52 - Fibromyalgia

52
Fibromyalgia
FREDERICK WOLFE • JOHANNES J. RASKER
KEY POINTS
Many issues that surround fibromyalgia are not scientific
ones—it is widely agreed that pain and suffering are real;
instead, the primary issues are often social, political, and
financial.
Fibromyalgia lies at the end of a continuum of
polysymptomatic distress rather than being a discrete
disorder.
Fibromyalgia may be diagnosed with American College of
Rheumatology (ACR) 2010 or 1990 criteria, but clinical care
does not require a diagnosis.
The ACR 2010 criteria should result in changes in the sex
ratio of patients with fibromyalgia because men have higher
pain thresholds and are therefore less likely to be diagnosed
as having fibromyalgia than women when the 1990 criteria
including tender points are used.
Advanced neuroimaging techniques showed dysfunctioning
of hippocampus and other cerebral abnormalities in
fibromyalgia patients, as well as greater gray matter loss
than in healthy controls.
The regions in which objective changes are demonstrated
may be functionally linked to core features of the
disorder including affective disturbances and chronic
widespread pain.
Advanced neuroimaging techniques indicate that central
factors are important in the processing of pain in people with
fibromyalgia and suggest that they have a narrow range of
tolerance for pain and perhaps other sensory stimuli before it
becomes noxious.
Pharmacologic treatment is of limited value, but caring,
comprehensive care can make a difference.
Fibromyalgia is a controversial disorder.1 Certain aspects of
the controversies surrounding fibromyalgia reflect scientific
disagreements about categorization, pathophysiology, and
treatment (Figure 52-1). But another important reason for
controversy is that the diagnosis carries with it profound
societal consequences. Whether fibromyalgia “exists” or is
“real” or should be valued matters a great deal to patients,
payers, pension systems, researchers, professional and
patient organizations, and pharmaceutical companies.2
Fibromyalgia is a clinical syndrome that is defined by
the presence of generalized pain, fatigue, unrefreshed sleep,
multiple somatic symptoms, cognitive problems, and other
symptoms, often including depression. Symptoms important
to the fibromyalgia case definition are shown in Figure 52-2
in order of their importance.3 The 2010 American College
of Rheumatology (ACR) preliminary diagnostic criteria for
fibromyalgia require the presence of widespread pain and
multiple symptoms (Table 52-1).3 The more restrictive
ACR 1990 classification criteria require the presence of
widespread pain plus the presence of tenderness on palpation in at least 11 of 18 specified “tender point” sites.4
Fibromyalgia can be diagnosed in the presence of other
medical conditions and is never a diagnosis of exclusion.
However, concomitant disorders associated with musculoskeletal pain and fatigue will always need to be identified.
THE FIBROMYALGIA CONSTRUCT
One Syndrome or One of Many?
The central features of fibromyalgia that were noted earlier
are also found in illnesses such as chronic fatigue syndrome,
irritable bowel syndrome, headache syndromes, and multiple
chemical sensitivities, among many others (see Figure
52-1).5 Taken together, these syndromes have been called
functional somatic syndromes (FSS).6 Because the symptom
content of the syndromes is similar, as are the treatments
and the demographic characteristics of patients who have
the disorders, it has been suggested by many that a single
diagnostic term, rather than individual syndrome names,
should be used for diagnosis. These suggestions derive mostly
from the psychiatric literature.7-9 Terms suggested include
FSS and bodily pain disorder.9 However, if fibromyalgia is
just a name given to the disorder primarily by rheumatologists, but does not differ essentially from other somatic
syndromes, then fibromyalgia does not exist as a separate
syndrome. Fibromyalgia versus FSS creates a series of problems. FSS connotes a strong psychologic component, which
is undesirable to patients, pharmaceutical companies, and
medical researchers. In addition, there is the logical inconsistency in which regulatory authorities such as the U.S.
Food and Drug Administration (FDA) approve treatments
for the select fibromyalgia indication, when fibromyalgia
is not different from other FSS. The FDA mandate strengthens the position of fibromyalgia as a “separate” disease,
although there is little evidence that it is such an entity.7,10
A Separate Syndrome or Part of a Continuum?
Fibromyalgia is properly considered to lie “at the extreme
end of the spectrum of polysymptomatic distress.”11 Fibromyalgia diagnosis depends on splitting the distress continuum, placing on one side of the divide those with
fibromyalgia and on the other side all other persons. Poly­
symptomatic distress refers to problems in many symptom
areas—pain, fatigue, sleep disturbance, functional impairment, psychologic status, and so on. Because symptoms are
correlated, persons with high levels of one symptom will
733
734
PART 6 | DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN
Functional
Somatic
Syndromes
One syndrome
or many?
Irritable Bowel Syndrome
Chronic Fatigue
Chronic Pelvic Pain
TMJ
Noncardiac Chest Pain
Multiple Chemical Sensitivities Tension Headache
Fibromyalgia
Does central sensitization
explain FM and CSS?
Continuous
Disorder
Central
Sensitization
A continuum or a
separate disorder?
Somatization and
Psychological
Mechanisms
How should FM and
FSS be treated?
Discrete
Disorder
What constitues
treatment?
A socially constructed
disorder?
• Societal
Interaction
• Social
Construction
• Medicalization
• Pharma and
Disease
Mongering
Is treatment
effective?
Figure 52-1 Fibromyalgia controversies. CSS, central sensitivity syndrome; FM, fibromyalgia; FSS, functional somatic syndromes; TMJ,
temporomandibular joint.
WPI (C)
Muscle tenderness
Muscle pain
Somatic symptoms (C)
Cognition (C)
IBS
Unrefreshed sleep (C)
Mood (C)
Cognitive symptoms
Abdominal pain
Headache
Fatigue (C)
Dizziness
Fatigue
Pain (C)
Bladder symptoms
Sleep problem (C)
Depression
Paresthesias
Diarrhea
Constipation
Sleep problem
Muscle weakness
Anxiety
WPI (C)
Muscle tenderness
Unrefreshed sleep (C)
Cognitive symptoms
Somatic symptoms (C)
Cognition (C)
Muscle pain
Mood (C)
Fatigue (C)
IBS
Sleep problem (C)
Headache
Pain (C)
Abdominal pain
Constipation
Dizziness
Paresthesias
Muscle weakness
Depression
Diarrhea
Anxiety
Fatigue
Bladder symptoms
Sleep problem
−.5
0
.5
1
1.5
Mean decrease accuracy
0
10 20 30 40 50
Mean decrease Gini
Figure 52-2 Symptoms that differentiate patients who satisfy American College of Rheumatology 1990 criteria from other rheumatic disease patients
with noninflammatory rheumatic pain disorders sorted by strength of association.3 The two figures represent different measures of association. Higher
scores mean stronger associations. (C), categorical variable; IBS, irritable bowel syndrome; WPI, Widespread Pain Index.
CHAPTER 52 | Fibromyalgia
735
Table 52-1 American College of Rheumatology 2010 Preliminary Diagnostic Criteria for Fibromyalgia3
Criteria
A patient satisfies diagnostic criteria for fibromyalgia if the following 3 conditions are met:
1. Widespread Pain Index (WPI) ≥ 7 and Symptom Severity Score ≥ 5 or
WPI between 3 and 6 and Symptom Severity Score ≥ 9.
2. Symptoms have been present at a similar level for at least 3 months.
3. The patient does not have a disorder that would otherwise explain the pain.
Ascertainment
1. WPI: Note the number areas in which the patient has had pain over the past week. In how many areas has the patient had pain? Score will be
between 0 and 19.
Shoulder girdle, Lt.
Shoulder girdle, Rt.
Upper arm, Lt.
Upper arm, Rt.
Lower arm, Lt.
Lower arm, Rt.
Hip (buttock, trochanter), Lt.
Hip (buttock, trochanter), Rt.
Upper leg, Lt.
Upper leg, Rt.
Lower leg, Lt.
Lower leg, Rt.
Jaw, Lt.
Jaw, Rt.
Chest
Abdomen
Upper back
Lower back
Neck
2. Symptom Severity Score:
Fatigue
Waking unrefreshed
Cognitive symptoms
For the each of the three symptoms above, indicate the level of severity over the past week using the following scale:
0 = No problem
1 = Slight or mild problems; generally mild or intermittent
2 = Moderate; considerable problems; often present and/or at a moderate level
3 = Severe: pervasive, continuous, life-disturbing problems
Considering somatic symptoms* in general, indicate whether the patient has:
0 = No symptoms
1 = Few symptoms
2 = A moderate number
3 = A great deal of symptoms
The Symptom Severity Score is the sum of the severity of the three symptoms (fatigue, waking unrefreshed, cognitive symptoms) plus the
extent (severity) of somatic symptoms in general. The final score is between 0 and 12.
*For reference purposes, here is a list of somatic symptoms that might be considered: muscle pain, irritable bowel syndrome, fatigue/tiredness, thinking or
remembering problem, muscle weakness, headache, pain/cramps in abdomen, numbness/tingling, dizziness, insomnia, depression, constipation, pain in
upper abdomen, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud’s phenomenon, hives/welts, ringing
in ears, vomiting, heartburn, oral ulcers, loss/change in taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing difficulties,
easy bruising, hair loss, frequent urination, painful urination, and bladder spasms.
tend to have high levels of other symptoms. As an aggregate
concept, polysymptomatic distress cannot be measured
directly but can be approximated with the use of surrogate
variables. One such surrogate measure of polysymptomatic
distress is the fibromyalgia symptom scale—also called the
fibromyalgianess scale.12 This scale represents the summation of the Widespread Pain Index (the number of body sites
reported as painful) and characteristic fibromyalgia symptoms used in the ACR 2010 preliminary diagnostic criteria.3
In patients with various rheumatic diseases followed in the
U.S. National Data Bank for Rheumatic Diseases,13 the
upper part of Figure 52-3 shows the relation between the
scale and the Short Form-36 (SF-36) Physical Component
Summary (PCS) score, the EQ5D Quality of Life score, and
the patient’s estimate of global severity. A value of 13 on the
fibromyalgianess scale best divides fibromyalgia-positive and
fibromyagia-negative patients.14 It can also be seen that the
Widespread Pain Index alone is similarly associated with
these three measures of illness severity (see Figure 52-3,
lower part). About 2% to 4% of the adult population meets
criteria for fibromyalgia. One can sense in the figure the
distribution of polysymptomatic distress and its correlation
with quality of life. Note that polysymptomatic distress is a
quantity that exists in all persons, not just in those with
fibromyalgia, though it is greater in those with fibromyalgia.
The higher the score on the polysymptomatic distress
scale and the Widespread Pain Index, the more likely we
are to find evidence of social disadvantage such as lower
income, less education, and childhood mistreatment, and
we will also find more psychologic distress and abnormality;
it appears that these factors play a role in the development
of fibromyalgia-like symptoms and symptom intensification.14 Fibromyalgianess differs from other measures of polysymptomatic distress by the centrality of musculoskeletal
pain because nonarticular musculoskeletal pain is a central
component of the scale.
To define fibromyalgia by criteria, we must, in effect,
draw a line on the distress continuum and say that those
beyond this line have fibromyalgia and those before it do
not. In the ACR 2010 criteria (see Table 52-1),3 the cut
point is identified by the extent of widespread pain and
fibromyalgia symptoms. In the 1990 criteria (Table 52-2),
the cut point is represented by a combination of tender
points and widespread pain. Both cut points, though aided
by data analyses, are determined by committees. There is
nothing intrinsic in the polysymptomatic distress scale that
tells us where the dividing point is. But in the general population a PCS score of 50 represents the population mean,
with each standard deviation representing 10 units. At a
fibromyalgianess score of 13, patients designated as
50
1
40
.8
30
.6
.4
20
10
1013
20
30
10
Fibromyalgia Severity
Scale
45
.9
40
.8
35
.6
25
.5
5
10
15
20
6
4
2
0
30
.7
30
0
1013
8
10
20
Widespread Pain Index
0
5
10
15
20
Widespread Pain Index
1013
20
30
Fibromyalgia Severity
Scale
Fibromyalgia Severity
Scale
EQ5D
SF-36 Physical Component
Summary score
Patient global severity
DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN
Patient global severity
| EQ5D
PART 6 SF-36 Physical Component
Summary score
736
7
6
5
4
3
2
0
5
10
15
20
Widespread Pain Index
Figure 52-3 Assessment of polysymptomatic distress. A value of 13 on the Fibromyalgia Severity Scale is the best dividing point between fibromyalgia criteria–positive and fibromyalgia criteria–negative patients. EQ5D, EuroQoL; SF-36, Short Form-36.
fibromyalgia have a PCS score about 2 standard deviations
below the mean (see Figure 52-3, upper left). Thus fibromyalgia diagnosis identifies persons with substantially reduced
quality of life—those at the “extreme end of the spectrum
of polysymptomatic distress.”11
Social Construction and Medicalization
Many physicians doubt the existence of fibromyalgia as a
separate entity, considering instead that it is a primarily a
psychologic illness—not a “real disease”11,15-17 (see Figures
52-1 and 52-4). Epidemiologic and clinical studies give no
support to the idea that fibromyalgia is a distinct entity18-20;
instead, they support the contrary idea that fibromyalgia
represents the end of a spectrum of polysymptomatic
distress.
Illnesses exist within societies, and their existence and
phenotype are often a function of the degree of acceptance
of the disorder.21 The idea and consequences of fibromyalgia
as a socially constructed, medicalized disorder has been discussed at length.2 An illness may be considered to be socially
constructed when it is at least in large part the consequence
Table 52-2 1990 American College of Rheumatology Criteria for the Classification of Fibromyalgia*
1. History of Widespread Pain
Definition: Pain is considered widespread when all of the following are present: pain in the left side of the body, pain in the right side of the
body, pain above the waist, and pain below the waist. In addition, axial skeletal pain (cervical spine or anterior chest or thoracic spine or low
back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved side. “Low back” pain is considered
lower segment pain.
2. Pain in 11 of 18 Tender Point Sites on Digital Palpation
Definition: Pain, on digital palpation, must be present in at least 11 of the following 18 sites:
Occiput: bilateral, at the suboccipital muscle insertions.
Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5-C7.
Trapezius: bilateral, at the midpoint of the upper border.
Supraspinatus: bilateral, at origins, above the scapula spine near the medial border.
Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces.
Lateral epicondyle: bilateral, 2 cm distal to the epicondyles.
Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle.
Greater trochanter: bilateral, posterior to the trochanteric prominence.
Knee: bilateral, at the medial fat pad proximal to the joint line.
Digital palpation should be performed with an approximate force of 4 kg.
For a tender point to be considered “positive,” the subject must state that the palpation was painful. “Tender” is not to be considered “painful.”
*For classification purposes, patients will be said to have fibromyalgia if both criteria are satisfied. Widespread pain must have been present for at least 3
months. The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia.
From Wolfe F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the
Multicenter Criteria Committee, Arthritis Rheum 33(2):160–172, 1990.
CHAPTER 52 Patient perspective
| Fibromyalgia
737
Recognition
• Not a psychiatric disease
• A biologically real disease
• Specific biologic cause
• Cause is neurobiologic
dysfunction
Professional
organizations
Government
bodies
ACR/EULAR
WHO
FDA
NIH
Specific
treatments
Pharma and Disease Mongering
Research
Public
• Neurobiologic
causes
• Central
sensitization
Advertising
Physicians
Grants to physicians
Grants to patient
support groups
Financial
support
Research grants to
professional organizations
Support for professional
organization meetings
Support for “educational”
symposia
Recognition
Friendly “opinion leaders”
Figure 52-4 Nonmedical and societal issues and concerns in fibromyalgia. ACR/EULAR, American College of Rheumatology/European League Against
Rheumatism; FDA, U.S. Food and Drug Administration; NIH, National Institutes of Health; WHO, World Health Organization.
of societal factors22 that result in “the creation (or construction) of new medical categories with the subsequent expansion of medical jurisdiction.”23 Medicalization is “a process
in which nonmedical problems become defined and treated
as medical problems, usually in terms of illness and disorders
[and are] described using medical language, understood
through the adoption of a medical framework, or treated
with a medical intervention.”24
Ivan Illich’s 1976 description of medicalization in society
set out some markers that are germane to understanding
fibromyalgia and opposition to it.25 Illich wrote: “In a morbid
society the belief prevails that defined and diagnosed illhealth is infinitely preferable to any other form of negative
label or to no label at all” and that “people want to hear
the lie that physical illness relieves them of social and political responsibilities.” He called these people “innocent
victim[s] of biological mechanisms. … ” In addition, he said
diagnosed “ill-health” provides access to disability programs
and access to additional health care.25 Data from research
about the neurobiologic investigations of pain mechanisms
are offered as strong support that persons with fibromyalgia
are “innocent victim[s] of biological mechanisms …”26
Given the social construction of fibromyalgia, medicalization is driven primarily by three components (see Figure
52-4). The first is the primary need for patients with fibromyalgia and other FSS for legitimization: Others need to
understand that the problem is real and serious, and not
primarily a psychosomatic illness.2 The diagnosis of a “valid”
fibromyalgia provides entry to medical insurance and treatment and is grounds for work disability and pension. Extensive networks of patient organizations throughout the world
work toward this purpose.2 The second pillar of medicalization in fibromyalgia is the pharmaceutical industry.27 Directto-patient advertising is ubiquitous. Often deceptive, it
seeks to expand the definition of fibromyalgia, entice persons
with pain and fatigue into the diagnosis, and strongly
promote its treatments as effective.27 Industry financially
supports patient and professional organization, medical education and symposia,2,28 and advertising in professional
and lay journals. Virtually all major authors of fibromyalgia
studies have received pharmaceutical company support.
The influence of drug companies has increased dramatically
in the past two decades to the extent that “ … companies
are having an increasing impact on the boundaries of the
normal and the pathological, becoming active agents of
social control.23
Although “medicalization is now more driven by commercial and market interests than by professional claimsmakers,”23 physicians and professional organizations remain
the importance sources of scientific support, and National
Institutes of Health grants for fibromyalgia research have
become common.
The more fibromyalgia is seen as a “real disease” with
strong criteria, reliable assessments and professional support,
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PART 6 | DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN
the more the claims of patients will be taken seriously, the
more drugs will be sold and consumed, and the more financial and intellectual support will come to researchers and
professional organizations. By contrast, perceiving fibromyalgia as an FSS and part of a continuum with assessments
that are not always reliable weakens support for the syndrome and those who have it. The issues that surround
fibromyalgia are not scientific ones—it is widely agreed that
pain and suffering are real; instead, the issues are social,
political, and financial.
Historical Development
Attempts to characterize and diagnose fibromyalgia have
gone through several changes in conceptualization. The
earliest roots of the syndrome can be found in the nineteenth century perception of abnormal connective tissue
and muscles. In various forms, this concept held sway until
the late 1970s when a new emphasis on sleep disturbance
and tender points led to proposed clinical criteria that
included sleep disturbance and tenderness to palpation at
12 of 14 selected sites.29 In the early 1980s, most of the other
fibromyalgia-associated symptoms were identified, and unofficial criteria were proposed that combined symptoms
with tenderness.30 With the publication of the ACR criteria
in 1990,4 the fibromyalgia case definition was reduced
to generalized pain and the presence of multiple tender
points. The 1990 criteria, supported by the imprimatur of
the ACR, gave the syndrome official sanction. With the
criteria publication, professional opposition to fibromyalgia
solidified and has continued until the present.2,31-37 In 2010
the ACR preliminary diagnostic criteria3 were published.
These criteria expanded the case definition and criteria
items to include widespread pain and multiple symptoms
including fatigue, disturbed sleep, cognitive symptoms, and
multiple somatic symptoms. Despite scientific data questioning the validity of fibromyalgia as a distinct entity, fibromyalgia has become a dominant paradigm, supported
strongly by funding and influence of the pharmaceutical
industry. At present there are currently several opposing
views of fibromyalgia. One view holds that it is not distinct
and is a part of FSS,7,9,10 with a functional symptom being
defined as one that “after appropriate medical assessment,
cannot be explained in terms of a conventionally defined
medical disease.”7 The second view, and the dominant
paradigm, supports the concept that fibromyalgia is a dis­
order of “ … aberrant central pain transmission … [in which]
purely behavioral or psychologic factors are not primarily
responsible for the pain and tenderness … ”38 A third view
holds that fibromyalgia is the end of a spectrum of polysymptomatic distress and is not a distinct entity.2,11 Perhaps,
not surprisingly, these views are not mutually exclusive.
CLINICAL FEATURES
Fibromyalgia is characterized by high levels of pain, sleep
disturbance, and fatigue combined with a general increase
in medical symptoms (Table 52-3) including problems of
memory or thinking and often psychologic distress.39
Individuals with the syndrome are unusually sensitive to
digital pressure (tender points) in certain body areas. Clinically, fibromyalgia is often identified or suspected by the
Table 52-3 Prevalence of Specific Symptoms
among 2784 Patients with Fibromyalgia in the
National Data Bank for Rheumatic Diseases
Symptom
Sleep problems
Fatigue or tiredness
Muscle pain
Muscle weakness
Paresthesias
Cognitive problems
Headache
Dry mouth
Insomnia
Easy bruising
Dry eyes
Depression
Blurred vision
Irritable bowel syndrome
Heartburn
Itching
Dizziness
Constipation
Pain/cramps in the abdomen
Ringing in ears
Pain in upper abdomen
Nervousness
Nausea
Diarrhea
Shortness of breath
Hearing difficulties
Hair loss
Oral ulcers
Wheezing
Loss of appetite
Raynaud’s phenomenon
Chest pain
Rash
Sun sensitivity
Loss/change of taste
Fever
Hives/welts
Vomiting
Seizures
%
89.1
88.6
85.2
70.2
67.6
66.3
64.7
53.3
51.8
49.1
47.5
47.5
47.0
46.3
44.4
44.3
42.1
41.9
41.5
41.4
40.3
39.7
37.7
33.6
32.3
29.8
23.6
22.4
21.4
21.1
20.1
19.2
17.1
16.7
14.4
13.4
9.3
9.1
1.7
inexplicability and severity of symptoms and by their
number. The most common defining symptom is that of
generalized pain (“pain all over”), and pain all over, or
widespread pain, is a requirement of the 1990 and 2010
criteria. The clinician may be surprised by the extent and
severity of symptoms (see Table 52-3 and Figure 52-3) and
surprised at unexpected emotional distress. Fibromyalgia has
a quality of inexplicability and unexpectedness.
Upper and lower back pain is the most common pain
problem (>80%). Many patients, at the clinical interview,
emphasize only a few areas of pain. Questions specifically
directed to other areas may elicit reports of pain that were
not stated spontaneously. Patients with fibromyalgia may
complain of greater pain in an osteoarthritic joint than
patients without fibromyalgia. Although musculoskeletal
pain is central to fibromyalgia, patients may be more concerned about fatigue or memory problems.
Fibromyalgia patients perform more poorly in formal cognitive testing than age-matched controls.40 In the National
Data Bank for Rheumatic Diseases in 2006, 66% of 2784
fibromyalgia patients complained of memory or thinking
problems compared with 31% of 24,479 patients with other
rheumatic conditions. The most common symptoms, found
CHAPTER 52 in more than two-thirds of patients, are sleep problems,
fatigue, muscle pain, paresthesias, and cognitive problems
(see Table 52-3). In addition, the prevalence of other
important symptoms is as follows: headache, 65%; depression, 48%; and irritable bowel syndrome, 46% (see Table
52-3). A high count of symptoms is characteristic of fibromyalgia and is frequently a key item in the 2010 diagnostic
criteria to diagnosis (see Figure 52-2). Fibromyalgia is also
associated with increased reporting of comorbid conditions.41,42 The typical picture of fibromyalgia emphasizes
certain symptoms (pain, fatigue, sleep disturbance, cognitive problems) and an abundance of symptoms and comorbidities. Given the high levels of symptom variables and
membership at the tail of the pain-distress continuum, it is
not surprising that evidence of psychosocial disruption and
high rates of lifetime psychiatric illness are found.43,44
Fibromyalgia occurs frequently in other rheumatic dis­
orders including rheumatoid arthritis, osteoarthritis, and
systemic lupus erythematosus, in which the prevalence of
fibromyalgia exceeds 20%. The clues to identifying fibromyalgia in the presence of other painful disorders are location
of pain (nonarticular), continued pain and distress despite
objective improvement in the concomitant disorder, and
unusual fatigue.
ASSESSMENT AND DIAGNOSIS OF A
PATIENT WITH FIBROMYALGIA
Diagnosis and Diagnostic Criteria
A number of approaches to fibromyalgia diagnosis are available. To treat patients, recognition of the degree of pain,
fatigue, and other symptoms is necessary, but a specific diagnostic term is not.2,11 Chronic pain syndrome, FSS, or fibromyalgia will all suffice for a diagnostic term in most settings.
But in countries such as the United States, chronic pain
syndrome or FSS often may not be sufficient for access to
insurance reimbursement or pension systems. In addition,
direct-to-patient advertising may influence diagnostic terminology and diagnosis toward fibromyalgia.
Today, two sets of valid criteria for fibromyalgia are
used in most of the world, although country-specific criteria
also exist.45 The approach to fibromyalgia diagnosis should
differ according to the setting and the physician’s underlying beliefs about fibromyalgia acceptability. The 1990 ACR
classification criteria (see Table 52-2)4 require the presence
of widespread pain and the identification of pain on palpation at 11 or more of 18 tender points. Until 2010, with
the publication of the ACR preliminary diagnostic criteria,3
the 1990 criteria was the only method for an official diagnosis. The 2010 diagnostic criteria are easier in some ways
and more difficult in others. They are easier because they
eliminate the tender point examination that may be difficult for some examiners. The 2010 criteria are more difficult because they require a thorough symptom evaluation.
One advantage of the 2010 criteria is that the examiner/
interviewer becomes much more familiar with the spectrum
and degree of the patient’s problem. But for the criteria
to work correctly, the interviewer must be comprehensive
and thorough. The 2010 criteria provide two scales to
evaluate the degree of polysymptomatic distress: the
symptom severity scale and the fibromyalgianess scale, both
| Fibromyalgia
739
of which are discussed earlier. The fibromyalgianess scale
has the advantage that it is a continuous measure of polysymptomatic distress. It is suitable for use in all patients
whether or not they satisfy fibromyalgia criteria now or
have satisfied them in the past. The scale is also useful
when the physician or examiner does not believe in the
fibromyalgia concept because it does not require a criteria
diagnosis to be useful. The ACR 2010 criteria have been
modified by the authors so that self-report forms can be
used.14 Although these self-report, form-based criteria can
be useful for survey and clinical research, they have not
been endorsed by the ACR and they should never be used
for clinical diagnosis.
Primary, Secondary, and
Secondary-Concomitant Fibromyalgia
Fibromyalgia is sometimes divided into primary, secondary,
and secondary-concomitant fibromyalgia. The term primary
fibromyalgia is most often used when there is not another
condition with symptoms that could explain fibromyalgia
symptoms. This division between primary and secondary
fibromyalgia is artificial, however. Back pain in older individuals when age-related radiographic changes are present
might be considered secondary fibromyalgia, whereas the
same symptoms in younger individuals might be considered
primary fibromyalgia. The ACR 1990 criteria study4 showed
no difference between primary and secondary fibromyalgia
with regard to symptoms and diagnosis. The usefulness of
primary fibromyalgia occurs in clinical trials, in which it is
desirable to ensure those symptoms are not coming from
another well-established illness. A fibromyalgia diagnosis
implies understanding of issues such as pain, fatigue, sleep,
and cognitive and emotional problems. When fibromyalgia
is considered only in patients without other musculoskeletal
conditions, the “benefit” of fibromyalgia diagnosis—its consideration of symptom issues and extent of pain—is lost. If
fibromyalgia is to be diagnosed or considered, such consideration should be applied to all patients. As noted earlier,
fibromyalgia is never a diagnosis of exclusion. When fibromyalgia is diagnosed in the presence of another condition,
treatment is indicated for one or both disorders, as determined clinically.
Differential Diagnosis
The primary symptoms of fibromyalgia, widespread pain
and fatigue, can be found in many medical disorders. Similarly, fibromyalgia can coexist with other medical conditions. The proper approach to avoiding misdiagnosis is to
ascertain the presence or absence of fibromyalgia and then
to determine whether other disorders with widespread pain
and fatigue are present. Practically, the categories are fibromyalgia AND other disorders, fibromyalgia AND NOT
other disorders, and other disorders AND NOT fibromyalgia. Conditions with fibromyalgia-like features include polymyalgia rheumatica, polymyositis, lupus, cervical spine
disorders, hypermobility syndromes, endocrine and paraneoplastic disorders, and forms of polyarthritis including
rheumatoid arthritis and ankylosing spondylitis. When differential diagnosis is problematic, it is because the other
medical condition is difficult to diagnose or has not been
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PART 6 | DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN
evaluated properly. The clue to understanding a patient’s
illness is thoroughly evaluating the patient with a careful
history, physical examination, and laboratory evaluation.
ASSESSMENT OF
FIBROMYALGIA SEVERITY
Self-Report Measures
The ACR 2010 preliminary diagnostic criteria provided a
new measure of fibromyalgia severity, the Symptom Severity
Score (see Table 52-1).3 Used in the diagnosis of fibromyalgia, this scale also functions as a measure of the severity of
fibromyalgia symptoms and can be useful independently of
the criteria. Another scale that is an effective measure is
the fibromyalgianess scale.14,46 It is the sum of the two items
used in the 2010 criteria, the Widespread Pain Index and
the Symptom Severity Score. It is suitable for use in all
patients, regardless of fibromyalgia status, thereby integrating fibromyalgianess and fibromyalgia symptoms into general
patient care.
Symptom severity, physical function, and work status are
the key status and outcome variables in fibromyalgia, as in
other rheumatic disorders. Assessments that can be useful
routinely to clinicians include measurements of pain,
fatigue, physical function, sleep quality, anxiety, depression,
and work status. At minimum, assessments should include
visual analog scales (VAS) for pain and fatigue and a
measure of functional status. Function can be assessed by
one of the family of health assessment questionnaires
including the Health Assessment Questionnaire (HAQ),47
the Health Assessment Questionnaire–II (HAQ-II),48 and
the Multidimensional Health Assessment Questionnaire
(MDHAQ).49 The HAQ is a 33-item questionnaire; the
function scale of the HAQ-II and MDHAQ is a 10-item
questionnaire. Simple scales for the assessment of anxiety,
depression, and sleep disturbance also can be added. For
simplicity and ease of administration, however, we recommend VAS assessments of pain and fatigue and either the
HAQ-II or MDHAQ.
The Fibromyalgia Impact Questionnaire (FIQ) is a
widely used 21-item research assessment scale that addresses
all of the key fibromyalgia variables and can be used in
clinical care.50-52 The limitation of the FIQ is that it is suitable only for use in fibromyalgia patients, whereas the previously mentioned health assessment questionnaires are useful
and have been used across the entire range of rheumatic
disorders. In addition, the FIQ total scale has no simple
interpretation.
Functional questionnaire results have reduced validity
among fibromyalgia patients. Compared with patients with
rheumatoid arthritis and ankylosing spondylitis, there was
striking discordance between observed and questionnairereported activities in patients with fibromyalgia.53 This discordance limits slightly the usefulness of functional
questionnaires and alters their interpretation: Results may
represent perceived rather than actual functional difficulties.
Research Questionnaires
The Outcome Measures in Rheumatoid Arthritis Clinical
Trial committee has recommended research domains and
questionnaires for fibromyalgia clinical trials.54 These
domains include pain, fatigue, sleep, depression, physical
function, quality of life and multidimensional function,
patient’s global impression of change, tenderness, dyscognition, anxiety, and stiffness. The recommendations include
use of the FIQ and the Medical Outcomes Scale SF-36.55,56
A recent study using observational data has shown that
pain, HAQ, and fatigue explained more than 50% of fibromyalgia severity variance57 and that the main determinants
of global severity and health-related quality of life in fibromyalgia are pain, function, and fatigue. On the basis of
the ACR 2010 preliminary diagnostic criteria, criteria and
survey assessments have been developed.14 The Symptom
Intensity Scale, which combines the Widespread Pain Index
and a VAS fatigue scale, is another self-report measure of
fibromyalgia severity that is suitable for clinical and survey
research.43
Physical Measures
With the exception of the performance of the tender point
examination, the physical examination of a patient suspected to have fibromyalgia does not differ from the examination of any other rheumatic disease patient or pain
patient. Measurement of pain threshold by the tender
point examination is the only routinely useful physical measurement. Although helpful for diagnosis using the ACR
1990 classification criteria (see Table 52-2), the tender
point count is poorly correlated with other fibromyalgia
symptoms and with change in symptom severity among
fibromyalgia patients.58 Patients may improve or worsen
substantially without important differences in the tender
point count.
How to Perform the Tender Point Examination
Fibromyalgia patients have a lower threshold for pain than
do subjects without fibromyalgia.59 In the clinic, two
methods exist by which tenderness can be elicited and
measured60—digital palpation and dolorimetry.61 Tender
point sites represent specific areas of muscle, tendon, and
fat pads that are much more tender to palpation than surrounding sites. Sites selected as part of ACR 1990 criteria4
represent tender point sites that best discriminate between
patients with and without fibromyalgia. To test for pain with
digital palpation, the ACR 1990 criteria indicate that the
examiner should press the tender point site with an approximate force of 4 kg. Usually the second and third fingers or
the thumb is used for palpation, and a rolling motion is
helpful in eliciting tenderness. The amount of force that the
examiner uses is important because a large force would elicit
pain in a subject without fibromyalgia, whereas a small force
may miss tenderness. The amount of force that does not
elicit tenderness in an individual without fibromyalgia (just
below the pressure pain threshold) is the correct force to
use. In practice, less force is required in smaller, thinner,
less-muscled individuals. The pressure used by the examiner
and the examiner’s interpretation of the patient’s response
can influence results of palpation. The best and most appropriate way to perform the tender point count is to ask the
patient if the palpation is painful, accepting only a “yes” as
a positive reply, regardless of facial expression or body
CHAPTER 52 movement. Specifically, the frequently heard comment of
patients to the digital examiner’s question regarding pain,
“It’s tender,” is a negative rather than a positive response
and should be followed by another question such as, “Yes,
but is it painful?”
Limitations to the Tender Point Examination
Although the tender point examination can provide clinically useful information when properly performed, it can be
influenced by external factors. Physicians who believe the
patient does or does not have fibromyalgia can influence the
results by the amount of pressure applied. The meaning and
use of the examination are widely known among physicians,
patients, and patient support groups; in some circumstances
where a positive or negative examination would seem to be
desirable (e.g., in a disability or medicolegal examination),
results might differ from those obtained during a routine
examination. In addition, the tender point examination is
inherently inaccurate around the “diagnostic” tender point
count of 11.
Epidemiology
Most of the information about fibromyalgia is based on
sampling using the ACR 1990 criteria. Fibromyalgia is diagnosed more frequently in women (9 : 1 ratio) in clinical
studies. However, in population-based studies the femaleto-male ratio is lower. A recent five-country European study
noted the female-to-male ratio to be about 1.7 : 1,62 though
a U.S. study found a ratio of 6.8 : 163 and the ratio varies
from high to low in other countries.62
Using ACR criteria, the prevalence of fibromyalgia in
the adult general population is generally similar across the
world. The prevalence of fibromyalgia in Wichita, Kansas,
was 3.4% among women, 0.5% among men, and 2%
overall63; among women in New York City, it was 3.7%.64
In Ontario, Canada, the estimated prevalence was 4.9%
among women, 1.6% among men,65 and 3.3% overall. The
prevalence of fibromyalgia in these studies increased with
age until about age 70, after which it decreased slightly.
Outside of North America, reports indicate the prevalence
in five European countries was 4.7% and 2.9% according
to different screening methods62; in studies in Bangladesh
it was 5.3% to 7.5% in women and 0.2% to 1.4% in
men66; in North Pakistan, it was 2.1% overall67; in Italy,
it was 2.2%68; in Turkey, it was 3.6% for ages 20 to 6469;
in Brazil, it was 2.5%70; and in Southwest Sweden, it was
1.3%.71
The prevalence of fibromyalgia in children in three
studies was 1.2%,72 1.4%,73 and 6.2%.74 At a follow-up
time of 1 year, approximately 25% of individuals meeting
ACR criteria initially still satisfied the criteria.73,74 These
data should not be interpreted as evidence of prognosis
because some individuals not meeting criteria initially meet
them at the 1-year follow-up. Instead, the data suggest
that the concept of fibromyalgia in children may be dubious,
particularly when dependent on tender point assessment.
The prevalence of fibromyalgia is generally greater in clinical settings than in epidemiologic studies. It was noted
to be 5.7% in general medical clinics75 and 2.1% in family
practice settings.76 In rheumatology clinics, fibromyalgia
| Fibromyalgia
741
prevalence was expectedly higher: 12%77 to 20%30 of new
patients.
The ACR 2010 criteria should result in changes in the
sex ratio because men have higher pain thresholds and are
therefore less likely to be diagnosed as having fibromyalgia
than women when the 1990 criteria are used. The proportion of men with fibromyalgia in the community in a large
German population study was 40.3%.78 This study included
criteria79 that used the Regional Pain Scale80 and measurement of fatigue. Diagnosis by this method yields results that
are similar to survey modifications on the ACR 2010 preliminary criteria.14 The overall prevalence in the German
study was 3.8%.78 Additional studies are necessary to determine the prevalence of fibromyalgia when the 2010 criteria
are used.
ETIOLOGY AND PATHOPHYSIOLOGY
In the 30-year period following the establishment of the
fibromyalgia case definition and criteria, there have been
substantial advances in understanding mechanisms associated with fibromyalgia pain and other symptoms.81 Although
most of the recent study data are robust, the interpretation
of the data is often questionable and misleading. Because
these research data form the basis of “scientific” support for
fibromyalgia, the objections should be considered carefully
and seriously. We outline some of the objection before providing the research data themselves.
1. Research data treat fibromyalgia as a disease associated with at least 11 tender points (ACR 1990 criteria
definition), but it is exceedingly unlikely that the
observed pathophysiologic abnormalities are confined
to greater than or equal to 11 tender points because
the body of clinical and epidemiologic evidence does
not support a dichotomous condition. It seems likely
that observed abnormalities are also found in nonfibromyalgia patients. Studies need to be performed to
determine the distribution of the observed abnormalities in pain patients not satisfying the fibromyalgia
classification criteria definition.
2.Almost all of the data linking the observed abnormalities to fibromyalgia are correlational, but they are
often interpreted causally—a direction of causality
that may be wrong. The causal path in fibromyalgia
may be complex. All human processes and sensations
are expressed biologically. It would be surprising not
to find associations.
3.Even assuming causal associations, the explanatory
power of these associations have not been described
and may be weak. The noted associations do not necessarily predict development of fibromyalgia.
4.The pathogenetic associations attributed to fibromyalgia are noted in other disorders.82,83
5.The literature of fibromyalgia pathogenesis is filled
with inadequate proofs because authors have drawn
strong conclusions from limited correlative data.
6.Selection of patients and controls can be a problem.
Specifically, patients may be too “good” and control
subjects represent “healthy controls” rather than other
pain patients. Healthy controls will always be different from patients with illnesses.
742
PART 6 | DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN
Muscles and Microtrauma
Originally thought to be important in pathogenesis, muscle
and tendon disorders have fallen out of favor because they
do not explain adequately the systemic symptoms of fibromyalgia. In addition, changes found in muscle biopsy specimens are nonspecific, consistent with many types of muscle
damage, ranging from ischemia to simple deconditioning,
and are not different from changes found in individuals
without fibromyalgia.
Genetic and Familial Factors
Compared with patients with rheumatoid arthritis, fibromyalgia aggregated strongly in families: the odds ratio measuring the odds of fibromyalgia in a relative of a proband
with fibromyalgia versus the odds of fibromyalgia in a
relative of a proband with rheumatoid arthritis was 8.5.84
Genetic factors may predispose individuals to fibromyalgia.81 Patients with chronic widespread pain and
fibromyalgia have been found to have low gene expres­sion
for the proinflammatory cytokines interleukin-4 and
interleukin-10 and reduced levels of serum concentrations
compared with controls. These findings might indicate a
role for cytokines in the pathophysiology of fibromyalgia or
as a sequel of chronic pain and its treatment.85 However, a
study of 31,318 twins in the Swedish Twin Registry suggested that the co-occurrence of FSS in women can be best
explained by affective and sensory components in common
to all these syndromes, as well as by unique influences specific to each of them, suggesting a complex view of the
multifactorial pathogenesis of these illnesses.83
Psychosocial Factors
Psychosocial factors, which include reduced education,
nonmarried status, lower household income, smoking, and
obesity, have been identified in many studies. The chicken
or egg question remains.82
There has been disagreement as to whether psychiatric
abnormalities represent reactions to chronic pain or whether
the symptoms of fibromyalgia are a reflection of psychiatric
disturbance. Psychiatric disorders may interact with the
neuroendocrine system as part of a stress reaction.44 The
most common psychiatric conditions observed in patients
with fibromyalgia include depression, dysthymia, panic disorder, and simple phobia.86 In the National Data Bank for
Rheumatic Diseases 64% of patients report prior depression,
and 8% report mental illness. Fibromyalgia also occurs in
patients without significant psychiatric problems, however.
Some individuals with fibromyalgia satisfy the American
Psychiatric Association criteria for somatoform disorders
(DSM 307.80 and 307.89).87
Sleep Disturbance
Fibromyalgia patients often report unrefreshing and nonrestorative sleep.88 Electroencephalographic abnormalities
initially were thought to play a major role in the pathogenesis of fibromyalgia, but it is now clear that such abnormalities are nonspecific findings. Sleep electroencephalographic
studies show abnormalities of delta wave or stage 4 sleep by
repeated alpha wave intrusion. Similar abnormalities are
found in healthy individuals and in individuals with emotional stress, fever, osteoarthritis, rheumatoid arthritis, and
Sjögren’s syndrome.
Stress-Related Neuroendocrine Dysfunction
Stress responses and endocrine axes are disturbed in fibromyalgia, but many of these changes are commonly seen in
patients who have known external sources of chronic pain.
It is unclear whether these endocrine disturbances in fibromyalgia are primary to the disorder or are secondary to the
pain or distress associated with fibromyalgia. Patients with
fibromyalgia report more past stressful life events and more
daily stressful hassles than patients with rheumatoid
arthritis or pain-free healthy controls. Similarly, fibromyalgia is associated with increased reports of virus and other
infections (Epstein-Barr virus, parvovirus, Lyme disease);
hormonal alterations such as hypothyroidism; and catastrophic events where the patient is the victim of actions
of others (e.g., war, car accidents) but not natural disaster58
preceding fibromyalgia; and a higher frequency of sexual
abuse in childhood. Work-related psychologic factors such
as work demands and factors such as job control, social
support, and psychologic distress are associated with reporting of musculoskeletal pain, particularly when pain is
reported at multiple sites.89
Primary Neuroendocrine Dysregulation
Primary neuroendocrine dysregulation found in fibro­­
myalgia can be divided into changes in the two major
stress systems: the hypothalamic-pituitary-adrenal axis
and the autonomous nervous system. In fibromyalgia,
almost all hormonal feedback mechanisms controlled by
the hypothalamus are disrupted. After stimulation of
the hypothalamic-pituitary-adrenal axis with exogenous
corticotropin-releasing hormone or by insulin-induced
hypoglycemia, an exaggerated pituitary adrenocorticotropic
hormone release has been observed with relative adrenal
hyporesponsiveness.90
Serum thyroid hormone levels are normal, but after
intravenous injection of thyrotropin-releasing hormone,
patients with primary fibromyalgia responded with a significantly reduced secretion of thyrotropin and thyroid hormones.91 Growth hormone is secreted during stage 4 sleep
and is important for muscle repair and strength. Low levels
might explain extended periods of muscle pain after exertion in fibromyalgia patients. Serum growth hormone levels
and levels of somatomedin C (insulin-like growth factor-I)
have often been reported to be low, but results are inconsistent.92 It is possible that physical deconditioning, related
to avoidance of physical activities because of pain, could
lead to more fatigue, stiffness, and, via altered growth
hormone metabolism, sleep disturbance.
Autonomous Nervous System
Sympathetic function in fibromyalgia patients has been
reported as low, normal, or functionally high. There is a
derangement of sympathetic tone and reaction in some
patients, being high or low, depending on the situation. One
CHAPTER 52 explanation for this finding may be that most studies did
not control for physical activity levels of participants.93 It
has also been suggested that fibromyalgia is a generalized
form of complex regional pain syndromes such as reflex
sympathetic dystrophy.94
Abnormal Pain Processing
There are major differences between the sexes with respect
to analgesic responses, across all animal species. This may
explain the decreased pain tolerance in women with fibromyalgia compared with men. Patients with fibromyalgia
have reduced pain tolerance to stimuli that are normally
not painful such as pressure, heat, and electric pulse, at the
classic tender points and control points (allodynia). They
also perceive pain as being more intense and extending for
a longer time (hyperalgesia).
This abnormal sensory pain processing could be explained
by increased pain facilitation and reduced pain-inhibiting
mechanisms on the spinal and cerebral levels. Fibromyalgia
patients also displayed abnormal temporal summation of
pain after a series of thermal stimulations, called “wind-up.”95
The concentration of substance P, a neuromodulator of
pain, in the cerebrospinal fluid was threefold greater in
fibromyalgia patients than in controls. Substance P may
play a role in spreading of muscle pain. This elevation of
substance P is not specific to fibromyalgia, however, and has
been shown in patients with pain due to other causes. Measures of pain intensity in fibromyalgia patients are correlated
with levels of metabolites of the excitatory amino acid neurotransmitters glutamate and aspartate. Sensitization of
nociceptive neurons in the spinal dorsal horn by hyperexcitable receptors such as the glutamate receptor N-methyl-daspartate could be one of the mechanisms responsible for
pain in fibromyalgia.96
Decreased Pain Inhibition
Pain inhibitory pathways, descending from the cortex,
limbic system, hypothalamus, thalamus, and brain stem,
modulate the activity of spinal nociceptive neurons. In fibromyalgia patients, regional blood flow seems to be reduced in
the most important pain processing areas in the brain, the
thalamus and caudatum, compared with controls.97
Serotonin is a neurotransmitter in the descending inhibitory pathways that inhibits release of substance P and excitatory amino acids from the terminals of primary afferent
neurons. Serotonin also regulates nonrapid eye movement
sleep. Low levels of serotonin metabolites have been
reported in the cerebrospinal fluid and serum of patients
with fibromyalgia and low back pain.96 Serotonin antibodies
are found in fibromyalgia patients four times as frequently
as in controls. Although serotonin antibodies have no diagnostic relevance, they could potentially play a role in pathogenesis.98 The role of serotonin in the pathophysiology of
fibromyalgia is unclear. Drugs that affect serotonin metabolism or action do not have a dramatic effect.
Concentrations of enkephalins in the cerebrospinal
fluid are roughly twice as high in fibromyalgia and idiopathic low back pain patients, consistent (but not pathognomonic) with the hypothesis that there is increased release
of endogenous mu opioid ligands in fibromyalgia, leading to
| Fibromyalgia
743
high baseline occupancy of the receptors. This is consistent
with the anecdotal clinical experience that opioids are generally ineffective analgesics in patients with fibromyalgia.58
CENTRAL NERVOUS SYSTEM
(CNS) INVOLVEMENT IN
FIBROMYALGIA SYNDROME
Proton Magnetic Resonance Spectroscopy and
Functional Brain Imaging in Assessment of CNS
Involvement in Fibromyalgia
Why Search in the Brain For an Explanation of the
Riddle of Fibromyalgia?
Fibromyalgia is complex and variably expressed but almost
always features some degree of pain amplification. Interestingly, this hyperalgesia is not confined to pressure stimuli
but also involves heightened responses to heat, noise, and
smell, suggesting an important role for central pain processing abnormalities.99 Although the pathology of fibromyalgia
is poorly understood, a growing body of evidence suggests
involvement of the CNS. The hippocampus is a brain
center that is sensitive to the effects of stress exposure
and has been demonstrated to be affected in a variety of
disorders that, like fibromyalgia, began with a stressful
experience.100
Ultimately, there is central sensitization to pain in which
low-intensity stimuli in peripheral tissues such as skin and
muscle generate an exaggerated nociceptive response that
is interpreted centrally as pain. The central mechanisms
underlying this amplified pain perception have been
explored using a number of advanced imaging techniques
that aim to localize and characterize abnormalities in specific areas of the brain called the pain “matrix.”101
ADVANCED IMAGING TECHNIQUES
Studies with single photon emission computed tomography,
using injected radioactive compounds in the bloodstream
that decay over time, have reported an abnormal reduction
of regional cerebral blood flow in thalamic and caudate
nuclei of patients with fibromyalgia during rest.97,102 In two
other studies that used functional magnetic resonance
imaging, fibromyalgia patients exhibited enhanced responses
to painful and nonpainful stimulation in multiple areas
of the brain such as the somatosensory cortices, insula,
putamen, anterior cingulate cortex, and cerebellum, as compared with healthy control subjects.103,104 These findings
were consistent with a left shift in the stimulus-response
function, which is characteristic of centrally mediated
hyperalgesia and reduced noxious threshold to sensory
stimuli.81
Hippocampus Dysfunction in Fibromyalgia and
Neurometabolic Assessment by Proton
Magnetic Resonance Spectroscopy
The hippocampus plays crucial roles in maintenance of
cognitive functions, sleep regulation, and pain perception,
and in studies using single-voxel magnetic resonance
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PART 6 | DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN
spec­troscopy, metabolic dysfunction of the hippocampus
was found in fibromyalgia patients.105,106 Others found
proton magnetic resonance spectroscopy abnormalities at
the basal ganglia and the supraventricular white matter and
right dorsolateral prefrontal cortex.107
Gray matter loss in fibromyalgia patients was suggested
by magnetic resonance voxel-based morphometric analysis.108 In this study fibromyalgia patients had significantly
less total gray matter volume and showed a 3.3 times greater
age-associated decrease in gray matter than healthy controls. The longer the individuals had had fibromyalgia, the
greater the gray matter loss, with each year of fibromyalgia
being equivalent to 9.5 times the loss in normal aging. In
addition, fibromyalgia patients demonstrated significantly
less gray matter density than healthy controls in several
brain regions including the cingulate, insular, and medial
frontal cortices and parahippocampal gyri.108 In particular,
fibromyalgia appears to be associated with an acceleration
of age-related changes in the very substance of the brain.
Moreover, the regions in which objective changes are demonstrated may be functionally linked to core features of the
disorder including affective disturbances and chronic widespread pain.
Sensory Gating and Reduced Brain Habituation
to Somatosensory Stimulation in Patients
with Fibromyalgia
The attenuation effect of the event-related brain responses
following stimulus repetition in healthy subjects is a wellknown psychophysiologic phenomenon called sensory
gating.109,110 Montoya and colleagues examined brain activity elicited by repetitive nonpainful stimulation in patients
with fibromyalgia in order to determine possible psychophysiologic abnormalities in their ability to inhibit irrelevant sensory information. Their findings suggest that in
fibromyalgia patients, there is abnormal information processing, which may be characterized by a lack of inhibitory
control to repetitive nonpainful somatosensory information
during stimulus coding and cognitive evaluation. These
data further extend previous findings111-113 of an abnormal
brain processing of nonpainful somatosensory information,
rather than a generalized information processing dysfunction, in patients with fibromyalgia.110
Deficits of Nociceptive Information Processing
In this regard, findings of Montoya and colleagues114 add to
a growing literature in which fibromyalgia patients have
been shown to have some deficits of nociceptive information processing relative to healthy controls such as enhanced
sensitivity to repetitive pain pressure, abnormal maintenance of pain sensations after repetitive thermal stimulation,115,116 or deficits in the endogenous pain inhibitory
system,117 In another work Wood and colleagues118 investigated presynaptic dopaminergic function in six female fibromyalgia patients in comparison with eight age- and
sex-matched controls as assessed by positron emission
tomography (PET) with 6-fluoro-l-DOPA as a tracer. Their
findings indicate a disruption of presynaptic dopamine
activity wherein dopamine plays a putative role in natural
analgesia. Harris and colleagues119 demonstrated by PET
decreased mu opioid receptor availability in fibromyalgia.
Further, it has been suggested that hyperalgesia and allodynia in fibromyalgia, as well as in other chronic pain states,
are the behavioral consequences of central sensitization.
Thus it would be possible that the observed disruption of
the inhibitory brain mechanism involved in the early processing of non-nociceptive repetitive stimulation might be
a further consequence of those neuroplastic changes due to
central sensitization associated with chronic pain.110
These findings indicate that central factors are important
in the processing of pain in people with fibromyalgia. The
neuroimaging findings are highly consistent with studies
done in pain more generally.120 These findings suggest that
individuals with fibromyalgia have a narrow range of tolerance for pain and perhaps other sensory stimuli, before it
becomes noxious.58
MANAGEMENT OF FIBROMYALGIA:
RESEARCH STUDIES AND
RECOMMENDATIONS
The value of contemporary treatment can be gauged by
review of outcome studies. Fibromyalgia outcome has been
the subject of a number of reports, usually in small studies
encompassing short periods of time. In general, results of
these studies tend to suggest little change in symptoms,
suggesting a limited effect of treatment. Most long-term
observational studies do not show improvement in fibromyalgia symptoms and outcomes, even when patients are followed in centers with special interest and knowledge of
fibromyalgia.121,122 In a recent longitudinal study, 1555
patients displayed continuous high levels of self-reported
symptoms and distress despite treatment over a mean of 4
years of follow-up. Service utilization (a measure of symptom
activity) does not lessen after diagnosis.123 Benefit of treatment is generally not sustained in long-term randomized
clinical trials.124,125 These data should be kept in mind
when evaluating the results of treatment clinical trials. The
null hypothesis for a chronic, painful disorder should not
be no short-term treatment effect, but instead no longterm treatment effect. Short-term studies should be
regarded with suspicion, and most fibromyalgia studies are
short term.
Compliance with treatment is an important problem in
fibromyalgia, and in fibromyalgia clinical trials the dropout
rate is high. Even when intention-to-treat analyses are performed, the effectiveness of treatment is overestimated.
Patients who follow exercise recommendations have better
outcomes than patients who do not; however, most patients
in clinical practice do not or will not perform aerobic exercises. It is fair to conclude that exercise prescription is often
an ineffective recommendation, rather than concluding
that it is an effective treatment.
Treatment trials without a true, contemporaneous control
group cannot provide meaningful estimates of efficacy
because they often exaggerate efficacy. In evaluating study
results, the degree of improvement must be examined and
the degree of improvement must be clinically meaningful.
Even when improvement is clinically meaningful, the
CHAPTER 52 baseline and final outcome values such as values of pain and
fatigue must be considered. If the patients are selected for
trials in relative (temporary) flare conditions, they may
improve “significantly” but still have high levels of the
outcome variables at the conclusion of the trial.
Numerous useful reviews of the short-term treatment in
fibromyalgia are available.126-134 Most such reviews rely on
the concept of efficacy and rank evidence as a function of
study quality. One review indicates that “evidence for treatment efficacy was ranked as strong (positive results from a
meta-analysis or consistently positive results from more
than one randomized controlled trial [RCT]), moderate
(positive results from one RCT or largely positive results
from multiple RCTs or consistently positive results from
multiple non-RCT studies), and weak (positive results from
descriptive and case studies, inconsistent results from RCTs,
or both).”126 As noted by these authors, studies are necessary
“… to determine whether the improvement is maintained
over months or years.” Recent meta-analyses have included
measurements of standardized mean differences (effect
sizes)127-134 but still do not assess long-term benefit.
Still another problem with the interpretation of fibromyalgia studies relates to study scales. Because patients
diagnosed as having fibromyalgia have problems with pain,
fatigue, cognition, and anxiety and depression, to name
some issues in fibromyalgia, studies may select different
scales and outcomes according to the interests of the investigators. This leads to problems in comparing study results.
In addition, when multiple outcomes and study instruments
are selected, frequently studies can show positive results
for one outcome and negative results for another. Even
when an outcome such as pain is being measured, if there
is more than one pain scale, positive results may be found
with one pain scale and not with another. Complex scales
are also difficult to interpret, as is the case with the commonly used FIQ total scale. This composite summary scale
has no simple interpretation: A reader may note an
improvement but not have a clear idea of what such
improvement means.
From 6750 fibromyalgia patients screened in the National
Data Bank for Rheumatic Diseases, the mean (standard
deviation) VAS pain and fatigue scores were 6.3 (2.5) and
7.0 (2.5). As an aid in interpreting effect sizes, the following
data are presented; assuming a baseline score of 7.0 on a 0
to 10 VAS scale, the following are the effect size, change
score, post-treatment score, and percent improvement at
the last assessment: 0.3, 0.75, 6.25, 10.7%; 0.4, 1.25, 6.0,
14.3%; 0.5, 1.25, 5.75, 17.9%; 0.6, 1.5, 5.5, 21.4%.
Finally, the main limitations of results and inferences
from fibromyalgia clinical trials is that they cannot be
extrapolated to patients in practice because of the artificial
nature of clinical trials, issues of compliance, and absence
of long-term results.
Häuser and colleagues135 have provided a detailed compendium of the full range of fibromyalgia therapy, citing
research evidence and committee recommendations. In
making recommendations for therapy, these reviewers also
considered costs and adverse effects. Readers should find
this review particularly helpful, although they should keep
in mind the degree of observed benefit, its persistence, and
other issues mentioned earlier.
| Fibromyalgia
745
Diagnosis
Diagnosis may be an important aspect of treatment. Diagnosing fibromyalgia in individuals with short-term stressrelated illnesses is harmful and leads to prolonged illness
and medicalization. No valid evidence supports the assertion that diagnosis of fibromyalgia in patients with longterm symptoms has a salutary effect. A study of primary care
patients in the United Kingdom reported that “ … patients
who had been diagnosed as having [fibromyalgia] reported
higher rates of illness and health care resource use for at
least 10 years prior to their diagnosis, which suggests that
illness behavior may play a role. … Diagnosis has a limited
impact on health care resource use in the longer term, possibly because there is little effective treatment.”136
At the patient level, there is no evidence that diagnosis
is harmful. Using the diagnostic term in the presence of
severe symptoms often makes it easier for physicians and
patients to discuss the condition; when fibromyalgia is not
diagnosed, patients sometimes ask directly, “Do I have fibromyalgia?” In considering making the diagnosis of fibromyalgia, the physician should consider the following comment
by Barsky and Borus6: “The hyperbole, litigation, compensation, and self-interested advocacy surrounding the FSS can
exacerbate and perpetuate symptoms, heighten fears and
concerns, prolong disability, and reinforce the sick role.
Excessive medical testing and treatment expose patients to
iatrogenic harm and amplify symptoms.” But if fibromyalgia
is “diagnosed,” it is important to be clear to the patient that
fibromyalgia is a name given to the symptoms, not a cause
of the symptoms.
When a fibromyalgia diagnosis is applied to the larger
community, rather than at the level of the individual
patient, it has been suggested that a virulent idea and a
maladaptive social construction of disease such as fibromyalgia can induce and sustain illness in susceptible persons:
a psychosomatic meme, acting as a transmissible template.137
Direct-to-patient advertising and disease mongering by
drug companies expand the definition of fibromyalgia
and recruit patients to the diagnosis, offering support to
this idea.
Education
Education in some reports may have a modest effect on
fibromyalgia symptoms such as fatigue, anxiety, and depression but has limited to no effect on pain.138,139 What is called
education is actually composed of two components—
education and rapport or engagement—and it is impossible
to distinguish the two components. Most education studies
are derived from formal university-based treatment programs; only one study was applicable to clinical practice,139
and the sample size was too small to evaluate the effect of
the intervention in fibromyalgia. All studies had deficiencies in the validity of the control groups; there are no longterm data on the effect of education. Although it is sensible
that education should always be part of any treatment
program and is part of establishing rapport, its content
should depend on the patient, the duration of illness, and
the diagnostic label already present. The goal of education
is to help the patient understand and manage his or her
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symptoms optimally, reduce dependence on the medical
system, and work effectively within that system when necessary. There are no data, however, as to whether, within the
clinical setting, extensive education is more or less effective
than limited education. In a group of 100 consecutive
enrollees in a 1.5-day multidisciplinary group outpatient
fibromyalgia treatment program, after 30 days a 12.8%
improvement was noted in the 78 who completed the
study.140
Exercise
Aerobic exercise increases cardiovascular fitness and reduces
pain and other fibromyalgia symptoms. In a short-term
RCT, exercise improved aerobic performance by 16% and
pain by 13%.141 A carefully done, well-powered RCT of a
12-week community-based exercise program compared with
relaxation controls showed a 4% difference in FIQ scores at
1 year but nonsignificant changes in McGill pain scores and
SF-36 scores.142 At the 12-month follow-up, 38% of subjects
in the exercise arm and 22% in the control arm rated themselves much better or very much better. Only 53% of
patients attended more than half of the intervention sessions. A follow-up report at 12 months on patients who
participated in a 23-week, three-times-per-week exercise
program indicated general improvement compared with
baseline values.143 The degree of improvement as measured
by the FIQ was 5%.
The Cochrane collaboration evaluated 34 studies that
included exercise, noting that there is moderate-quality evidence that aerobic-only exercise training at recommended
intensity levels has positive effects on global well-being
(standard mean difference [SMD], 0.49) and physical function (SMD, 0.66) and possibly on pain. The researchers
concluded that “supervised aerobic exercise training has
beneficial effects on physical capacity and fibromyalgia
symptoms.”144 A noncontrolled study comparing waterbased exercise with land-based exercise showed an average
36% reduction in pain.145 Exclusions in this study included
67 for work schedule incompatibility and 32 for nonspecified refusals; 60 patients were randomly assigned, and 52
completed the study.
Practically, the problem with exercise prescription is that
it is difficult to get fibromyalgia patients to participate. Exercise may produce “short-term increases in pain and fatigue
that should abate within the first few weeks of exercising,”146
but this may be unacceptable to patients in ordinary clinical
settings. Even in formal programs, adherence to exercise is
poor.147,148 In a 4.5-year follow-up of a randomized trial of
exercise, only 20% of patients maintained an adequate
physical activity level.149 In the National Data Bank for
Rheumatic Diseases from 1999 to 2010, 16% of 3115 fibromyalgia patients reported performing some aerobic exercise
weekly, but only 5% performed at levels substantial enough
to result in increasing or maintaining aerobic fitness.
Pharmacotherapy
Analgesics and Nonsteroidal
Anti-inflammatory Drugs
Many drugs frequently used by patients diagnosed as having
fibromyalgia have not been formally evaluated for efficacy
or effectiveness.126 With respect to analgesics and non­
steroidal anti-inflammatory drugs (NSAIDs), a 1998 multicenter study of 538 fibromyalgia patients noted the following
usage in a 6-month period: aspirin, 20.6%; NSAIDs, 55.9%;
acetaminophen, 27.6%; strong opioid analgesics, 6.4%; and
nonopioid analgesics, 21.5%.160 Tramadol use was 15%.
Tramadol use remained at 15% in 2010 in the National
Data Bank for Rheumatic Diseases. These data, showing the
substantial use of NSAIDs, are important because it is often
suggested that NSAIDs are ineffective.126
A few analgesic and NSAID treatments have been formally evaluated. Naproxen, 500 mg twice daily (n = approximately 15), which is the only NSAID that has been studied,
was indistinguishable from placebo (n = approximately 15)
in a controlled clinical trial of relatively young subjects (age
48 years).161 The combination of tramadol and acetaminophen reduced pain 18.5% more than did the use of placebo.162
In this trial, 48% in the active treatment group and 62% of
placebo users were noncompleters in this 3-month trial.
Psychotropic Agents
Many drugs that have antidepressant and other psychotropic attributes have been used in fibromyalgia treatment.
Such drugs reduce pain centrally, even in the absence of
depression, and may be employed at doses that are insufficient to treat depression. Because of the many different
trials and classes of drugs studied, meta-analyses have provided a useful overall overview.129,163,164 We summarize the
results of Häuser and colleagues.129 In their meta-analysis
of 18 RCTs (1427 participants), there was strong evidence
for an association of antidepressants with reduction in
pain (SMD, 0.43); fatigue (SMD, 0.13); depressed mood
(SMD, .26); and sleep disturbances (SMD, 0.32).
The major classes of drugs included tricyclic and tetracyclic antidepressants (TCAs): amitriptyline and nortriptyline; selective serotonin reuptake inhibitors (SSRIs):
paroxetine, fluoxetine, and citalopram; serotonin and noradrenaline reuptake inhibitors (SNRIs): duloxetine, milnacipran; and monoamine oxidase inhibitors (MAOIs):
moclobemide and pirlindole. In subanalysis by class, effect
sizes for pain reduction were large for TCAs (SMD, 1.64);
medium for MAOIs (SMD, 0.54); and small for SSRIs
(SMD, 0.39) and SNRIs (SMD, 0.36). Similar, although
slightly weaker, results are noted with cyclobenzaprine.
Compared with clinical trial results, results in longitudinal studies and clinical practice show marginal effectiveness
of tricyclic antidepressants and similar treatments. A highquality RCT found no difference in the response to amitriptyline and cyclobenzaprine.165
Cognitive Behavioral Therapy
Cognitive behavioral therapy is a form of short-term, goaloriented psychotherapy. It has been the subject of some
positive reports,150-154 some less positive reports,124,155,156 and
some completely negative studies.157-159
Other Pharmacologic Treatments
On the basis of clinical trial criterion for efficacy, there is
no evidence for efficacy of NSAIDs, corticosteroids, benzodiazepine and nonbenzodiazepene hypnotics, guaifenesin,
CHAPTER 52 melatonin, calcitonin, opioids, thyroid hormone, dehydroepiandrosterone and magnesium, or anti–tumor necrosis
factor therapy.126
Nonpharmacologic Treatments
There is some evidence for efficacy of numerous nonmainstream treatments including strength training127,149,166 and
hypnosis.167 There is weak evidence for chiropractic, manual,
and massage therapy and no evidence of efficacy for tender
or trigger point injections or flexibility exercise. Evidence
for acupuncture is contradictory,168,169 as is evidence for the
efficacy of biofeedback170-172 and balneotherapy.173-175 Local
injections in muscular areas of pain are also commonly
employed by rheumatologists. The authors surveyed rheumatologists regarding the use of injections and found them
to be used frequently, in agreement with others.126 Rheumatologists reported that patients “like injections,” but also
that the rheumatologists did not know what else to do. A
comprehensive review of nonpharmacologic therapies is
available.176
Combination Therapy
Although most studies reported earlier concern monotherapy, in practice most fibromyalgia treatments combine
multiple therapies. Ordinarily these treatment regimens
use analgesics, antidepressants, education, and exercise (at
least, exercise recommendations). The extent to which
several or many therapies is superior to one or few therapies
is not clear. But the effect seems small. So one cannot
simply add effect sizes of individual therapies to gauge the
multitherapy effect.
A meta-analysis of multicomponent treatment in RCTs
(at least one educational or other psychologic therapy with
at least one exercise therapy) included nine RCTs with
1119 patients.128 The authors reported: “There was strong
evidence that multicomponent treatment reduces pain
(SMD, 0.37;); fatigue (WMD, 0.85); depressive symptoms
(SMD, 0.67); and limitations to health-related quality of
life (HRQOL) (SMD, 0.59) and improves self-efficacy pain
(SMD, 0.54) and physical fitness (SMD, 0.30) at posttreatment. There was no evidence of its efficacy on pain,
fatigue, sleep disturbances, depressive symptoms, HRQOL,
or self-efficacy pain in the long term. There was strong
evidence that positive effects on physical fitness (SMD,
0.30) can be maintained in the long term (median follow-up
7 months).” Overall, these data indicated increased benefits
of multicomponent treatment as defined here, compared
with “other” therapies. But the benefit is still modest and
cannot be clearly extrapolated to the long term.
Practical Recommendations in the Approach to a
Patient with Fibromyalgia
The goal of fibromyalgia treatment is to improve the physical and mental health of patients and their quality of life.
This goal implies helping patients manage distressing symptoms, but with decreased dependence on the medical care
system. There are no studies as to how often the simple
recommendations of education, exercise, and limited pharmacologic treatment provide results at an acceptable level
| Fibromyalgia
747
of symptoms and functional ability. Data from the National
Data Bank for Rheumatic Diseases show, however, that 61%
of 3276 fibromyalgia patients observed from 1998 to 2010
were somewhat or very dissatisfied with their health compared with 35% of 24,891 patients with rheumatoid arthritis. These data indicate that contemporary treatment of
fibromyalgia is generally unsatisfactory.
This high level of dissatisfaction is reflected in physician
and patient interactions. An unknown but probably small
proportion of rheumatology experts refuse to accept referral
of fibromyalgia patients. A larger proportion is unhappy
seeing such patients or is uncomfortable providing care.
Patients, sensing this attitude, are equally unhappy with
physicians: Patient support groups provide specific advice
on finding positive, sympathetic physicians including identifying them by name. Physician behavior results from a
general uncomfortableness with illnesses that are often
unresponsive to treatment and have strong psychologic and
psychosocial components. There is no simple resolution to
this problem. Physicians who are unable to provide helpful
care to patients with fibromyalgia should make that known
to the patients.
Interest in fibromyalgia and drug company support has
resulted in extensive studies of treatment,127 often with recommendations for treatment.127 The practical result of
applying recommendations based on short-term clinical
trials to an often poorly responsive chronic illness is uncertain because there is as yet no evidence of long-term effectiveness of treatment. In the face of ineffectiveness,
treatment recommendations can lead to switching from one
therapy to the next and increased medicalization.
In considering fibromyalgia treatment, physicians should
determine what resources are available in the community,
and whether the resources are effective and helpful. The
educational, exercise, and cognitive behavioral therapy programs described in the research studies earlier are often not
available to U.S. community physicians. Available programs may or may not be competent, appropriate, or helpful.
Pain management programs sometimes mean little more
than spinal blocks and “trigger point” injections, and physical therapy referral often results in treatments that are ineffective for fibromyalgia. The referring physicians should
investigate the quality and outcomes of referral resources.
Although the common recommendations of education,
exercise, and pharmacotherapy are often appropriate, particularly in newly diagnosed cases, patients with established
fibromyalgia have often experienced these recommendations and treatments. Whether such treatments have strong
evidence for effectiveness or not, as measured by clinical
trials, they are often not clinically effective enough, and
patients return to the physician for additional suggestions
and care.
The European League Against Rheumatism (EULAR)
task force points out, on the basis of limited evidence127 and
consensus recommendation, that full understanding of
fibromyalgia requires comprehensive assessment of pain,
function, and psychosocial context. Fibromyalgia should be
recognized as a complex and heterogeneous condition where
there is abnormal pain processing and other secondary features. Optimal treatment requires a multidisciplinary
approach with a combination of nonpharmacologic and
pharmacologic treatment modalities tailored according to
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pain intensity; function; and associated features such as
depression, fatigue, and sleep disturbance in discussion with
the patient.
The question arises as to how to approach a resistant
patient with fibromyalgia, given the knowledge that after
failure with several standard treatments, success with other
medications is unlikely. Should the physician simply go
from one (dubious) treatment to another? Should the physician use treatments of dubious or uncertain value? The
adverse effects of inappropriate or unnecessary treatments
are not inconsequential and include dependence, medicalization of common symptoms, overuse of medical care,
increased costs, and side effects. One point of importance
is that the physician should at least measure pain using a
VAS scale. A similar simple measure is available for fatigue.
One really cannot know how the patient is doing without
such measurements.
The physician must be friendly and interested—a
resource the patient can rely on. Testing should be limited
and reserved for times when it is truly necessary to investigate comorbid conditions. Comorbid conditions such as
arthritis and obesity should be treated because they can
contribute to increasing physical and mental symptoms.
The worst problem should be identified. Sometimes identifying where the pain problem began can offer clues to appropriate treatment of the coexisting condition. If many
fibromyalgia treatments have been tried and have been
unsuccessful, it is generally not a good idea to try even more
similar, and soon to be unsuccessful, therapies. We often ask
patients, “Which treatment has been most helpful?” and
suggest (assuming treatment is necessary and helped at all)
that they return to that treatment.
There is no blanket rule on the use of opioids. Experience has shown that they often do not truly help and often
cause problems. Strong opioids are generally not recommended.127 There are exceptions to this recommendation,
however, and physicians should exercise clinical judgment
and use opioids when they think such therapy is necessary,
provided that appropriate guidelines are followed.177 “Tender
points” never need injection therapy. Painful areas in muscle
may respond to local injections of local anesthetics; corticosteroids are never indicated. If injections relieve pain for
more than short periods of time, they may represent a reasonable therapy. In illnesses with strong psychosocial components, medically ineffective therapies can result in overall
benefit to patients. The circumstances where dubious therapies might be used are limited. The physician should understand clearly why he or she is administering such therapies
and what results are anticipated.
Physical Therapy and Spa Treatment
Physical therapy is not recommended because the aerobic
exercise required in fibromyalgia does not usually require
formal physical therapy and increases medicalization.
Because medical therapy is unsatisfactory, patients find their
way to alternative therapies. Some of these therapies may
be helpful to individual patients such as massage, water
therapy, spa treatment, and acupuncture. These therapies
tend to have high cost-effectiveness ratios, and the decision
to use such therapies is often best left to the patients and
the reimbursement authority. That is not to say that such
treatments do not help—everything helps—but they do not
help often enough and importantly enough, and some decision point is required. One important goal of therapy is to
reduce medicalization and increase independence.
In Europe and the Mediterranean a long-standing tradition of spa treatments exists and many U.S. patients, especially those whose parents came from Europe, fly over to be
treated. It appears that fibromyalgia patients significantly
improve after different spa treatments. In a controlled study
in Tunis there was a significant improvement directly after
2 weeks of treatment and after 3 months regarding general
well-being, function, pain, depression, and fatigue in 58
fibromyalgia patients compared with 76 controls.175,178 Comparable results were seen in Turkey179 and the Dead Sea in
Israel.180 Reviews showed good results of spa treatment
and hydrotherapy regarding pain, general well-being, and
tender points continuing after 14 weeks,181,182 and a EULAR
advisory committee concluded that treatment with hot
baths with or without exercises had a good effect in
fibromyalgia.127
Complementary or Alternative Treatments
There is insufficient evidence on any complementary and
alternative medicine or alternative treatment, taken orally
or applied topically for fibromyalgia. The small number of
positive studies lack replication.
A frustrated physician may not know where to turn next
in a nonresponsive patient. Should the patient be referred
to a pain clinic? Sometimes such a referral is inevitable. The
quality of pain clinics varies, however, and the results
in fibromyalgia are often not good. The decision to refer
should depend on the experience with the available clinics
and the results that they have produced. In some countries,
reimbursement authorities limit referrals, providing a costeffectiveness analysis that may be alien to the physicianpatient relationship.
Treatment options sort themselves out over time. Decisions that are difficult resolve. In the end, the physician who
provides support and interest is a strong resource and a guide
for patients with fibromyalgia, even when medical therapies
are limited.
Medicolegal Issues and Fibromyalgia
Frequently, fibromyalgia becomes a medicolegal issue when
an individual with fibromyalgia asserts that he or she is
unable to work because of fibromyalgia. Because fibromyalgia symptoms are felt only by the patient, there are no
objective medical findings to help in the disability assessment. Gaining a disability award is complex, depending on
the source of payment (e.g., government vs. private insurance), the physician’s belief and documentation, the availability of legal services, and the impact of the illness on the
patient. Various guidelines have been suggested for evaluating disability as they apply to fibromyalgia. Determination
of disability does not depend on proving the existence of
fibromyalgia.
The second medicolegal issue arises when an individual
claims that trauma caused him or her to develop or exacerbate fibromyalgia and that the fibromyalgia is disabling.
Although it is proposed that trauma can alter the CNS
CHAPTER 52 (“neural plasticity”) and cause fibromyalgia, the relationship
between the severity of trauma and the report of fibromyalgia is weak. There is no way to determine scientifically if
trauma causes or caused fibromyalgia. In addition, it is often
difficult to establish the severity of the fibromyalgia symptoms. In reality, the relationship between trauma and disability does not require a diagnosis of fibromyalgia because
symptom severity and work impairment are important, not
the presence or absence of fibromyalgia.
OUTCOME OF FIBROMYALGIA
The outcome of fibromyalgia can be studied in the context
of change and level of symptoms, use of services, and work
disability. Many studies have addressed the issue of outcome.
Some have suggested that “ … knowledge of the potential
reversibility of the syndrome [is] resulting in improved outcomes”183 and that “ … outcome is good with minimal intervention.”184 In a prospective study of fibromyalgia patients
referred to a specialty clinic, 70 of 82 were reassessed after
3 years. The returnees were generally improved (pain
reduced from 6.8 to 5.4 and fatigue reduced from 6.8 to 5.7).
The authors concluded that the overall outcome was favorable.185 In 33 of 51 patients seen 6 to 8 years after initial
participation in a fibromyalgia treatment study, pain was
reduced from 6.7 to 5.3 and fatigue was reduced from 7.5 to
6.5. The authors concluded that the results of these returnees suggest a benign long-term outcome in patients with
fibromyalgia.186A six-center, 7-year study of 538 patients
noted that, “Although functional disability worsened
slightly and health satisfaction improved slightly, measures
of pain, global severity, fatigue, sleep disturbance, anxiety,
depression, and health status were markedly abnormal at
study initiation and were essentially unchanged over the
study period. Half the patients are dissatisfied with their
health, and 59% rate their health as fair or poor.”122 In one
report of 45 of 70 patients who had participated in a 3-week
trial 6 years earlier, symptoms of fibromyalgia persisted over
6 years.121 A study of prediagnosis and postdiagnosis use of
services found that no changes in the high-use rates were
seen over time.136
In a longitudinal study of 1555 fibromyalgia patients
during 7448 semiannual observations for up to 11 years,
there was minimal improvement in symptoms. The SMDs
(improvement effect sizes) between start and study completion were patient global, 0.03; pain, 0.22; sleep problems,
0.20; SF-36 PCS, 0.11; SF-36 Mental Component Summary,
0.03; and EuroQoL (EQ-5D), 0.10. These data suggested
that the course of fibromyalgia was one of continuous high
levels of self-reported symptoms and distress despite available treatments.187
A study of 27 of 48 (56%) patients had a 2-year
follow-up.188 In general, the patients showed no improvement in their symptoms over the observation period, regardless of the type of therapy they had received. General
satisfaction with quality of life improved, as did satisfaction
regarding health status and the family situation, although
the degree of pain experienced remained unchanged. In
comparison with the initial examination, there was no
change in either work capacity or disability-pension status.
Taken as a whole, although some patients improve, the
data tend to suggest minimal improvement in most cases
| Fibromyalgia
749
despite treatment. Even among the positive studies cited,
the degree of improvement is small. These data, which are
representative of the actual outcome of fibromyalgia patients
in practice, provide a more realistic evaluation of treatment
effect than the assessments based on clinical trials.
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46. Wolfe F: New criteria for fibromyalgia: a twenty year journey, Arthritis
Care Res 62(5):583–584, 2010.
47. Fries JF, Spitz PW, Kraines RG, Holman HR: Measurement of patient
outcome in arthritis, Arthritis Rheum 23:137–145, 1980.
48. Wolfe F, Michaud K, Pincus T: Development and validation of the
health assessment questionnaire II: a revised version of the health
assessment questionnaire, Arthritis Rheum 50(10):3296–3305, 2004.
49. Pincus T, Swearingen C, Wolfe F: Toward a multidimensional Health
Assessment Questionnaire (MDHAQ): assessment of advanced
activities of daily living and psychological status in the patientfriendly health assessment questionnaire format, Arthritis Rheum
42(10):2220–2230, 1999.
50. Burckhardt CS, Clark SR, Bennett RM: The fibromyalgia impact
questionnaire: development and validation, J Rheumatol 18(5):728–
733, 1991.
51. Bennett R: The Fibromyalgia Impact Questionnaire (FIQ): a review
of its development, current version, operating characteristics and
uses, Clin Exp Rheumatol 23(5 Suppl 39):S154–S162, 2005.
52. Bennett R, Friend R, Jones K, et al: The revised Fibromyalgia Impact
Questionnaire (FIQR): validation and psychometric properties,
Arthritis Res Ther 11(5):415, 2009.
53. Hidding A, van Santen M, De Klerk E, et al: Comparison between
self-report measures and clinical observations of functional disability
in ankylosing spondylitis, rheumatoid arthritis and fibromyalgia,
J Rheumatol 21(5):818–823, 1994.
54. Choy EH, Arnold LM, Clauw D, et al: Content and criterion validity
of the preliminary core dataset for clinical trials in fibromyalgia syndrome, J Rheumatol 36:2330, 2009.
55. Ware JE, Sherbourne CD: The MOS 36-Item Short-Form Health
Survey (SF-36).1. Conceptual Framework and Item Selection, Med
Care 30:473–483, 1992.
56. Wolfe F, Michaud K, Li T, Katz RS: EQ-5D and SF-36 quality of life
measures in systemic lupus erythematosus: comparisons with RA,
non-inflammatory rheumatic disorders, and fibromyalgia, J Rheumatol
37:296–304, 2010.
57. Wolfe F, Hassett AF, Katz RS, Michaud K: Do we need core sets of
fibromyalgia domains? The assessment of fibromyalgia (and other
rheumatic disorders) in clinical practice, J Rheumatol 38:1104–1112,
2011.
58. Jacobs JW, Rasker JJ, Van der Heide A, et al: Lack of correlation
between the mean tender point score and self-reported pain in fibromyalgia, Arthritis Care Res 9(2):105–111, 1996.
59. Simms RW, Goldenberg DL, Felson DT, Mason JH: Tenderness in 75
anatomic sites. Distinguishing fibromyalgia patients from controls,
Arthritis Rheum 31:182–187, 1988.
60. Wolfe F: When to diagnose fibromyalgia, Rheum Dis Clin N Am
20:485–501, 1994.
61. Fischer AA, Rachlin ES: Pressure algometry (dolorimetry) in the differential diagnosis of muscle pain. Myofascial pain and fibromyalgia:
trigger point management, St. Louis, 1994, Mosby, pp 121–140.
62. Branco J, Bannwarth B, Failde I, et al, editors: Prevalence of fibromyalgia: a survey in five European countries, St Louis, 2009, Elsevier.
63. Wolfe F, Ross K, Anderson J, et al: The prevalence and characteristics
of fibromyalgia in the general population, Arthritis Rheum 38(1):19–
28, 1995.
64. Raphael KG, Janal MN, Nayak S, et al: Psychiatric comorbidities in
a community sample of women with fibromyalgia, Pain 124(1-2):
117–125, 2006.
65. White KP, Speechley M, Harth M, Ostbyte T: The London Fibromyalgia Epidemiology Study: the prevalence of fibromyalgia syndrome
in London, Ontario, J Rheumatol 26(7):1570–1576, 1999.
66. Haq SA, Darmawan J, Islam MN, et al: Prevalence of rheumatic
diseases and associated outcomes in rural and urban communities
in Bangladesh: a COPCORD study, J Rheumatol 32(2):348–353,
2005.
67. Farooqi A, Gibson T: Prevalence of the major rheumatic disorders in
the adult population of north Pakistan, Br J Rheumatol 37(5):491–
495, 1998.
68. Salaffi F, De Angelis R, Grassi W: Prevalence of musculoskeletal
conditions in an Italian population sample: results of a regional
community-based study. I. The MAPPING study, Clin Exp Rheumatol
23(6):819–828, 2005.
69. Topbas M, Cakirbay H, Gulec H, et al: The prevalence of fibromyalgia in women aged 20-64 in Turkey, Scand J Rheumatol 34(2):140–
144, 2005.
70. Senna ER, De Barros AL, Silva EO, et al: Prevalence of rheumatic
diseases in Brazil: a study using the COPCORD approach, J Rheumatol 31(3):594–597, 2004.
71. Lindell L, Bergman S, Petersson IF, et al: Prevalence of fibromyalgia
and chronic widespread pain, Scand J Primary Health Care 18(3):149–
153, 2000.
72. Clark P, BurgosVargas R, MedinaPalma C, et al: Prevalence of
fibromyalgia in children: a clinical study of Mexican children,
J Rheumatol 25(10):2009–2014, 1998.
73. Mikkelsson M: One year outcome of preadolescents with fibromyalgia, J Rheumatol 26(3):674–682, 1999.
74. Buskila D, Neumann L, Hershman E, et al: Fibromyalgia syndrome
in children—an outcome study, J Rheumatol 22(3):525–528,
1995.
75. Campbell SM, Clark S, Tindall EA, et al: Clinical characteristics of
fibrositis. I. A “blinded,” controlled study of symptoms and tender
points, Arthritis Rheum 26:817–824, 1983.
76. Hartz A, Kirchdoerfer E: Undetected fibrositis in primary care practice, J Fam Pract 25:365–369, 1987.
77. Wolfe F, Cathey MA: Prevalence of primary and secondary fibrositis,
J Rheumatol 10:965–968, 1983.
78. Hauser W, Schmutzer G, Brahler E, Glaesmer H: A cluster within
the continuum of biopsychosocial distress can be labeled
CHAPTER 52 “fibromyalgia syndrome”—evidence from a representative German
population survey, J Rheumatol 36(12):2806–2812, 2009.
79. Katz RS, Wolfe F, Michaud K: Fibromyalgia diagnosis: a comparison
of clinical, survey, and American College of Rheumatology criteria,
Arthritis Rheum 54(1):169–176, 2006.
80. Wolfe F: Pain extent and diagnosis: development and validation of
the regional pain scale in 12,799 patients with rheumatic disease,
J Rheumatol 30(2):369–378, 2003.
81. Williams D, Clauw D: Understanding fibromyalgia: lessons from the
broader pain research community, J Pain 10(8):777–791, 2009.
82. Williams D, Gracely R: Biology and therapy of fibromyalgia. Functional magnetic resonance imaging findings in fibromyalgia, Arthritis
Res Ther 8(6):224, 2007.
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45. Uceyler N, Hauser W, Sommer C: [Fibromyalgia syndrome: diagnostic criteria and treatment], MMW Fortschr Med 151(36):46–49,
2009.
46. Wolfe F: New criteria for fibromyalgia: a twenty year journey, Arthritis
Care Res 62(5):583–584, 2010.
47. Fries JF, Spitz PW, Kraines RG, Holman HR: Measurement of patient
outcome in arthritis, Arthritis Rheum 23:137–145, 1980.
48. Wolfe F, Michaud K, Pincus T: Development and validation of the
health assessment questionnaire II: a revised version of the health
assessment questionnaire, Arthritis Rheum 50(10):3296–3305, 2004.
49. Pincus T, Swearingen C, Wolfe F: Toward a multidimensional Health
Assessment Questionnaire (MDHAQ): assessment of advanced
activities of daily living and psychological status in the patientfriendly health assessment questionnaire format, Arthritis Rheum
42(10):2220–2230, 1999.
50. Burckhardt CS, Clark SR, Bennett RM: The fibromyalgia impact
questionnaire: development and validation, J Rheumatol 18(5):728–
733, 1991.
51. Bennett R: The Fibromyalgia Impact Questionnaire (FIQ): a review
of its development, current version, operating characteristics and
uses, Clin Exp Rheumatol 23(5 Suppl 39):S154–S162, 2005.
52. Bennett R, Friend R, Jones K, et al: The revised Fibromyalgia Impact
Questionnaire (FIQR): validation and psychometric properties,
Arthritis Res Ther 11(5):415, 2009.
53. Hidding A, van Santen M, De Klerk E, et al: Comparison between
self-report measures and clinical observations of functional disability
in ankylosing spondylitis, rheumatoid arthritis and fibromyalgia,
J Rheumatol 21(5):818–823, 1994.
54. Choy EH, Arnold LM, Clauw D, et al: Content and criterion validity
of the preliminary core dataset for clinical trials in fibromyalgia syndrome, J Rheumatol 36:2330, 2009.
751.e2
PART 6 | DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN
55. Ware JE, Sherbourne CD: The MOS 36-Item Short-Form Health
Survey (SF-36).1. Conceptual Framework and Item Selection, Med
Care 30:473–483, 1992.
56. Wolfe F, Michaud K, Li T, Katz RS: EQ-5D and SF-36 quality of life
measures in systemic lupus erythematosus: comparisons with RA,
non-inflammatory rheumatic disorders, and fibromyalgia, J Rheumatol
37:296–304, 2010.
57. Wolfe F, Hassett AF, Katz RS, Michaud K: Do we need core sets of
fibromyalgia domains? The assessment of fibromyalgia (and other
rheumatic disorders) in clinical practice, J Rheumatol 38:1104–1112,
2011.
58. Jacobs JW, Rasker JJ, Van der Heide A, et al: Lack of correlation
between the mean tender point score and self-reported pain in fibromyalgia, Arthritis Care Res 9(2):105–111, 1996.
59. Simms RW, Goldenberg DL, Felson DT, Mason JH: Tenderness in 75
anatomic sites. Distinguishing fibromyalgia patients from controls,
Arthritis Rheum 31:182–187, 1988.
60. Wolfe F: When to diagnose fibromyalgia, Rheum Dis Clin N Am
20:485–501, 1994.
61. Fischer AA, Rachlin ES: Pressure algometry (dolorimetry) in the differential diagnosis of muscle pain. Myofascial pain and fibromyalgia:
trigger point management, St. Louis, 1994, Mosby, pp 121–140.
62. Branco J, Bannwarth B, Failde I, et al, editors: Prevalence of fibromyalgia: a survey in five European countries, St Louis, 2009, Elsevier.
63. Wolfe F, Ross K, Anderson J, et al: The prevalence and characteristics
of fibromyalgia in the general population, Arthritis Rheum 38(1):19–
28, 1995.
64. Raphael KG, Janal MN, Nayak S, et al: Psychiatric comorbidities in
a community sample of women with fibromyalgia, Pain 124(12):117–125, 2006.
65. White KP, Speechley M, Harth M, Ostbyte T: The London Fibromyalgia Epidemiology Study: the prevalence of fibromyalgia syndrome
in London, Ontario, J Rheumatol 26(7):1570–1576, 1999.
66. Haq SA, Darmawan J, Islam MN, et al: Prevalence of rheumatic
diseases and associated outcomes in rural and urban communities in
Bangladesh: a COPCORD study, J Rheumatol 32(2):348–353, 2005.
67. Farooqi A, Gibson T: Prevalence of the major rheumatic disorders in
the adult population of north Pakistan, Br J Rheumatol 37(5):491–
495, 1998.
68. Salaffi F, De Angelis R, Grassi W: Prevalence of musculoskeletal
conditions in an Italian population sample: results of a regional
community-based study. I. The MAPPING study, Clin Exp Rheumatol
23(6):819–828, 2005.
69. Topbas M, Cakirbay H, Gulec H, et al: The prevalence of fibromyalgia in women aged 20-64 in Turkey, Scand J Rheumatol 34(2):140–
144, 2005.
70. Senna ER, De Barros AL, Silva EO, et al: Prevalence of rheumatic
diseases in Brazil: a study using the COPCORD approach, J Rheumatol 31(3):594–597, 2004.
71. Lindell L, Bergman S, Petersson IF, et al: Prevalence of fibromyalgia
and chronic widespread pain, Scand J Primary Health Care 18(3):149–
153, 2000.
72. Clark P, BurgosVargas R, MedinaPalma C, et al: Prevalence of
fibromyalgia in children: a clinical study of Mexican children,
J Rheumatol 25(10):2009–2014, 1998.
73. Mikkelsson M: One year outcome of preadolescents with fibromyalgia, J Rheumatol 26(3):674–682, 1999.
74. Buskila D, Neumann L, Hershman E, et al: Fibromyalgia syndrome
in children—an outcome study, J Rheumatol 22(3):525–528, 1995.
75. Campbell SM, Clark S, Tindall EA, et al: Clinical characteristics of
fibrositis. I. A “blinded,” controlled study of symptoms and tender
points, Arthritis Rheum 26:817–824, 1983.
76. Hartz A, Kirchdoerfer E: Undetected fibrositis in primary care practice, J Fam Pract 25:365–369, 1987.
77. Wolfe F, Cathey MA: Prevalence of primary and secondary fibrositis,
J Rheumatol 10:965–968, 1983.
78. Hauser W, Schmutzer G, Brahler E, Glaesmer H: A cluster within
the continuum of biopsychosocial distress can be labeled “fibromyalgia syndrome”—evidence from a representative German population
survey, J Rheumatol 36(12):2806–2812, 2009.
79. Katz RS, Wolfe F, Michaud K: Fibromyalgia diagnosis: a comparison
of clinical, survey, and American College of Rheumatology criteria,
Arthritis Rheum 54(1):169–176, 2006.
80. Wolfe F: Pain extent and diagnosis: development and validation of
the regional pain scale in 12,799 patients with rheumatic disease,
J Rheumatol 30(2):369–378, 2003.
81. Williams D, Clauw D: Understanding fibromyalgia: lessons from the
broader pain research community, J Pain 10(8):777–791, 2009.
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