Scientific Basis for Understanding
Pain in Fibromyalgia
Robert Bennett MD, FRCP
see pdf version
is a clinical construct that has been developed, for the most part, by
rheumatologists. It is a direct descendent of "fibrositis", a
that was first coined in 1904
There are always problems inherent in defining a disorder in purely
descriptive terms. Nevertheless the publication of the American College of
Rheumatology's 1990 Classification Criteria for fibromyalgia
has been coincident with an impressive resurgence of research in this
area. This article attempts to synthesize contemporary research findings.
1990 American College of Rheumatology's guidelines for making a diagnosis
of fibromyalgia are the most widely used criteria in current use
They comprise the historical feature is widespread pain of 3 months
or more and the physical finding of 11 or more out of 18 specified tender
point sites on digital palpation with an approximate force of 4 kg. The
1990 criteria suggested abolishing the distinction between primary and
secondary FM. This concept is important as some FM patients get extensive
workups to exclude another diagnosis. The number of tender points of 11or more
was originally derived from a receiver-operating curve and relates to the
number giving the best sensitivity and specificity. In clinical practice,
the diagnosis of FM can be entertained when less than 11 tender points are
core symptom of the FM syndrome
is chronic widespread pain
The pain is usually perceived as arising from muscle, however many
fibromyalgia patients also report joint pain
Stiffness, worse in the early morning, along with the perception of
articular pain this may reinforce the impression of an arthritic
condition. Fibromyalgia pain and stiffness typically have a diurnal
variation, with a nadir during the hours of about 11.00 am to 3.00 pm
Symptoms also wax and wane in intensity over days and weeks; with
flares occurring with increased exertion, systemic infections, soft tissue
injuries, lack of sleep, cold exposure, and psychological stressors.
fatigability from physical exertion, mental exertion and psychological
stressors are typical of fibromyalgia. The etiology of fatigue in
fibromyalgia is multifaceted and is thought to include non-restorative
sleep, deconditioning, depression, poor coping mechanisms and secondary
endocrine dysfunction involving the hypothalamic pituitary adrenal axis
and growth hormone deficiency
Patients with the chronic fatigue syndrome (CFS) have many
similarities with FM patients
Characteristically, patients with CFS have an acute onset of
symptoms after an infectious type illness, with subsequent persistence of
debilitating fatigue and post-exertional malaise. About 75% of patients
meeting the diagnostic criteria of CFS also meet the criteria for
diagnosis of FM
patients invariably report disturbed sleep
Even if they report 8 to 10 hours of continuous sleep they wake up feeling
tired. Most relate to being light sleepers, being easily aroused by
low-level noises or intrusive thoughts. Many exhibit an alpha-delta EEG
but this is not an invariable in fibromyalgia and nor is it specific
The experimental induction of
alpha-delta sleep in healthy individuals has been reported to induce
musculoskeletal aching and/or stiffness as well as increased muscle
is not unusual for fibromyalgia patients to have an array of somatic
complaints other than musculoskeletal pain
It is now thought that these symptoms are in part a result of the
abnormal sensory processing as described elsewhere.
This refers to daytime (usually maximal in the evening) symptoms of (1)
unusual sensations in the lower limbs (but can occur in arms or even
scalp) that are often described as paresthesia (numbness, tingling,
itching, muscle crawling) and (2) a restlessness, in that stretching or
walking eases the sensory symptoms. This
symptomatology is nearly always
accompanied by a sleep disorder - now referred to as periodic limb
movement disorder (formerly nocturnal myoclonus)
. Restless leg syndrome has been
reported in 31% of fibromyalgia patients compared to 2% of controls
Irritable bowel syndrome:
This common syndrome
of GI distress that occurs in about 20% of the general population is found
in about 60% of fibromyalgia patients
The symptoms are those of abdominal pain, distension with an
altered bowel habit (constipation, diarrhea or an alternating
disturbance). Typically the
abdominal discomfort is improved by bowel evacuation.
Irritable bladder syndrome:
This is found in 40-60% of fibromyalgia patients
The initial incorrect diagnoses are usually recurrent urinary tract
infections, interstitial cystitis or a gynecological condition.
Once these possibilities have been ruled out a diagnosis of
irritable bladder syndrome (also called female urethal syndrome) should be
considered. The typical
symptoms are those of suprapubic discomfort with an urgency to void, often
accompanied by frequency and dysuria.
This is a common problem for many fibromyalgia patients
. It adversely affects the
ability to be competitively employed and may cause concern as to an early
presentation of a neurodegenerative disease. The cause of cognitive
dysfunction is in part related to the distracting effects of chronic pain,
mental fatigue and psychological distress
About 30% of
fibromyalgia patients complain of cold intolerance
. Some patients develop a true
primary Raynauds phenomenon, which may lead to misdiagnoses such as SLE
One result of disordered sensory processing is that many sensations are
amplified in fibromyalgia patients. Thus patients with fibromyalgia are
more likely to receive other diagnoses such as multiple chemical
sensitivity (MCS), sick building syndrome and drug intolerance.
One report cites a prevalence of 52% of MCS in fibromyalgia
. Buchwald found a large overlap
between fibromyalgia, chronic fatigue syndrome and MCS
This is a common
complaint of fibromyalgia patients
. In many cases no obvious cause
is found, despite sophisticated testing.
Treatable causes related to fibromyalgia include: proprioceptive
dysfunction secondary to muscle deconditioning, proprioceptive dysfunction
secondary to myofascial trigger points in the sterno-cleido-mastoids and
other neck muscles, neurally mediated hypotension and medication side
Neurally mediated hypotension (NLM):
This syndrome is a
lesser variant of neurocardiogenic syncope. Its prevalence in one
report was 60%
. NLM results from a paradoxical
reflex when venous pooling reduces filling of the heart (right ventricle).
In predisposed patients, this causes an inappropriately high secretion of
catecholamines. This in turn leads to a vigorous contraction of the volume
depleted ventricle leading to an over-stimulation of ventricular
mechanoreceptors which signal the midbrain to reduce sympathetic tone and
increase vagal tone, with resulting syncope or presyncope. In fibromyalgia
patients this may be manifest by severe fatigue after exercise, on
prolonged standing or in response to stressful situations.
and maintenance of fibromyalgia
fibromyalgia patients causally relate an acute injury, repetitive work
related pain, athletic injuries or another pain state to the onset of
their problems. Others attribute stress, infections and toxins to its
onset. Fibromyalgia is commonly found as an accompaniment of rheumatoid
, systemic lupus erythematosus (SLE)
low back pain
osteoarthritis. One recent study from Israel documented a 22% prevalence
of fibromyalgia, one year after automobile accidents causing whiplash;
this compares to a 1% prevalence after accidents involving leg fractures
. However most injured subjects
do not develop fibromyalgia, and only 2035% of patients with rheumatoid
arthritis or SLE have a concomitant fibromyalgia syndrome. Buskila has
reported a strong familial prevalence of fibromyalgia
. This suggests that subjects
destined to develop fibromyalgia are either genetically predisposed
(nature), or have past life events or experiences that favor its later
development (nurture). Chronic pain states may also develop during or
after some infections
. A series of elegant experiments
in rats has described a complex neural pathway whereby pro-inflammatory
cytokines can cause a hyperalgesic state
. This pathway involves
pro-inflammatory cytokines (IL1, IL-6, and TNF) that activate cytokine
binding sites on vagal paraganglia with afferent impulses travelling to
the nucleus of the tractus solitarus. Subsequent cross-stimulation of the
nucleus raphe magnus activates descending spinal tracts which sensitize
second order dorsal horn neurons via an NMDA / substance P / nitric oxide
cascade. Thus one can hypothesize that several discrete stimuli may
initiate fibromyalgia via a common final pathway that involves the
generation of a central pain state through the sensitization of second
order spinal neurons.
and Felson reported on follow up of 39
patients, mean age 55, who had experienced fibromyalgia symptoms for 15
years. All of them still had fibromyalgia. Moderate to severe pain or
stiffness was present in 55% of patients; significant sleep difficulties
were reported in 48%; and notable levels of fatigue were present in 59%.
Despite continuing symptoms, 66% of patients reported that FMS symptoms
were somewhat improved compared to when first diagnosed.
Wolfe et al analyzed 1604 fibromyalgia patients followed for
7 years in academic rheumatology centers
Symptoms of pain, fatigue, sleep
disturbance, functional status, anxiety, depression, and health status
were abnormal at initiation and were the same after 7 years of follow up.
Fifty nine percent of the patients rated their health as only fair or
poor. There is some evidence that fibromyalgia patients seen in the
community, rather than tertiary care centers, have a better prognosis.
Granges et al reported a 24% remission rate after 2 years of patients seen
in an ambulatory care setting
consequences of pain and fatigability influence motor performance.
Henriksson, et al, have noted that every-day activities take longer
in fibromyalgia patients, they need more time to get started in the
morning and often require extra rest periods during the day
They have difficulty with repetitive sustained motor tasks, unless
frequent time-outs are taken. Tasks
may be well tolerated for short periods of time, but when carried out for
prolonged periods become aggravating factors
Prolonged muscular activity, especially under stress or in
uncomfortable climatic conditions, was reported to aggravate the symptoms
The adaptations that fibromyalgia patients have to make in order to
minimize their pain experience, has a negative impact on both vocational
and avocational activities.
the superficial appearance of normality many fibromyalgia patients have
difficulty with remaining competitive in the work force
FM patients report that chronic pain and fatigue adversely affect the
quality of their life and negatively impact their ability to be
The extent of reported disability in FM varies greatly from country
probably reflecting differences in political philosophies and
socio-economic realities. A survey of fibromyalgia patients seen in 6 US centers reported that 42%
were employed and 28% were homemakers. Seventy percent perceived
themselves as being disabled. Twenty
six percent were receiving at least one form of disability payment
Sixteen percent were receiving Social Security benefits (SSD); this
compares to 2.2% in the overall US population.
articles commonly begin with the admonition that "the cause of
fibromyalgia is not known". This assertion is no longer justified.
Impressive advances have been made in understanding the neurobiology of
chronic pain. As fibromyalgia is now considered part of the spectrum of
chronic pain, these advances are relevant to understanding pain in
persistent pain is common. Wolf found that the prevalence of chronic
widespread musculoskeletal pain was more common in women and increased
progressively from ages 18 to 70 -- with 23 % prevalence in the seventh
decade (3). The American College of Rheumatology has defined fibromyalgia
in terms of chronic widespread pain involving 3 or more segments of the
body plus the finding of at least 11 out of 18 designated tender points
When Wolfe's patients were examined, 25.2% of females and 6.8% of
men had 11 or more tender points. The
overall (M+F) prevalence of fibromyalgia was 2%, with a prevalence of 3.4%
in women and 0.5% in men. Croft reported prevalence rates of 11.2% for
chronic widespread pain, 43% for regional pain and 44% for no pain
When subjects with widespread pain were examined, 21.5% had 11 or
more tender points, 63.8% had between 1 and 10 tender points and 14.7% had
no tender points
Interestingly the tender point count did not correlate with widespread
pain, but it did correlate with depression, fatigue, and poor sleep. The
results of these 2 studies indicate that a history of chronic widespread
pain is more prevalent than the strictly defined diagnosis of
fibromyalgia. Thus the concept is emerging that fibromyalgia is towards
one end of a continuous spectrum of chronic pain.
are several lines of evidence to suggest that the pain experience of
fibromyalgia patients is in part the result of disordered sensory
processing at a central level.
differences in pain
study using an electronic dolorimeter recorded the subjects assessment
of pain intensity on a 0 to 10-cm visual analogue scale (VAS) at varying
levels of applied force
. Distinctly different response
curves were obtained for controls and fibromyalgia patients.
It was found that in pain free controls exhibited a logarithmic
type of increase in pain intensity whereas fibromyalgia subjects showed a
linear increase. Similar abnormalities of pain processing in fibromyalgia
patients have also been reported for heat and cold
pain modulation in response to repeated thermal stimuli
of pain threshold can be demonstrated in normal individuals by subjecting
them to repeated skin stimulation. This effect, known as diffuse noxious
inhibitory control (DNIC), was investigated in female fibromyalgia
patients and compared to age-matched healthy women
thermal stimuli at painful and non-painful intensities were used to induce
pain inhibition. Concurrent tonic thermal stimuli, at both painful and
non-painful levels, significantly increased the electrical pain threshold
in the healthy subjects but not in the fibromyalgia patients.
somatosensory induced potentials
et al reported an increased late nociceptive (CO2-laser stimulation of
skin) evoked somatosensory response in 10 FM patients compared to 10
Lorenz et al
have recently reported increased
amplitude of the N170 and P390 brain somatosensory potentials in
fibromyalgia compared to controls evoked by laser stimulation of the skin.
Furthermore they observed a response in both hemispheres in controls
the somatosensory potential was strictly localized to one side of the
brain. These 2 studies provide direct objective evidence of altered
processing of nociceptive stimuli in fibromyalgia patients.
hyperalgesia on electrocutaneous stimulation
hyperalgesia refers to pain elicited from uninjured tissues
. Arroyo and Cohen, while
attempting to treat fibromyalgia patients with electrical nerve
stimulation, noted that the pain was made worse and often caused dysthetic
Compared to controls fibromyalgia patients had a reduced pain
tolerance and 2 unexpected phenomena: (i) a spread of dysthesia (mainly
tingling and burning) that was felt both distally and proximally to the
stimulator, and (ii) a persistence of dysthesia around the stimulated
locus that lasted for 12 to 20 minutes after the stimulation was
electrical stimulation of the skin in fibromyalgia patients resulted in
several features that are characteristic of secondary hyperalgesia.
on SPECT imaging
CNS changes can be demonstrated by several different imaging techniques.
It is interesting that chronic pain states have been associated with reduced
thalamic blood flow, whereas acute pain increases thalamic blood
flow. The reason for this
difference is postulated to be a disinhibition of the medial thalamus
which results in activation of a limbic network. Mountz et al reported
that fibromyalgia patients had a decreased thalamic and caudate blood flow
compared to healthy controls on SPECT (single-photon-emission-computed
A similar finding has been reported in-patients with unilateral chronic
neuropathic pain, using O-15 positron emission tomography
Thus functional imaging studies are supportive of an altered processing of
sensory input in fibromyalgia patients.
levels of substance P in the CSF
P lowers the threshold of synaptic excitability, permitting the unmasking
of normally silent interspinal synapses and the sensitization of second
order spinal neurons
. An increased production of
neurotransmitters within the spinal cord may be detected as increased
levels in cerebrospinal fluid (CSF)
. Animal models of hyperalgesia
and hypoalgesia, have implicated substance P as a major etiological factor
in central sensitization. There are 2 definitive studies that have shown a
3 fold increase of substance P in the CSF of fibromyalgia patients
compared to controls
response to an NMDA receptor antagonist
is persuasive evidence that glutamine reacting with NMDA (N-Methyl-D-Aspartic
acid) receptors plays a central role in the generation of non-nociceptive
pain. Two studies from Sweden reported that intravenous ketamine (an NMDA
receptor antagonist) attenuates pain and increases pain threshold, as well
as improving muscle endurance in FM patients
In some patients a single intravenous infusion over a course of 10 minutes
(0.3 mg/kg) resulted in a significant reduction in pain that persisted for
up to 7 days. This therapeutic pain analysis supports the notion that
activation of NMDA receptors is relevant to disordered sensory processing
in fibromyalgia patients.
induced central hyperexcitability
et al injected hypertonic saline (2 ml of 5.7% saline over 8 mins.) into
the asymptomatic anterior tibial muscle of fibromyalgia patients and
Compared to controls fibromyalgia patients experienced a longer duration
of pain and a larger area of referral. The same subjects were also
compared as to pressure pain threshold over the anterior tibial muscle,
and pain threshold to both single and repetitive electrical stimulation of
the overlying skin and electrical intramuscular stimulation. Pressure pain
and the intramuscular summation pain threshold was significantly lower in
fibromyalgia patients. These results further support a state of disordered
sensory processing in fibromyalgia.
in many chronic conditions there is an increased prevalence of
psychological diagnoses in fibromyalgia patients
however the converse is not true. For instance, fibromyalgia is not common
in patients with major depression; even depressed individuals who complain
of pain did not have multiple tender points in one study
Psychological distress in fibromyalgia may in part determine who becomes a
psychiatric diagnoses that are often considered in the differential
diagnosis of fibromyalgia are the somatoform disorders, especially somatization
disorder and pain disorder - as defined DSM-IV
a management aspect it is seldom useful to characterize fibromyalgia as
being solely a psychological problem or solely as an organic problem.
Considering the preponderance of studies pointing to a dysfunction of
sensory processing in fibromyalgia, one would expect these patients to
have an amplification of bodily sensations resulting in a wide range of
somatic symptoms. A diagnosis
of a somatoform disorder will become a non-psychiatric diagnosis once the
symptomatology is adequately explained by disordered physiology
There is now good evidence that links pain to "emotional neuro-circuits".
Different cortical and sub-cortical structures are involved in different
aspects of the pain experience. For instance removal of the somatosensory
cortex does not abolish chronic pain, but excision or lesions of the
anterior cingulate cortex reduces the unpleasantness of pain
The anterior cingulate cortex is involved in the integration of affect,
cognition and motor response aspects of pain
and exhibits increased activity on PET studies of pain patients
Other structures involved in cortical pain processing include the
prefrontal cortex (activation of avoidance strategies, diversion of
attention and motor inhibition), the amygdala (emotional significance and
activation of hypervigilance) and the locus ceruleus (activation of the
fight or flight response)
All these structures are linked to the medial thalamus, whereas the
lateral thalamus is linked to the somatosensory cortex (pain
localization). A recent
experiment convincingly showed how the prevailing mental attitude of an
individual can influence the unpleasantness of a standardized pain
stimulus and how this correlated to blood flow changes in the anterior
Thus prefrontal cortical activity (i.e. positive or negative thoughts) can
influence the perception of pain. Is this the neural basis of somatization
and cognitive-behavioral therapy?
current treatment modalities for fibromyalgia seldom lead to long term
relief. Basically the current management philosophy is to help the patient
constructively adapt to an existence plagued by pain, fatigue and other
symptoms. The resistance of fibromyalgia symptoms to contemporary
treatments was recently highlighted
In a follow up of 530 fibromyalgia patients followed in 6 US
tertiary referral centers over 7 years, there was no significant
improvement in pain, functional disability, fatigue, sleep disturbance, or
psychological status. Half the patients were dissatisfied with their
health, and 59% rated their health as fair or poor. Fibromyalgia patients
used an average of 2.7 fibromyalgia-related drugs in every 6-month period.
The mean yearly per-patient cost in 1996 dollars was $2,274.
this gloomy picture there is some evidence that fibromyalgia patients can
be helped, but not cured, by a multi-disciplinary approach that emphasizes
education, cognitive behavioral therapy, therapeutic treatment of pain,
participation in a stretching and aerobic exercise program, prompt
treatment of psychological problems and attention to associated syndromes
The fibromyalgia treatment group at Oregon Health Sciences University has
employed a multi-disciplinary treatment using a team of interested health
professionals (nurse practitioners, clinical psychologists, exercise
physiologists, mental health care workers, and social workers)
In this way groups of 10-30 patients can be seen in designated
sessions several times a month. Patients are usually appreciative of meeting others who share
similar problems and the dynamics of group therapy is often a powerful aid
to cognitive-behavioral modifications.
Such groups can be encouraged to develop a sense of camaraderie in
solving mutual problems. This
form of therapy has proved beneficial in one 6 month program, with
continuing improvement out to 2 years after leaving the program
Turk's group has recently published similar encouraging results
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