1. health and fitness
2. disease

Section 13 Rheumatology
Chapter
96
Fibromyalgia: Does it Exist? If so,
What is the Management?
V Nagaraajan
ABSTRACT
Fibromyalgia is a symptom complex syndrome most commonly seen
in women. The exact incidence of the disease is yet to get worked out
in India, but a fair incidence has been reported in western literature to
3.6%. Till now no definite criteria have been laid for the diagnosis of FM.
American Rheumatologic Association (ARA) has laid out some criteria
and diagnostic points, but they are being modified now. It appears
that this disorder is a manifestation of abnormal pain perception in
the central level of pain perception rather than the peripheral joints
or muscles, a phenomenon known as allodynia. Treatment is mainly
concentrated toward alleviation of symptom complex, but definite
management is yet to be tailored.
INTRODUCTION
Fibromyalgia was once considered as a waste diagnosis, since there
were no objective signs and no relevant laboratory evaluations.
However, of late basic and clinical investigations have clarified the
neurophysiologic bases for FM and led to its current classification as
a central sensitivity syndrome (CSS).1,2
Fibromyalgia can now be considered a chronic relapsing
neurosensory disorder characterized in part by abnormalities in pain
processing by the central nervous system (CNS)3 leading to a specific
pharmacologic therapy.
At the clinical level, FM is pain syndrome complex. It overlaps
substantially with other CSS, such as the following:
• Chronic fatigue syndrome
• Irritable bowel syndrome (IBS)
• Tension type of headaches, atypical migraine
• Post-traumatic stress disorder (PTSD)
• Restless leg syndrome and many
Fibromyalgia gains diagnosis with the specialist the patient sees.
If a neurologist sees, it may be FM, and if a gastro specialist sees, it
is observed as IBS. Coexisting diseases do occur like rheumatoid
arthritis (RA),4 systemic lupus erythematosus (SLE)5 and chronic
active hepatitis syndrome with hepatitis C infection.6 Of late
evidence-based medicine tools, confers a diagnosis of FM. Still,
approach requires compassion and skill of the physicians.
Toward the historical issues, FM was not defined until late 20th
century and never gained recognition in bodies like ARA and World
Health Organization (WHO). It was observed to be another vague
diagnosis called “polymyalgia rheumatica”, which is also an illdefined syndrome. In 1987, AMA recognized FM as a true illness
followed by many bodies such as National Institutes of Health
(NIH) and WHO, and accepted as a legitimate clinical entity. During
the Second World Congress on myofascial pain and FM (1992),
diagnostic criteria of FM were redefinied.7
RECENT CONCEPTS IN PATHOPHYSIOLOGY
Fibromyalgia is late recognized to be a disorder of central pain
processing, or recognizing syndrome, depending on the central
sensitivity of the inputs, whether nociceptive or non-nociceptive.
Clauw describes FM as a diffuse problem of sensory “volume
control”. He observes that the FM patients’ pain threshold is very low,
so that non-nociceptive sensory stimuli such noise, visual, touch and
odors are observed painful. This happens because of hypervigilance
centers in the brain pain centers with neurobiologic changes due to
altered neuropeptides.8
Researchers in FM syndrome observed biochemical, metabolic
and immune regulatory dysfunctions, which make one to think that
it is no longer a subjective pain condition (Figure 1).
It appears that differential appreciation of nociception and
afferent inputs from somatic reflexes, which are modulated by
emotional, motivational and cognitive aspects of pain often helps
to discriminate the pain threshold and quality of pain. These
differentiating aspects appear to have lost in FM syndrome (Flow
chart 1).
In addition to strictly sensory-discriminative elements of
nociception and afferent input from somatic reflexes, major
contributions from pathways and regions of the brain that are
associated with emotional, motivational and cognitive aspects of
pain are evident and help determine the subjective intensity of pain.
The two principal effectors of the stress response, the hypothalamicpituitary-adrenocortical (HPA) axis and the sympathetic nervous
system (SNS), are also activated.
It appears that the patients are normally adaptive, but the stress
response will become maladaptive in patients who also suffer from
chronic pain, fatigue syndromes, which could be designated along with
FM.9-12 Negative emotions, psychological factors, beliefs, attributions
can act as triggering point as stressors precipitating FM syndrome
complex, as it amplifies the pain syndrome especially in women.13
Patients with FM who manifest with such emotional disturbances,
resulting in neuroendocrinal disorders, lead to flu-like syndromes,
diffuse pain all over the body and poor sleep situations. The important
biologic elements here include proinflammatory cytokines, the HPA
axis, other neuroendocrine axes and the autonomic nervous system.
Section 13
Chapter 96 Fibromyalgia: Does it Exist? If so, What is the Management?
Flow chart 1: Algorithm for fibromyalgia
Figure 1: What is pain? Parallel processing. A neurophysiologist’s view of
pain.Courtesy: Alan R Lightdelete
Growth hormone abnormalities are also thought to contribute to
symptoms in FM.14 Non-nociceptive impulses such as touch and
warmth are realized as nociceptive pain owing to enhancement of
pain threshold, which can be proved with an algometry measuring
scale.
Various types of abnormalities in pain perception and processing
have been demonstrated with various research studies.15-19
• Excessive pro-nociceptive excitatory peptides like substance P,
glutamate, especially in insular cortex
• Similarly low levels of inhibitory neuropeptides like serotonin,
norepinephrine, in the antinocieptive pathways in posterior
spinal column
• Dysregulated endogenous opioid analgesic response in several
areas of brain dealing with pain modulation added to dopamine
dysregulation
• Enhanced temporal summation of second pain generation
It is also observed that high throughout genotyping is in identifying
a series of single nucleotide polymorphism (SNP) haplotypes
that influence neuropeptide levels and receptor sensitivity in
the brain, thus contribute to the various malperception of pain
processing.20 Those SNP haplotypes contribute to the vulnerable
elements in the development of FM and allied CSS. This concept
helps to deal with FM pharmacologically, such as use of drugs like
duloxetine, which increases the inhibitory neurotransmitters, or like
gabapentin and pregabalin, which decrease the levels of excitatory
neurotransmitters.21,22
As FM is a polygenic syndrome with genetic polymorphisms,
modulating through gene response to the therapy would be a further
research. It is also postulated that there could be a dysregulation in
the dopaminergic system in the limbic brain. Pain-associated peptide,
especially serotonin, found to be low in the platelets, serum and brain,
in FM and other pain syndromes. Low levels of serotonin precursor
tryptophan and 5-hydroxyindole acetic acid have been observed in
brain ultimately associating FM with low serotonin level, has high
propensity for FM-associated low ATP.23 Many neuroendocrine
studies have observed revealing dysfunction of the HPA axis, which
is responsible for the stress-related activity of the brain dealing with
release of corticosterols in FM.24
Growth hormone, produced during delta sleep, is involved in
tissue repair. Therefore, disrupted stage 4 (delta) sleep associated
with FM may account for low levels of growth hormone. In FM, growth
435
Rheumatology
hormone stimulates the production of insulin-like growth factor
I (IGF-I) in the liver. Some authors have found that most patients
with FM have low levels of IGF-I and that low levels are specific and
sensitive for FM25 increased levels of nerve growth factors (NGFs)
have found to be raised, which enhances the sensitivity of substance
P.25
COGNITIVE DYSFUNCTIONS IN FIBROMYALGIA
It is observed that a definite decline in episodic, semantic, verbal
and procedural skills memory in FM show a similarity to the levels
of function in people who are older than them by 20 years.26 Another
possible cause of cognitive dysfunction is the distracting quality of
pain in FM. Cognitive performance of patients with FM is correlated
with their reported level of pain. Other studies have implicated glial
cell water retention and glial cell abnormalities as causes of cognitive
dysfunction in FM.
Cognitive dysfunction has been linked to CNS imbalances.
Abnormal levels of neurotransmitters such as substance P, serotonin,
dopamine, norepinephrine and epinephrine may cause cognitive
dysfunction. Neuroendocrine imbalance of the HPA axis may play a
role along with the distracting quality of pain.
Fibromyalgia is very common in women, owing to their phasic
gonadal pain modulating hormones’ maladaptation to the pituitary
functions, poor pain adaptation and increased propensity to stress
syndromes. They do have poor stress-induced analgesia and opioid
system with high level of substance P.27,28
IMAGING IN FIBROMYALGIA
1. Single-photon emission computed tomography (SPECT)
scanning has defined abnormities with decreased blood flow in
the both caudate nuclei and thalamus.
2. More brain areas are extracted in functional magnetic resonance
imaging (fMRI) in FM cases than normal controls, suggestive
of collective efforts in alphabetization, with lower activation in
attention networks, attracting other resources for help.
Engel’s biopsychosocial model of chronic illness (i.e. health status
and outcomes in chronic illness are influenced by the interaction of
biologic, psychological and sociologic factors) provides a useful way
to conceptualize FM.29 The model is pictured in Figure 2.
Section 13
• Anticipation of pain (medial frontal cortex, cerebellum)
• Attention to pain (dorsal anterior cingulate gyrus, dorsolateral
prefrontal cortex)
• Emotional aspects of pain (claustrum, closely connected to the
amygdala)
Physical Examination
Till now, there were no specific criteria to decide on the diagnosis
of FM, and no considerable points were recognized in physical
examinations till ARA laid criteria of diagnosis on physical
examination (Figure 3).
Site Locations of Tender Points as Specified by ARA
The 18 possible tender points exist as nine pairs (in addition to 3
control sites), four on the anterior of the body and five on the posterior
of the body.7 Tender points may be found in any palpable muscle, but
18 sites are consistently present in patients with FM. But of late ARA,
has disagreed in testing all the 18 points, as it would be more painful
for the patients with remote practicality and unreliability especially
when psychogenic allodynia dominates over this disease. Hence,
testing for one or two tender points would be useful.
Pressure Algometry
A reasonable tool for quantification of pain perception and pain
tolerance is the pressure algometer or dolorimeter. It provides a
simple assessment tool for the pain in the suspected tender points
in FM. Normal values are 4 kg/cm2 and allodynia represents pain
perception less than the normal. It is more useful tool in the follow-up
of treatment in FM.
DIFFERENTIAL DIAGNOSIS
•
•
•
•
•
Thyroid and parathyroid dysfunctions
Diffuse osteoporosis
Certain viral myositis
Polymyositis
Personality disorders
Biologic Variables
Many of the biological variance is inherited but they are uncertain
in the genesis of FM. A probable link would be decreased collagen
cross-linking, hypermobility, and environmental chemicals. Many
issues related to the cortical and subcortical appreciation of pain
could be related to the following:
Figure 2: Psychosocial model in fibromyalgia
436
Figure 3: Tender points described in the American Rheumatologic
Association (ARA) (Ref. ARA CHARTER)
Section 13
Chapter 96 Fibromyalgia: Does it Exist? If so, What is the Management?
• Regional pain syndromes
• Polymyalgia rheumatic
• Post-traumatic stress disorder (PTSD)
• SLE
• Dermatomyositis
• Paget’s disease
• Malignancy-associated syndromes
• Infectious chronic viral syndromes and other painful syndromes.
Recently, it has been reported that mitochondrial myopathy
presented with syndrome of FM.30
MANAGEMENT
Most of the drugs in FM are designed in such a way to interfere with
the central pain processing modules, and it is strange that analgesics
and anti-inflammatory drugs react very little. This again makes one
think that the problem appear to be central than peripheral. The
common drugs used are as follows.
For a long time, dextromethorphan, an N-methyl-D-Aspartate
(NMDA) receptor was tried for a long time. Beta-blockers found
to be of slight use. The US Food and Drug Administration has
approved Pregabalin for this neuropathic pain associated with FM,
along with Milnacipran as antidepressant. Among the analgesics,
opioid like Tramadol, which has additional effects on serotonin and
norepinephrine receptors, moderately improves tolerance to the
pain especially in patients with allodynia. Selective estrogen receptor
modulator Raloxifene 60 mg every alternate day has some effect
in reducing the tender point count, especially in postmenopausal
women.31,32 Experimental data suggest that the synthetic cannabinoid
nabilone in doses escalating from 0.5 mg daily to 1 mg twice daily
improves the tolerance to pain and reduces the anxiety related to
FM.33 Other drugs are vitamins, minerals, malic acid with magnesium,
antioxidants and amino acids.
The associated depression and anxiety state has to be managed
with psychotherapy, mood elevators and anti-anxiety drugs. A
moderate doses of alprazolam, etizolam, short-acting hypnotics
especially combination of melatonin with Zolpidem (Zolsoma;
melatonin 3 mg with 5/10 mg zolpidam) with good advice for sleep
hygiene would be useful in the management of sleep disturbances
in FM. Sodium oxybate is an inhibitory chemical neurotransmitter
in the brain acting on specific receptors for gamma hydroxybutyrate
(GHB) and gamma aminobutyric acid (GABA). Sedative and hypnotic
prolongs stage III/IV restorative sleep in FM. Other drugs tried are like
Trazodone, (which inhibits serotonin uptake by brain synaptosomes),
buspirone and temazepam.
Skeletal Muscle Relaxants
Most of the skeletal muscle relaxants have short-term benefit except
cyclobenzaprine, which has long-term improvement over placebo
as a single night time dose in combination with anxiolytic drugs.
Cyclobenzaprine acts centrally and reduces the somatic tonic
signals, influencing alpha and gamma motor neurons, but not very
beneficial in FM. Other drugs approved by FDA are Pramipexole and
Gabapentin in restless leg syndrome with FM.
Psychosocial and behavioral therapy finds a place in the
management of FM, along with the following:
• Relaxation training
• Activity pacing
• Guided imagery
• Written emotional disclosure
• Distraction strategies
• Instruction in proper sleep hygiene.
PROGNOSIS
Fibromyalgia is a chronic relapsing condition, and reversing the
allodynia and hyperalgesia may be impossible. Tachyphylaxis as
well progressive decrease in the response to therapy is also noted.
Hence the treatment goal is restricted to least response to therapy
and improvement in day to day activity. A prospective study from
Denmark reported a 10 fold increased risk of death from suicide in
patients with FM who were followed for as long as 16 years.34 This
study also found a 6 fold increased risk of liver cirrhosis/biliary tract
disease and a 3 fold increased risk of cerebrovascular disease.34 This
association also needs to be studied in other populations.
CONCLUSION
Whatever may be the situation, the physician is bound to manage
cases of FM, which is really a practical challenge. It is often found
that the patient changes the physicians, various specialists, and
ultimately when the psychosocial aspects overwhelms as a problem
in their life, which is more important, they often forget the syndrome
of FM.
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