 6 months [31].
The results of subsequent open RCT studies conducted for up to 6 months showed
a sustained reduction in symptoms for only a subset of patients.
Duration of endurance training
Evidence-based recommendation
The patients who experience an improvement with aerobic endurance training should continue this training permanently. EL 1a, strong recommendation,
strong consensus
Comment. Only for aerobic training was
it shown through RCTs that the positive
effects at the initiation of training disappear after some time, yet persist with
continuous exercise [35, 36]. At the beginning of endurance training, instruction by trainers/physical therapists experienced in the care of chronically ill people may be useful to match the intensity
level to individual performance, which is
necessary to achieve symptom reduction,
e.g., in the form of formulated functional training. The purpose of this guide is to
enable afflicted individuals to have independent endurance training (either alone
or in a sports group) [28].
Long-term therapy
Clinical point of consensus
For long-term therapy, procedures that
afflicted individuals can perform independently (e.g., individual performance
for adapted endurance and/or strength
training, stretching or heat therapy)
should be used for the purpose of selfmanagement. Strong consensus
4 | Der Schmerz 3 · 2012
Comment. For this consensus point, procedures that have a proven efficacy for
their temporary use have been recommended. The long-term use of these measures can be implemented to a large extent
and carries little risk.
F cognitive behavioral therapy: patient
education, psychoeducation and exercises/homework on behavioral change
with individual feedback by a psychotherapist (direct personal contact or
Internet contact).
Coordination of care
For the analysis, the two methods of education and psychoeducation were combined. Studies with cognitive behavioral therapy are referenced in the psychotherapy paper [34]. The literature search
yielded 934 hits. The results of two studies were published twice [6, 7, 25, 37]. One
study was excluded from the meta-analysis because patient education was combined with other methods [21]. One study
was excluded because the results for the
FMS subgroup were not reported [30].
Fourteen studies (of which four were with
psychoeducation) with 1,053 patients and
an average treatment duration of 10 (6–
20) weeks were qualitatively analyzed (Evidence report, Tab. 1) [5, 7, 8, 10, 13, 14, 16,
19, 20, 24, 27, 29, 33, 39].
The quality of evidence was moderate (moderate methodological quality,
moderate external validity; Evidence report, Tab. 2). Patient education was inferior in the control groups with respect to
the selected target variables (Evidence report, Tab. 3 and Fig. 1). The standardized
mean differences (SMDs; patient education group versus control group) were not
very useful for determining effectiveness
because in some studies, patient education
served as the control group and a higher therapeutic dose was used in the active treatment group. The results of selfefficacy for pain were inconsistent; three
studies showed no improvement in selfefficacy (at the beginning and the end of
therapy) in the education group [8, 16,
20], and three studies showed an improvement [19, 26, 28]. Education was superior
to pain self-efficacy with respect to pain
improvement in one study of a wait-list
control group [29]. In one study, aerobic
training and multimodal therapy were superior to education with respect to the improvement in pain self-efficacy [27].
The acceptance was low (38% dropout
rate) and did not differ significantly from
that of the control group (Evidence report,
Fig. 1). The side effects were not systematically collected or reported. The side ef-
Long-term therapy
Clinical point of consensus
Treatment coordination should, if possible, be performed by a doctor who has
the necessary knowledge and experience
in the treatment of FMS. Consensus
Comment. No specialist in Germany
considers him/herself to be predestined
to assume a “pilot” role for FMS patients.
It is therefore recommended that affected individuals consult a doctor who has
knowledge and experience in the treatment of FMS patients and who is prepared
to assume a pilot role. Based on the experience of those afflicted, it may be difficult
in rural areas of Germany to find a suitable physician close to home.
Patient education
Evidence-based recommendation
Patient and psychological education can
be considered a basic measure. EL 1a,
open recommendation, strong consensus
Comment. The boundaries between patient education, psychoeducation and
cognitive behavioral therapy are fluid. The
various education methods have been distinguished as follows:
F education (patient education): information regarding the disease and
course of treatment in a group and/or
in writing and/or on the Internet by
a qualified person, fostering discussion and emotional exchange within
a group;
F psychoeducation: patient education
and information/motivation for selfmanagement (e.g., physical activity
and stress reduction) in group lectures
and/or in writing and/or on the Internet by a qualified person; and
fects of patient education are very rare and
minor.
Patient education sessions are offered
by FMS self-help organizations on an outpatient basis and are part of (semi-)inpatient treatment programs. Informing patients regarding the diagnosis and treatment possibilities is an ethical obligation.
Due to the high feasibility, low risks and
ethical obligation, an upgrade of the recommendation level by two levels was recommended. Psychoeducation is essential
as a preparation for active therapy.
Patient-centered communication
Evidence-based recommendation
Patient-centered communication can
be used. EL 3a, open recommendation,
strong consensus
Comment. This analysis included studies in which the doctors received special
training in patient communication, such
as shared decision-making [6] and communication skills (e.g., information exchange, conversational structure and empathy) [23].
The literature search yielded 20 hits.
Two studies with 148 patients and treatment durations of 1 and 52 weeks were
used in the analysis [2, 5, 6, 23]. In one
study, a follow-up examination was conducted after 52 weeks (Evidence report,
Tab. 4). Due to the small sample size,
gradation of the evidence was decreased
by 2°.
Quantitative data synthesis was not
possible due to the different time measurement points. Patient-centered communication was not effective based on
the specified endpoints. Patient-centered
communication and shared decision making improved the quality of the doctor–
patient relationship from both the patient
and physician points of view [6]. The patients appreciated the communication
skills of doctors who had received training in patient-centered communication
more than those of doctors in the control
group (typical medical communication).
The acceptance was moderate. The
dropout rate was 25/107 (23.4%) and did
not differ significantly from that of the
control group. Side effects were not detected and were not expected. Patient-
centered communication can be provided within psychosomatic primary care.
Including patients in the decision-making process is an ethical obligation. Due
to the lack of risks, the high feasibility and
ethical obligations, an upgrade of the recommendation by 2° was made.
The following recommendations
of the first guideline remain valid
Transfer to the hospital by
general practitioner/specialist
Clinical point of consensus
Treatment of FMS is usually on an outpatient basis. In the following situations,
admission to a hospital is recommended:
Finpatient treatment needs for comorbid physical and mental disorders and
F(semi-)inpatient multimodal pain
therapy.
The indication for (semi-)inpatient treatment from the hospital doctor is based
on the inclusion-indication lists of medical societies such as the inclusion indication list (“Aufnahmeindikationsliste”,
AIL) of the German Society for the Study
of Pain [1].
Strong consensus
Cause for (semi-)inpatient
rehabilitation measurements
Clinical point of consensus
Instigation of (semi-)inpatient rehabilitation measures is recommended, based
on the criteria of the International Classification of Functioning (ICF), when
Fparticipation in the labor force is at
risk,
Fparticipation in social life or ability for
self-sufficiency is at risk, and
Fstrongly recommended outpatient
therapeutic measures are unavailable
or insufficiently effective.
Strong consensus
Discussion
established doctors, hospitals and physicians in acute care hospitals and rehabilitation facilities), the strong consensus
that was reached for all recommendations
is emphasized. The recommendations for
treatment and coordination of care were
adapted to the existing health care structure in Germany.
In addition to the first guideline, stepwise care (depending on the response to
recommended therapies) graded according to the severity of FMS treatment was
included.
The following care and research requirements exist:
FFurther development of care structures and processes:
1cooperationandnetworkingacross
fields,
1avoidance of overcare, undercare
and lack of care, and
1advancement of existing care structures, including a comprehensive
offering of high quality care near
the patient’s home.
F
Therapy:
1definition of responder criteria (a
combination of several core symptoms of FMS),
1identification of predictors for a
positive and negative treatment
outcome,
1studies on “optimal dose finding”
for non-drug therapies,
1evaluation of graded treatment
models, and
1studies on the indication for and effectiveness of rehabilitation.
Corresponding address
Prof. Dr. W. Eich
Department of General Internal and
Psychosomatic Medicine,
Heidelberg Medical University Hospital
Im Neuenheimer Feld 10, 69210 Heidelberg
Germany
[email protected]
Conflict of interest. See Tab. 5 in “Methodological
fundamentals used in developing the guideline” by W.
Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
Given the different interests of the people involved in establishing the guidelines
(patients, clinicians, doctors, psychologists, general practitioners, specialists,
Der Schmerz 3 · 2012 | 5
Schwerpunkt
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Schwerpunkt
English Version of "Physiotherapie und
physikalische Verfahren beim
Fibromyalgiesyndrom.
Systematische Übersicht, Metaanalyse und
Leitlinie".
DOI 10.1007/s00482-012-1171-3
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
A. Winkelmann1 · W.  Häuser2 · E. Friedel3 · M. Moog-Egan4 · D. Seeger5 · M. Settan6 ·
T. Weiss7 · M. Schiltenwolf8
1 Klinik und Poliklinik für Physikalische Medizin und Rehabilitation,
Klinikum der Universität München, Munich
2 Innere Medizin 1, Klinikum Saarbrücken
3 Klinik Bad Kissingen, Kissingen
4 Neuro Orthopaedic Institute, Adelaide
5 Schmerztagesklinik und –ambulanz, Universitätsmedizin Göttingen
6 Deutsche Fibromyalgie Vereinigung, Bad Seckach
7 Praxisklinik Mannheim
8 Konservative Orthopädie, Orthopädische Universitätsklinik, Heidelberg
Physiotherapy and
physical agent therapies
for fibromyalgia syndrome
Systematic review, meta-analysis
and guidelines
The board of the working groups proposed following questions for the planned
revision of the guidelines:
1.Do physiotherapy and therapy agent
treatments provide short- and longterm effect for the treatment of fibromyalgia syndrome (FMS)?
2.Which risks are associated with the
use of physiotherapy and therapy
agents (i.e., passive treatment modalities such as hot/cold packs, massage,
electrotherapy, laser and ultrasound)
for the treatment of FMS?
3.Which physiotherapy and therapy
agent treatments are not recommended for the treatment of FMS?
Results
Materials and methods
Aerobic training with low to moderate intensity (e.g. faster walking, Nordic walking, cycling or ergometer training, dancing, aqua jogging) should be implemented 2–3 times per week for at least 30 continuous minutes. EL1a, strong recommendation, strong consensus
The methods used for the literature search
and analysis, and for the compilation of
the recommendations are reported in the
article “Methodological fundamentals
used in developing the guidelines”.
Preliminary note: the following statements and recommendations are aimed
at adults. For the general treatment objectives and treatment coordination for children and teenagers, please refer to the article “Definition, diagnosis and therapy for
chronic pain and so-called fibromyalgia
syndrome in children and adolescents”.
Key recommendations are italicized.
Strong recommendation
Aerobic training
Evidence-based recommendation
Comment. For the analysis, studies with
physical training, in which at least 60%
of the therapy time was spent on aerobic
training, were included. Studies, in which
aerobic training was combined with psychological therapies, are included and listed in the article “Multicomponent therapy
for fibromyalgia syndrome”.
For the classification of the intensity
of the aerobic training, following criteria
were used:
Flow intensity: 50–70% Hfmax (maximal heart rate),
Fmoderate intensity: 70–85% Hfmax
and
Fhigh intensity: 85–100% Hfmax.
The literature search produced 285 results. Two studies were excluded from the
analysis, as the reported clinical end stage
did not meet our inclusion criteria [102,
112]. Fourty two studies [1, 4, 10, 15, 19, 22,
27, 28, 29, 33, 36, 40, 44, 45, 49, 53, 55, 58,
60, 66, 67, 70, 72, 74, 76, 77, 81, 82, 84, 87,
89, 90, 91, 93, 95, 100, 101, 105, 109, 111, 112,
116], with a total of 2,071 patients and an
average duration time of the study of 12
(3–24) weeks, were included in the qualitative analysis. A total of 16 studies carried
out a follow-up at an average of 41 (4–208)
weeks (Evidence Report, Tab. 6).
Der Schmerz 3 · 2012 | 1
Schwerpunkt
The quality of the evidence was moderate
(moderate methodological quality, moderate external validity) (Evidence Report,
Tab. 7)
The efficacy was high. The standard
mean differences (SMDs; aerobic training—controls) at the end of the therapy on
pain, fatigue and quality of life were low.
The SMDs (aerobic training—controls) at
follow-up for pain and quality of life were
low (Evidence Report, Tab. 8 and Fig. 2).
The subgroup analysis showed no difference between land-based and waterbased, or a combination of both, aerobic training. Studies in which the patients continued to implement the aerobic
training program showed long-term (>3
months) effectiveness at follow-up. Most
of the studies implemented an aerobic
training program with low to moderate
intensity for 30 min at least twice a week.
The acceptance was moderate (dropout
rate 223/932=24%) and was not greatly
different from that of the controls (Evidence Report, Fig. 2). Side effects were not
systematically recorded. Relevant side effects, such as stress fractures, high blood
pressure and cardiac dysrhythmia were
reported as individual cases.
Aerobic training can be done independently or a part of a sports group, if necessary with guidance as part of the physiotherapy treatment or sport therapy group.
Strength training
Evidence-based recommendation
Low to moderate intensity strength
training should be employed. There is evidence for a training frequency of 60 min
twice a week. EL1a, strong recommendation, strong consensus
Comment. The literature search produced 57 studies. Three studies were excluded from the analysis, as they did not
meet the inclusion criteria; one study was
excluded, as it did not have an appropriate
control group [51, 78, 107, 108].
Six randomised, controlled trials
(RCTs) with 246 patients and average
study duration of 17 (12–21) weeks were
analysed [5, 50, 57, 61, 87, 109]. A followup was only carried out in one study after 12 weeks (Evidence Report, Tab. 9).
The quality of the evidence was moderate
2 | Der Schmerz 3 · 2012
(moderate methodological quality, moderate external validity; Evidence Report,
Tab. 10).
The efficacy was moderate. The effect
size in comparison to the controls (usual care, stretching) on pain, sleep and fatigue at the end of the therapy was moderate (Evidence Report, Tab. 11 and Fig. 3).
Side effects were not systematically recorded. The dropout rate in the studies
was 18.6% and not greatly different than
that of the control groups (Evidence Report, Fig. 3).
Strength training is available as part of
the physiotherapy treatment paid for by
the social health insurance and/or can be
performed independently following initial
guidance by the physiotherapist or sport
instructor.
ties budget2. The quality assurance of the
additional qualification and continuous
education of the therapists is the sole responsibility of the association offering the
functional training [83]. The German fibromyalgia association and the German
rheumatism league offer courses for functional trainers. These courses are recognised by both the social health insurance
and pension insurance. Functional training consists of both aerobic training and
stretching exercises. Thus there exists indirect evidence for the efficacy (see recommendations “Aerobic training” and
“Functional training”). As it is coupled
with low risks and high patient preference,
a higher recommendation has been made.
Functional training1
Thermal baths
Recommendations
Evidence-based recommendation
Evidence-based recommendation
Functional training (land- and waterbased callisthenics) should be carried out
twice a week, for at least 30 min each. EL
2a, strong evidence, strong consensus
Thermal baths should be used. There is
evidence available, which supports thermal baths 5 times a week over a period
of 2–3 weeks. EL 1a, recommendation,
strong consensus
Comment. Functional training (landand water-based callisthenics in groups
under the guidance of a physiotherapist)
is a benefit offered by the social health insurance and pension insurance and can
be prescribed for FMS for a duration of
24 months. A prescription for a longer period of time is possible, but only after individual revision and when the benefits are
necessary, appropriate and affordable. It
can be particularly necessary, when cognitive or psychological impairment does
not allow for the long-term accomplishment of the exercise program without the
guidance of a physiotherapist [59]. The
functional training in qualified exercise
groups is encouraged as additional service to rehabilitation related to § 43, paragraph 1 sentence 1 SGB V in combination
with § 44 paragraph 1 number 4 SGB IX
and is not part of the healthcare modali-
Comment. The literature search found
142 studies. Studies which included physical exercise (aerobic training, stretching,
breathing exercises) in warm water are
included in the section “Aerobic training”
and “Stretching”. In this section studies regarding balneo therapy (moor bath, steam
bath, sand bath and sauna), hydrotherapy (warm water including whirlpool),
spa therapy (bathing in mineralised water) and thalasso therapy (bathing in salt
water) are summarised. Studies, which
included hydrogalvanic baths, were analysed separately.
One study, which included sauna treatment, was excluded due to missing randomisation [80]. One study, which used
moor packs as treatment, was also excluded, as an additional therapy with trazadone was included [14]. Two studies were
2
1
Functional training and rehabilitation sport
were devised by the pension insurance and the
rheumatic league in Germany to encourage
patients with pain and chronic mobility limitation to move (again) as well as improve social
interaction in a group setting.
In Germany, the prescription of physiotherapy
treatment and related therapy agents is regulated by a healthcare modalities budget (“Heilmittel Budget”). This budget determines the number and modalities of treatment that can be prescribed and must be strictly adhered to by the
medical practitioner.
Abstract · Zusammenfassung
excluded from the meta-analysis, as these
studies included a combination of multimodal treatment [63, 118]. One study was
excluded, as the results of the FMS patients were not recorded separately [96].
The results from one study was published
twice [20, 75]. Seven studies with 396 patients and average treatment duration of 4
(1.2–12) weeks were included in the analyses [4, 6, 7, 20, 31, 32, 39, 63]. Five studies
included follow-ups after an average of 20
(6–36) weeks (Evidence Report, Tab. 12).
A quantitative analysis of five studies,
which included thermal baths as treatment, was possible. The quality of the evidence was moderate (moderate methodological quality, moderate external validity) (Evidence Report, Tab. 13).
The efficacy was low. The SMD (thermal bath—controls) on pain at the end of
the therapy was high (Evidence Report,
Tab. 14 and Fig. 4).
The acceptance was high (drop-out
rate of 5%) and did not differ greatly from the controls (Evidence Report,
Fig. 4).
The risks were presumably moderate:
side effects were not systematically recorded. Individual cases of skin changes
and cardiac dysrhythmia were described.
Thermal baths as a treatment of choice
for chronic pain syndromes are not listed in the health care catalogue3. The availability is reduced (costs for self payment,
not available in all rehabilitation centers).
Open recommendations
Stretching
Evidence-based recommendation
Stretching and flexibility training can
be considered. There is evidence available for a training frequency of 2–3 times
60 min/week. EL 2a, recommendation
open, strong consensus
Comment. The literature search found
85 studies. Seven studies with eight treatment arms and a total of 322 patients and
3 In Germany a so-called health care catalogue
(“Heilmittel Katalog”) governs what can be prescribed for which diseases and diagnoses. It also
governs the total amount of treatments that
can be prescribed and is closely related to the
health care budget.
Schmerz 2012 · DOI 10.1007/s00482-012-1171-3
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
A. Winkelmann · W.  Häuser · E. Friedel · M. Moog-Egan · D. Seeger · M. Settan · T. Weiss ·
M. Schiltenwolf
Physiotherapy and physical agent therapies for fibromyalgia
syndrome. Systematic review, meta-analysis and guidelines
Abstract
Background. 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.
Materials and methods. 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. The formulation and
grading of recommendations was accomplished using a multi-step, formal consensus
process. The guidelines were reviewed by the
boards of the participating scientific medical societies.
Results and conclusion. Low to moderate
intensity aerobic exercise and strength training are strongly recommended. Chiropractic,
laser therapy, magnetic field therapy, massage and transcranial current stimulation are
not recommended.The English full-text version of this article is available at SpringerLink
(under “Supplemental”).
Keywords
Fibromyalgia syndrome · Review, systematic ·
Meta analysis · Guideline · Aerobic exercise
Physiotherapie und physikalische Verfahren beim
Fibromyalgiesyndrom.
Systematische Übersicht, Metaanalyse und Leitlinie
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer 041/004)
wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie wurde
unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie (DIVS) von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potenzielle Interessenkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolgte über die Datenbanken Medline, PsycInfo, Scopus und Cochrane Library (bis Dezember 2010). Die Graduierung der Evidenzstärke
average treatment duration of 14 (5–20)
weeks were included in the analysis [5, 21,
69, 70, 105]. Three studies included a follow-up after 12 weeks (Evidence Report,
Tab. 15).
erfolgte nach dem Schema des Oxford Center
for Evidence Based Medicine. Die Formulierung und Graduierung der Empfehlungen erfolgte in einem mehrstufigen, formalisierten
Konsensusverfahren. Die Leitlinie wurde von
den Vorständen der beteiligten Fachgesellschaften begutachtet.
Ergebnisse und Schlussfolgerung. Ausdauer- und Krafttraining geringer bis mittlerer Intensität werden stark empfohlen. Chirotherapie, Lasertherapie, Magnetfeldtherapie, Massage und transkranielle Magnetstimulation
werden nicht empfohlen.
Schlüsselwörter
Fibromyalgiesyndrom · Systematische
Übersicht · Metaanalyse · Leitlinie · Aerobes
Training
The quality of evidence was moderate
(minimal methodological quality, high external validity) (Evidence Report, Tab. 16).
The low methodological quality meant that
the level of evidence was adjusted down.
Der Schmerz 3 · 2012 | 3
Schwerpunkt
At the end of treatment, the effect of
stretching on the reduction of pain and restrictions on the quality of life was inferior
to the active control groups (Evidence Report, Tab. 7 and Fig. 4).
The acceptance was moderate (dropout rate of 15%) and did not differ greatly from the controls (Evidence Report,
Fig. 5).
The practical applicability is high:
within the treatment scope for physiotherapy, stretching is included in the
health care catalogue and/or can be accomplished by the patients on their own
following supervision by the physiotherapist. Based on the minimal risks and the
practicality of stretching, the recommendation level is upgraded by one level.
Strong negative recommendations
Massage
Evidence-based recommendation
Massage should not be used. EL 2a, EG
strong negative recommendation, strong
consensus
Comment. The literature search found
228 studies. One study with self-massage
and stretching was excluded [36]. One
study was excluded, as the clinical endpoints did not meet the inclusion criteria
[63]. Six RCTs with 213 patients and average treatment duration of 8 (3–20) weeks
were analysed [3, 17, 25, 34, 37, 97]. Three
studies included a follow-up after 25 (24–
26) weeks (Evidence Report, Tab. 18).
The quality of evidence was low (Evidence Report, Tab. 9). Due to the low quality of the evidence, a downgrade of the evidence level was made. Massage was not
effective (Evidence Report, Tab. 20 and
Fig. 6). The acceptance was high (dropout <10%) and did not differ significantly from the controls (internet evidence
report illustration 6). Side effects were
not systematically recorded or reported.
The availability is complete. Massage for
chronic pain syndromes (including FMS)
is listed in the health care catalogue.
Quadrant intervention
Evidence-based observation
An operative quadrant operation should
not be performed. EL 4, strong negative
recommendation, strong consensus
Comments. The literature search found
three studies. In contrast to current
knowledge of the ethiopathogenesis and
pathophysiology for FMS, Bauer [11, 12]
assumes that FMS can be traced to the
compression of vascular-neural bundles
at acupressure points. The efficacy of this
is not clearly established. A microsurgical
release of the ‘adhesion’ (so called quadrant intervention) in a case study of 118 patients lead to freedom from pain in 60%
of the patients [11, 12]. The results of the
follow-ups (up to 12 months later) of 700
patients, who were operated on between
2003 and 2005, have only been published
on Bauer’s homepage on the internet.
The for spring 2009 announced data for
the three year follow-up, have to date not
been published [13]. This treatment method has as yet not been tested by other authors or in other studies. Neither has the
author of the quadrant intervention compared this treatment method with effective treatment methods such as medication and aerobic training. The potential
risks of the operation (e.g., wound infection, adhesion) are high.
The applicability is minimal. The costs
of the operation are not covered by the
social health insurance or by the private
health insurance.
Based on the potential risks, the lack
of applicability, and the ethical obligations
(preservation of the patient from physical
and financial damages), the level of recommendation has been downgraded by
2 levels.
Negative recommendations
Chiropractic
Evidence-based recommendation
Chiropractic should not be implemented.
EL 3a, negative recommendation, strong
consensus
Comment. Studies with craniosacral
therapy are listed in a separate heading.
4 | Der Schmerz 3 · 2012
The literature search found 25 studies.
One study was published as a poster for a
study protocol [115]. Three RCTs with 100
patients were analysed (Evidence Report,
Tab. 21). As the methodological quality
of the studies was low (Evidence Report,
Tab. 22) and the number of studies analysed also low, the level of evidence was
downgraded by two levels. A quantitative
data analysis could not be carried out, as
the predetermined variables were not recorded or reported. The qualitative data
analysis did not result in a consistent indication of the efficacy of treatment. In one
study, chiropractic was no more effective
than being on the waiting list in regards
to pain reduction [16]. In another study,
chiropractic in combination with electrotherapy resulted in a reduction in pain
in some patients [102]. In a further study,
strength training alone and in combination with chiropractic treatment lead to
an improvement in the quality of life [78].
None of the studies reported side effects
to the treatment. The dropout rate was between 0 and 10%. Rare and grave complications (e.g., dissection of the carotid artery) have been reported in the literature
[43]. Chiropractic is not listed as a prescribed treatment for chronic pain syndromes in the health care catalogue.
Hyperbaric oxygen therapy
Evidence-based statement
Hyperbaric oxygen therapy should not
be used. EL 3a, negative recommendation, strong consensus
Comment. The literature search found
nine studies. In one RCT 26 patients, who
had 15 sessions of hyperbaric oxygen therapy, were compared with 24 patients in the
control group (usual care). At the end of
the treatment series, there was a greater
reduction in the level of pain in the patients in the hyperbaric oxygen therapy
group compared with the control group.
Side effects were not reported [117]. The
quality of evidence in the study was low.
Hyperbaric oxygen therapy for the
treatment of FMS is not included in the
health care catalogue. Serious complications are reported in the literature [71,
85]. Thus a negative recommendation was
made.
Cold (chamber) therapy
Laser therapy
Evidence-based recommendation
Evidence-based recommendation
Cold chamber therapy should not be
used as a treatment of choice. EL 3b, negative recommendation, strong consensus
Laser therapy should not be used. EL 3a,
negative recommendation, strong consensus
Comment. The literature search found
36 studies. The results of a nonrandomised crossover study were not included, as the clinical end point was reached
after 24 h after the treatment [88].
In a case study with 120 patients (41%
with FMS) the short-term effects of full
body cold treatment (cold chamber) were
examined. A separate analysis of the FMS
patients was not published. A short-term
reduction in pain, (average of 1.5 h) by
half of the initial pain level, was reported.
At the end of the 4-week treatment period, an average pain reduction of 13% was
reported, which most likely is due to the
treatments, which were carried out along
side the cold chamber treatment. A total
of 55 of 120 patients, mainly with FMS,
discontinued the cold chamber treatment
[73]. In regards to side effects, 7% of the
participants reported burns, headaches,
shortness of breath, dizziness, increase in
pain intensity and anxiety.
In one RCT 28 patients were treated
with infrared light and 38 patients with
cold chamber. The dropout rate for the
cold chamber was 47%, for the infrared
light treatment 0%. The patients, who
discontinued the cold chamber treatment, did not differentiate in the level of
pain reduction from the group receiving
the infrared light treatment (both groups
showed significant improvement in the
level of pain reduction) [63]. The methodological quality of the studies was low. The
quality of evidence for cold therapy is low.
Efficacy (continued pain reduction) is not
shown. The level of acceptance is low, the
potential risks high. Thus the recommendation level is reduced by one level.
Dissenting opinion from the patient selfhelp groups: The experience of individual
patients is very positive.
Comment. The literature search found 46
studies. Two studies were excluded from
the analyses as laser therapy was combined with other physical therapy modalities [62, 69].
Three studies with 122 patients, and average treatment duration of 2 weeks, were
analysed [8, 47, 48] (Evidence Report,
Tab. 23). The quality of evidence was low
(Evidence Report, Tab. 24). Due to the
small number of cases and the low quality level of evidence, a downgrade of 2 levels of evidence was made.
The level of efficacy was moderate.
The SMDs (laser—sham laser) at the end
of the treatment were high for pain and
moderate for tiredness and sleep (Evidence Report, Tab.  25 and Fig.  7).
The level of acceptance was high (dropout rate 0%) (Evidence Report, Fig. 7).
Side effects were not reported.
In the studies, laser therapy was applied at a low level of energy. At higher
levels of energy, e.g., 7-W Laser, improper
use can not only lead to heat reaction, but
also to tissue damage. The practicality is
low. Laser therapy for FMS is not listed in
the health care catalogue. This treatment
method is not offered in routine clinical
practice. Due to the potential risks and the
lack of availability, a downgrade of the recommendation level followed.
Magnetic field therapy
Evidence-based recommendation:
Magnetic field therapy should not be
used. EL 2a, negative recommendation,
strong consensus
Comment. The literature search found 30
studies. One experimental study with one
single treatment was excluded from the
analysis [94]. Four studies with five study
arms and 178 patients and average treatment duration of 11 (1–26) weeks were included in the analysis (Evidence Report,
Tab. 26; [2, 26, 98, 99]). The low number
of participants (<200) in the studies re-
sulted in a downgrading of the level of evidence. The quality of evidence was moderate (high methodological quality, moderate external validity) (Evidence Report,
Tab. 27).
The efficacy of magnetic field therapy
was moderate. The SMDs (magnetic field
therapy—sham magnetic field therapy)
on pain and the quality of life at the end
of the intervention period were high (Evidence Report, Tab. 28 and Fig. 8).
The acceptance was moderate (dropout rate 16%) and did not differ greatly from the controls (Evidence Report,
Fig. 8). Three quarters of the studies reported side effects.
The practicality is minimal. Magnetic field therapy for FMS is not listed in
the health care catalogue. There are not
enough medicinal and patient reports
available about the efficacy of this system
in Germany. Thus a downgrade of the evidence level followed.
Based on the formal criteria, an open
recommendation would be possible. This
is however not in line with the preferences
of the involved company representatives
and patient groups. This resulted in a further downgrading in the recommendation
of the level of evidence.
Transcutaneous nerve stimulation
Evidence-based recommendation
Transcutaneous nerve stimulation (TENS)
should not be used. EL 3a, negative recommendation, consensus
Comment. The literature search found 31
studies. One study was excluded, as TENS
was combined with other physical agents
interventions [62]. Three RCTs with 82
patients and average study duration of 5
(3–5) weeks were analysed (Evidence Report, Tab. 29; [30, 64, 97]). The quality
of evidence was moderate (low methodological quality, moderate external validity; Evidence Report, Tab. 30). The clinical end points of the studies were published incompletely. Due to the low number of studies and the low methodological quality, the evidence was downgraded by two levels.
A quantitative analysis was completed despite incomplete data presentation.
TENS was not effective (Evidence ReDer Schmerz 3 · 2012 | 5
Schwerpunkt
port, Tab. 31 and Fig. 9). Even the pre- and
post comparisons showed no significant
SMDs. The acceptance was high (dropout
rate 4%) and did not differ greatly from
the controls. Side effects were not reported. Relevant side effects are not described
in the literature. TENS as treatment option is provided in the health care catalogue.
Transcranial direct
current stimulation
Evidence-based recommendation
Transcranial direct current stimulation
should not be used. EL 2a, negative recommendation, strong consensus
Comment. The literature search found 45
studies. The results of one of the studies
was published twice [41, 110].
Four studies with six treatment arms
and 129 patients and average treatment
duration of 15 (5–20) treatments were analysed [23, 41, 79, 110]. All studies carried
out a follow up after an average of 4 (3–
8) weeks (Evidence Report, Tab. 32). The
low number of study participants (<200)
resulted in a downgrading of the evidence
level.
The quality of the evidence was moderate (high methodological quality, moderate external validity) (Evidence Report,
Tab. 33).
The efficacy was low. The SMD (transcranial direct current stimulation vs
sham transcranial direct current stimulation) on sleep was low at the end of the
studies (Evidence Report, Tab. 34 and
Fig. 10).
The acceptance was high (dropout rate
of 5%; Evidence Report, Fig. 10). The side
effects rate was high: head and neck pain
was 10% greater than in the control group.
This treatment is an experimental treatment method for chronic pain, which, as
yet, is not part of the routine clinical treatment.
As a result of the high risks and low
availability, the level of recommendation
was downgraded by two levels.
6 | Der Schmerz 3 · 2012
Neither positive nor negative
recommendation possible
Full body heat treatment with
water-filtered mild infrared-A
radiation and hot full body packs
Evidence-based statement
Due to the limited availability of studies,
no negative or positive statement is possible. Strong consensus
Comment. Here RCTs are summarised,
in which full body heat treatment was induced by other methods than described
in the section “Thermal baths” (balneo,
spa and thalossa therapy). The literature
search found 11 studies. No placebo-controlled studies were found for the full
body heat treatment with water-filtered
mild infrared-A-radiation (6×15 min in 3
weeks). In one RCT full body heat therapy was combined with a 3-week multimodal in-patient treatment (69 patients).
Here the therapy group was superior to
the multimodal only in-patient (70 patients) treatment in regards to pain reduction and improvement in the quality of
life. The positive effects on pain and quality of life were maintained at follow-up at
3 and 6 months. One patient dropped out
due to intolerance to the heat treatment
[18]. This procedure is not part of the routine clinical intervention.
In one RCT 7 patients received full
body hot packs (no details were reported), 8 patients received aerobic training
and 11 patients received general exercises. None of the groups showed a significant change in pain, fatigue, insomnia and
quality of life [77].
Hydrogalvanic bath
Evidence-based statement
It is not possible to make either a positive
or negative statement due to the limited
number of studies. Strong consensus
Comment. In one RCT one group of 25
patients received 10 mg amitriptyline over
a period of 8 weeks and the other group
received 10 mg amitriptyline plus a total
of 10 treatments hydrogalvanic baths at
20 min for each treatment. At the end of
the treatment period, both groups showed
improvement in the quality of life. The
combined treatment was superior to the
mono-therapy with amitriptyline in the
improvement of quality of life. No side effects were established [35]. In one study,
12 patients were treated with hydrogalvanic baths (20 min twice a week) or with
progressive muscle relaxation over a period of 5 weeks. At the end of the treatment period both groups significantly reduced their pain intensity without there
being a significant difference between the
two groups [46].
Craniosacral therapy
Evidence-based statement
It is not possible to make either a positive
or negative statement due to the limited
number of studies. Strong consensus
Comment. The literature search found 27
studies. The data from one RCT was published twice [24] 68). In one RCT 52 patients were treated with craniosacral therapy (60 min twice a week for 9 weeks) and
compared with 52 patients in a placebo
group (disconnected ultrasound). A follow-up followed after 1 year. The quality
of evidence in the study was low. Craniosacral therapy was superior to the control
group in regards to the reduction of pain,
tiredness and insomnia, and at follow-up
in regards to insomnia [68].
Lymphatic drainage
Evidence-based statement
It is not possible to make either a positive
or negative statement due to the limited
data level. Strong consensus
Comment. The literature search found
seven studies. In one RCT 25 patients received connective tissue massage and 25
patients received manual lymphatic drainage over a period of 3 weeks. At the end of
the treatment period, lymphatic drainage
resulted in a significant reduction in pain,
insomnia, tiredness and restrictions in the
quality of life and was superior to the connective tissue massage in regards to improvement of the quality of life [34].
In a case study, 17 patients were treated for 12 sessions (60 min each) over a period of 4 weeks. At the end of the treat-
Tab. 1 Changes in the recommendation levels for physical agents and physiotherapy in the
first and second version of the guidelines
Intervention
Chiropractic
Functional training
Strength training
Full body heat treatment with
water filtered mild infrared-A
radiation
Full body cold therapy
Exercise therapy
Recommendation level
2008
Open
Open
Not considered
Recommended
Open
Open
Laser
Lymphatic drainage
Open
Open
Magnetic field therapy
Massage
Osteopathy
Open
Negative
Open
Physiotherapy
Open
Transcranial direct current stimulation
Ultrasound/electrotherapy
Open
Open
ment, pain, tiredness and insomnia were
reduced and the quality of life had improved. At a follow-up after 5 months,
pain and tiredness were reduced [9]. The
dropout rate was between 0 and 4%. Side
effects were not recorded. Relevant side
effects are not reported in the literature.
Lymphatic drainage for FMS is not
specifically contained in the health care
catalogue.
Physiotherapy (combined active
and passive intervention)
Evidence-based statement
It is not possible to make either a positive
or negative statement due to the limited
number of studies. Strong consensus
Comment. Individual content of physiotherapy treatment are analysed in the sections “Strength training” and “Stretching”
as well as in the article “Complementary
and alternative therapies in fibromyalgia
syndrome” under the section “Meditative
movement therapies”.
Physiotherapy uses passive—for example movement carried out by the therapist—and active—independently car-
Recommendation level 2012
Negative recommendation
Strong recommendation
Strong recommendation
Neither positive nor negative
recommendation possible
Negative recommendation
Neither positive nor negative
recommendation possible
Negative recommendation
Neither positive nor negative
recommendation possible
Negative recommendation
Strong negative
Neither positive nor negative
recommendation possible
Neither positive nor negative
recommendation possible
Negative recommendation
Neither positive nor negative
recommendation possible
ried out—movements and interventions
as well as the inclusion of physical agents
for the treatment and prevention of diseases. For the inclusion in this analysis
it was required that passive and active
movements were combined. The combination with physical agents was optional. Studies, which included active movements only (with and without physiotherapy guidance) are analysed in the sections “Stretching” and “Strength training”.
Studies, which included active movements only (with and without physiotherapy guidance) in combination with movement, breathing exercises and relaxation
or meditation are described in the article
“Complementary and alternative therapies in fibromyalgia syndrome” under the
section “Meditative movement therapies”’.
The literature search found 442 studies. One study was excluded, as it did not
include randomisation and the physiotherapy program was not described adequately [56]. One study was excluded, as
the as “Physiotherapy” described program
did not include passive movement [114].
Two RCTs with the above-described criteria were found. In one RCT, 34 patients
served as a control group receiving a kine-
siotherapy treatment to the cervical spine
and ultrasound to pain points over a period of 3 weeks on 5 days for a total of 15
treatments. The experimental group received 50 mg of sertraline per day over a
period of 6 months. In the physiotherapy group no significant reduction in pain
and insomnia was ascertained, but in the
sertraline theses were attained [42]. In one
RCT 2 physiotherapy programs were compared: 10 patients received kinesiotherapy
and active muscle stretching, and 10 patients received myofascial release according to Mézières twice a week for 75 min
each over a duration of 12 weeks. At the
end of the treatment period both groups
showed a significant improvement in the
quality of life. This was not maintained at
follow-up 12 weeks later [104].
Discussion
In comparison to the first version of the
guidelines [91], a stronger recommendation could be given by the quantitative data analysis for aerobic training. The indirect evidence for the efficacy of functional training resulted in a stronger recommendation in the current version of the
guidelines. The new version of the guidelines provides a stronger recommendation
for strength training. In the first version
this intervention was not dealt with. The
evidence for the lack of efficacy of massage resulted in a strong negative recommendation. The quantitative data synthesis with absent proof of efficacy resulted in
a negative recommendation for TENS and
transcranial direct current stimulation,
the consideration of limited availability
and risks in a negative recommendation
for chiropractic, full body cold treatment,
laser and magnetic field therapy. Changed
criteria for a positive recommendation
(presence of at least two studies) resulted in, after an open recommendation for
physiotherapy, lymphatic drainage and ultrasound in the first version of the guidelines, the statement that neither a positive
nor a negative recommendation is possible due to the restricted current level of
data available (. Tab. 1).
Further research, in the form of randomised clinical trials, is required for
functional training, physiotherapy, lymphatic drainage, magnetic field theraDer Schmerz 3 · 2012 | 7
Schwerpunkt
py, TENS (with adequate stimulation) as
well as long-term studies looking into selfmanagement with infrared cabins and ‘bio
sauna’.
Conclusion for clinical practice
It is strongly recommended that aerobic training (e.g., faster walking, Nordic walking, cycling or ergometer training, dancing, aqua jogging) and strength
training should be performed on a regular basis at least 2–3 times a week.
Recommended is functional training, as
well as from the therapy agents, the thermal baths.
Stretching can be considered.
The current state of research means that
no recommendation can be given for
physiotherapy (defined as the implementation of active and passive treatment interventions), craniosacral therapy, hydrogalvanic bath, lymphatic drainage and
full body heat treatment with water-filtered mild infrared-A radiation.
Not recommended are chiropractic, hyperbaric oxygen therapy, cold chamber
treatment, laser therapy, TENS and transcranial direct current stimulation.
Strong negative recommendations are issued for operative quadrant intervention
and massage.
Corresponding address
Dr. A. Winkelmann
Klinik und Poliklinik für Physikalische Medizin
und Rehabilitation,
Klinikum der Universität München, Munich
Ziemssenstr. 1, 80336 Munich
Germany
[email protected]
Conflict of interest. See Tab. 5 in “Methodological
fundamentals used in developing the guidelines” by W.
Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
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10 | Der Schmerz 3 · 2012
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Schwerpunkt
English Version of "Multimodale Therapie
des Fibromyalgiesyndroms. Systematische
Übersicht, Metaanalyse und Leitlinie".
DOI 10.1007/s00482-012-1173-1
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
B. Arnold1 · W. Häuser2 · M. Arnold3 · M. Bernateck4 · K. Bernardy5 · W. Brückle6 ·
E. Friedel7 · H.J. Hesselschwerdt8 · W. Jäckel9 · V. Köllner10 · E. Kühn11 · F. Petzke12 ·
M. Settan13 · M. Weigl14 · E. Winter15 · M. Offenbächer16
1 Abteilung Schmerztherapie, Klinikum Dachau
2 Innere Medizin 1, Klinikum Saarbrücken
3 Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit
und Umwelt (GmbH), München
4 Interdisziplinäre Schmerzambulanz, Medizinische Hochschule Hannover
5 Klinik Der Fürstenhof Bad Pyrmont
6 Abteilung für Schmerztherapie, Berufsgenossenschaftliche Universitätsklinik Bergmannsheil GmbH,
Ruhr Universität Bochum
7 Klinik Bad Kissingen
8 Abteilung Orthopädie und Rheumatologie, Theresienklinik, Bad Krozingen
9 Abteilung Qualitätsmanagement und Sozialmedizin, Universität Freiburg
10 Fachklinik für Psychosomatische Medizin, Bliestal Kliniken, Blieskastel
11 Deutsche Rheuma-Liga, Ellwangen
12 Schmerz-Tagesklinik und –Ambulanz, Universitätsmedizin Göttingen, Georg-August Universität Göttingen
13 Deutsche Fibromyalgie Vereinigung, Seckach
14 Klinik für Physikalische Medizin und Rehabilitation, Klinikum Großhadern, München
15 Klinik für Anästhesiologie, Klinik Havelhöhe, Berlin
16 Humanwissenschaftliches Zentrum, Ludwig-Maximilians-Universität München
Multicomponent therapy
of fibromyalgia syndrome
Systematic review, meta-analysis
and guideline
For the planned revision of the guideline, the steering group of the workgroup
posed the following questions:
1.Is multicomponent therapy in FMS
effective short-term and long-term?
2.What study duration is needed for a
multicomponent therapy to be effective?
3.Which patients should be offered a
multicomponent therapy?
4.What are the crucial components in
multicomponent therapy?
Materials and methods
Details on literature search and analysis
as well as on the development process of
the recommendations are listed in the article “Methodological fundamentals used
in developing the guideline” in this issue.
Results
The following conclusions are valid for
adult patients. For multicomponent therapy of chronic pain in several body parts of
children and adolescents, see article “Definition, diagnosis and therapy of chronic widespread pain and so-called fibromyalgia syndrome in children and adolescents”. Key recommendations are italicized.
Multicomponent therapy
Evidence-based recommendation
Multicomponent therapy should be applied. EL1a, strong recommendation,
strong consensus
Duration of multicomponent
therapy
Evidence-based recommendation
Duration of therapy should be at least
24 h. EL1a, strong recommendation,
strong consensus
Comment to the two recommendations above. In the German Operation
and Procedure Code (“Operationen- und
Prozedurenschlüssel”, OPS), multicomponent therapy is applicable in the context
of a multicomponent complex treatment
such as inpatient/outpatient multicomponent pain therapy (OPS items 8-91c and
8-918.x, respectively) or an inpatient psychosomatic–psychotherapeutic clinical
treatment (OPS items 9-60.x to 9-64.x).
According to OPS item 8-918.x, a multicomponent pain therapy requires interDer Schmerz 3 · 2012 | 1
Schwerpunkt
disciplinary diagnostics by at least 2 distinct disciplines (obligatory one psychiatric, psychosomatic or psychological discipline) and is defined by the simultaneous application of at least 3 of the following therapies under medical administration: psychotherapy, special psychotherapy, relaxation techniques, ergotherapy,
medical training therapy, sensomotoric training, employment training, art or
music therapy or other practicing therapies. Furthermore, multicomponent pain
therapy involves monitoring of the treatment progress via a standardized therapeutic assessment through interdisciplinary team meetings [7]. In the literature, “multidisciplinary approaches” in
FMS are defined as the combination of
at least one activating procedure (endurance, strength or flexibility training) with
at least one psychotherapeutic procedure
(patient education and/or cognitive behavioral therapy) [4]. Accordingly, studies combining at least one activating with
at least one psychotherapeutic procedure
were classified as “multicomponent studies” and therefore included into the analysis. Literature search obtained 760 such
studies. One study was excluded as the
clinical endpoints did not meet the criteria for inclusion [21]. A second study
was excluded because multicomponent
therapy was combined with amitriptyline
treatment [22]. The outcomes of one study
were published twice [17, 18]. All studies
that were included in the analysis met
the criteria of a multidisciplinary therapy.
Whether these studies meet the criteria of
a multicomponent therapy (monitoring of
the treatment progress via a standardized
therapeutic assessment through interdisciplinary team meetings) could not be investigated based on the published study
descriptions.
Seventeen studies with 18 study arms,
1,572 patients and an average study duration of 11 weeks (3–26 weeks) were analyzed [2, 3, 4, 6, 8, 9, 10, 12, 13, 14, 15, 16,
18, 19, 21, 23, 24]. In 8 studies, followups after an average of 8 months (range
4–24 months) were conducted (Evidence
Report Tab. 35).
The quality of evidence was moderate
(high quality of methods, moderate external validity) (Evidence Report, Tab. 36).
2 | Der Schmerz 3 · 2012
Multicomponent therapy was highly
effective. The standardized mean differences (SMDs) of multicomponent therapy vs. controls at the end of therapy were
low for pain and fatigue and moderate for
quality of life. The SMDs for multicomponent therapy vs. controls at follow-up
were low for fatigue and quality of life (Evidence Report, Tab. 37 and Fig. 11). Subgroup analysis showed that significant effects on pain, fatigue and quality of life
were obtained only at a study duration of
24 h or more (the maximum within the
included studies was 64 h) [10]. The acceptance was moderate [dropout rate
107/712 (12%)] and was not significantly
different compared to controls (Evidence
Report Fig. 11). Side effects were not systematically determined (or reported, respectively). According to clinical experience, multicomponent therapy has no significant side effects.
As in the majority of the analyzed studies patients with comorbid depression or
anxiety disorder were excluded, multicomponent therapy in more severe cases
is not sufficiently represented. For treatment in cases of more severe disease progression, more intensive multicomponent
programs are recommended (see recommendation in the article “Fibromyalgia
syndrome: general principles of and coordination of clinical care and patient education”).
Discussion
Quantitative data analysis confirmed the
outcome of the first version of this guideline [1] where multicomponent therapy
(MT) was strongly recommended.
The following recommendations
should be considered to avoid methodological constraints in future studies of
MT in FMS:
1.medication and concomitant treatment should be documented along
the study progress and should be taken account of as covariates,
2.comorbidity of mental conditions,
psychosocial stress and coping with
stress should be determined at the beginning, the end, and at follow-up of
therapy and should also be included
as covariates,
3.predefined dichotomous parameters
of the outcome (return to employment, number of patients with defined reduction of pain etc.) allow for
the determination of prognostic parameters to MT,
4.identification of predictors of positive
as well as negative outcomes of therapy,
5.randomized comparative clinical trials to identify the crucial components
in MT,
6.randomized comparative clinical trials on the efficiency of MT dependent
on therapy intensity including the
documentation of long-term effects,
and
7.randomized comparative clinical trials to identify the needed duration
of therapy in a multicomponent program dependent on the severity of
disease.
Conclusion for clinical practice
The review of more recent literature confirmed the strong recommendation of
multicomponent therapy as given in the
first version of this guideline. In the analyzed studies, multicomponent therapy was defined as a combination of one
somatically activating therapy with one
psychological procedure and was implemented in an outpatient setting. The
studies included in the analysis did not
meet the high quality standards of an
inpatient/outpatient multicomponent
therapy as specified in the German OPS.
There are no studies at hand which could
validate the recommendation of a scaling of the intensity of treatment based
on case severity. Therefore, the recommendation of the application of more intensive multicomponent programs in
cases of more severe disease progressions relies on clinical consensus.
Corresponding address
Dr. B. Arnold
Abteilung Schmerztherapie, Klinikum Dachau
Krankenhausstr. 15, 85221  Dachau
Germany
[email protected]
Conflict of interest. See Tab. 5 in “Methodological
Abstract · Zusammenfassung
fundamentals used in developing the guideline” by W.
Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
Schmerz 2012 · DOI 10.1007/s00482-012-1173-1
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
References
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Multicomponent therapy of fibromyalgia syndrome.
Systematic review, meta-analysis and guideline
Abstract
Background. 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.
Materials and methods. 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 EvidenceBased Medicine. The formulation and grading of recommendations was accomplished
using a multi-step, formal consensus process. The guidelines were reviewed by the
boards of the participating scientific medical societies.
Results and conclusion. The use of multicomponent therapy (the combination of aerobic exercise with at least one psychological therapy) for a minimum of 24 h is strongly recommended for patients with severe
FMS.The English full-text version of this article is available at SpringerLink (under “Supplemental”).
Keywords
Fibromyalgia syndrome · Review, systematic ·
Meta-analysis · Guideline · Multimodal
therapy
Multimodale Therapie des Fibromyalgiesyndroms.
Systematische Übersicht, Metaanalyse und Leitlinie
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer
041/004) wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie
wurde unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie DIVS von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potentielle Interessenkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolgte über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke er-
17. Mannerkorpi K, Ahlmén M, Ekdahl C (2002) Sixand 24-month follow-up of pool exercise therapy and education for patients with fibromyalgia.
Scand J Rheumatol 31:306–310
folgte nach dem Schema des Oxford Center
for Evidence Based Medicine. Die Formulierung und Graduierung der Empfehlungen erfolgte in einem mehrstufigen, formalisierten
Konsensusverfahren. Die Leitlinie wurde von
den Vorständen der beteiligten Fachgesellschaften begutachtet.
Ergebnisse und Schlussfolgerung. Der Einsatz von multimodaler Therapie (Kombination von aerobem Training mit mindestens einem psychologischen Verfahren) mit mindestens 24 h Therapiedauer wird für Patienten mit schwereren Verläufen des FMS stark
empfohlen.
Schlüsselwörter
Fibromyalgiesyndrom · Systematische
Übersicht · Metaanalyse · Leitlinie ·
Multimodale Therapie
18. Mannerkorpi K, Nordeman L, Ericsson A et al
(2009) Pool exercise for patients with fibromyalgia or chronic widespread pain: a randomized controlled trial and subgroup analyses. J Rehabil Med
41:751–760
Der Schmerz 3 · 2012 | 3
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19. Rooks DS, Gautam S, Romeling M et al (2007)
Group exercise, education, and combination selfmanagement in women with fibromyalgia: a randomized trial. Arch Intern Med 167:2192–2200
20. Skouen JS, Grasdal A, Haldorsen EM (2006) Return to work after comparing outpatient multidisciplinary treatment programs versus treatment in
general practice for patients with chronic widespread pain. Eur J Pain 10:145–152 (excluded: target variables not suitable for analysis)
21. Souza JB, Bourgault P, Charest J, Marchand S
(2008) Interactional school of fibromyalgia: learning to cope with pain – a randomised controlled
study. Rev Bras Reumatol 48:281–225
22. Targino RA, Imamura M, Kaziyama HH et al (2008)
A randomized controlled trial of acupuncture added to usual treatment for fibromyalgia. J Rehabil
Med 40:582–588 (excluded: combination with defined medication)
23. Koulil S van, Lankveld W van, Kraaimaat FW et al
(2010) Tailored cognitive-behavioral therapy and
exercise training for high-risk patients with fibromyalgia. Arthritis Care Res (Hoboken) 62:1377–
1385
24. Zijlstra TR, Laar MA van de, Bernelot Moens HJ et
al (2005) Spa treatment for primary fibromyalgia
syndrome: a combination of thalassotherapy, exercise and patient education improves symptoms
and quality of life. Rheumatology (Oxford) 44:539–
546
4 | Der Schmerz 3 · 2012
Schwerpunkt
English Version of "Psychotherapie von
Patienten mit Fibromyalgiesyndrom.
Systematische Übersicht, Metaanalyse und
Leitlinie".
DOI 10.1007/s00482-012-1179-8
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
V. Köllner1 · W. Häuser2 · K. Klimczyk4 · H. Kühn-Becker5 · M. Settan6 · M. Weigl7 ·
K. Bernardy3
1 Department of Psychosomatic Medicine, Mediclin Bliestal Clinics, Blieskastel
2 Department of Internal Medicine 1, Klinikum Saarbrücken
3 Department of Pain Medicine, University Clinic Bergmannsheil GmbH, Ruhr University Bochum
4 Interdisciplinary Pain Center, Clinic Enzensberg, Hopfen am See
5 Pain Center Zweibrücken
6 German Organisation for Fibromyalgia, Seckach
7 Department of Physical Medicine and Rehabilitation, University Clinic Großhadern Munich
Psychotherapy
for patients with
fibromyalgia syndrome
Systematic review, meta-analysis
and guideline
For the planned revision of the guideline
the steering group posed the following
questions:
1.Is psychotherapy in fibromyalgia syndrome (FMS) effective in short- and
long-term?
2.What are the risks involved when implementing psychotherapy in FMS?
3.Which types of psychotherapy are not
recommended in FMS?
fibromyalgia syndrome in children and
adolescents”. Key recommendations are
italicized.
Methods
Psychotherapy in FMS is recommended
in the following clinical constellations:
Fmaladaptive disease management
(e.g. catastrophizing, inappropriate
physical avoidance behavior or dysfunctional perseverance) and/or
Frelevant modulation of the symptoms
due to stress of daily life and/or interpersonal problems and/or
Fcomorbid mental disorders.
The methods used in the literature search
and analysis, and preparation of the recommendations can be found in the article “Methodological fundamentals used in
developing the guideline”.
Results
Preliminary note
The following findings pertain to adults.
For information on the psychotherapy
of children and adolescents with chronic
pain in several body regions, refer to the
paper “Definition, diagnosis and therapy
of chronic widespread pain and so-called
Indication for psychotherapy
Note: The following recommendation of
the first version of the guideline is still valid.
Clinical consensus
Strong consensus
Strong recommendations
Relaxation training combined
with aerobic exercise
(multicomponent therapy)
Evidence-based recommendation
Relaxation training combined with aerobic exercise (multicomponent therapy)
should be used. EL 1a, strong recommendation, strong consensus
Comment. Four studies of multicomponent therapy [3] with 414 patients and an
average study duration of 16 (6–26) weeks
used a combination of relaxation training
and aerobic exercise (Evidence Report,
Tab. 38; [11, 30, 36, 37]). The quality of the
evidence was moderate (Evidence Report,
Tab. 39). The efficacy was low. Low effects
on pain and quality of life were found at
the end of treatment (Evidence Report,
Tab. 40 and Fig. 12).
Der Schmerz 3 · 2012 | 1
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Cognitive behavioral therapy
combined with aerobic exercise
(multicomponent therapy)
Evidence-based recommendation
Cognitive behavioral therapy combined
with aerobic exercise (multicomponent
therapy) should be used. EL1a, strong
recommendation, strong consensus
Comment. Six studies with 7 study arms
of multicomponent therapy [3] with 542
patients and an average study duration
of 10 (6–16) weeks used a combination
of cognitive behavioral therapy and aerobic exercise (Evidence Report, Tab. 41;
[8, 18, 26, 50]). Methodological quality
was moderate (Evidence Report, Tab. 42).
The efficacy was moderate: moderate effects on fatigue at the end of treatment and
follow-up and moderate effects on quality
of life at the end of treatment were found
(Evidence Report, Tab. 43 and Fig. 13).
Open recommendations
Biofeedback
Evidence-based recommendation
Biofeedback can be used. EL 2a, open
recommendation, strong consensus
Comment. The literature search resulted
in 147 hits. Seven RCTs (5 with EMG biofeedback, 2 with EEG biofeedback) with
321 patients and an average therapy duration of 22 (1–104) weeks were included in
the analysis. Four studies conducted a follow-up after an average of 13 (1–26) weeks
(Evidence Report,  Tab. 44; [4, 7, 15, 29,
33, 41, 51]).
The quality of the evidence was moderate (low methodological quality, moderate external validity; Evidence Report,
Tab. 45). The low methodological quality resulted in a downgrade of the level of
evidence.
The efficacy was low: the standardized mean difference (SMD; biofeedback
vs. controls) of pain at the end of therapy
was significant (Evidence Report, Tab. 46
and Fig. 14).
The dropout rate was 12% and did not
significantly differ from controls (Evidence Report, Fig. 14).
2 | Der Schmerz 3 · 2012
Side effects were reported inconsistently. One study of EEG biofeedback reported twice as many side effects in the
biofeedback group as in the control group
[33], whereas another study reported no
“significant” side effects in both groups
[41]. No indication of serious side effects
was found in the literature.
The availability of biofeedback is limited (can be an element of cognitive behavioral therapy).
Hypnosis and guided imagery
Evidence-based recommendation
Hypnosis/guided imagery can be used.
EL 3a, open recommendation, strong
consensus
Comment. The literature search resulted in 55 hits. The data of one study were
specified in two publications [19, 20]. Four
studies were excluded because they were
either experimental (one single session)
[10, 19, 20] or because they were combined
with cognitive behavioral therapy [9, 39].
Five randomised controlled trials (RCTs)
with an average therapy duration of 16 (6–
26) weeks and 146 patients and were analysed. A follow-up examination was reported in two studies with an average duration of 8 weeks (4 and 12 weeks; Evidence Report, Tab. 47; [1, 23, 25, 40, 45]).
The quality of the evidence was moderate (low methodological quality, moderate external validity; Evidence Report,
Tab. 48). The low case number and the
low methodological quality in the studies
resulted in a downgrade of the level of evidence by 2 levels.
The efficacy was average. The SMDs of
pain at the end of therapy and follow-up
were high compared to controls (conventional therapy, cognitive behavioral therapy, relaxation training; Evidence Report,
Tab. 49, Fig. 15). Side effects were not documented systematically. Risks were probably infrequent but potentially severe [32].
The dropout rate in the studies was 15%
and did not differ from controls (Evidence
Report, Fig. 15).
Hypnosis is covered in compulsory
health insurance (psychosomatic primary care).
Cognitive behavioral therapy
Evidence-based recommendation
Cognitive behavioral therapy can be
used as monotherapy. EL 1a, open recommendation, consensus
Comment. The umbrella term cognitive
behavioral therapy includes studies involving cognitive therapy, operant conditioning, behavior therapy and cognitive behavioral therapy. Studies involving
mindfulness-based stress reduction (MBSR) can be found in the paper “Complementary and alternative therapies for fibromyalgia syndrome”. Studies covering psychoeducation can be found in the
paper “Fibromyalgia syndrome. General principles and coordination of clinical
care and patient education”. Studies combining cognitive behavioral therapy and
medical training therapy can be found in
the paper “Multicomponent therapy of fibromyalgia syndrome”.
Literature research resulted in 439 hits.
Three studies were excluded because they
combined cognitive behavioural therapy with other psychotherapeutic methods [10, 34, 39]. One study was published
twice [52, 53].
A total of 13 studies with 659 patients
and an average study duration of 11 (5–15)
weeks were evaluated. Eleven studies conducted a follow-up after an average of 52
(6–208) weeks (Evidence Report, Tab. 50;
[2, 8, 13, 14, 18, 21, 28, 31, 42, 43, 46, 47, 48,
53, 54]).
The quality of the evidence was moderate (moderate methodological quality,
moderate external validity; Evidence Report, Tab. 51).
Cognitive behavioral therapy was not
effective in relation to the target variables.
However, the SMDs (cognitive behavioral
therapy vs. controls) at the end of therapy
and at follow-up showed a positive trend
regarding pain (Evidence Report, Tab. 52,
Fig. 16).
The SMDs (cognitive behavioral therapy vs. controls) of depression at the end
of therapy and at follow-up were low. The
SMDs (cognitive behavioral therapy vs
controls) of self-efficacy regarding pain at
the end of therapy and at time of catamnesis were high [5].
Abstract · Zusammenfassung
The dropout rate was moderate (14%)
and did not differ significantly from controls (Evidence Report, Fig. 16). Side effects were not reported systematically
(possible symptom increase). Severe side
effects were not illustrated in the literature [32].
Cognitive behavioral therapy is included in the guidelines for psychotherapy of the statutory health insurance and is
therefore covered.
Due to the low risks and wide availability, the recommendation was upgraded by
one level.
Negative recommendations
Relaxation training
Evidence-based recommendation
Relaxation training should not be used
as monotherapy. EL 2a, negative recommendation, strong consensus
Comment. The literature search resulted in 207 hits. One study was excluded
because the target variables of the study
did not fulfill the inclusion criteria of the
systematic review [35]. Eight studies with
460 patients and an average study duration of 10 (3–26) weeks were analysed.
Three studies conducted a follow up after
an average of 22 (16–26) weeks. In all studies relaxation training served as the control group and was compared with other
forms of active therapy [16, 17, 24, 26, 30,
38, 44, 45] (Evidence Report, Tab. 53). The
quality of the evidence was moderate (low
methodological quality, moderate external validity; Evidence Report, Tab. 54).
Due to the low methodological quality the
recommendation was downgraded.
Relaxation training was not effective.
As far as pain reduction, relaxation training was inferior to active controls at the
end of therapy. No significant differences in sleep disturbance and restrictions on
quality of life were found (Evidence Report, Tab. 55 and Fig. 17).
The dropout rate was moderate (16%)
and did not differ significantly from controls (Evidence Report, Fig. 17). Side effects were not reported systematically. Severe side effects were not described in the
literature.
Schmerz 2012 · DOI 10.1007/s00482-012-1179-8
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
V. Köllner · W. Häuser · K. Klimczyk · H. Kühn-Becker · M. Settan · M. Weigl · K. Bernardy
Psychotherapy for patients with fibromyalgia syndrome.
Systematic review, meta-analysis and guideline
Abstract
Background. 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.
Materials and methods. 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. The recommendations were
based on level of evidence, efficacy (metaanalysis of the outcomes pain, sleep, fatigue
and health-related quality of life), acceptability (total dropout rate), risks (adverse events)
and applicability of treatment modalities in
the German health care system. The formulation and grading of recommendations was
accomplished using a multi-step, formal consensus process. The guidelines were reviewed
by the boards of the participating scientific
medical societies.
Results and conclusion. Cognitive behavioral therapy combined with aerobic exercise
(multicomponent therapy) is strongly recommended. Relaxation as single therapy should
not be applied.The English full-text version of
this article is available at SpringerLink (under
“Supplemental”).
Keywords
Fibromyalgia syndrome · Systematic review ·
Meta-analysis · Guideline · Psychotherapy
Psychotherapie von Patienten mit Fibromyalgiesyndrom.
Systematische Übersicht, Metaanalyse und Leitlinie
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom AWMF Registernummer 041/004
wurde ab März 2011 vorgenommen.
Methodik. Die Leitlinie wurde unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie DIVS von neun
wissenschaftlichen Fachgesellschaften und
zwei Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen mit insgesamt
50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potentielle Interessenkonflikte und hierarchische Position im medizinischen bzw. wissenschaftlichen System besetzt.
Die Literaturrecherche erfolgte über die
Datenbanken Medline, PsycInfo, Scopus und
Cochrane Library (bis Dezember 2010). Die
Graduierung der Evidenzstärke erfolgte nach
dem Schema des Oxford Center for EvidenceBased Medicine. Grundlage der Empfehlungen waren die Evidenzstärke, die Wirksam-
Relaxation training is included in the
list of medical services covered by the
statutory health insurance (psychosomat-
keit (Metaanalyse der Zielvariablen Schmerz,
Schlaf, Müdigkeit und gesundheitsbezogene
Lebensqualität), die Akzeptanz (Abbruchrate
in Studien), Risiken (Nebenwirkungen) und
die Anwendbarkeit der Therapieverfahren
im deutschen Gesundheitssystem. Die Formulierung und Graduierung der Empfehlungen erfolgte in einem mehrstufigen, formalisierten Konsensusverfahren. Die Leitlinie
wurde von den Vorständen der beteiligten
Fachgesellschaften begutachtet.
Ergebnisse und Schlussfolgerung. Kognitive Verhaltenstherapie in Kombination mit
Ausdauertraining (multimodale Therapie)
wird stark empfohlen. Entspannungstraining als Monotherapie soll nicht eingesetzt
werden.
Schlüsselwörter
Fibromyalgiesyndrom · Systematische
Übersicht · Metaanalyse · Leitlinie ·
Psychotherapie
ic primary care, element of cognitive behavioral therapy).
Der Schmerz 3 · 2012 | 3
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Tab. 1 Modifications of level of recommendation for psychotherapy in the first and second
version of the guidelines
Therapy method
Biofeedback
Cognitive behavioral
therapy
Therapeutic writing
Level of recommendation 2008
Negative recommendation
Strong recommendation
Level of recommendation 2012
Recommended
Open recommendation
Recommended
Negative recommendation
Therapeutic writing
Evidence-based finding
Therapeutic writing should not be used
as monotherapy. EL 2a, negative recommendation, strong consensus
Comment. The literature search resulted
in 13 hits. One study was published twice
[6, 27]. Two studies with 166 patients were
analysed [6, 22]. Due to the short study
duration (one week), the first examination was not conducted at the end of therapy but rather after 4 and 12 weeks, and
the last follow-up after 12 and 40 weeks
respectively. To have comparable time intervals the data was chosen for the analysis 12 weeks after the end of the intervention (Evidence Report, Tab. 56).
The quality of the evidence was moderate (high methodological quality, moderate external validity) (Evidence Report,
Tab. 57). The evidence level was downgraded due to insufficient data.
No efficacy was found compared to
controls (conventional writing; Evidence
Report, Tab. 58, Fig. 18).
Acceptability was moderate. The dropout rate was 16% and did not differ from
controls (Evidence Report, Fig. 18). Side
effects were not reported. Based on psychotherapeutic experience, psychological
decompensation resulting from the measure is possible.
Principally, the measure may be used
based upon psychosomatic primary care
or psychotherapeutic guidelines.
No positive or negative
recommendation possible
Other forms of psychotherapy
(client-centered therapy
(Rogers), couple and family
therapy, humanistic therapy,
systematic therapy)
Evidence-based finding
Neither a positive nor negative recommendation of other forms of psychotherapy (client-centered therapy (Rogers), couple and family therapy, humanistic therapy, systematic therapy) is possible due to insufficient data. Strong consensus
Comment. The literature search resulted in 60 hits. Neither controlled or uncontrolled nor case studies were found
in other forms of psychotherapy used as
monotherapy (client-centered therapy
(Rogers), couple and family therapy, humanistic therapy, systematic therapy). In
a Dutch non-randomized study, 50 patients received a combination of cognitive behavioral therapy (9 sessions) and
couple therapy (10 sessions) over a period of 9 months. No significant differences
in pain and sleep were found at the end of
therapy when compared to controls [12].
Psychodynamic psychotherapy
and psychoanalysis therapy
Evidence-based finding
Due to insufficient data, neither a positive nor negative recommendation of
psychodynamic psychotherapy and psychoanalysis therapy is possible. Strong
consensus
Comment. The literature research resulted in 21 hits. Neither (un-)controlled studies of psychodynamic therapy nor studies of interpersonal therapy were found.
4 | Der Schmerz 3 · 2012
In Germany, 2 RCTs were found using
psychodynamic therapy in patients with
FMS/somatoform pain disorder, the results of which have not yet been published (Egle 2007, personal communication: Scheidt 2010, personal communication).
In 1 RCT, 54 patients received equal
parts of cognitive behavioral therapy and
interpersonal therapy over a period of
8 weeks, 2 h per week. They were compared with the waiting group of 47 patients. No significant differences were
found in pain and quality of life at the end
of therapy and at follow-up (12 weeks)
[34].
Discussion
In comparison with the first version of the
guidelines [49], lower recommendations
for cognitive behavioral therapy were
made because of the modifications made
in establishing the recommendations (taking into account the quantity and quality of evidence, meta-analysis, taking into consideration the risks and availability
instead of qualitative analysis of the main
results of the studies). Due to the quantitative data synthesis, the recommendation for therapeutic writing changed from
positive to negative, and for biofeedback,
from negative to positive (. Tab. 1).
Research desiderata:
F
studies of dose–response relationships of psychotherapy,
F
randomized clinical trials comparing
standard psychotherapy with “customized” psychotherapy (e.g. different approaches for subgroups of various types of pain management or
with comorbid major depression) and
F
development of easily assessable
short-term psychotherapy for minor
manifestations and review of cost effectiveness.
Corresponding address
Prof. Dr. V. Köllner
Department of Psychosomatic Medicine,
Mediclin Bliestal Clinics
66440 Blieskastel
Germany
[email protected]
Conflict of interest. See Tab. 5 in “Methodological
fundamentals used in developing the guideline” by W.
Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
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46. Soares JJF, Grossi G (2002) A randomised, controlled
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47. Thieme K, Gromnica-Ihle E, Flor H (2003) Operant
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(2010) Tailored cognitive-behavioral therapy and
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MEJB (2005) Efficacy of a cognitive-educational
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Der Schmerz 3 · 2012 | 5
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English Version of "Medikamentöse Therapie
des Fibromyalgiesyndroms. Systematische
Übersicht und Metaanalyse".
DOI 10.1007/s00482-012-1172-2
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
C. Sommer1 · W. Häuser2 · R. Alten3 · F. Petzke4 · M. Späth5 · T. Tölle6 · N. Üçeyler1 ·
A. Winkelmann7 · E. Winter8 · J. Bär9
1 Neurologische Klinik, Universitätsklinikum Würzburg
2 Innere Medizin 1, Klinikum Saarbrücken gGmbH, Saarbrücken
3 Schlossparkklinik Berlin
4 Schmerz-Tagesklinik und -Ambulanz, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen
5 Rheumatologische Praxis, München-Gräfelfing, Munich-Gräfelfing
6 Klinik für Neurologie, Technische Universität München, Munich
7 Klinik und Poliklinik für Physikalische Medizin und Rehabilitation,
Klinikum der Universität München, Munich
8 Klinik für Innere Medizin mit Schwerpunkt Psychosomatik, Charité Universitätsmedizin Berlin
9 Klinik für Psychiatrie und Psychotherapie, Friedrich-Schiller-Universität Jena
Pharmacological
treatment of fibromyalgia
syndrome
Systematic review and meta-analysis
For the revision of the guideline the working groups asked the following questions:
1.Is pharmacological treatment effective in the short- and long-term in fibromyalgia syndrome (FMS)?
2.Which risks are associated with pharmacological treatment of FMS?
3.Which drugs should be avoided in
treatment of FMS?
Materials and methods
The methodology of literature search and
analysis, and preparation of recommendations are presented separately in the article “Methodological fundamentals used in
developing the guideline”.
Results
Preliminary notes
a)The following findings apply to adults.
For the pharmacological treatment
of FMS and chronic widespread pain
in children and adolescents please refer to the paper “Definition, diagnosis and therapy of chronic widespread
pain and so-called fibromyalgia syndrome in children and adolescents”.
b)In Germany no drug is licensed for
the treatment of FMS. We performed
quantitative analyses for drug classes but not for individual drugs. Exceptions are duloxetine, milnacipran
(MLN) and pregabalin (PGB), since
these substances have been investigated in several large studies during registration trials.
Recommendations
Duloxetine
Evidence-based recommendation
FMS patients with comorbid depressive
disorder and/or generalized anxiety disorder should be treated with duloxetine
(60 mg/day) for a limited period of time.
EL 1a, recommendation, consensus
Remark: In Germany duloxetine is not licensed for the treatment of FMS. It is licensed for the treatment of depressive
disorders and generalized anxiety disorders.
Comment. Duloxetine is a serotonin–
noradrenalin reuptake inhibitor with a
five-fold stronger effect on serotonin than
on noradrenalin.
Literature search revealed 46 hits. One
study was excluded from meta-analysis,
because it contained an 8 week non-blinded pre-phase and did not have a placebo
group during the double-blind phase [29].
For quantitative analysis of data on drug
effectiveness five randomized, controlled
trials (RCT) with 8 drug treatment arms
(different dose regimens of duloxetine)
were included investigating 1,397 patients. The mean study duration was 20
(12–26) weeks (Evidence Report, Tab. 59;
[4, 5, 8, 30, 94]).
Quality of evidence was moderate (Evidence Report, Tab. 60). In contrast to the
RCT with milnacipran (MLN) and pregabalin (PGB), patients with major depression (all studies) and with generalized
anxiety disorders (one study) were included in duloxetine studies. The effectiveness
of duloxetine was moderate (Evidence Report, Tab. 61 and Fig. 19). Standardized
mean differences (SMD) of duloxetine
versus placebo for pain, sleep, and healthrelated quality of life were low. Small posDer Schmerz 3 · 2012 | 1
Schwerpunkt
itive effects of duloxetine on sleep were
reported only in one study, although data were obtained in all studies. Sleep disturbance is a frequent side effect of duloxetine; therefore the reported positive results should be interpreted with caution.
The acceptance of duloxetine was low:
the dropout rate was high (33%) and did
not differ from placebo controls (Evidence Report, Fig. 19). Risks were high:
several subjectively relevant side effects of
duloxetine were observed in >10% compared to placebo. Very rare severe (potentially life-threatening) complications like
suicidality and liver toxicity have been reported during duloxetine treatment [29].
The recommendation was downgraded due to the limited availability and the
potential risks.
Tricyclic antidepressants
Evidence-based recommendation
Amitriptyline (AMT; 10–50 mg/day)
should be used for a limited period of
time. EL 2a, recommendation, strong
consensus
Remark: In Germany AMT is not licensed
for the treatment of FMS. It is licensed for
the treatment of chronic pain in the context of a comprehensive therapy concept.
Comment. Literature search revealed
103 hits. Three studies were excluded due
to inappropriate endpoints [20, 66, 83];
3 studies were excluded due to the combination of AMT with other treatment
methods [44, 64, 106], and 1 study because
of missing randomization. Data of 1 study
were only available as an abstract [40].
For quantitative analysis 18 studies
with 19 drug treatment arms and a mean
study duration of 8 (2–24) weeks were assessed investigating 1,014 patients. AMT
was applied in 14 studies, nortriptyline
and dothiepin were used in one study each
(Evidence Report, Tab. 62, [11, 13, 24, 25,
26, 27, 28, 39, 46, 49, 52, 53, 57, 59, 61, 69,
99, 114]).
Quality of evidence was moderate;
methodological quality and external validity were low (Evidence Report, Tab. 63).
Evidence was downgraded by one point
due to low methodological quality.
2 | Der Schmerz 3 · 2012
Effectiveness was moderate. SMD of
tricyclic antidepressants versus placebo at the end of treatment were moderate for pain, sleep, and fatigue and also for
health-related quality of life (Evidence Report, Tab. 64, Fig. 20).
Acceptance was moderate with a dropout rate of 14% that did not differ from
placebo (Evidence Report, Fig. 20).
Side effects were not assessed systematically. According to the Summary of
Product Characteristics (SmPC) subjective relevant side effects are reported in
>10% of patients under AMT compared
to placebo. These include symptoms like
drowsiness and dry mouth. Potentially
life-threatening side effects like liver and
bone marrow toxicity were very rarely reported (<0.1%).
AMT is licensed for the treatment of
chronic pain in the context of a comprehensive therapy concept.
Open recommendations
Duloxetine
Evidence-based recommendation
Treatment with duloxetine (60 mg/day)
can be considered for a limited time period in patients without comorbid depressive disorder or generalized anxiety disorder, if treatment with AMT is not possible (e.g. due to contraindications), was
not effective or was not tolerated (“off-label use”). EL 1a, open recommendation,
consensus
Comment. When using duloxetine in patients without comorbid depressive disorder or generalized anxiety disorder the
following criteria for “off-label use” should
be considered:
F proven effectiveness,
F positive risk–benefit profile,
F lack of alternatives,
F individual trial for curing the disease.
Therefore “off-label use” is permitted only
in severe cases when alternative treatment
options are missing. The perspective for
treatment success on the basis of current
scientific knowledge is mandatory. Moreover, detailed patient information is obligatory. Patients must be informed about of
“off-label use” and about possible liabili-
ties. It is necessary to reach a decision in
consensus with the patient.
Pregabalin
Evidence-based recommendation
Treatment with pregabalin (PGB; 150–
450 mg/day) can be considered for a limited time period, if treatment with AMT
is not possible (e.g. due to contraindications), was not effective or was not tolerated (“off-label use”). EL 1a, open recommendation, consensus
Comment. When using PGB in patients
without comorbid depressive disorder or
generalized anxiety disorder the following
criteria for “off-label use” should be considered:
F proven effectiveness,
F positive risk–benefit profile,
F lack of alternatives,
F individual trial for curing the disease.
Therefore “off-label use” is permitted only in severe cases when treatment alternatives are lacking. The perspective for treatment success on the basis of current scientific knowledge is mandatory. Moreover,
detailed patient information is obligatory.
Patients must be informed about of “offlabel use” and about possible liabilities. It
is necessary to reach a decision in consensus with the patient.
Literature search for anticonvulsants
revealed 154 hits. Studies on PGB and gabapentin (GPT) were found. The study using GPT is referred to in the section on evidence-based recommendations for GPT.
One study investigating PGP could
not be used for quantitative analysis
[34]; 4 studies with 12 drug treatment
study arms and a study duration of 12 (8–
14) weeks investigating 4,132 patients were
analyzed (Evidence Report, Tab. 65; [7, 33,
76, 86]).
Quality of evidence was moderate with
moderate quality of methods and low external validity. Patients with generalized
anxiety disorders were not explicitly included (Evidence Report, Tab. 66). The
effectiveness of PGB was moderate: SMD
of PGB versus placebo at the end of treatment were small for pain and sleep and
not significant for fatigue and health-re-
Abstract · Zusammenfassung
lated quality of life (Evidence Report,
Tab. 67, Fig. 21).
Acceptance was low: the dropout rate
was 32%; the relative risk for dropout was
higher in the drug treatment compared
to the placebo group. Risks of PGB were
high: the difference of the frequency of
some subjectively relevant side effects
was >10% in the drug treatment group
compared to placebo (Evidence Report,
Fig. 21; [60]).
Practicability is limited. In Germany PGB is not licensed for the treatment
of FMS, but for the treatment of generalized anxiety disorders and of neuropathic
pain. Due to the low patients’ acceptance,
the limited license, and the ethical commitment to protect patients from harm
the recommendation was downgraded by
two points.
Serotonin reuptake inhibitors
Evidence-based recommendation
Serotonin reuptake inhibitors (SSRI;
fluoxetine: 20–40 mg/day, paroxetine:
20–40 mg/day) can be considered for a
limited time period in patients with comorbid depressive disorder and anxiety
disorder. EL 2a, open recommendation,
consensus
Note: In Germany fluoxetine and paroxetine are licensed for the treatment of
depressive and anxiety disorders, but not
for FMS.
Comment. The literature search revealed
130 hits. Three studies were excluded because study endpoints did not fulfill inclusion criteria [23, 48, 81]. Thirteen studies with a mean study duration of 10 (4–
26) weeks were qualitatively analyzed including 610 patients (Evidence Report,
Tab. 68; [1, 3, 11, 24, 40, 53, 54, 56, 64, 80,
83, 100, 115]).
Methodological quality of evidence
was low; external validity was moderate
(Evidence Report, Tab. 69). Therefore the
level of evidence was downgraded.
Effectiveness was moderate. SMD of
SSRI versus placebo were significant for
pain, sleep, and health-related quality of
life; effect size was small (Evidence Report, Tab. 70, Fig. 22).
Acceptance was moderate. The dropout rate was 19% and did not differ from
Schmerz 2012 · DOI 10.1007/s00482-012-1172-2
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
C. Sommer · W. Häuser · R. Alten · F. Petzke · M. Späth · T. Tölle · N. Üçeyler · A. Winkelmann ·
E. Winter · J. Bär
Pharmacological treatment of fibromyalgia syndrome.
Systematic review and meta-analysis
Abstract
Background. 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.
Materials and methods. The development
of the guidelines was coordinated by the
German Interdisciplinary Association for Pain
Therapy (“Deutsche Interdisziplinäre 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 EvidenceBased Medicine. The recommendations were
based on level of evidence, efficacy (meta-
analysis of the outcomes pain, sleep, fatigue
and health-related quality of life), acceptability (total dropout rate), risks (adverse events)
and applicability of treatment modalities in
the German health care system. The formulation and grading of recommendations was
accomplished using a multi-step, formal consensus process. The guidelines were reviewed
by the boards of the participating scientific
medical societies.
Results and conclusion. Amitriptyline
and—in case of comorbid depressive disorder or generalized anxiety disorder—duloxetine are recommended. Off-label use of duloxetine and pregabalin can be considered in
case of no comorbid mental disorder. Strong
opioids are not recommended.The English
full-text version of this article is available at
SpringerLink (under “Supplemental”).
Keywords
Fibromyalgia syndrome · Systematic review ·
Meta-analysis · Guideline · Combined
modality therapy
Medikamentöse Therapie des Fibromyalgiesyndroms.
Systematische Übersicht und Metaanalyse
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer
041/004) wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie
wurde unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie (DIVS) von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potenzielle Interessenkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolgte über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke erfolgte nach dem Schema des Oxford Center
for Evidence Based Medicine. Grundlage der
Empfehlungen waren die Evidenzstärke, die
Wirksamkeit (Metaanalyse der Zielvariablen
Schmerz, Schlaf, Müdigkeit und gesundheitsbezogene Lebensqualität), die Akzeptanz
(Abbruchrate in Studien), Risiken (Nebenwirkungen) und die Anwendbarkeit der Therapieverfahren im deutschen Gesundheitssystem. Die Formulierung und Graduierung der
Empfehlungen erfolgte in einem mehrstufigen, formalisierten Konsensusverfahren. Die
Leitlinie wurde von den Vorständen der beteiligten Fachgesellschaften begutachtet.
Ergebnisse und Schlussfolgerung. Amitriptylin und – bei komorbiden depressiven
Störungen oder generalisierter Angststörung
– Duloxetin werden empfohlen. Der Off-label-Gebrauch von Duloxetin oder Pregabalin kann im Falle von fehlenden komorbiden
depressiven Störungen oder fehlender generalisierter Angststörung erwogen werden.
Starke Opioide werden nicht empfohlen.
Schlüsselwörter
Fibromyalgiesyndrom · Systematische
Übersicht · Metaanalyse · Leitlinie ·
Multimodale Therapie
Der Schmerz 3 · 2012 | 3
Schwerpunkt
placebo (Evidence Report, Fig. 22). Side
effects were not systematically assessed in
the studies. Rare severe side effects are described in literature, e.g. bleedings [2].
Practicability is limited: in Germany
the analyzed SSRI are not licensed for the
treatment of FMS, but for the treatment
of depression and partly of anxiety disorders. The evidence level was downgraded
due to potential risks and the lack of a license for FMS in Germany.
Stong negative recommendations
Antiviral drugs
Evidence-based recommendation
Antiviral drugs should not be used. EL 2b,
strong negative recommendation, strong
consensus
Comment. The literature search revealed five hits. In one RCT 30 patients
each received valaciclovir 1 g or placebo for 6 weeks. At the end of treatment
no differences were found regarding pain
and health-related quality of life. In both
groups 4 out of 30 patients stopped treatment [70]. Severe side effects of virostatics
are reported in the literature. Virostatics
are neither licensed for FMS nor for frequent comorbidities. Due to the high risks
and the low availability the negative recommendation was further downgraded.
Anxiolytics
Evidence-based recommendation
Anxiolytics should not be used. EL 2a,
strong negative recommendation, strong
consensus
Comment. The literature search revealed
36 hits. Two studies were suitable for analysis: one study each with alprazolam and
bromazepam [88, 92]. A quantitative data synthesis could not be performed. Due
to the limited data the evidence level was
downgraded.
Quality of evidence was moderate [see
studies on nonsteroidal antirheumatics
(NSAR)]. Anxiolytics were ineffective:
in a study over 8 weeks no difference was
found between treatment with placebo
plus alprazolam (up to 3 mg/day; 17 patients) and treatment with double placebo
4 | Der Schmerz 3 · 2012
(14 patients) with regard to pain reduction
and improvement of health-related quality of life [92]. In a study over 8 weeks no
difference was found between treatment
with bromazepam (3 mg/day; 42 patients)
and placebo (42 patients) with regard to
the number of patients that experienced a
reduction in pain intensity or in morning
stiffness of at least 25% [88]. Bromazepam
is not licensed for the treatment of FMS,
but for the treatment of chronic anxiety
and of chronic stress (limited practicability). Anxiolytics can be used for the treatment of anxiety disorders [12]. Due to the
high risks, the ethical commitment to protect patients from harm, and the limited
availability the negative recommendation
further downgraded.
Dopamine agonists
Evidence-based recommendation
Dopamine agonists should not be used.
EL 2a, strong negative recommendation,
strong consensus
Comment. The literature search revealed
56 hits. Three studies with a study duration of 12 weeks including 300 patients
were analyzed (Evidence Report, Tab. 71;
[37, 51, 62]). Due to the limited data the
evidence level was downgraded.
The quality of evidence was moderate with moderate quality of methodology and external validity (Evidence Report,
Tab. 72).
Dopamine agonists were not effective
(no superiority to placebo in reducing
pain or increasing health related quality
of life; Evidence Report, Tab. 73, Fig. 23).
Acceptance was low: the dropout rate
was 55.5% and was not higher than in the
placebo group (Evidence Report, Fig. 23).
Frequent side effects (>10% compared to
placebo) were sleep disturbance, nausea,
weight loss, and abdominal pain. Rare severe side effects of dopamine agonists are
reported in the literature.
Dopamine agonists are licensed for the
treatment of FMS. Pramipexole is licensed
for the treatment of Parkinson’s disease
and of the moderate and severe restless
legs syndrome.
The level of negative recommendation
was downgraded by one point because do-
pamine agonists are not licensed for FMS
and due to the low patients’ acceptance.
Hormones (calcitonin, testosterone,
estrogens, glucocorticosteroids,
thyroid hormones, growth factors)
Evidence-based recommendation
Hormones (calcitonin, testosterone, estrogens, glucocorticosteroids, thyroid
hormones, growth factors) should not be
used. EL 3a, strong negative recommendation, strong consensus
Comment. The literature search revealed
128 hits. The level of evidence was downgraded due to the limited number of studies. Due to the potential risks and the lacking license for FMS or for frequent comorbidities a downgrade of evidence levels by
one point was performed for all substances.
One RCT was found for calcitonin.
In a cross-over RCT 11 patients received
100 IU calcitonin s.c. or saline for 4 weeks.
No intergroup difference was found with
regard to pain, fatigue, sleep, and pain reduction. One of the 11 patients stopped
treatment with calcitonin because of side
effects. Side effects appeared frequently
(nausea, erythema) [18].
One RCT was found using testosterone-like substances. In a cross-over RCT
52 postmenopausal women were treated
with dehydroepiandrosterone (DHEA;
50 mg/day) for 1 month; results were not
different compared to placebo with regard to pain, sleep disturbance, and fatigue [53].
One RCT was found using estrogen-like substances. In an Iranian study
50 postmenopausal women were treated
with the selective estrogen modulator raloxifene 60 mg for 16 weeks; 50 women received placebo. Raloxifene was superior to
placebo with regard to pain, sleep, and fatigue. The dropout rate was 4% [95]. No
relevant side effects were reported.
Estrogens or the combination of estrogen and gestagen can be used for the
treatment of climacteric symptoms like
hot flush considering possible risks [36].
One RCT was found investigating the
effect of glucocorticosteroids. In a USAmerican cross-over RCT with 20 patients, oral prednisone (15 mg/day) treat-
ment for 14 days was not superior to placebo in reducing pain, sleep disturbance,
and fatigue [31].
In another RCT of 8 and 9 months duration, 7 and 4 euthyroid patients, respectively, were alternately treated with supraphysiological doses of T3 (93.75–150 μg/
day) or placebo. Significant pain reduction was reported at the end of the T3
treatment phase. No side effects were reported in this study; however, they seem
possible (induction of hyperthyroidism;
[71, 72]).
Two studies were found investigating
growth hormones [15, 35]. Quantitative
analysis was not possible. In one study
25 patients were treated with growth hormone (0.0125 mg/kg s.c.) or placebo for
9 months. Health-related quality of life
was higher in the growth hormone group
compared to the placebo group. In another study 12 patients were treated with
growth hormone (0.0125 mg/kg s.c.) or
placebo for 1 year in addition to a multimodal and pharmacological treatment
(AMT, fluoxetine, tramadol). At the end
of the study health-related quality of life
was higher in the group with additional
growth hormone treatment; also pain and
fatigue were lower compared to the placebo group.
Dropout rates were low (0–13.6%). Side
effects (edema, anemia, carpal tunnel syndrome, hyperglycemia, hypertriglyceridemia) were observed only in the growth
hormone group.
Hypnotics
Evidence-based recommendation
Hypnotics should not be used. EL 3a,
strong negative recommendation, strong
consensus
Comment. The literature search revealed
143 hits. Three RCT were found. A quantitative analysis was not possible due to a
lack of appropriate data. Due to the low
methodological quality of evidence and
the limited number of RCT available the
level of evidence was downgraded by two
points.
The effectiveness of hypnotics is not
proven. In a cross-over RCT 19 patients
were treated with 5–15 mg zolpidem or
placebo for 2 weeks [76]. No intergroup
differences were found for pain, sleep,
and fatigue. In another RCT 14 patients
were treated with zopiclone 7.5 mg/day
and 19 patients with placebo [55]. After
8 weeks no significant differences were
found with regard to pain and sleep. In
one RCT 22 patients were treated with
zopiclone 7.5 mg/day and 23 patients with
placebo [38]. At the end of treatment zopiclone was superior to placebo in reducing sleep disturbances and fatigue, but
not in pain reduction. Dropout rates were
4–10%.
Hypnotics can be misused. Hypnotics
are not licensed for the treatment of FMS.
However, they are licensed for the treatment of sleep disturbances during a limited time period. Due to the high risks and
the limited practicability the negative recommendation was further downgraded
by one point.
Interferons
Evidence-based recommendation
Interferons should not be used. EL 3a,
strong negative recommendation, strong
consensus
Comment. The literature search revealed
5 hits. In one RCT 28 patients each received placebo, 15 IU, 50 IU or 150 IE
interferon-α s.c. At the end of treatment
no intergroup difference was found for
pain, sleep, and fatigue. Dropout rates
were not reported separately for each
group [93]. The side effects reported were
mild and as for the authors not related to
the medication. Severe side effects are reported in the literature after treatment
with high doses of interferons. Due to the
high risks and the low practicability the
negative recommendation was further
downgraded by one point.
Intravenous (i.v.) ketamine
Evidence-based recommendation
I.v. ketamine should not be used. EL 4a,
strong negative recommendation, strong
consensus
Comment. The literature search revealed
17 hits. Two experimental studies (infusion therapy once and twice) were exclud-
ed [10, 104]. No studies with oral ketamine
application were found.
In a cross-over study 20 patients received ketamine 1 mg/kg body weight
for 3 days versus placebo [78]. No intergroup differences were found for pain intensity and health-related quality of life.
Study quality was low. Due to the limited data and the low methodological quality the recommendation was downgraded
by two points.
Severe neuropsychiatric side effects are
reported. Due to the potential risks and
the low practicability the negative recommendation was further downgraded by
one point.
Local anesthetics
Evidence-based recommendation
Intravenous local anesthetics should not
be used. EL 3a, strong negative recommendation, strong consensus
Comment. The literature search revealed
62 hits. Three studies investigating 177 patients and with a study duration of 4 weeks
each were included in qualitative analysis.
The quality of evidence and methodology were low and also the number of patients investigated. Therefore the level of
evidence was downgraded by two points.
Local anesthetics were ineffective. A
quantitative data analysis was not possible due to insufficient data presentation
in the publications. In both placebo-controlled studies no intergroup difference
was found for pain reduction when using
lidocaine or placebo [73, 86]. In one study
no intergroup difference was found for
the reduction of fatigue [73]. The add-on
therapy with lidocaine or placebo in addition to AMT did not increase pain reduction [112].
Acceptance was moderate (dropout
rate: 0–16%). The risks are high. Pain
was >10% more frequently reported during lidocaine infusion than during placebo [73]. In an observational study using 550 mg lidocaine/6 h for 6 consecutive days lung edema and supraventricular tachycardia were reported [91].
Due to the potential risks, the ethical commitment to protect patients from
harm, and the low practicability the negaDer Schmerz 3 · 2012 | 5
Schwerpunkt
tive recommendation was downgraded by
two points.
Neuroleptics
Sodium oxybate
Neuroleptics should not be used. EL 3a,
strong negative recommendation, strong
consensus
Serotonin receptor
(5-HT3) antagonists
Comment. The literature search revealed
17 hits. One RCT and three case series
were found. Due to the limited data the
grade of evidence was downgraded.
In the RCT 24 female patients were
treated with ritanserin 10 mg/day and
27 female patients were treated with placebo for 16 weeks [81]. At the end of treatment no intergroup difference was found
for pain, sleep, and fatigue. Three patients
in the ritanserin group discontinued the
study.
In Germany neuroleptics is neither licensed for the treatment of FMS nor for
the treatment of frequent psychiatric comorbidities. Due to the potential risks, the
ethical commitment to protect patients
from harm and the low practicability the
negative recommendation was downgraded by two points.
Serotonin receptor (5-HT3) antagonists
should not be used. EL 3a, strong negative recommendation, strong consensus
Evidence-based recommendation
Sodium oxybate should not be used. EL
3a, strong negative recommendation,
strong consensus
Comment. Sodium oxybate increases the
turnover of 5-hydroxytryptamine, interacts with the opioid system, and GABA
antagonistic effects are assumed.
The literature search revealed 13 hits.
Three studies with five study arms investigating 358 patients were included in the
analysis; the mean study duration was 7
(4–8) weeks (Evidence Report, Tab. 74;
[77, 95, 98]).
Methodological quality of evidence
was low (Evidence Report, Tab. 75). The
obtained data were incompletely reported (selective reporting). Therefore the
level of evidence was downgraded by two
points.
The effectiveness of sodium oxybate
was moderate (Evidence Report, Tab. 76,
Fig. 24). SMD of sodium oxybate versus placebo for pain, sleep, fatigue, and
health-related quality of life were significant at the end of treatment. SMD was low
for health-related quality of life and moderate for pain, fatigue, and sleep.
Acceptance was moderate (dropout
rate: 24%) and was not different from placebo (Evidence Report, Fig. 24). Risks
were high. Frequent side effects (>10% difference to placebo) were nausea, drowsiness, and headache or paresthesias. In 6%
of the patients treated with 6 g/day urinary incontinence was observed. In Germany sodium oxybate is neither licensed
for the treatment of FMS nor for the treatment of frequent psychiatric comorbidities. Sodium oxybate is licensed for the
treatment of narcolepsy. Due to the high
risks, the ethical commitment to protect
patients from harm, and lack of license the
recommendation was downgraded by two
points.
6 | Der Schmerz 3 · 2012
Evidence-based recommendation
Strong opioids
Evidence-based recommendation
Strong opioids should not be used. EL 4b,
strong negative recommendation, strong
consensus
Comment. One RCT was excluded from
analysis, because it was an experimental
study with one-time morphine application [103]. No RCT were found for other
strong opioids (buprenorphine, fentanyl,
hydromorphone, oxycodone). In one case
series 16 patients received fentanyl 25 µg/h
transdermally over 72 h. Treatment was
continued for 4–8 weeks. No pain reduction or increase in health-related quality of life was found. All patients reported
on side effects (confusion, nausea, vomiting). Seven of the 16 patients discontinued
treatment [22].
The availability is limited. In Germany fentanyl is not licensed for the treatment of FMS, but for the treatment of severe pain.
Due to the low patients’ acceptance, the
high risks, and the limited license the rec-
ommendation was downgraded by two
points.
Evidence-based recommendation
Comment. The literature search revealed
43 hits. Three RCT were analyzed. In one
study three different dosages of tropisetron (5, 10, 15 mg) were compared with
placebo. For quantitative analysis only the
5 mg study arm was considered, because
the two other study arms did not differ
from placebo [104]. Three studies investigating 260 patients and with a mean study
duration of 1 week (5–10 days) were analyzed (Evidence Report, Tab. 77; [41, 63,
105]).
Due to the limited data and the low
quality of evidence (low methodological quality and low external validity) the
level of evidence was downgraded by two
points (Evidence Report, Tab. 78).
The difference of SMD comparing serotonin receptor (5-HT3) antagonists with
placebo was not significant (Evidence Report, Tab. 79, Fig. 25).
The dropout rate was low (4.6%) and
was not different from placebo (Evidence
Report, Fig. 25).
One frequent subjective side effect
(>10% versus placebo) was obstipation.
Serotonin receptor (5-HT3) antagonists
are not licensed for the treatment of FSM
or of comorbidities.
Due to the side effects and the lack of
license the negative recommendation was
further downgraded by one point.
Negative recommendations
Cannabinoids
Evidence-based recommendation
Cannabinoids should not be used. EL 3a,
negative recommendation, strong consensus
Comment. The literature search revealed
9 hits. Two RCT were analyzed [101, 113].
A quantitative data analysis was not possi-
ble, because none of the studies were placebo-controlled. Due to the limited data the evidence level was downgraded by
one point.
The quality of evidence was moderate. A quantitative data analysis was not
possible. The effectiveness was low. In a
cross-over study 32 patients were treated with nabilone 0.5 mg or AMT 10 mg
[113]. Nabilone was superior to AMT in
improving sleep quality. No intergroup
difference was found for pain reduction
or improvement of health-related quality of life. In a RCT 20 patients received
nabilone 0.5–1 mg/day and 20 patients received placebo for 4 weeks. At the end of
the study nabilone was superior to placebo with regard to pain reduction and improvement of health-related quality of life.
In one study 3 of 32 patients discontinued.
The other study does not give details [101].
Frequently observed side effects were dizziness (nabilone: 47%; placebo: 6%; [110]),
drowsiness (nabilone: 35%; AMT: 14%),
and nausea (nabilone: 31%; AMT: 14%;
[101]). Misuse of nabilone is rare [114].
In Germany nabilone is neither licensed for the treatment of FMS, nor for
the treatment of frequent psychiatric comorbidities.
Due to potential risks and the lack of
license the recommendation was downgraded by one point.
Flupirtine
Evidence-based recommendation
Flupirtine should not be used. EL 4, negative recommendation, consensus
Comment. Flupirtine is not a muscle relaxant [109].
Only two small case series are available investigating the effect of flupirtine in
FMS; both report on pain reduction [106,
116]. Severe liver toxicity as a side effect is
reported in the literature [87].
Due to a lack of licence and the potential side effects the recommendation was
downgraded by one point.
Milnacipran
Evidence-based recommendation
Milnacipran (MLN) should not be used.
EL 1a, negative recommendation, consensus
Comment. MLN is a serotonin–noradrenalin reuptake inhibitor with a threefold higher effect on serotonin than on
noradrenalin.
Literature search revealed 37 hits. Two
studies were published twice [47, 111]. Five
studies with 8 study arms and investigating 4,088 patients were analyzed; mean
study duration was 19 (15–27) weeks (Evidence Report, Tab. 80; [9, 21, 32, 75, 111]).
The quality of evidence and of methodology was moderate; external validity
was low (Evidence Report, Tab. 81).
SMD of MLN versus placebo at the
end of therapy were significant for pain
and health-related quality of life but not
substantially (Evidence Report, Tab. 82,
Fig. 26). Acceptance for MLN was low:
dropout rate was high (33%) and was not
different from placebo (Evidence Report,
Fig. 26). The risks of MLN were high: the
difference of the frequency of some subjectively relevant side effects was >10%
compared to placebo. In Germany MLN is
neither licensed for the treatment of FMS
nor for the treatment of frequent psychiatric comorbidities.
Monoamine oxidase inhibitors
Evidence-based recommendation
Monoamine oxidase inhibitors should
not be used. EL 2a, negative recommendation, strong consensus
Comment. The literature search revealed
27 hits. One RCT was excluded because
moclobemide and placebo, respectively,
were combined with biofeedback therapy [117]. Two RCT were analyzed investigating 149 patients and with a mean study
duration of 7 (4–12) weeks (Evidence Report, Tab. 83; [50, 59]). Due to limited data the level of evidence was downgraded.
The quality of evidence was moderate with moderate methodological quality and low external validity (Evidence Report, Tab. 84). With regard to pain, sleep,
and fatigue monoamine oxidase inhibi-
tors did not differ from placebo (Evidence
Report, Tab. 85, Fig. 27).
Acceptance was moderate (dropout
rate: 22%) and was not different from placebo (Evidence Report, Fig. 27).
Nausea was a relevant side effect with
a difference of >10% compared to placebo. Rare severe side effects are reported in
literature.
Monoamine oxidase inhibitors are not
licensed for the treatment of FMS, but for
the treatment of depressive disorders.
Muscle relaxants
Evidence-based recommendation
Muscle relaxants should not be used. EL
2a, negative recommendation, strong
consensus
Comment. The literature search revealed
45 hits. Eleven studies were analyzed.
One study was excluded from quantitative analysis, because carisoprodol was
combined with caffeine and acetaminophen [110]. Due to a lack of standard deviations one study with several study arms
(e.g. 7 patients treated with cyclobenzaprine 10 mg) could not be used for quantitative analysis [46].
Nine studies with a mean study duration of 6 (1–26) weeks and investigating 527 patients could partially be used
for analysis; six of these studies were performed placebo-controlled [14, 23, 26, 45,
46, 85, 97, 110]. In eight RCT the centrally
active agent cyclobenzaprine was applied.
Cyclobenzaprine additionally has properties of tricyclic antidepressants. In one
RCT chlormezanone was used; chlormezanone additionally has properties of benzodiazepines (Evidence Report, Tab. 86).
The quality of evidence was moderate (Evidence Report, Tab. 87). Due to the
low methodological quality the level of
evidence was downgraded by one point.
The quantitative data synthesis was limited due to a lack of standard deviations in
the majority of studies. Drug effectiveness
can only be assessed for the endpoint pain.
Effectiveness was low: SMD of muscle relaxants versus placebo at the end of treatment was low for pain (Evidence Report,
Tab. 88, Fig. 28).
Acceptance and tolerability were moderate: the dropout rate in the RCT was
Der Schmerz 3 · 2012 | 7
Schwerpunkt
20% and did not differ from placebo (Evidence Report, Fig. 28). The relative risk
for dropout was lower compared to placebo. The risks of cyclobenzaprine are high:
very rare, but potentially life-threatening
side effects (confusion, skin lesions, liver toxicity) are described in the literature.
None of the substances that have been
investigated in the studies is licensed in
Germany. Due to the potential risks, the
lack of license, and ethical commitment
to protect patients from harm the recommendation was downgraded by two
points.
Nonsteroidal antirheumatics
Evidence-based recommendation
Nonsteroidal antirheumatics (NSAR)
should not be used. EL 3a, negative recommendation, strong consensus
Comment. The literature search revealed
79 hits. Four studies with a mean duration of 5 (1.2–8) weeks and investigating
181 patients were considered for quantitative analysis (three studies with ibuprofen,
one study with tenoxicam; Evidence Report, Tab. 89; [42, 45, 92, 118]). No studies
were found with cyclooxygenase (COX)2 inhibitors.
The quality of evidence was moderate with moderate methodological quality and high external validity (Evidence
Report, Tab. 90). Due to the low methodological quality and the low number of
cases the level of evidence was downgraded by two points.
A quantitative data synthesis was only
possible for the outcome pain. No effectiveness was reported. SMD of NSAR versus placebo was not significant at the end
of treatment (Evidence Report, Tab. 91,
Fig. 29). One study found no intergroup
difference between placebo and tenoxicam concerning the number of subjects
that reached pain reduction and reduction in morning fatigue scores of at least
25% [42]. Reduction of pain and of sleep
disturbance was not different between cyclobenzaprine monotherapy and the combination of cyclobenzaprine with ibuprofen 600 mg [45].
Side effects were not systematically
assessed in the studies. In the SmPC on
NSAR, e.g. gastrointestinal bleeding is
8 | Der Schmerz 3 · 2012
reported as frequent and severe side effect. The dropout rate was moderate in
the studies (20%) and was not different
compared to placebo (Evidence Report,
Fig. 29). In Germany NSAR are not licensed for the treatment of FMS, but for
the treatment of mild and moderate pain
of the musculoskeletal system.
Due to potential risks and the ethical commitment to protect patients from
harm the recommendation was further
downgraded by one point.
No positive or negative
recommendation possible
Gabapentin
Evidence-based recommendation
Due to the limited data available for gabapentin (GPT) neither a positive nor a
negative recommendation is possible.
Strong consensus
Comment. One RCT was found which
investigated the effect of GPT 1,200–
2,400 mg versus placebo in 75 patients
each for 12 weeks [6].
The quality of evidence was moderate
with high methodological quality and low
external validity.
At the end of treatment GPT was superior to placebo in reduction of pain and
sleep disturbance and improvement of
health-related quality of life.
Patients’ acceptance was moderate:
the dropout rate was 24% for GPT and
17.3% for placebo. Side effects with a difference of >10% to placebo were dizziness
and drowsiness. Very rare (<0.01%) severe
side effects (hematological impairment,
liver toxicity, acute renal failure, dermatological problems) are given for GPT in expert reports.
The practicability is low: in Germany
GPT is licensed for the treatment of epilepsy and of neuropathic pain, but not for
the treatment of FMS or comorbid psychiatric disorders.
Noradrenaline reuptake inhibitors
Evidence-based recommendation
Due to the limited data available for noradrenaline reuptake inhibitors (NRI) nei-
ther a positive nor a negative recommendation is possible. Strong consensus
Comment. The results of one study with
esreboxetine [79] were not yet published.
One published study with the NRI esreboxetine was found [10]. In this study
134 patients were treated with esreboxetine (dose increase from 1 to 8 mg/day)
and 133 patients received placebo for
8 weeks. The dropout rate was 20.1% in
the esreboxetine group and 20.3% in the
placebo group. Esreboxetine was superior
to placebo in terms of reducing pain, fatigue, and improving health-related quality of life. Study quality was high, the external validity was low. Reported side effects
were insomnia, drowsiness, dry mouth,
nausea, hyperhidrosis, voiding disturbance (only in men) and urinary retention (only in men).
Esreboxetine is not available worldwide. Pfizer has stopped registration trials for esreboxetine in FMS.
Weak opioids
Evidence-based recommendation
Due to the limited data available (tramadol) or lack of data (other weak opioids)
neither a positive nor a negative recommendation is possible for weak opioids.
Strong consensus
Comment. The literature search revealed
74 hits. Only RCT with tramadol, but not
with tilidine or codeine were found. One
RCT was excluded from the analysis, because it was an experimental study with
twice i.v. application of tramadol [19]. One
further study was excluded due to double
publication [16, 17].
One study with tramadol and tramadol/acetaminophen, respectively, was
included into the analysis investigating
384 patients and with a mean treatment
duration of 9.5 (6–13) weeks [16]. Due to
the limited number of studies the level of
evidence was downgraded.
In both studies tramadol and tramadol/acetaminophen, respectively, were superior to placebo with regard to pain reduction and improvement of health-related quality of life. Acceptance was low
(dropout rate: 40%). However, the dropout rate was higher the placebo groups
Tab. 1 Changes in level of recommendation for pharmacological treatment of FMS in the first and second version of the guidelines
Treatment
Amitriptyline
Anxiolytics
Cannabinoids
Dopamine agonists
Duloxetine
Recommendation 2008
Strong recommendation
Negative recommendation
Not considered
Open recommendation
Recommendation
Flupirtine
Hormones (calcitonin, testosterones, estrogens, glucocorticosteroids, thyroid hormones, growth hormones)
Hypnotics
Ketamine
Local anesthetics
Milnaciprane
Monoamine oxidase inhibitors
Sodium oxybate
Neuroleptics
Nonsteroidal antirheumatics
Metamizole
Muscle relaxants
Weak opioids (tramadole)
Strong opioids
Acetaminophen
Pregabalin
Serotonin reuptake inhibitors (fluoxetine, paroxetine)
No statement
Negative recommendation
Negative recommendation
Negative recommendation
Negative recommendation
No statement
Open negative recommendation
Negative recommendation
Negative recommendation
Negative recommendation
Negative recommendation
Open negative recommendation
Open recommendation
Open recommendation
Negative recommendation
Open recommendation
Recommendation
Serotonin receptor agonists (tropisetrone)
Virostatics
Open recommendation
Negative recommendation
compared to the tramadol groups. The
most frequently reported side effect with
a difference of >10% to placebo was nausea. Rare severe side effects (misuse) are
reported in the literature [108].
The availability is limited. In Germany
tramadol is not licensed for the treatment
of FMS, but for the treatment of moderate
to severe pain.
Acetylsalicylic acid, acetaminophen,
and metamizole
Evidence-based recommendation
Due to the lack of data neither a positive
nor a negative recommendation is possible for acetyl salicylic acid, acetaminophen, and metamizole. Strong consensus
Comment. No studies were found for
acetylsalicylic acid, acetaminophen, and
metamizole.
Recommendation 2012
Recommendation
Strong negative recommendation
Negative recommendation
Strong negative recommendation
Recommendation when comorbid depressive disorder or generalized anxiety disorder
Negative recommendation
Strong negative recommendation
Strong negative recommendation
Strong negative recommendation
Strong negative recommendation
Strong negative recommendation
Negative recommendation
Strong negative recommendation
Strong negative recommendation
Strong negative recommendation
No positive or negative recommendation
Negative recommendation
No positive or negative recommendation
Strong negative recommendation
No positive or negative recommendation
Open recommendation (“off-lable use”)
Open recommendation when comorbid depressive
disorder
Strong negative recommendation
Strong negative recommendation
Discussion
Compared to the first version of the
guideline the basis of recommendations
was changed: Quantity and quality of
evidence were considered, meta-analysis was performed, risks and availability were considered instead of pure qualitative analysis of the main study results.
This led to a downgrade of recommendations for some drugs (e.g. AMT) [102].
Taking into account the licensed indications, a positive recommendation resulted
only for FMS with comorbid psychological disorders for duloxetine, fluoxetine,
and paroxetine. Due to insufficient data
the open recommendation for the weak
opioid tramadol was abolished (. Tab. 1).
The following research objectives were
identified:
a)studies investigating the sustained effect after treatment cessation,
b)randomized, controlled studies comparing “old” (cheap) drugs like AMT
with “new” (expensive) drugs like
PGB,
c)direct comparison of active treatments (e.g. two forms of psychotherapy or psychotherapy versus pharmacological treatment) and
d)inclusion of patients with comorbid
psychological disorders and eventually their subgroup analysis.
Corresponding address
Prof. Dr. C. Sommer
Neurologische Klinik,
Universitätsklinikum Würzburg
Josef-Schneider-Str. 11, 97080 Würzburg
Germany
[email protected]
Conflict of interest. See Tab. 5 in the “Methodological fundamentals used in developing the guideline” by
W. Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
Der Schmerz 3 · 2012 | 9
Schwerpunkt
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Schwerpunkt
English Version of "Komplementäre
und alternative Verfahren beim
Fibromyalgiesyndrom. Systematische
Übersicht, Metaanalyse und Leitlinie".
DOI 10.1007/s00482-012-1178-9
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
J. Langhorst1 · W. Häuser2 · K. Bernardy3 · H. Lucius4 · M. Settan5 · A. Winkelmann6 ·
F. Musial7
1 Innere Medizin V, Naturheilkunde und Integrative Medizin, Kliniken Essen-Mitte, Essen
2 Klinikum Saarbrücken, Innere Medizin 1, Klinikum Saarbrücken
3 Abteilung für Schmerztherapie, Berufsgenossenschaftliche Universitätsklinik Bergmannsheil GmbH,
Ruhr Universität Bochum
4 Schmerzambulanz Schlei-Klinikum/FKSL, Schleswig
5 Deutsche Fibromyalgie Vereinigung, Seckach
6 Klinik und Poliklinik für Physikalische Medizin und Rehabilitation, Klinikum der Universität München
7 National Research Center in Complementary and Alternative Medicine (NAFKAM),
Department of Community Medicine, Faculty of Health Science, University of Tromsø
Complementary and
alternative therapies for
fibromyalgia syndrome
Systematic review, 
meta-analysis and guidelines
In revising the guidelines, the task groups
considered the following questions:
1.Are the complementary and alternative therapies for fibromyalgia syndrome (FMS) effective over short and
long periods of time?
2.What are the risks of using complementary and alternative procedures
to treat FMS?
3.Which complementary and alternative procedures should be refused in
treating FMS?
Methodology
The procedures utilized for researching
and analyzing the literature are presented in the article “Methodological fundamentals used in developing the guideline”.
Results
The following findings apply to adults.
Complementary and alternative procedures for chronic pain affecting multiple body regions in children and youths
are discussed in the article entitled “Def-
inition, diagnosis and therapy of chronic widespread pain and so-called fibromyalgia syndrome in children and adolescents”. Key recommendations are italicized.
Highly recommended
Meditative movement therapies
(tai chi, qigong, yoga)
Evidence-based recommendation
Meditative movement therapies (tai chi,
qigong, yoga) should be considered.
EL1a, highly recommended, strong consensus
Comment. The meditative movement
therapies analyzed included body-awareness therapy, qigong, tai chi, yoga, and
Feldenkrais therapy.
A search of the literature identified 46
reports. One trial on Feldenkrais therapy
was excluded because it was not randomized [39]. One randomized controlled trial (RCT) with yoga was available only as
an abstract [31].
Nine RCTs with 420 patients in therapeutic trials lasting an average of 11 (6–
20) weeks were analyzed. Seven of the trials included follow-up assessments performed on average 20 (6–78) weeks after
the treatments had been completed (Evidence Report, Tab. 92; [4, 9, 11, 17, 28, 39,
42, 52, 59]).
The evidence was of moderate quality
(moderate methodological quality, moderate external validity) (Evidence Report,
Tab. 93), as was the efficacy. However,
meditative movement therapies were superior to the control group therapies in reducing pain, fatigue, and sleep disorders
as assessed at the completion of the respective trials (Evidence Report, Tab. 94
and Fig. 30). Acceptance in the treatment
groups was moderate (dropout rate 19%)
and did not differ significantly from that
of the placebo groups (Evidence Report,
Fig. 30).
Adverse effects were not reported in
the analyzed trials. Availability is limited. Exercise therapies are not covered by
health insurance in Germany. They are a
part of multimodal therapeutic inpatient
Der Schmerz 3 · 2012 | 1
Schwerpunkt
programs at some hospitals and are offered by some adult education centers.
Acupuncture
Acupuncture for comorbid back pain
is covered by health insurance in Germany.
Because of its potential risks and limited availability, the strength of recommendation was downgraded one level.
Evidence-based recommendation
Negative recommendation
Recommendation open
Treatment with acupuncture for a limited
period of time may be considered. EL 2a,
degree of recommendation open, strong
consensus
Comment. A search of the literature identified 340 reports. Three RCTs were excluded because the target variables did not
fulfill the inclusion criteria [27] or because
acupuncture was combined with other active therapeutic procedures [36, 54]. One
review [10] included four Chinese trials:
two compared acupuncture with amitriptyline and two compared acupuncture in
combination (one with cupping and one
with an antidepressant) with an antidepressant alone. These studies, which were
not contained in the designated databanks
and were only published in Chinese, were
excluded from the analysis.
Thus, 9 RCTs with 414 patients treated for an average of 7 (2–15) weeks were
analyzed. Three trials included follow-up
assessments after a median of 17 (12–28)
weeks (Evidence Report, Tab. 95; [2, 18,
29, 30, 34, 41, 43, 49, 53]).
The evidence was of moderate quality (poor methodological quality, moderate external validity) (Evidence Report,
Tab. 96). The quality of evidence was
downgraded due to the limited methodological quality.
Efficacy was limited. The standard
mean deviation (SMD) (verum acupuncture vs. sham acupuncture) at the completion of therapy with regard to pain indicated a small effect size (Evidence Report,
Tab. 97 and Fig. 31).
The dropout rate was 8.2%, which did
not differ from that of the control group
(Evidence Report, Tab. 31). Adverse effects
were systematically reported in only one
study. The frequency of severe adverse effects from acupuncture is controversial.
However, severe complications such as
bleeding or pneumothorax have been reported in the literature [16].
2 | Der Schmerz 3 · 2012
Mindfulness-based stress
reduction as monotherapy
Evidence-based recommendation
Mindfulness-based stress reduction
should not be used as monotherapy. EL
2a negative recommendation, consensus
Comment. A search of the literature
identified 8 relevant reports. Four RCTs
with 371 patients treated with mindfulness-based stress reduction (MBSR) for
an average of 8 weeks were analyzed [4,
26, 50, 51]. In three of the trials patients
of both arms of the studies were assessed
at follow-up an average of 8 weeks after
treatment. In one of the trials [26] follow-up evaluations of the MBSR, but not
the control group, were carried out after
3 years in 26 of 39 patients (Evidence Report, Tab. 98).
The evidence was of moderate quality (poor methodological quality, moderate external validity; Evidence Report,
Tab. 99). The secondary end points of
one trial were not reported and not made
available upon inquiry [51]. Since it is possible that negative results had not been
published, the level of evidence was downgraded.
MBSR was not effective and was not
superior to control treatments with respect to reducing pain or improving quality of life (Evidence Report, Tab. 100 and
Fig. 32).
Acceptance was moderate (dropout
rate 22%) and did not differ significantly from that of the controls (Evidence Report, Fig. 32). Adverse effects were not reported nor have any been mentioned in
the literature.
Availability is limited. MBSR is not
covered by health insurance in Germany. MBSR is offered as part of multimodal therapeutic inpatient programs in a few
hospitals.
Homeopathy
Evidence-based recommendation
Homeopathy should not be considered.
EL1a negative recommendation, consensus
Minority opinion (Complementary and
Alternative Medicine Work Group: Langhorst J, Bernardy K, Lucius H, Settan M,
Winkelmann A, Musial F): homeopathic therapy may be considered. EL 1a, recommendation open
Comment. A search of the literature identified 20 reports. The data of one trial were
published twice [7, 8]. Five RCTs with 204
patients and an average trial length of 15
weeks were qualitatively analyzed (Evidence Report, Tab. 101; [7, 8, 23, 24, 46]).
The evidence was of moderate quality
(moderate methodological quality, moderate external validity), and moderate external validity (Evidence Report, Tab. 102).
There was no consistent evidence
that homeopathy was effective. Two trials could be quantitatively evaluated [8,
46]. The SMDs (homeopathy versus control at completion of therapy) showed that
homeopathy tended to positively affect
quality of life (Evidence Report, Tab. 103
and Fig. 33). In the two trials that could
not be meta-analyzed, qualitative analysis revealed no consistent evidence that
homeopathy was effective. In one trial
there was no statistical difference in the
reduction of pain and sleep disturbance.
One subgroup analysis did show significantly reduced pain and sleep disturbance
for those patients who presented at least
more than three characteristic symptoms
of the prescribed homeopathic medication [23]. One trial showed that a homeopathic treatment reduced pain and sleep
disturbance better than a placebo [24]. A
subsequent analysis of that trial with appropriate statistical methods did not confirm a significant difference between homeopathic and placebo treatments in the
first crossover treatment phase [15].
Acceptance was moderate. The dropout rate, 13%, did not differ significantly
from that of the placebo group (Evidence
Report, Fig. 33). The risks are probably
low: adverse effects were not determined.
Relevant side effects are not known from
the literature.
Abstract · Zusammenfassung
Schmerz 2012 · DOI 10.1007/s00482-012-1178-9
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
J. Langhorst · W. Häuser · K. Bernardy · H. Lucius · M. Settan · A. Winkelmann · F. Musial
Complementary and alternative therapies for fibromyalgia syndrome.
Systematic review, meta-analysis and guidelines
Abstract
Background. 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.
Materials and methods. 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 EvidenceBased Medicine. The recommendations were
based on level of evidence, efficacy (metaanalysis of the outcomes pain, sleep, fatigue
and health-related quality of life), acceptability (total dropout rate), risks (adverse events)
and applicability of treatment modalities in
the German health care system. The formulation and grading of recommendations was
accomplished using a multistep, formal consensus process. The guidelines were reviewed
by the boards of the participating scientific
medical societies.
Results and conclusion. Meditative movement therapies (qigong, tai chi, yoga) are
strongly recommended. Acupuncture can be
considered. Mindfulness-based stress reduction as monotherapy and dance therapy as
monotherapy are not recommended. Homeopathy is not recommended. In a minority
vote, homeopathy was rated as “can be considered”. Nutritional supplements and reiki
are not recommended.The English full-text
version of this article is available at SpringerLink (under “Supplemental”).
Keywords
Fibromyalgia syndrome · Systematic review ·
Meta-analysis · Guidelines · Complementary
therapies
Komplementäre und alternative Verfahren beim Fibromyalgiesyndrom.
Systematische Übersicht, Metaanalyse und Leitlinie
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer
041/004) wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie
wurde unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie (DIVS) von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potenzielle Interessenkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolg-
The availability is limited: the costs are
covered by only a few of the health insurance funds.
Minority vote: In the trial reported by
Fischer in 1989, homeopathic treatment
reduced pain and improved sleep better
than a placebo [24].
A subsequent analysis of this trial with
modified statistical methods did not show
that the homeopathic treatment was sig-
te über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke erfolgte nach dem Schema des Oxford Center
for Evidence Based Medicine. Grundlage der
Empfehlungen waren die Evidenzstärke, die
Wirksamkeit (Metaanalyse der Zielvariablen
Schmerz, Schlaf, Müdigkeit und gesundheitsbezogene Lebensqualität), die Akzeptanz
(Abbruchrate in Studien), Risiken (Nebenwirkungen) und die Anwendbarkeit der Therapieverfahren im deutschen Gesundheitssystem. Die Formulierung und Graduierung der
Empfehlungen erfolgte in einem mehrstufigen, formalisierten Konsensusverfahren. Die
Leitlinie wurde von den Vorständen der beteiligten Fachgesellschaften begutachtet.
nificantly better than the placebo in the
initial crossover treatment phase. The author assumed that there is a carry-over
effect, i.e., that the effects of the treatment period being observed are partly
determined by the effects of the preceding treatment period [15]. However, this
was not established by statistical analysis
(p=0.07). Since the carry-over effect was
not formally demonstrated, the homeo-
Ergebnisse und Schlussfolgerung. Meditative Bewegungstherapien (Qigong, Tai-Chi,
Yoga) werden stark empfohlen. Die Therapie mit Akupunktur kann erwogen werden.
Achtsamkeitsbasierte Stressreduktion als
Monotherapie und Tanztherapie als Monotherapie werden nicht empfohlen. Homöopathie wird nicht empfohlen, wobei in einem
Minderheitenvotum eine offene Empfehlung
(„kann erwogen werden“) favorisiert wurde.
Nahrungsmittelergänzungsprodukte und
Reiki werden nicht empfohlen.
Schlüsselwörter
Fibromyalgiesyndrom · Systematische
Übersicht · Metaanalyse · Leitlinie ·
Komplementäre Therapien
pathic treatment would remain statistically superior.
Nutritional supplements
Evidence-based recommendation
Nutritional supplements (algae and malic acid/magnesium preparations; anthocyanins; carnitine; S-adenosyl methionine, SAM; soya oil; vitamin–dietary minDer Schmerz 3 · 2012 | 3
Schwerpunkt
eral preparations) should not be applied.
EL3, negative recommendation, strong
consensus
Comment. Anthocyanins are plant pigments. In the European Union, they are
permitted in unlimited amounts as food
additives under the number E163.
S-adenosyl methionine (SAM) is an essential amino acid. In the USA, SAM is
sold as a nutritional supplement under
the Dietary Supplement Health and Education Act of 1999. Under this law, nutritional supplements circumvent regulation by the Food and Drug Administration (FDA). SAM can be obtained over the
internet.
Carnitine is a vitamin-like substance.
It can be produced by the body but is usually provided by meat in the diet. In Germany it is permitted for treating the carnitine deficiency of renal insufficiency and
special forms of muscular dystrophy. Carnitine can be obtained over the internet.
5-Hydroxytryptophan is an amino acid naturally occurring in bananas and the
seeds of African black beans. The substance is not an authorized medication in
Germany but can be obtained over the internet as a “natural mood-elevator”.
A search of the literature identified 130
reports. Two trials with SAM were excluded from the analysis because the clinical
endpoint [53] or the presentation thereof
[54] was not suitable for analysis.
Eleven trials with 12 arms and 517 patients and an average length of treatment
of 6 (1–12) weeks were analyzed. None of
the trials included a follow-up [1, 12, 21, 22,
25, 35, 44, 47, 48, 57, 58]. Only one preparation (SAM) was the subject of more
than one trial (3 trials, 121 patients) (Evidence Report, Tab. 104). The evidence
was initially downgraded because so few
trials were available. And since the quality of evidence was limited (limited methodological quality, limited external validity; Evidence Report, Tab. 105), it was further downgraded. The efficacy was limited. The SMDs (nutritional supplements
versus controls) on pain, sleep, and fatigue at the completion of therapy were
showed small effect sizes (Evidence Report, Tab. 106 and Fig. 34).
Acceptance was moderate (dropout
rate 12%) and did not differ significantly
4 | Der Schmerz 3 · 2012
from that of the placebo groups; Evidence
Report, Fig. 34).
The risks were high: gastrointestinal
adverse effects were 10% more frequent
with SAM and 5-HT than in the control
group.
The recommendation was downgraded a further level because of the high risks
and low availability.
Reiki
Evidence-based recommendation
Reiki should not be applied. EL 2b, negative recommendation, strong consensus
Comment. A search of the literature
identified 19 reports. One trial had no
control group [19]. In one trial the 25 patients were treated for 8 weeks by either a
reiki master or an actor, receiving either
reiki (direct contact) or a “distance treatment”. None of the treatments had a significant effect on pain, fatigue, sleep, or
quality of life [3]. In spite of the limited
data available, a statement on this treatment is included here because of the negative results of the trial.
Dance therapy
Evidence-based recommendation
Dance therapy should not be applied as
monotherapy. EL 2b, negative recommendation, strong consensus
Comment. A search of the literature identified 9 reports. The data of one trial listed in the NIH databank as completed and
evaluated could not be found in the other databanks [6]. In a Swedish RCT with
36 patients, dance therapy (once a week
for 6 months) did not reduce pain in the
therapy group when compared with controls neither at the completion of the trial
nor at follow-up assessment 6 months later [32]. Although few data are available,
a statement about this therapy is included here because of the negative results of
the trials.
Neither positive nor negative
recommendation possible
Dietary intervention
(vegetarian diet, elimination
diet, therapeutic fasting)
Evidence-based assessment
Due to the limited available data, neither
a positive nor a negative recommendation is possible. Strong consensus
Comment. A search of the literature identified 27 reports. In one RTC, 37 patients
were given a vegetarian diet, and 41 patients, amitriptyline (AMT; 10–100/day),
depending on the severity of the patient’s
sleep disorder, for a period of 6 weeks.
Both treatments resulted in pain reduction. At the completion of therapy, AMT
was more effective than the vegetarian diet in reducing pain [5].
In a controlled trial, a 3-month lowsalt uncooked vegetarian diet (18 patients)
was superior to a normal diet in reducing
pain and improving function [37].
In a controlled trial from the US, 40
patients received an exclusion diet (e.g.,
of wheat, nutritional supplements) based
on immunological tests. They were compared with 11 patients who continued their
normal diets. Patients of both groups participated in group discussions. At the end
of the trial, the patients on exclusion diets
reported a 50% reduction in pain, whereas the controls reported no changes [20].
Melatonin
Evidence-based assessment
Due to the limited data available, neither
a positive nor a negative recommendation is possible. Strong consensus
Comment. A search of the literature
identified 34 reports. In a non-controlled
Argentinean trial with 19 patients, 3 mg
melatonin/day for 4 weeks improved sleep
and decreased the tender-point score [14].
In a RTC, 24 patients received 5 mg melatonin/day, 24 patients 20 mg fluoxetine/
day, 27 patients 20 mg fluoxetine/day
plus 3 mg melatonin/day, and 23 patients
20 mg fluoxetine/day plus 5 mg melatonin/day. A placebo control was not carried out. Pain was significantly reduced
Tab. 1 Changes from the first edition of the guidelines in the degree of recommendation for
complementary and alternative therapies
Therapeutic procedure
Mindfulness-based stress
reduction as sole treatment
Acupuncture
Breathing therapy
Elimination diet
Foot reflexology massage
therapy
Homeopathy
Meditative Movement Therapies
Reiki
Vegetarian diet/therapeutic
fasting
Recommendation 2008
No statement possible
Recommendation 2012
Strongly negative
Strongly negative
Minority opinion: open
Open
Open
Open
Open
Open
Negative
Minority vote: open
Strongly positive
Negative
No statement possible
Open
No statement
Open
in all arms of the trial, but sleep was significantly improved only in the melatonin
groups [33]. Melatonin is approved for the
short-term treatment of primary insomnia in patients older than 55 years.
Music therapy
Evidence-based assessment
Due to the limited data available, neither
a positive nor a negative recommendation is possible. Strong consensus
Comment. In a US RCT with 26 patients
and passive musical therapy, musically
fluctuating vibrations (60–300 Hz) were
not superior to sinusoidal vibrations in
reducing the intensity of pain [13]. In a
German controlled trial, a program of active music therapy in a group of 12 patients
with various pain syndromes including
FMS patients was superior to control therapy in reducing pain and pain-related disability at the completion of therapy [45].
Discussion
As pointed out in the first edition of the
guidelines [40], complementary and alternative medicine (CAM) is widely used
by patients with FMS (87–91%). However,
these various therapies remain to be satisfactorily evaluated and their effectiveness
established, since few good controlled trials on CAM therapies for fibromyalgia are
available. Further research in this area is
desirable and necessary.
Not considered
No statement possible
No statement
In the first edition of the guidelines
[40], the recommendations were designated “open” for breathing therapy, elimination/vegetarian diets, and foot massage
therapy. In this update, they again cannot
be either positively or negatively recommended because of the absence of satisfactory trials. The open recommendation
for homeopathy has been changed to a
negative recommendation due to the results of a quantitative data synthesis. However, the relatively sparse data can be interpreted in different ways (see Minority
opinion). The recommendation for acupuncture was changed from negative to
open as a result of new trials and quantitative data synthesis (Tab. 1).
As a rule, complementary procedures
are applied in an interdisciplinary and integrative medical setting. Frequently they
constitute a useful supplement within the
framework of a multimodal therapeutic concept. One advantage of some complementary therapeutic procedures (e.g.,
qigong or tai chi) is that patients can apply the procedures themselves and are not
dependent on a therapist.
Especially needed are randomized
clinical trials on the effectiveness of music and dance therapies, homeopathy, and
dietary intervention.
Many basic therapeutic approaches of
complementary medicine, e.g., acupuncture, are thought to activate intrinsic physiological mechanisms. Frequently the exact mediators of potential therapeutic effects are still not understood. Thus, not
only clinical trials to evaluate the complementary therapies are needed, but also trials in the realm of basic research. In addition, more information about how frequently FMS patients in Germany utilize
complementary procedures and what motivates them to do so is needed.
Conclusion with regard to practice
FMS patients frequently utilize complementary and alternative medicine therapies. Complementary procedures as a
rule are applied in an interdisciplinary
and integrative medicine setting. They
can be a useful supplement within the
framework of a multimodal therapeutic
concept. The use of meditative exercise
therapies (tai chi, qigong, yoga) is strongly recommended. Acupuncture can be
applied for a limited period of time. Dietary supplements and Reiki should not
be utilized, nor should mindfulnessbased stress reduction or dance therapy
be utilized as the sole treatments.
Corresponding address
Prof. Dr. J. Langhorst
Innere Medizin V, Naturheilkunde und
Integrative Medizin, Kliniken Essen-Mitte
Am Deimelsberg 34a, 45276 Essen
Germany
[email protected]
Conflict of interest. See Tab. 5 in “Methodological
fundamentals used in developing the guideline” by W.
Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
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Der Schmerz 3 · 2012 | 7
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English Version of "Definition, Diagnostik
und Therapie von chronischen Schmerzen
in mehreren Körperregionen und des
sogenannten Fibromyalgiesyndroms bei
Kindern und Jugendlichen. Systematische
Literaturübersicht und Leitlinie".
DOI 10.1007/s00482-012-1168-y
© Deutsche Schmerzgesellschaft e.V.
Published by Springer-Verlag all rights reserved 2012
B. Zernikow1, 2 · K. Gerhold3 · G. Bürk4 · W. Häuser5 · C.H. Hinze6 · T. Hospach7 ·
A. Illhardt8 · K. Mönkemöller9 · M. Richter10 · E. Schnöbel-Müller6 · R. Häfner6
1 Deutsches Kinderschmerzzentrum, Vestische Kinder- und Jugendklinik,
Universität Witten/Herdecke, Datteln
2 Vodafone Stiftungslehrstuhl für Kinderschmerztherapie und Pädiatrische Palliativmedizin,
Universität Witten/Herdecke, Witten
3 Universitätskinderklinik, Charité – Universitätsmedizin Berlin
4 MVZ Kinder und Jugendliche Herne
5 Innere Medizin 1, Klinikum Saarbrücken, Klinikum Saarbrücken gGmbH, Saarbrücken
6 Deutsches Zentrum für Kinder- und Jugendrheumatologie, Garmisch-Partenkirchen
7 Olgahospital - Kinderklinik Stuttgart
8 St. Josef-Stift Sendenhorst
9 Kinderkrankenhaus der Stadt Köln
10 Kinderklinik, Universitätsklinik Dresden
Definition, diagnosis and therapy
of chronic widespread pain and
so-called fibromyalgia syndrome
in children and adolescents
Systematic literature review and guideline
Epidemiologic studies reveal a high prevalence (between 25% and 46%) of chronic pain in children and adolescents, an increased prevalence with age and a higher prevalence in girls [14, 32, 58, 68]. The
most common locations of pain—in order
of descending frequency—are head, abdomen and musculoskeletal system; some of
the children and adolescents report pain
in several regions [14, 32, 58, 67]. About
3% of children and adolescents develop
severe, disabling chronic pain with negative effects on school attendance, recreational activities, contact with peers and
family and emotional distress, such as
anxiety and depression [32, 55]. A subset of these children and adolescents suffer from additional symptoms, for example disordered sleep [45, 57] or fatigue
[19]. In children and adolescents who suffer from generalized pain of the musculoskeletal system, additional symptoms and
muscle tenderness, the diagnosis juvenile
fibromyalgia syndrome (JFMS) is used.
The definitions of JFMS, however, have
substantial operationalizational problems.
The authors of the update of these guide-
lines therefore chose to use the term “socalled JFMS”.
For the planned update of the guidelines, the following research questions
were addressed by use of a comprehensive literature review:
1.What are the core symptoms of the
so-called JFMS?
2.What differences/overlap exist between so-called JFMS and somatoform pain disorder?
3.According to which criteria should
the so-called JFMS be diagnosed?
4.Which diagnostic examinations are
required to rule out alternative diagnoses?
5.When is a psychological evaluation
reasonable?
6.Are there different courses or degrees
of severity of the so-called JFMS?
7.Which information about symptoms,
therapeutic goals and treatment opportunities should be made available
at the time of diagnosis?
8.Is patient education useful?
9.Which subspecialty should coordinate the care of the so-called JFMS?
10.Is a graded treatment approach useful?
11.Which physical, physical therapeutic, psychotherapeutic, pharmacologic and complementary approaches are
useful in the so-called JFMS?
12.Which physical, physical therapeutic, psychotherapeutic, pharmacologic and complementary approaches should be advised against in the socalled JFMS?
13.When is an inpatient multimodal
treatment indicated?
Materials and methods
The methods of literature search and
preparation of recommendations are presented in the article “Methodological fundamentals used in developing the guidelines”.
Results
The literature search yielded 265 hits. Due
to the low number of high quality studies,
there was no gradation of the level of eviDer Schmerz 3 · 2012 | 1
Schwerpunkt
dence according to the quantity or quality
of the evidence.
Definition and classification
Clinical consensus
For children and adolescents there are
currently no standardized and validated
criteria for defining chronic pain in multiple body regions leading to clinically significant impairment in everyday life and
that does not occur within a defined somatic disease. Strong consensus
Comment. In childhood and adolescence, pain, regardless of its location, is
defined as chronic if it lasts for at least
3 months or is recurrent over this time
period [33, 47, 54]. Persistent or recurrent
pain may fluctuate greatly in intensity,
quality, frequency, predictability and may
occur either in single or multiple body regions. The focus on the temporal dimension of chronic pain has recently been criticized. Studies indicate that children, who
suffer from shorter-lasting pain, are often
significantly impaired in their daily lives
and require treatment [28, 33]. The aspect of pain-related impairment has only recently been explicitly considered in
the context of epidemiological and clinical studies [29, 30, 54]. Rief et al. [64] included the issue of impairment as a central criterion within a new diagnostic category of “chronic pain disorder with somatic and psychological factors” (ICD-10
F45.41). Studies on the incidence of this
diagnosis in childhood and adolescence
are lacking.
According to Sherry [46, 73], in the
case of chronic pain in children and adolescents with mostly musculoskeletal pain,
“diffuse” and “idiopathic localized” musculoskeletal pain can be defined. Another commonly used term is “chronic widespread (musculoskeletal) pain (CWP)”
[15, 50]. For further consideration, it is
important to note that not all CWP goes
along with pain-related impairment in everyday life, distress or a subjective sense of
illness. However, this is described for the
so-called juvenile fibromyalgia syndrome
(JFMS).
Traditionally, the so-called JFMS is
defined according to the Yunus criteria
[83]:
2 | Der Schmerz 3 · 2012
a)generalized musculoskeletal aching at
≥3 sites,
b)duration for at least 3 months,
c)normal laboratory test results,
d)at least 5 of 11 tender points,
e)at least 3 of the following 10 features:
1.chronic anxiety or tension,
2.fatigue,
3.poor sleep,
4.chronic headaches,
5.irritable bowel syndrome,
6.subjective soft tissue swelling,
7.numbness,
8.pain modulation of physical activity,
9.pain modulation by weather factors,
10.pain modulation by anxiety and/
or stress.
Other publications on JFMS used the definition of the American College of Rheumatology (ACR) in 1990 for adults. The
specificity and sensitivity of the Yunus criteria and the ACR criteria have rarely been
investigated in children and adolescents.
In a study by Reid [61], only 75% of pediatric patients fulfilled both the Yunus as
well as the 1990 ACR criteria. The pain is
typically highly variable; therefore, the Yunus criteria are met only irregularly. Both
the Yunus and the 1990 ACR criteria have
substantial problems in their operationalization:
1.The so-called tender points are problematic for the following reasons:
a)From studies on quantitative sensory testing (QST) in children and
adolescents it is known that the
pressure pain threshold when using a pressure gauge device (FDN
100, Wagner Instruments, USA)
depends on the age and sex of
the child and the location tested [3]. Fifty percent of healthy
children report pain at a pressure ranging from 163–1,039 kPa
(100 kPa=1 kg/cm2), whereas the
upper and lower 95% confidence
interval (95% CI) vary according
to age, sex and location of pressure
application between 82–1,890 kPa.
The testing of tender points using thumb pressure or technical devices with a pressure independent of the age, sex and loca-
tion of pressure application may
not lead to valid results, since the
pressure–pain threshold in healthy
children is influenced by these factors. Tenderness thresholds from
about 3 kg/cm2 (300 kPa/cm2) or
3 kg/1.5 cm2 (depending on the
study and thumb size) or even
5 kg/1.5 cm2 were considered as
pathologic [7]. Depending on age,
gender and location of pressure
application, many healthy children
report pain at these pressures.
b)In the published studies, the socalled tender points were generally not standardized, often only examined by thumb pressure and
not examined in a double-blind
fashion. However, for the thumb
pressure not only the compressive
force, but also the support surface
is critical.
c)When two pediatric rheumatologists examined tender points in
the same child, their agreement
was around 44%, not better than
chance [9].
d)Some studies show that children
with juvenile idiopathic arthritis
(JIA) have identical tender point
pain thresholds as children with
so-called JFMS [62].
e)If tender points are positive, socalled control points are often positive as well [72]. Häfner et al. [21]
found that tender points were
variable and fluctuated.
2.The so-called minor symptoms of
the Yunus criteria have not been defined. Headaches should be classified according to the International
Headache Society (IHS) criteria, e.g.,
chronic tension headache, episodic
tension headache, migraine, medication-induced headache. The same is
true for the diagnosis irritable bowel
syndrome, for which the Rome criteria should be required [20].
3.For psychological symptoms such as
anxiety and depression and functional impairment due to chronic pain, a
standardized survey with established
instruments should be implemented
(see below).
Abstract · Zusammenfassung
Due to these limitations of operationalization, the term JFMS has been rejected by
leading rheumatologists and researchers
since it is not scientifically established or
clinically helpful [73]. The guideline committee agrees to this opinion.
Based on the work by Rief et al. the authors of the present guidelines suggest,
that, in the future, the diagnosis “chronic pain disorder in several body regions
with somatic and psychological factors”
should be used for children with chronic widespread pain (CWP), who also suffer from other symptoms such as headache or abdominal pain, non-restorative
sleep, muscle tenderness, fatigue, irritable bowel syndrome, anxiety, depression
and a strong pain-related impairment in
everyday life.
In adults, Rief et al. [64] suggested to
optimize the classification of chronic pain
in ICD-10 (section F) according to the
biopsychosocial model. Thus far, chronic pain has been classified as “somatoform pain disorder” (F 45.4). For this diagnosis, psychologic factors were considered to trigger the pain. Since this relationship could not always be confirmed
in studies, a new proposal for the diagnosis “chronic pain disorder with somatic and psychological factors” (F45.41) was
created [64]. The clinical picture is dominated by pain lasting for at least 6 months
in one or more anatomical regions. This
pain is assumed to have been triggered either by psychological processes or a physical disorder. Psychological factors are considered to play an important role in the
degree of severity, exacerbation or maintenance of pain, but to a minor degree a
causative role. The pain causes clinically
significant distress and impairment in social, occupational or other important areas of functioning. The pain is not voluntarily produced or pretended (as in factitious disorder or simulation). For children
and adolescents, the pain disorder should
last for at least 3 months (for reasoning,
see above).
In this guideline we will use the term
of the “so-called JFMS”, because the cited studies describe JFMS patients even
though the diagnosis JFMS cannot be operationalized (see above). The authors of
these guidelines agree that the diagnosis
JFMS is neither scientifically established,
Schmerz 2012 · DOI 10.1007/s00482-012-1168-y
© Deutsche Schmerzgesellschaft e.V. Published by Springer-Verlag - all rights reserved 2012
B. Zernikow · K. Gerhold · G. Bürk · W. Häuser · C.H. Hinze · T. Hospach · A. Illhardt ·  
K. Mönkemöller · M. Richter · E. Schnöbel-Müller · R. Häfner
Definition, diagnosis and therapy of chronic widespread
pain and so-called fibromyalgia syndrome in children and
adolescents. Systematic literature review and guideline
Abstract
Background. 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.
Materials and methods. 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 EvidenceBased Medicine. The formulation and grading of recommendations was accomplished
using a multi-step, formal consensus process. The guidelines were reviewed by the
boards of the participating scientific medical societies.
Results and conclusion. The diagnosis FMS
in children and adolescents is not established. In so-called juvenile FMS (JFMS), multidimensional diagnostics with validated
measures should be performed. Multimodal therapy is warranted. In the case of severe
pain-related disability, therapy should be primarily performed on an inpatient basis.The
English full-text version of this article is available at SpringerLink (under “Supplemental”).
Keywords
Chronic pain · Fibromyalgia syndrome ·
Review, systematic · Guideline · Children and
adolescents
Definition, Diagnostik und Therapie von chronischen
Schmerzen in mehreren Körperregionen und des sogenannten
Fibromyalgiesyndroms bei Kindern und Jugendlichen.
Systematische Literaturübersicht und Leitlinie
Zusammenfassung
Hintergrund. Die planmäßige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer 041/004)
wurde ab März 2011 vorgenommen.
Material und Methoden. Die Leitlinie wurde
unter Koordination der Deutschen Interdisziplinären Vereinigung für Schmerztherapie (DIVS) von 9 wissenschaftlichen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen entwickelt. Acht Arbeitsgruppen
mit insgesamt 50 Mitgliedern wurden ausgewogen in Bezug auf Geschlecht, medizinischen Versorgungsbereich, potenzielle Interessenkonflikte und hierarchische Position im
medizinischen bzw. wissenschaftlichen System besetzt.Die Literaturrecherche erfolgte über die Datenbanken Medline, PsycInfo,
Scopus und Cochrane Library (bis Dezember
2010). Die Graduierung der Evidenzstärke erfolgte nach dem Schema des Oxford Center
for Evidence Based Medicine. Die Formulierung und Graduierung der Empfehlungen erfolgte in einem mehrstufigen, formalisierten
Konsensusverfahren. Die Leitlinie wurde von
den Vorständen der beteiligten Fachgesellschaften begutachtet.
Ergebnisse und Schlussfolgerung. Die Diagnose eines juvenilen FMS (JFMS) wurde als
wissenschaftlich nicht etabliert eingestuft.
Beim sog. JFMS wird eine multidimensionale
Diagnostik mit validierten Instrumenten gefordert. Die Therapie sollte multimodal erfolgen, bei starker schmerzbedingter Beeinträchtigung auch primär stationär.
Schlüsselwörter
Chronische Schmerzen ·
Fibromyalgiesyndrom · Systematische
Übersicht · Leitlinie · Kinder und Jugendliche
Der Schmerz 3 · 2012 | 3
Schwerpunkt
nor helpful. Therefore, they propose to
use the term “chronic pain disorder in several body regions with somatic and psychological factors” instead.
Clinical diagnosis
Clinical consensus
In children and adolescents with chronic pain in multiple body regions (CWP) a
multidimensional diagnosis of pain and
other physical and psychological symptoms is recommended. Validated tools
and methods should be used. Strong
consensus
Comment. As no pathognomonic individual diagnostic findings for so-called
JFMS are available, the diagnosis is based
on the presence or absence of a characteristic constellation of symptoms and
signs after exclusion of all other diseases
that may also have such a constellation of
symptoms and signs. Therefore, the differential diagnosis and exclusion of other diagnoses is of particular importance.
The differential diagnosis itself depends
on the clinical picture. Various organic
diseases have to be considered: (systemic)
inflammatory conditions such as juvenile
idiopathic arthritis, malignant conditions
such as leukemias [8, 77] and endocrine–
metabolic diseases [42, 49]. Psychological
problems/disorders should be considered
since they are even more common, e.g.,
depression (subtypes according to DSMIV, see below), anxiety disorders (subtypes
according to DSM-IV, see below), posttraumatic stress disorders (PTSD) and
dissociative disorders with or without selfinjurious behavior. There is also the possibility of mental illness of parents, as seen
in Munchhausen by proxy syndrome.
In a study by Degotardi et al. [11] 2 of
77 children, all of whom met the Yunus
criteria and all of whom were diagnosed
by pediatric rheumatologists as JFMS,
were eventually diagnosed with severe
psychiatric disorders (“schizoaffective disorder” and “depression with suicidal ideation”) during further psychological evaluations. In the course of the study an additional 3% of the enrolled children had a
“need for psychiatric referral.” KashikarZuck et al. studied 102 adolescents with
the diagnosis of so-called JFMS regard-
4 | Der Schmerz 3 · 2012
ing psychiatric disorders using standardized tests and an extensive psychological
exploration: 19% suffered from depression according to DMS-IV criteria [major depression (n=7), dysthymic disorder (n=8), depressive disorder not otherwise specified (NOS) (n=5)], 55% an anxiety disorder [panic disorder (n=6), agoraphobia (n=4), specific phobia (n=0), social phobia (n=11), obsessive-compulsive
disorder (n=3), posttraumatic stress disorder (n=5), generalized anxiety disorder (n=17), or separation anxiety disorder (n=3)] and 24% suffered from attention deficit hyperactivity disorder (ADHD) [37, 38]. Therefore, the clinical assessment should include a profound medical and psychological examination, preferably by use of validated tools such as
the German Paediatric Pain Questionnaire (“Deutscher Schmerzfragebogen
für Kinder und Jugendliche”, DSF-KJ)
[71]. Specifically, the following examinations should be conducted:
Fbasic laboratory diagnostic, e.g.,
erythrocyte sedimentation rate, complete blood count with differential
count, C-reactive protein, creatine kinase. Further diagnostic studies (e.g.,
antinuclear antibodies, rheumatoid
factor, imaging, electroencephalography, electrocardiography, genetic
studies, biopsy) are indicated if there
is a clinical suspicion for an alternative cause of the pain, and
Fpsychological standard diagnostics
such as the “Depressionsinventar für
Kinder- und Jugendliche (DIKJ)” (depression inventory for children and
adolescents), “Angstfragebogen für
Schüler (AFS)” (fear questionnaire for
students).
If applicable, polysomnography
Epidemiology
Evidence-based observation
The prevalence of CWP is strongly agedependent and ranges between 1 and
15% in children and adolescents. Diffuse musculoskeletal pain in combination with other physical or psychological symptoms such as tension-type headaches, fatigue, sleep disturbance and
emotional distress is present in <1% of
children and adolescents between the
ages of 8–15 years in international studies. There is a female predominance.
Strong consensus
Comment. When reviewing epidemiological studies, distinction must be made
with regard to the sample studied—specifically, between studies that examined only the presence of CWP [15, 50] and studies that studied children who also suffered
from other symptoms indicative of the diagnosis of so-called JFMS.
Epidemiological studies in school children focused on children between 10 and
12 years and reported prevalences of CWP
of 1% [50], 7.5% [52] and 9.9% [51]. In a
follow-up study by Mikkelson et al. [50],
adolescents between the ages of 14 and 16
years had a prevalence of CWP of 15%.
In a German representative population sample, 302 adolescents were in the
age group between 14 and24 years; none
of them fulfilled the FMS criteria according to the survey criteria [22]. Since the diagnosis of adult FMS by means of tender
points was abandoned in the latest ACR
criteria [81], epidemiological studies of the
prevalence of so-called JFMS need to be
re-evaluated. Of the 7 children who were
classified as having so-called JFMS (prevalence approximately 1% among school
children 9–15 years) in the study by Clark
et al. in 1998 [9], there was only one child
who fulfilled all examined additional criteria (sleep disturbances, morning stiffness, fatigue, sadness). Three children
fulfilled only one criterion each; neither
the severity of symptoms nor the impairment of the children by the symptoms was
reported. Other studies that found a significantly higher prevalence of so-called
JFMS of 6.2% for 9- to 15-year-old school
children based their diagnosis mainly
on muscle tenderness [7], which, due to
the methodological difficulties described
above, can be criticized.
Disease course
Evidence-based observation
In most patients with CWP, or so-called
JFMS, the disease course is variable with
alternating episodes of increased, decreased or absent symptoms. Evidence
level 2b, strong consensus
Comment. In a study on the course of
CWP in childhood and adolescence, only
10% of children who had CWP at baseline
complained of persistent symptoms after
1 and 4 years [50].
The evaluation of studies on the course
of the so-called JFMS is complicated by
the fact that the diagnosis itself is not valid, due to the methodological problems
described in detail above. Moreover, in
most studies, the study population was
not assessed with standardized instruments. Essentially, children and adolescents with a pain disorder diagnosed in a
non-standard fashion were examined in a
non-standard fashion, and described by
the authors as having so-called JFMS.
In clinical studies, the persistence of
long-term symptoms is described in a
subset of patients. Malleson et al. [46]
conducted a retrospective survey based
on medical records. Twenty-eight of 35
patients diagnosed with JFMS had more
than one appointment in the rheumatology clinic. After a variable observation period between 1 and 48 months, 17 of 28 patients with so-called JFMS had persistent
symptoms after an average of 27 months
[46]. In a retrospective study, Siegel et
al. [74] assessed 44 patients over 6 years
with so-called JFMS. Subsequent phone
interviews, on average 2.6 years (range
0.1–7.6 years) after diagnosis, demonstrated an increase in the number of reported symptoms. On a visual analog
scale (VAS) from 1–10 (1=complete disability; 10=no disability), the patients assessed their current impairment as being less pronounced than in the previous
year (previous year 5.1±3.1 vs. currently 6.9±1.6). The patients received a standard outpatient treatment (tricyclic antidepressants, non-opioid analgesics, exercise program) [74]. The study results are
promising; however, there is a core critical point: the authors changed their study
methods between the time of outpatient
treatment (unstructured survey) and the
telephone interview (structured survey).
In addition, no standardized instrument
to assess pain-related disability was used,
e.g., the Functional Disability Inventory [36, 79]. Gedalia et al. [18] conducted a retrospective study over a period of
4 years. Fifty of 59 patients with so-called
JFMS were seen more than once in the
outpatient clinic. At an average follow-up
of 18 months (range 3–65 months), 60% of
the children improved, 36% experienced
no change and 4% experienced a worsening of pain symptoms. The therapy consisted of a combination of pharmacological and nonpharmacological interventions; at the time of follow-up 74% of children were taking medications [18].
Of 48 U.S. American children and adolescents diagnosed with JFMS, after an
average of 3.7 years, 62.5% suffered from
CWP, and 60.4% fulfilled criteria for socalled JFMS [40].
Population-based studies in children
and adolescents reveal a more favorable
disease course: In a population of Israeli
school age children, Buskila et al. [6] diagnosed so-called JFMS in 21 of 337 patients (6.2%) according to the ACR criteria; after 30 months of follow-up, the ACR
criteria were met by only 4 of 21 children.
In the Finnish study by Mikkelsson et al.
[52], only 4 of 16 school age children with
so-called FMS fulfilled the ACR criteria of
so-called JFMS after a follow-up of 1 year.
Exacerbating factors for CWP include
the following: daily hassles, pain-related
catastrophizing, lack of self-efficacy and
lack of positive family support [43]
Etiology
Somatic complaints (headache
and abdominal pain),
behavioral problems and
increased physical activity
Evidence-based observation
Somatic complaints (headache and abdominal pain), behavioral problems and
increased physical activity frequently occur prior to CWP. There are no studies on
the relationship of these factors to socalled JFMS. Evidence level 2b, strong
consensus
Psychosocial problems
Evidence-based observation
Studies regarding psychosocial problems
in patients with so-called JFMS demonstrate controversial findings. Evidence
level 3b, strong consensus
Comment. A biopsychosocial perspective is necessary to understand the origin
and maintenance of chronic pain [78].
Chronic pain in children is the result of a
dynamic process of biological factors (e.g.,
an underlying somatic disease), physical
components (e.g., a lowered threshold of
pain), psychological factors (e.g., painrelated fears, dealing with pain and pain
coping) and sociocultural conditions (e.g.,
pain-related parenting, social attitudes,
gender roles, social interactions in dealing with pain). All of these factors interact with each other.
Risk factors for the development of a
so-called JFMS or chronic pain disorder
of the musculoskeletal system have not
been investigated to date.
In an English population-based prospective follow-up study over a study period of 12 months, 1,440 school children
were examined for risk factors for the development of CWP. These risk factors included physical symptoms such as headache on more than 7 of 30 days [relative
risk (RR) 2.50, 95% CI 1.16–5.39], abdominal pain at 1–7, but not less than one or
more than 7 days per month (RR 1.8, 95%
CI 1.1–2.9), as well as increased physical
activity of more than 6 h per week (RR
2.03, 95% CI 1.05–3.94). Prosocial behavior was identified as a protective factor for
CWP (RR 0.50; 95% CI 0.28–0.90) [34].
In a case control study, no significant differences in psychological distress
were observed between patients with a
so-called JFMS and JIA [60]. In contrast,
Conte et al. [10] reported a higher incidence of anxiety and depression in patients with so-called JFMS compared to
healthy subjects and patients with JIA. In
a case control study of a private psychiatric hospital, 32 adolescents who met the
criteria of so-called JFMS reported more
physical and emotional problems than the
control group of 30 adolescents with other
mental disorders [44].
A case–control study of 55 patients
with so-called JFMS and 55 healthy controls showed that adolescent patients with
so-called JFMS described themselves as
more withdrawn and less popular and,
thus, were more likely than their peers to
be socially isolated [39]. This was not the
case for patients with JIA.
Der Schmerz 3 · 2012 | 5
Schwerpunkt
Family history
Pathophysiology
Evidence-based observation
Evidence-based observation
So-called JFMS and adult FMS occur together in families. Evidence level 2b,
strong consensus
Due to the lack of studies, no comment
can be made on the pathophysiology of
so-called JFMS. Strong consensus
Comment. The increased joined occurrence of adult FMS and so-called JFMS
in first-degree relatives has consistently been reported in several studies [1, 6,
53, 65, 76]. In an Israeli study of 37 families with FMS (at least 2 relatives), 74%
of siblings and 53% of parents were diagnosed with FMS according to the ACR
criteria [5]. The studies on familial clustering, however, do not provide evidence
that the increased incidence of adult FMS
and so-called JFMS is genetically determined. The results of an American study
of over 40 families with FMS (at least
2 first-degree relatives) were consistent
with a genetic linkage to the HLA region
[82]. A Finnish longitudinal cohort study
of 11-year-old twins (583 monozygotic
pairs, 588 same-sex dizygotic and 618 different-sex dizygotic pairs) demonstrated a CWP prevalence of 9.9% and mostly discordance; a genetic basis could not
be shown [51].
Non-genetic, psychological factors for
the increased incidence of chronic pain in
children of adult chronic pain patients are
much more likely to play a role than genetic models (role modeling etc.) [2, 56].
Coordination of care
Parental factors
Evidence-based observation
Parents of patients with so-called JFMS
frequently show increased anxiety, a history of chronic pain, depressive symptoms and chronic diseases. Evidence level 3b, strong consensus
Comment. Parents of children and adolescents with so-called JFMS:
Fmore frequently report chronic pain
[35, 70],
Ftend to show increased anxiety [10],
Fmore frequently demonstrate depressive symptoms [10, 35], and
Fsuffer from more somatic symptoms
[10].
6 | Der Schmerz 3 · 2012
Evidence-based recommendation
Children and adolescents with CWP
should be presented to a clinical specialist familiar with chronic pain in childhood on an outpatient basis. In the case
of long school absences, severe limitations in activities of daily living, physical
inactivity or increasing social isolation,
inpatient treatment in a facility that offers a special treatment program for children and adolescents with chronic pain,
should be recommended. Evidence level 4, strong consensus
Comment. In a study by Hechler et al.
[28] on the stratification of therapy in a
sample of children and adolescents with
chronic pain (headaches, abdominal
pain or musculoskeletal pain), the criteria for stratification of therapy were studied. The intensity of initial therapy (outpatient therapy, outpatient group therapy,
inpatient therapy) turned out to be correct for the majority of children. An intensification of therapy was rarely needed. In this study, children were assigned
to multimodal inpatient treatment based
on the following criteria: chronic pain for
at least 3 months, no successful therapy
in the previous setting, high pain-related
impairment [Pain Disability Index (PDI)
>36] and the presence of 3 of the following 4 criteria:
Fpain duration >6 months,
Faverage pain intensity in the last
7 days ≥5 [visual analog scale (NRS)
0–10],
Fpain peaks ≥8 (NRS 0–10) at least
twice a week, and
Fat least 5 school days of absence during the last 20 school days.
Children and adolescents with so-called
JFMS who do not (yet) express this level
of severe impairment, should initially be
treated as outpatients. Local or part-time
inpatient multimodal treatment is rarely
offered for children and adolescents with
chronic pain of the musculoskeletal system in Germany. Therefore, for the less
severely affected children, an individual
multimodal program should be planned
based on the existing facilities in Germany (e.g., outpatient psychotherapy, physical therapy, regular visits to the pediatrician). There are only a few centers offering multimodal inpatient therapy; thus,
treatment often takes place remote from
the hometown. Even though only studies
with a level of evidence grade 4 are available, the authors agreed in a unanimous
consensus to recommend this modality
with a strength level B given the following
criteria are met: low risk, high acceptance
rate among patients (adherence to therapy
between 95% [13] and 98% [16]) and ethical necessity, since normal childhood development is endangered.
General principles of treatment
Therapeutic goals
Evidence-based recommendation
Goals of treatment should be pain relief, restoration of functioning, reduction
of school absenteeism, dissolving social isolation, strengthening self-awareness, mobilizing domestic resources and
the development of strategies for coping with pain. The inclusion of the family,
the training of strategies in everyday life
and the treatment of mental co-morbidities are also important. Evidence level 2c,
strong consensus
Comment. The general principles of
therapy have been formulated comprehensively in prospective outcome trials
[12, 13, 16, 23, 24, 25, 26].
Patient education
Clinical consensus
Patient and parent education and selfhelp groups for children, adolescents
and parents may be offered. Strong consensus
Psychotherapy
Clinical consensus
Scientifically established methods of psychotherapy should be used for children
and adolescents with so-called JFMS part
of a multimodal pain therapy. Strong
consensus
Comment. A U.S. randomized study in
cross-over compared active coping with
pain to self-monitoring in 30 adolescents;
at the end of the study both groups demonstrated a reduction of functional limitations and depression [41]. A significant reduction of pain could not be demonstrated. This study had major methodological
problems; neither the sample size was calculated nor was a primary outcome measure predetermined.
The authors believe that, according
to experts and studies about multimodal pain therapy, scientifically established
psychotherapies (cognitive behavioral
therapy, trauma therapy, systemic family therapy, analytical therapy) in children with so-called JFMS should only be
carried out as part of a multimodal pain
therapy or for treatment of psychiatric
co-morbidity. The content of the therapy
should be adjusted to the individual child
or adolescent and his/her situation. Local
outpatient psychotherapy should be considered on a case-by-case basis.
Physical therapy and
physical measures
Clinical consensus
Physical therapy should be used as part
of multimodal pain therapy. Strong consensus
Comment. In a randomized-controlled
trial (RCT), 14 patients with so-called
JFMS were treated with aerobic exercise
of moderate intensity and 16 were treated with Qi-Gong. At the end of therapy, the group performing aerobic training reported a greater reduction in pain,
fatigue and impairment in quality of life
than the group performing Qi-Gong. In
the Qi-Gong group, there was significant
change in pain, fatigue and impairment
in quality of life [75]. A recent study by
Kashikar-Zuck [37] showed that adoles-
cents who suffered from so-called JFMS
and who were physically active (“high activity” as measured by actigraphy), had
less pain, were judged by their parents as
being less depressed and were functionally less impaired as compared to adolescents who were moving less (“low activity”). However, the cross-sectional design
did not allow establishing a cause-effect
relationship.
Studies on the efficacy of other methods of physical therapy and physical measures are not available. Nevertheless,
these therapies are recommended by the
authors with a level of recommendation
grade B since they are preferred by the patients, are accompanied by a high level of
adherence and have low risk of potential
adverse effects, and since they are easy to
implement in Germany, both on an outpatient and on an inpatient basis.
Pharmacologic therapy
Evidence-based recommendation
Pharmacologic therapy should not be
performed in children with CWP or socalled JFMS. Co-morbidities (e.g., depression in adolescence) should be treated
according to the available guidelines. Evidence level 4, consensus
Comment. Controlled drug studies
are not available. In a U.S. case series of
15 patients, it was reported that aspirin and nonsteroidal anti-inflammatory
drugs (NSAIDs) were not effective; 73%
of children responded to cyclobenzaprine 5–25 mg/day [66]. Two observational studies reported on the use of NSAIDs
and/or psychotropics in combination with
exercise therapy [74] or a complex multimodal treatment [63]. Saccomani et al.
[69] described a clinical improvement
with trazodone or amitriptyline in 2 Italian patients. Children and adolescents
were generally excluded from drug trials
in adult FMS patients.
Tricyclic antidepressants and selective
serotonin reuptake inhibitors (SSRI) are
not approved for the treatment of children and adolescents in Germany (off-label therapy). Clinical experience suggests
that there can be a role for drug therapy
in the treatment of comorbidities of the
individual multimodal therapy concept.
However, focusing on medications must
be avoided. The potential risks of drug
therapy, the lack of approval of most drugs
used as well as the failure to show a benefit
for the individual patient justify, according to the authors’ opinion, a recommendation against drug therapy.
Multimodal therapy
Clinical consensus
In patients with so-called JFMS, multimodal pain management should be performed. In cases of severe impairment
or unsuccessful other approaches, this
should be pursued in an inpatient unit, in
case of less severe impairment, initially in
an outpatient unit. Strong consensus
Comment. Multimodal pain therapy, in
the context of these guidelines, is understood to be a combination of at least one
method of activating physical therapy
with at least one method of psychotherapy, as described by the working group
multimodal therapy [4]. In the case of outpatient multimodal pain therapy, the pediatric rheumatologist or pediatric pain
specialist assumes the coordination of
care. Stipulations of inpatient multimodal pain therapy for children in Germany
are described in the OPS (“Operationenund Prozedurenschlüssel”) under paragraph 8–918.x.
There are no RCTs on the efficacy of
multimodal therapies in so-called JFMS.
In pediatric studies on the effectiveness of multimodal treatment programs
(outcome studies, level of evidence 2c),
there was always a more or less large proportion of children and adolescents with
CWP and additional psychosomatic/psychological complaints/abnormalities. The
proportion of these children was 40%
(n=23) in the study by Eccleston et al.
[17], and in the study by Hechler and Dobe [25], the proportion of children with
predominant musculoskeletal pain was
14% (n=28). In the latter work, the chronically ill children and adolescents in 40%
of cases reported pain in more than one
region (n=61). Three months after completion of inpatient multimodal pain therapy, 75% of children reported significant
positive changes in pain intensity, 63% a
significant improvement in pain-related
Der Schmerz 3 · 2012 | 7
Schwerpunkt
disability and 45% significant changes in
the days absent from school (30% of the
children had no significantly increased
school absenteeism at baseline). Clinically significant changes in the emotional impairment were exhibited in 13–26% of patients, whereby 50–60% had no emotional distress at baseline. More than half of
the children (55%) demonstrated overall
improvement 3 months following treatment [25].
In their recent analysis of 200 children
and adolescents with chronic pain, Dobe
et al. [13] showed that the success of the
multimodal inpatient program was independent of the site of pain.
It is recommended children and parents receive instructions for home therapy
during multimodal inpatient treatment.
The continuation of parts of the multimodal program in everyday life is crucial
for the prognosis. Relaxation techniques
and physical therapy, exercise therapy and
other athletic activities, physical activities
and the coping with stressors and psychological problems (e.g., by use of social support) are important tasks to take home [12,
23, 25, 27].
Contraindications for multimodal inpatient treatment are serious psychiatric
illnesses such as the presence of psychosis or anorexia nervosa [13]. Suicidal ideation in adolescents with chronic pain or
depression—a frequently described comorbidity in children with chronic pain
in multiple body regions—has been reported. Therefore, the diagnosis and treatment of children and adolescents with socalled JFMS should always be conducted by a multidisciplinary team, involving
child and adolescent psychologists or psychiatrists.
Discussion
The first version of the guideline for socalled JFMS was substantially revised
[48]. It has been shown that the diagnosis of JFMS is not yet scientifically established, so that the concept of so-called
JFMS was implemented in this paper. The
question of how children and adolescents
with chronic pain in several body regions
accompanied by other symptoms should
be diagnosed and classified is an urgent
question for future research. This raises
8 | Der Schmerz 3 · 2012
the question of whether the clinical picture of JFMS exists or whether the children and adolescents with these symptoms suffer from other specified diseases.
A second new feature of the guidelines is
the requirement for a standardized diagnostic procedure, which also includes validated psychological assessments. Since it
is known that the so-called JFMS does
not represent a well-established disease, it
is even more important to recognize defined organic and mental diseases, such
as posttraumatic stress disorder in order
to identify and deliver appropriate therapy. As in the first version of the guideline, multimodal treatment approaches are warranted for affected children. In
addition to the general principle of “outpatient before inpatient care”, we present
criteria that, when present, suggest assignment to multimodal inpatient treatment. These criteria do not relate primarily to pain intensity or duration of the disease, but in particular to pain-related adverse effects such as school absenteeism, a
marked reduction of the activities of daily
living or social withdrawal. As in the first
version of the guidelines, drug therapy is
not recommended for the treatment of the
so-called JFMS. Co-morbid mental disorders should be treated according to the respective guidelines.
In summary, the revised and updated second version of this guideline clearly recommends a comprehensive reassessment of the so-called JFMS taking into account current work on quantitative sensory testing (QST), psychological assessment of chronic pain as well as the success
of multimodal pain management programs in children and adolescents. Controlled studies for the diagnosis of children who present with a symptom complex that reminds of adult FMS, and RCTs
of children suffering from chronic musculoskeletal pain and other physical and
mental symptoms, are urgently needed to
clarify the diagnosis of JFMS and to provide evidence for multimodal pain treatment for these children.
Corresponding address
Prof. Dr. B. Zernikow
Deutsches Kinderschmerzzentrum,
Vestische Kinder- und Jugendklinik,
Universität Witten/Herdecke
Dr. Friedrich-Steiner-Str. 5, 45711 Datteln
Germany
b.zernikow@deutsches-kinderschmerzzentrum.
de
Conflict of interest. See . Tab. 5 in “Methodological
fundamentals used in developing the guidelines” by
W. Häuser, K. Bernardy, H. Wang, and I. Kopp in this issue.
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