Fibromyalgia: diagnosis, pathogenesis, and treatment

Rinie Geenena and Johannes W.G. Jacobsb

Fibromyalgia is characterized by chronic widespread pain and
the presence of tender points, often accompanied by several
non-specific symptoms, such as fatigue, depressive mood, and
sleep disturbances. The apparent overlap between fibromyalgia
and other syndromes, such as chronic fatigue and irritable
bowel, is not sufficient cause to consider all these syndromes
as manifestations of a single syndrome. Fibromyalgia is a
multifaceted problem. Central afferent pain amplification and
perhaps also impaired descending pain inhibition are supposed
to underlie widespread pain. Neuroendocrine perturbations,
sleep disturbances, health beliefs, mood disorder, and physical
deconditioning play a role in the modulation and perseverance
of pain and other symptoms. It is extremely difficult to mitigate
chronic generalized pain and to deal with other symptoms in
fibromyalgia. A uniform intervention strategy is missing.
Essential in the tailored management of fibromyalgia are an
enhancement of functional capacities and quality of life, and the
symptomatic treatment of individual symptoms such as pain,
distress, and sleep disturbances. Rather than analysing
monotherapy per se, the objective in future evaluations should
be to try to find the combined pharmacological or nonpharmacological treatment of choice for specific subgroups of
patients. Curr Opin Anaesthesiol 14:533539. # 2001 Lippincott Williams &
Wilkins.

Department of Health Psychology, Utrecht University, Utrecht, the Netherlands; and

Department of Rheumatology and Clinical Immunology, University Medical Center,
Utrecht, the Netherlands
b

Correspondence to Rinie Geenen, Utrecht University, Department of Health

Psychology, PO Box 80140, 3508 TC, Utrecht, the Netherlands.
Tel: +31 30 253 4916; fax: +31 30 253 4718; e-mail: r.geenen@fss.uu.nl
Current Opinion in Anaesthesiology 2001, 14:533539
Abbreviations
CNS
HPA
NMDA

central nervous system

hypothalamic pituitary adrenal
N-methyl-D-aspartate

# 2001 Lippincott Williams & Wilkins

0952-7907

Introduction

Fibromyalgia is one of the most common medical

conditions seen by rheumatologists. It is a disorder of
unknown aetiology, characterized by chronic widespread
pain and the presence of tender points [1]. The quality
of life of patients is severely disturbed, and functional
and work disability are serious concerns [2 .]. Patients
seek help because they suffer from pain and other
symptoms such as fatigue, depressive mood, and sleep
disturbances. We reviewed the literature of the past year
for recent developments with respect to diagnosis,
pathogenesis, and treatment. Some special attention will
be given to the ongoing discussion about the overlap of
bromyalgia with related functional somatic syndromes.
Notions about pathogenesis, perseverance, and consequences of the syndrome will be integrated into advice
about management.

Diagnosis

Fibromyalgia is commonly looked upon as a kind of soft

tissue rheumatism. Its central characteristic is chronic,
generalized pain in the joints, muscles and spine [1].
Although pain is felt in the joints, bromyalgia is nonarticular; the pain originates from ligaments and insertions of muscles (so-called soft tissues). Although most
patients experience early morning stiffness, there are no
signs of inammation at physical investigation, and the
erythrocyte sedimentation rate is normal. The old
synonym brositis, suggesting inammation, is therefore
misleading. Damage to joints or other tissues does not
occur. Being a non-articular non-inammatory condition,
bromyalgia is a somewhat atypical entity in the eld of
rheumatology, a medical specialty dealing typically with
articular, inammatory diseases. The main reason to
maintain the categorization of bromyalgia as a rheumatic condition is that rheumatologists are the specialists
best able to discriminate this condition from other
diseases, and to investigate whether there is an underlying primary condition, such as primary Sjogren's
syndrome or hypothyroidism.
Some prefer the expression `bromyalgia syndrome',
because, unlike several other chronic pain disorders,
bromyalgia is characterized by several symptoms. Each
individual symptom such as fatigue or headache is not
very specic, but the whole set of symptoms together is
typical of bromyalgia. Common symptoms of patients
with bromyalgia in a secondary referral centre are
fatigue (in +90% of patients with bromyalgia), early
morning stiffness (+80%), sleep disturbances (+70%),
paraesthesias (+60%), headache (+50%), anxiety
533

534 Pain medicine

(+50%), and irritable bowel (+40%) [3]. Another

characteristic of bromyalgia is that pain, in contrast to
articular rheumatic conditions, responds badly to pain
medication.
Patients practically always report a long history of
widespread pain. At physical examination no abnormalities are found, except for the presence of tender points:
muscles and tendon insertions, i.e. the soft tissues, are
tender on pressure. Laboratory investigation is normal.
There are no diagnostic criteria for bromyalgia.
Diagnosis is based on pattern recognition of the abovementioned symptoms and tender points, and the
exclusion of another condition causing the symptoms.
However, classication criteria have been provided,
consisting of the presence of widespread pain and
tender points (Table 1) [1]. There is some discussion
about the utility of the tender point criterion: does it
provide a reection of reduced pain threshold that is so
characteristic of bromyalgia [4], or should it be omitted
because it simply reects the severity of widespread
pain? [5 .]. Some examined the possibility of malingering
bromyalgia with these criteria [6 .]. However, the
criteria were not developed for the diagnosis of
individual patients, an evaluation of the severity of the
impairment, or the detection of malingering, but for
classication, that is, to identify groups, e.g. for research
studies [7 .]. It is, however, a valid question as to whether
patients who full the classication criteria form a
homologous group.

Overlap with related syndromes

Patients with bromyalgia and related `functional

somatic syndromes', such as chronic fatigue syndrome,
irritable bowel syndrome, burnout, and multiple chemical sensitivity, share demographics and the presence of
somatic symptoms that cannot be explained in terms of
medical disease. The existence of these separate
diagnoses is possibly largely an artefact caused by
medical specialties that focus on symptoms pertinent
to their specialty, rather than on real differences between
patients [8]. So one could hypothesize as to whether
bromyalgia and related syndromes, instead of being

Table 1. Classification criteria and diagnosis of fibromyalgia

The American College of Rheumatology criteria for the classification
of fibromyalgia are:
(1) Chronic (43 months) widespread pain (axial plus upper and lower
segment plus left and right sided); in combination with
(2) Pain in 11 or more of 18 specific tender point sites at palpation
with an approximate force of 4 kg [1]. The presence of a second
clinical disorder does not exclude the diagnosis of fibromyalgia.
Besides chronic widespread pain, several non-specific symptoms are
often present, such as fatigue, morning stiffness, sleep disturbance,
paraesthesias, headache, anxiety, and irritable bowel. These symptoms
are helpful in the diagnosis, but are not included in the classification
criteria [1,3].

separate diagnostic entities, are overlapping manifestations of a single syndrome.

First, denitions of functional somatic syndromes in
terms of specic symptoms seem of limited value,
because diagnostic features overlap. As a consequence,
patients frequently meet the diagnostic criteria of more
than one syndrome [8]. However, for example, patients
with systemic lupus erythematosus also frequently meet
the diagnostic criteria of rheumatoid arthritis, but that is
no reason to consider these two diseases as one disease.
Furthermore, several symptoms may be secondary
consequences reecting physical deconditioning and
the consequences of distinct primary symptoms, such
as generalized pain in the case of bromyalgia or
persistent debilitating fatigue in the case of chronic
fatigue syndrome. Moreover, the overlap of symptoms
appears to have been overestimated in research, because
the medically referred samples that were investigated are
likely to have a high prevalence of co-morbidity [9 .]. So,
we consider the overlap of symptoms not enough reason
to give up separate diagnoses.
The argument that patients with functional somatic
syndromes share non-somatic symptom characteristics,
such as a higher prevalence in women, an increased rate
of current and past emotional distress, and difculties in
doctorpatient relationships [8], is in our view not strong
enough to reject separate diagnoses. Also, sufferers from
rheumatic diseases are most often female, but distinctive
pathogenesis and therapeutic strategies justify separate
diagnoses. Indeed, emotional distress is high with
functional somatic syndromes, but this may reect that
these syndromes affect the psychological well-being, or
that individuals with emotional problems are more at risk
of developing a somatic disorder. Difculties in doctor
patient relationships may reect that both the patient
and the physician feel unable to cope with syndromes
with unknown pathogenesis and pharmacological cure,
that physicians are puzzled not to be able to distinguish
these syndromes from malingering [6 .,7 .], and that
patients experience too little empathy for their suffering.
Another reason to emphasize the uniform nature of
functional somatic syndromes is that they all seem to
respond to similar therapies [8]. However, more than by
theoretical considerations and empirically proven high
effectiveness, the choice of interventions appears to be
motivated by the fact that there is no cure or causal
therapy, and that palliative treatment must therefore be
directed at the management of the physical and
psychosocial consequences of the condition.
Crucial to the decision to classify functional somatic
syndromes as different dimensions of one syndrome
could be the pathophysiological similarity of the

Fibromyalgia Geenen and Jacobs 535

syndromes. In the past decade, hypotheses about

pathology in specic organ systems, such as muscles in
bromyalgia, have been largely replaced by an appreciation of abnormal processing in the central nervous
system (CNS) and neuroendocrine mechanisms [8].
Sensitization may be a phenomenon shared by functional somatic syndromes. Sensitization means that
repeated use of a neuronal chain increases the synaptic
efciency in that chain. Ursin [10,11 .] proposed that the
vulnerable amygdala nuclei and hippocampus neurons
may offer a synaptic substrate for the sensitization of
such divergent symptoms as pain, gastrointestinal
problems, or depression. This hypothesis offers a model
for cross-sensitization between stimuli and is worth
exploring further.
However, even if syndromes share central sensitization
of the limbic structures, distinctive features still exist.
For instance, in contrast to patients with primary
depression who often respond to exercise with mood
elevation, patients with functional somatic syndromes
often complain of postexertional malaise [12 .]. Also,
signicantly elevated cerebrospinal uid levels of substance P and other physiological reections of pain
differentiate bromyalgia from related non-pain syndromes [13]. Finally, although neuroendocrine dysfunctioning such as an alteration of hypothalamic pituitary
adrenal (HPA) axis activity may be shared by functional
somatic syndromes such as bromyalgia and chronic
fatigue syndrome, these patient groups appear to show
different patterns of dysregulation, that is, in bromyalgia hyperactivity and in chronic fatigue syndrome
hypofunction of the HPA axis [14 . .].
In conclusion, the plea to consider bromyalgia and
related syndromes as overlapping manifestations of one
syndrome is positively motivated by the apparent
correspondence of symptoms and dysfunctionality, and
is negatively motivated by the lack of knowledge of the
pathogenesis. At present, from a clinical perspective
because adequate alternatives are absent, it may be
fruitful to be guided by the apparent overlap. Eventually, however, treatment should be guided by more
knowledge of each individual syndrome. To that end the
resemblance as well as the differences between bromyalgia and related syndromes should be examined
further.

Pathogenesis

It is poorly understood why patients experience severe

pain without demonstrable tissue damage. Pain has
sensory, affective and behavioural dimensions that are
associated with different physiological components. At
present, it is a popular belief that bromyalgia is a
sensory processing disturbance [13,15]. Patients experience pain in response to stimuli that are normally

perceived as not painful, such as touch, moderate cold or

heat, electrical stimulation, and proprioceptive input.
This phenomenon is called allodynia. Moreover, exaggerated pain is experienced to painful stimuli:
hyperalgesia. The presence of generalized allodynia
and hyperalgesia distinguishes bromyalgia from less
widespread chronic musculoskeletal pain conditions [16].
Pain sensation is a result of the balance of the effects of
chemicals neurotransmitters, hormones, peptides in
the body that amplify or inhibit the transmission of pain
signals to the cerebral cortex, where pain is consciously
experienced. Aberrant sensitization of pain at the spinal
cord level has been proposed to be a crucial pathogenic
mechanism in bromyalgia [13,17 .,18]. Receptors such
as the glutamate receptor N-methyl-D-aspartate
(NMDA) appear to be hyperexcitable. In animal studies,
progressively increasing the neuronal ring of dorsal
horn cells after the repetitive activation of primary
afferent C bres (wind-up pain) has been shown to be
decreased by NMDA antagonists, and analogue human
studies in bromyalgia [18,19 . .] suggested that NMDA
antagonists may target central hyperexcitability in a
major subgroup of patients with bromyalgia. The
secondary allodynia and hyperalgesia appear to be a
widespread variant of pathophysiological mechanisms in
the complex regional pain syndrome [20,21 .,22 .].
Over and above increased activity in pain facilitating
(pronociceptive) pathways, reduced activity in paininhibiting (antinociceptive) pathways could lead to pain.
Findings from animal studies [23 . .] suggested that dorsal
descending systems have an inhibitory action on neurons
that mediate pain from deep tissues. If these systems
operate in a similar way in patients, an impairment of
their function could lead to spontaneous tenderness and
hyperalgesia of deep tissues in large areas of the body,
hence bromyalgia.
Fibromyalgia is also accompanied by neuroendocrine
perturbations. The levels and responses of the two major
stress systems, the sympathetic nervous system and the
HPA axis, deviate from normal. Several studies found a
blunted sympathetic response to experimental stress
[24]. Most studies have not controlled for the physical
activity levels of the subjects [24], but perhaps results
must be interpreted as being indicative of tonic
sympathetic hyperactivity [25]. Previously, HPA axis
studies were interpreted as being indicative of HPA
hypofunction [26,27 .], but it has recently been proposed
that HPA alterations in bromyalgia can be attributed to
hyperactivity of corticotropin-releasing hormone neurons
[14 . .,28 .]. HPA axis hyperactivity could reect elevated
serotonergic tonus in the CNS of patients, and may be at
the basis of the inhibition of growth hormone and
thyroid-stimulating hormone at the pituitary level [14 . .],

536 Pain medicine

and also of elevated tonic sympathetic tone [29]. It is

unclear whether endocrine deviations are primary
processes in the pathogenesis of bromyalgia or whether
they are an epiphenomenon.
At a group level, the mean neuroendocrine functioning
of patients tends to deviate from norm reference groups,
but apparently only subgroups of patients suffer from
clinical signicant dysautonomia [24,30], HPA axis
perturbations [14 . .], subnormal growth hormone secretion [31], or other neuroendocrine alterations. Future
research in large samples should be more clearly directed
at nding the determinants that differentiate between
patients who do and do not have specic neuroendocrine
disturbances. Candidate determinants are pain severity,
past and present mood disorder or life stress (such as war
or incest), sleep disturbance, and physical deconditioning. For instance, tonic sympathetic hyperactivity as well
as sympathetic hyporesponsiveness may be explained by
physical deconditioning, hyperreactivity of the HPA axis
may have more to do with the severity of mental
depression [14 . .], hypoactive sympathetic responsiveness may play a role in reduced antinociception [27 .],
and tonic sympathetic hyperactivity in enhanced nociception [20].
Although afferent central pain amplication and perhaps
also impaired dorsal descending pain inhibition are
supposed to be crucial for widespread allodynia and
hyperalgesia, many other processes may amplify or
inhibit the sensory or affective components of pain,
and play a role in the perseverance of pain and other
symptoms (Fig. 1). Neuroendocrine perturbations that
are constitutional or a consequence of stress, pain, or
sleep disturbance may play a role in the perseverance of
pain. Severe pain and disturbed sleep will strengthen
each other. Depressed mood and health beliefs about
the benecial role of resting will strengthen the
avoidance of physical effort and lead to physical
deconditioning, which in turn may affect pain. Heterogeneous
results
in
pharmacological
trials
[18,19 . .,32 .,33 . .,34 . .] suggested that in individual patients the different pathogenic mechanisms are not
equally important. Fibromyalgia is a multifaceted
problem, and patients are heterogeneous with respect
to symptoms, physical deconditioning, sleep and mood
problems, and neuroendocrinological status.

Treatment

A uniform and satisfactory treatment strategy for

bromyalgia is lacking. Treatment is palliative instead
of curing. To deal with the symptoms and physical and
psychosocial consequences of the chronic condition,
pharmacological, physical, and cognitive-behavioural
therapy are applied. First, we will consider pharmacological therapy.

Figure 1. A psychobiological model with five key elements that play

a role in the perseverance of fibromyalgia

Neuroendocrine
pertubations

Avoidance of physical effort,

physical deconditioning

Pain

Sleep
disturbance

Health beliefs,
mood disorder

All connections in the multifactorial model are bi-directional. Changes in

one element will give rise to changes in other elements.

As the stimulation of 5-hydroxytryptamine 3 receptors

may also enhance the release of substance P, increased
serotonergic activity might cause substance-P-mediated
pain. Therefore, 5-hydroxytryptamine 3 receptor antagonists such as tropisteron might alleviate pain [34 . .]. In a
prospective double blind parallel-group dose-nding
study [34 . .], 418 patients with bromyalgia received
either placebo, or 5, 10, or 15 mg tropisteron. The most
effective dose was 5 mg. It resulted in more than 35%
pain reduction in 39% of patients. The intravenous
administration of 2 mg tropisteron also produced a
benecial effect on bromyalgia symptoms that lasted
for 2 weeks to 2 months in the majority of patients [35 .].
This pharmaceutical could therefore be promising for a
subgroup of patients with bromyalgia.
In two meta-analyses [36 .,37 .] and a theoretical review
[38 .] the present state of the antidepressant treatment of
bromyalgia was summarized. The effects of the tricyclic
agent amitriptyline are documented best. For seven
outcomes, a mean treatment effect of 0.44 standard
deviations was calculated [37 .], which is a moderately
strong effect. Effect sizes in standard deviation units
after amitriptyline were 0.17 for tender points, 0.39 for
fatigue, 0.49 for sleep, and 0.52 for pain [36 .]. Amitriptyline remains the drug of rst choice in the pharmacological treatment of bromyalgia, but the general
conclusion that antidepressants are effective in bromyalgia would be too strong from a methodological and
clinical perspective [39]. Only approximately one third of
patients responded [38 .,40 . .], and the results of studies
are also heterogeneous.
We will not consider pharmacological treatment with
corticosteroids and other hormones, non-steroidal antiinammatory drugs, benzodiazepines, opioids, and mus-

Fibromyalgia Geenen and Jacobs 537

cle relaxants. Few trials, small sample sizes, and short

treatment duration limit the generalizability of treatment
results [38 .,41,42]. Without exception, pharmacological
studies [19 . .,32 .,33 . .,34 . .,38 .,41,42] reected that only
subgroups of patients respond to treatment. Therefore,
the challenge in future studies is to try to predict from
pre-treatment scores such as mood or sleep disturbance,
the number of tender points, physical deconditioning, or
demographic characteristics, which patients will and
which patients will not respond to specic pharmacological interventions.
A comparison of the efcacy of pharmacological and nonpharmacological therapy in a meta-analysis [42] suggested that the optimal treatment for bromyalgia would
include physical exercise and the reinstatement of
proper cognitions and behaviour, in addition to appropriate pharmacological management as needed for
symptoms.
Physical exercise therapy is aimed at physical deconditioning and muscle weakness as well as at fatigue, mood,
and sleep disturbance. Although it is not the primary aim
of exercise therapy, pain may also be affected. In the
short term, proprioceptive allodynia and other aspects of
central pain sensitization will increase pain. In the longer
term, it is unclear whether afferent nociceptive pain
processes are changed by exercise, but perhaps pain
decreases as a consequence of the increased release of
pain-inhibiting substances such as noradrenaline and
endogenous opiates. On average, the mixed results of
evaluations of exercise therapy in the past year were
disappointing [43 .,44 .,4547]. Exercise therapy as a
monotherapy for bromyalgia will probably be less
successful if not embedded in educational packages
aimed at motivation for change and maladaptive cognitions [41,48 .]. Psychological factors that prevent compliance to exercise treatment are: fear of an increase of
pain upon an increase of physical effort, and, as a
consequence, reinforcement of the cognition that
exercise will worsen the condition in the long run; poor
coping skills; low self-efcacy; helplessness beliefs; the
pessimistic belief that the worst possible outcome will
occur as a consequence of any behaviour (catastrophizing); and, depressive self-statements [40 . .,41,49 .,50 .].
The appreciation of the biopsychosocial nature of
problems in bromyalgia and the observation that
psychological factors are important for adherence to
therapy have led to cognitive interventions, many of
them in combination with exercise or pharmacological
therapy [12 .,51]. Long-term benets of cognitive-behavioural interventions have been insufciently proven
[40 . .], but it has been concluded that in the short term
cognitive-behavioural interventions lead to an improvement in physical status, bromyalgia symptoms, psycho-

logical status, and daily functioning [42]. However, this

conclusion is based on a meta-analysis, in which some
studies were included that did not meet stringent
inclusion criteria. A critical evaluation involving 802
subjects covered relaxation training, cognitivebehavioural therapy, education, and several other mindbody
therapies [52 .]. That study not only included divergent
mindbody therapies, but also such divergent control
reference groups as waiting list groups and physical
therapy groups. When analysing this, the conclusion
emerges that mindbody therapy is more effective for
some clinical outcomes compared with waiting list or
placebo, whereas compared with other treatment, results
are largely inconclusive [52 .]. Healthcare workers need
to be cognizant of the effect of bromyalgia on the
quality of life [53 .], for example, by guiding patients in
the wording of individualized realistic goals in life and
the stepwise ways to achieve those goals.
Researchers and clinicians should more clearly attend to
individual differences within the bromyalgia population
[54 .]. A rehabilitation programme that consisted of
education, aerobic exercise, pacing activities, and stress
management was particularly efcacious for dysfunctional patients, who are characterized by a high level of
pain, reduced quality of life, emotional distress, lack of
control over their lives, and elevated functional limitations. In contrast, patients characterized by an adaptive
coping style and interpersonally distressed patients
showed less improvement.
Some recommendations for the management of individual patients are summarized in Table 2.

Conclusion

Diagnostic criteria for bromyalgia are absent. Diagnosis

is based on the recognition of symptoms and the
presence of tender points. The pathogenesis is poorly
understood. It is now supposed that afferent central pain
amplication, and perhaps also the impairment of dorsal
descending pain inhibiting systems, underlie widespread
allodynia and hyperalgesia. In addition, neuroendocrine
perturbations, physical deconditioning, sleep disturbance, health beliefs, and mood disorder are all
supposed to play a role in the modulation of pain via
the amplication or inhibition of the sensory or affective
component of pain and in other symptoms.
It is extremely difcult to mitigate chronic generalized
pain and to deal with symptoms in bromyalgia. As it
now stands, there is no uniform therapy. In controlled
trials, only a moderate effect can be expected. At an
individual level, some kinds of therapies have been
shown to be effective for some kinds of outcome variable
in some kinds of patients. Fibromyalgia is a multifaceted
problem and the population of patients is heterogeneous

538 Pain medicine

Table 2. Management of fibromyalgia
It is extremely difficult to mitigate chronic generalized pain and to deal
with other symptoms in fibromyalgia. A uniform intervention strategy is
missing. Management should be tailored to symptoms, functioning and
the well-being of individual patients. Essential in the management of
fibromyalgia are the enhancement of functional capacities and quality of
life.
(1) Graded daily physical exercise is the key therapy to prevent the
progression of physical deconditioning, to enhance functional
capacities, and to manage fibromyalgia symptoms.
(2) Adherence to physical exercise will probably be improved if
treatment is embedded in educational packages aimed at
maladaptive cognitions and motivation for change.
(3) Cognitive behavioural therapy may be considered to help patients in
wording individualized realistic goals in life and the ways of
achieving those goals, to manage pain and other symptoms, and to
cope with the consequences of fibromyalgia, such as depressive
mood, activities of daily living, sleep disturbance, depressive
self-statements, and physical deconditioning.
(4) For symptomatic treatment pharmacological treatment may be
considered for individual patients. Analgesics may provide some
benefit. Tricyclic antidepressants may have a moderate modulating
effect on pain, mood, and sleep. For subgroups of patients with
severely invalidating pain, some other pharmaceutical agents may
prove to be valuable in future, for instance, NMDA or
5-hydroxytryptamine 3 receptor antagonists.
NMDA, N-methyl-D-aspartate.

with respect to symptoms, physical deconditioning, sleep

and mood problems, neuroendocrinological status, and
treatment effect. In a sense, bromyalgia is not the
condition that could be evaluated in a controlled trial in
which all patients are randomly assigned. Rather than
analysing monotherapy per se for this multidimensional
condition, the challenging objective in future evaluations
should be to nd the combination of non-pharmacological and pharmacological treatments of choice for
specic subgroups of patients, and how to discriminate
these subgroups.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:
.
of special interest
..
of outstanding interest

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22 Staud R, Vierck CJ, Cannon RL, et al. Abnormal sensitization and temporal
.
summation of second pain (wind-up) in patients with fibromyalgia syndrome.
Pain 2001; 91:165175.
This study is particularly interesting because of the methods that were used to
obtain evidence for the possibility that input to central nociceptive pathways is
abnormally processed in fibromyalgia.
23 Mense S. Neurobiological concepts of fibromyalgia the possible role of
. . descending spinal tracts. Scand J Rheumatol 2000; 29 (Suppl. 133):2429.
Among all papers about pain-facilitating (pronociceptive) pathways, this inspiring
paper hypothesizes about the possible role of impaired pain-inhibiting (antinociceptive) pathways in fibromyalgia.

Fibromyalgia Geenen and Jacobs 539

24 Petzke F, Clauw DJ. Sympathetic nervous function in fibromaylgia. Curr
Rheumatol Rep 2000; 2:116123.

39 Jacobs JWG, Geenen R. Antidepressants improve symptoms of fibromyalgia.

ALP J Club 2001; 134:85.

25 Cohen H, Neumann L, Alhosshle A, et al. Abnormal sympathovagal balance

in men with fibromyalgia. J Rheumatol 2001; 28:581589.

40 Richards S, Cleare A. Treating fibromyalgia. Rheumatology 2000; 39:343346.

26 Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping
clinical and neuroendocrine features and potential pathogenic mechanisms.
Neuroimmunomodulation 1997; 4:143153.
27 Dessein PH, Shipton EA, Stanwix AE, Joffe BI. Neuroendocrine deficiency.
mediated development and persistence of pain in fibromyalgia: a promising
paradigm? Pain 2000; 86:213215.
It is proposed that an insight into neuroendocrine deficiencies and their interaction
with pain may provide effective strategies in the prevention and treatment of
fibromyalgia.
28 Neeck G. Neuroendocrine and hormonal perturbations and relations to the
.
serotonergic system in fibromyalgia patients. Scand J Rheumatol 2000; 29
(Suppl. 113):812.
A review leading to the suggestion that drugs that reduce serotonergic tonus may
be beneficial in fibromyalgia, because enhanced hypothalamic pituitary adrenal
axis activity may also reflect elevated serotonergic tonus.
29 Webster EL, Elenkov IJ, Chrousos GP. The role of corticotropin-releasing
hormone in neuroendocrine-immune interactions. Mol Psychiatry 1997;
2:368372.
30 Raj SR, Brouillard D, Simpson CS, et al. Dysautonomia among patients with
fibromyalgia: a noninvasive assessment. J Rheumatol 2000; 27:26602665.
31 Dinser R, Halama T, Hoffmann A. Stringent endocrinological testing reveals
subnormal growth hormone secretion in some patients with fibromyalgia
syndrome but rarely severe growth hormone deficiency. J Rheumatol 2000;
27:24822488.
32 Russell IJ. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin
.
Rheumatol 2000; 6:250257.
A useful study, because tramadol activates mu-opioid receptor agonists and
inhibits the reuptake of norepinephrine and serotonin; two complementary
mechanisms that theoretically might mitigate fibromyalgia symptoms.
33 Wolfe F. Is tramadol `effective' in fibromyalgia? Implications for study design
. . and clinical effectiveness. J Clin Rheumatol 2000; 6:237238.
A very critical response to the conclusion that tramadol is safe and effective
`among patients who tolerate it and perceive a benefit'. Be aware of the Wolfe!
34 Farber L, Stratz T, Bruckle W, et al. Efficacy and tolerability of tropisetron in
. . primary fibromyalgia a highly selective and competitive 5-HT3 receptor
antagonist. Scand J Rheumatol 2000; 29 (Suppl. 113):4954.
A methodologically sound short-term effect study in a sample of 418 patients
showing that a low dose 5-hydroxytryptamine 3 receptor antagonist may reduce
pain in some patients.
35 Stratz T, Farber L, Varga B, et al. Treatment of fibromyalgia with intravenous
.
application of tropisetron. J Musculoskel Pain 2000; 8:3140.
A pilot study that provides insight into pathogenetic mechanisms in fibromyalgia
while evaluating the medication that may eventually prove to be promising for the
treatment of widespread pain in some patients.
36 O'Malley PG, Balden E, Tomkins G, et al. Treatment of fibromyalgia with
.
antidepressants. A meta-analysis. J Gen Intern Med 2000; 15:659666.
A profound meta-analysis leading to the somewhat too strongly formulated
conclusion that antidepressants are efficacious in treating many of the symptoms in
fibromyalgia.
37 Arnold LM, Keck PE, Welge JA. Antidepressant treatment of fibromyalgia: a
.
meta-analysis and review. Psychosomatics 2000; 41:104113.
In this meta-analysis it is suggested that to be able to choose antidepressant
treatment unambiguously in fibromyalgia, double-blind, placebo-controlled, parallel-group studies of sufficient size and adequate duration in patients with
fibromyalgia are still needed.
38 Lautenschlager J. Present state of medication therapy in fibromyalgia syndrome.
.
Scand J Rheumatol 2000; 29 (Suppl. 113):3236.
This study reviews pharmacological therapy and concludes that treatment of
fibromyalgia should not be based on medication therapy alone.

..

A balanced, realistic, and scientific sound editorial about the treatment of

fibromyalgia, specifying the theoretical, empirical, and clinical rationale for specific
treatments as well as some pitfalls.
41 Crofford LJ, Appleton BE. The treatment of fibromyalgia: a review of clinical
trials. Curr Rheumatol Rep 2000; 2:101103.
42 Rossy LA, Buckelew SP, Dorr N, et al. A meta-analysis of fibromyalgia
treatment interventions. Ann Behav Med 1999; 21:180191.
43 Ramsay C, Moreland J, Ho M, et al. An observer-blinded comparison of
.
supervised and unsupervised aerobic exercise regimens in fibromyalgia.
Rheumatology 2000; 39:501505.
The results of this study question the view that aerobic exercise programmes are a
major useful treatment strategy in fibromyalgia.
44 Mannerkorpi K, Nyberg B, Ahlmen M, Ekdahl C. Pool exercise combined with
.
an education program for patients with fibromyalgia syndrome. A prospective,
randomized study. J Rheumatol 2000; 27:24732481.
One of the few randomized studies in the past year showing the beneficial effects
of physical exercise combined with education.
45 Meiworm L, Jakob E, Walker UA, et al. Patients with fibromyalgia benefit from
aerobic endurance exercise. Clin Rheumatol 2000; 19:253257.
46 Hakkinen A, Hakkinen K, Hannonen P, Alen M. Strength training induced
adaptations in neuromuscular function of premenopausal women with
fibromyalgia: comparison with healthy women. Ann Rheum Dis 2001;
60:2126.
47 Jentoft ES, Kvalvik AG, Mengshoel AM. Effects of pool-based and landbased aerobic exercise on women with fibromyalgia/chronic widespread
muscle pain. Arthritis Care Res 2001; 45:4247.
48 Earnshaw SM, MacGregor G, Dawson JK. Fibromyalgia-monotheories,
.
monotherapies and reductionism. Rheumatology 2001; 40:348349.
A short but convincing attack on monotherapies in fibromyalgia accompanied by a
plea to embrace a biopsychosocial model and adopt a range of tailored
interventions.
49 Kashikar Zuck S, Graham TB, Huenefeld MD, Powers SW. A review of
.
biobehavioral research in juvenile primary fibromyalgia syndrome. Arthritis Care
Res 2000; 13:388397.
This study proposes a preliminary conceptual model for juvenile primary
fibromyalgia syndrome using a biopsychosocial perspective.
50 Hassett AL, Cone JD, Patella SJ, Sigal LH. The role of catastrophizing in the pain
.
and depression of women with fibromyalgia syndrome. Arthritis Rheum 2000;
43:24932500.
This study is important because it suggests that cognitive factors such as
depressive self-statements may hamper improved outcomes after physical or
pharmacological therapy.
51 Creamer P, Singh BB, Hochberg MC, Berman BM. Sustained improvement
produced by nonpharmacologic intervention in fibromyalgia: results of a pilot
study. Arthritis Care Res 2000; 13:198204.
52 Hadhazy VA, Ezzo J, Creamer P, Berman BM. Mindbody therapies for the
.
treatment of fibromyalgia. A systematic review. J Rheumatol 2000; 27:2911
2918.
A complex effort to draw a conclusion from the comparison of such divergent
mindbody therapies as cognitivebehavioral and relaxation therapies.
53 Bernard AL, Prince A, Edsall P. Quality of life issues for fibromyalgia patients.
.
Arthritis Care Res 2000; 13:4250.
An interesting study for its claim that healthcare workers need to be cognizant of
the effects of fibromyalgia on the quality of life.
54 Turk DC, Okifuji A. Pain in patients with fibromyalgia syndrome. Curr Rheumatol
.
Rep 2001; 2:109115.
This interesting review emphasizes that we need to move forward to examine what
treatment works best for which patient.