FibromyalgiaWRAP
Principles and Practice Strategies for
Fibromyalgia
Fibromyalgia Controversies
► Is it real?
► What is the relationship with other functional somatic
syndromes?
► Can it be reliably diagnosed?
► Is it physical or psychological?
► Is there any effective treatment?
► Is a diagnosis helpful or harmful?
► What is role of rheumatology?
Primary Care and Functional Illnesses
► Account for 30-50% of office visits
► Medical classification: FM, IBS, irritable
bladder, vulvodynia, non-cardiac chest pain,
TMJ, multiple chemical sensitivity, tension
headaches
► Psychiatric classification: Somatization
disorder, hypochondriasis, conversion
disorder, PTSD
► Commonest primary care problem
► Specialty referral based on most distressing
syndrome
Chronic Pain/Suffering Syndromes
►
FM is the prototype for a fundamentally different
type of pain syndrome where pain is
●
●
►
Not due to damage or inflammation of peripheral
tissues
Frequently accompanied by a variety of other somatic
symptoms and syndromes
There are many different “labels” that one can
legitimately use for an individual with this type of
pain (if one decides to use any label)
●
●
There is no agreed upon, all encompassing term to
describe this entire spectrum of illness
No medical specialty has accepted “ownership” of
these patients
American College of Rheumatology (ACR)
Diagnostic Criteria for FM
►
ACR diagnostic criteria
● History of chronic
widespread pain ≥3
months
● Patients must exhibit ≥11
of 18 tender points
►
FM can be identified from
among other rheumatologic
conditions with use of ACR
criteria with good sensitivity
(88.4%) and specificity
(81.1%)
FM Diagnosis is Very “Physician Dependent”
History
History of
ofchronic,
chronic,
widespread pain for ≥3 months
Rule outRule
other conditions
out other conditions
that may present
that may
with
present
chronic
with
widespread
chronic pain
Depending onwidespread
physician: Mental
pain (“Operator
health evaluation,
dependent”)
sleep evaluation
General physical exam, neurologic exam, selected
General physical exam, neurologic exam, selected laboratory
laboratory testing (ESR, thyroid tests; avoid screening
testing (ESR, thyroid tests; avoid screening serologic tests)
serologic tests)
Confirm
Confirm presence
presenceofoftender
tenderpoints
points
(Fibromyalgia
(Fibromyalgia may
maybe
bepresent,
present,even
evenifif<11
<11of
of18)
18)
Confirm
Confirm diagnosis
diagnosis
of fibromyalgia
Modified from Goldenberg JAMA 2004
6
Problems in Defining Fibromyalgia
►
“Real” if no clear pathophysiologic basis?
►
Gold standard is “expert opinion”
►
Tender points, symptoms are subjective
►
Fewer than 11 tender points?
►
Symptoms are not dichotomous
►
Same diagnostic criteria and dilemma for any
illness lacking objective biologic markers
(depression, migraine, IBS, CFS)
Earlier Diagnosis of Fibromyalgia



Long delay in diagnosis adversely affects outcome
Characteristic symptoms speed diagnosis:
 “I hurt all over”
 “It feels like I always have the flu”
 Fatigue, Sleep and Mood disturbances
 IBS, Irritable bladder, multiple other somatic
complaints
Exclusion of structural or systemic disease
 Not a “fishing” expedition
 Avoid “screening” rheumatology tests
 Early subspecialty referral
Structured Interview for Fibromyalgia
A. Widespread pain (axial + upper and
lower + L and R sides)
B. 11 of 18 reproducible
tender points
OR
C. At least 4 of: generalized fatigue, headache,
sleep disturbance, neuropsych complaints,
numbness/tingling, IBS
Explained by no other
condition
Fibromyalgia
A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower
segments, plus left and right sides of the body
C. At least 4 of the following symptoms
1. Generalized fatigue
2. Headaches
3. Sleep disturbance
4. Neuropsychiatric complaints
5. Numbness, tingling sensations
6. Irritable bowel symptoms
Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232
Why Do A Tender Point Exam?
► Confirm Dx impression
► Proxy for pain sensitivity
► Compare to joint tenderness
► Potential prognostic factor
Who Gets Fibromyalgia?
►
No concurrent medical illness
●
Any age, but peak age 40-60
●
60-90% female in clinic, although less gender
difference in population-based studies
►
Concurrent medical illness (e.g., SLE, RA, OA,
hypothyroidism, hepatitis). Important to consider
in patients with rheumatic or chronic pain
disorders
►
Prior medical illness (e.g., Lyme disease,
viral illness)
►
Medications (steroid taper)
Medically Unexplained Illnesses Concurrent
With Fibromyalgia
►
►
►
►
►
►
►
Chronic fatigue syndrome
Irritable bowel syndrome
Muscle, migraine headaches
Irritable bladder syndrome
Mood disturbances
Vulvodynia
Temporomandibular joint (TMJ) disorder
►IN EACH OF THESE: Diagnosis dependent on:
► Exclusion of disease
►Symptoms rather than signs
►No reproducible laboratory findings
►Gold standard is “expert opinion”
Is FM Physical or Psychological?
►
Is it a psychiatric illness?
►
What is the interaction with depression?
►
Is it a maladaptive psychosocial response?
►
Is it somatization?
►
What is the role of stress?
FM and Mood Disorders
►
At the time of FM diagnosis, mood disorders
are present in 30-50%, primarily depression.
►
Increased prevalence of mood disorders is
primarily in tertiary-referral patients.
►
Increased lifetime and family history of mood
disorders in FM vs RA (Odds = 2.0).
►
Fibromyalgia co-aggregates with major mood
disorder in families (OR 1.8 [95% CI 1.1, 2.9),
p=0.01).
Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952
Is Fibromyalgia a Medical
or Psychiatric Illness?
►
Harmful and unproductive argument
►
Fruitless quandary to work out what
came first
►
For all patients, symptoms are real and can be
disabling
►
Need a dual treatment approach targeting both
physical and psychological symptoms
FM and Fragmented Sleep
► Some patients with FM have fragmented sleep,
which is associated with involuntary sleep-related
periodic disturbances during the night. These
disturbances include




Periodic limb movements (PLMs)
Restless leg syndrome (RLS)
Sleep apnea
An underlying periodic arousal disturbance in the sleep
EEG known as sleep related periodic K-alpha or
frequent cyclic alternating EEG sleep pattern (CAP)
Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287.
EEG, electroencephalogram.
Jennum P et al. J Rheumatol. 1993;201756-1759.
CAP, cyclic alternating pattern.
Shared Features of FM and Depression:
Clues to Pathophysiology
►
Both have strong genetic predisposition and similar
co-morbidity
►
Similar sleep disturbances
►
Similar cognitive disturbances
►
Orthostatic features, ANS dysfunction
►
Childhood abuse, stress
►
Catastrophizing
►
Imaging studies
►
Neuroendocrine studies
FM Pathophysiologic Pathways
►
Genetic factors
●
●
►
Fibromyalgia is strongly familial (the odds ratio is 8.5 for firstdegree relatives)
No single candidate gene identified
Central pain augmentation
●
●
CSF substance P
Neuroimaging studies
►
Autonomic/neuroendocrine dysfunction
►
Immune dysfunction?
►
Structural changes?
Genetics of Fibromyalgia
►
Familial predisposition
●
►
Most recent work by Arnold, et al suggests >8 odds
ratio (OR) for first-degree relatives, and much less
familial aggregation (OR 2) with major mood
disorders, much stronger with bipolarity, obsessive
compulsive disorder1
Genes that may be involved
●
●
●
●
5-HT2A receptor polymorphism T/T phenotype2
Serotonin transporter3
Dopamine D4 receptor exon III repeat
polymorphism4
COMT (catecholamine o-methyl transferase)5
1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et
al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int.
2003;23:104-107.
“Pain Matrix” – Pain is Processed in at Least
Three Domains in CNS
►
Sensory - Where it is and how much it hurts
●
●
●
►
Affective – Emotional valence of pain
●
●
●
►
Primary and secondary somatosensory cortices
Thalamus
Posterior insula
Anterior cingulate cortex
Anterior insula
Amygdala
Cognitive – Similar to affective plus pre-frontal
regions
Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153.
Specific Underlying Mechanisms
in Fibromyalgia
►
Global problem with sensory processing (i.e.
interoception)
● FM patients equally sensitive to loudness of
auditory tones1
● Insular hyper-reactivity consistently seen2-4
● H-MRS studies of glutamate levels in posterior
insula5
1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis
Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907
(2008).
Neuroimaging in Fibromyalgia
►
Hypoperfusion of thalamus and head of the caudate
nucleus
►
fMRI of cortical response to pain consistent with
augmentated pain perception
►
►
►
In FM, levels of depression did not modulate the sensory
aspects of pain but correlated with the magnitude of brain
activation in the medial region of the brain.
Castrophizing correlated with pain response in these
medial brain regions.
Changes in posterior insula glutamate in PET scans
Gracely et al. Arthritis Rheum. 2002;46:1333-1343.
Giesecke, et al Arthritis Rheum 2005 52:1577
Harris, et al Arthritis Rheum 2008 58, 903-907
Alterations in Descending
Analgesic Activity in FM
Opioids
Noradrenergic/Serotonergic
►
►
Elevated levels of substance P
in CSF in fibromyalgia3
►
Nearly any class of drug that
raises both serotonin and
norepinephrine levels has
demonstrated efficacy in
fibromyalgia
►
►
Normal or high levels of
CSF enkephalins1
Never administered in
RCT, but most feel that
opioids are ineffective or
marginally effective
Harris recently used
PET to show decreased
mu-opioid receptor
binding in fibromyalgia2
CSF=cerebrospinal fluid; PET=positron emission tomography.
1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al.
Arthritis Rheum. 1992;35:550-556.
Is There Any Effective Management of
Fibromyalgia?
►
All patients
● Reassurance re diagnosis
● Give explanation, including, but not solely,
psychological factors
● Promote return to normal activity, exercise
►
Most patients
● Medication trial (esp antidepressants,
anticonvulsants)
● Cognitive behavior therapy, counseling
● Physical rehabilitation
Initial Treatment of Fibromyalgia
Confirm diagnosis
Identify important symptom domains, their severity,
and level of patient function
Evaluate for comorbid medical and
psychiatric disorders
Assess psychosocial stressors, level of
fitness, and barriers to treatment
Provide education about fibromyalgia
Modified from Arnold LM. Arthritis Res Ther 2006;8:212.
May require referral to a specialist for
full evaluation; for example:
To psychiatry, sleep clinic
FM: From Mechanism to Treatment
►
►
►
►
►
This is primarily a neural
disease and “central” factors
play a critical role
This is a polygenic disorder
There is a deficiency of
noradrenergic-serotonergic
activity and/or excess levels of
excitatory neurotransmitters
Lack of sleep or exercise
increases pain and other
somatic sx, even in normals
How FM patients think about
their pain (cognitions) may
directly influence pain levels
►
Treatments aimed at the periphery
(ie, drugs, injections) are not very
efficacious
►
There will be sub-groups of FM
needing different treatments
►
Drugs that raise norepinephrine and
serotonin, or lower levels of
excitatory neurotransmitters, will be
efficacious in some
►
Exercise, “sleep hygiene,” and other
behavioral interventions are effective
therapies for biological reasons
►
Cognitive therapies are effective in
FM and have a biological substrate
Rationale for the Use of Central Nervous
System Active Medications in FM
►
►
►
►
►
No evidence for muscle pathology
Current research supports role of augmented central pain mechanisms
● Genetic predisposition
• 5-HT2A receptor polymorphism
• ↑ Pain severity in FM patients with T/T genotype
• ↑ Frequency of S/S genotype in FM patients compared with healthy
controls
• ↑ Incidence of COMT polymorphism in FM patients
● Substance P increased in CSF
● 5-HT and NE serum levels decreased in some studies
● Imaging studies
Elevated lifetime rates of mood disorders in patients with FM
Elevated rates of mood disorders in first-degree relatives of FM patients
Sleep disturbances
Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis
Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:3956. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907.
Medications in FMS
►
Strong evidence for efficacy
●
●
●
●
●
●
►
Modest evidence for efficacy
●
●
►
►
Amitriptyline, 25-50 mg at bedtime
Cyclobenzaprine, 10-30 mgs at bedtime
Pregabalin, 300-450 mg/day
Gabepentin, 1600-2400 mg/day
Duloxetine, 60-120 mg/day
Milnacipran, 100-200 mg/day
Tramadol, 200-300 mg/day
SSRIs (fluoxetine, sertraline)
Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth
hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine
No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene
hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including
guaifenesin
Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95.
Tricylics in Fibromyalgia
AMITRIPTYLINE
► Four placebocontrolled trials
●
●
●
Goldenberg,1985
Carette,1986
Carette,1994
Dose 25 – 50 mg
► Duration 6-26 weeks
► All showed modest
efficacy
►
Arnold L et al. Psychosomatics 2000;41:104-113.
CYCLOBENZAPRINE
► Four placebo-controlled
trials
●
Quimby, 1989
●
Carette, 1994
●
Reynolds,1991
►
Dose 10 – 40 mg
►
Duration 4 – 12 weeks
►
2 showed efficacy
Pregabalin in Fibromyalgia
Patient Global Impression of Change
Worse
No Change
% Patients
100
Improved
p < 0.01
vs PBO
80
p < 0.01
vs PBO
60
40
20
0
PBO
PGB 150
PGB 300
Treatment Group (mg/day)
Crofford L, et al. Arth Rheum 2005; 52: 1264-1273
PGB 450
Improvement in Average Pain
Severity with Duloxetine
Phase III Study: Female Patients (N=354)
Weeks
0
1
2
4
6
8
10
12
LS Mean Change from Baseline
0
Placebo
Duloxetine 60 mg QD
Duloxetine 60 mg BID
-1
*P<.05
***
-2
***
***P≤.001 vs placebo
***
***
-3
Arnold LM, et al. Pain 2005; 119:5-15.
***
*
*
***
***
***
*** *** ***
***
Milnacipran
(J Rheumatol 2005;32:1975–85)
Milnacipran (3:1)
Not currently available in US. Hlife 8 h, no liver metab
Milnacipran
Milnacipran Phase III (3 months,)
Number – 1196
Parallel, PL controlled, double blind
Randomized to M 100 or 200 mg or placebo for 3 months
Completers – 810 (68%)
Pain composite – VAS - 30% + very much or much impr on PGIC
FM composite – pain composite + 6 pt impr on PCS of SF36
Secondary – PGIC, SF36 (PCS and MCS) and FIQ total
Baseline observation carried forward (BOCF) at 3 mnths
39,46% achieved Pain composite, v 25% PL (0.011, 0.015)
25,26% achieved FM composite, v 13% PL (0.025, 0.004)
Generally well tolerated (discontinuations 34,35% v 28% PL)
Common AEs – nausea M – 37%, PL -20%
(both studies)
headache M – 18%, PL -14%
constipation M – 16%, PL -4%
hyperhidrosis M – 9%, PL - 2%
NB – no sig hypertension or wt gain
Milnacipran
Milnacipran Phase III (6 months)
Number – 888
Randomized to M 100 or 200 mg or placebo for 6 months
Completers – 511 (58%)
Pain composite - VAS, 30% + very much or much impr on PGIC
FM composite – pain composite + 6 pt impr on PCS of SF36
Secondary – PGIC, SF36 (PCS and MCS) and FIQ total
Baseline observation carried forward (BOCF) at 6 mnths
44,45% achieved Pain composite, v 28% PL (0.056, 0.032)
33,32% achieved FM composite, v 19% PL (0.028, 0.017)
Nonpharmacologic Strategies:
Evidence of Efficacy
Strong Evidence
Modest Evidence
Exercise
Physical and psychological benefits
May increase aerobic performance and tender
point pain pressure threshold,
and improve pain
Efficacy not maintained if exercise stops
Strength training
Acupuncture
Hypnotherapy
EMG biofeedback
Balneotherapy (medicinal bathing)
Transcranial electrical stimulation
Cognitive-behavioral therapy
Improvements in pain, fatigue, mood,
and physical function
Improvement often sustained for months
Weak Evidence
Patient education/self-management
Improves pain, sleep, fatigue, and
quality of life
Combination (multidisciplinary therapy)
Chiropractic
Manual and massage therapy
Ultrasound
No Evidence
Tender-point injections
Flexibility exercise
Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:12801286; Busch AJ, et al. Cochrane Database Syst Rev. 2002
FM and Prognosis
► Children
and individuals treated in primary care
settings and those with recent onset of symptoms
generally have a better prognosis
► Longer-term
studies with larger study populations are
needed to define risk factors for prognosis and to
determine outcome relative to those risk factors
Modified from Horizon A and Weisman MH.
In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401.
Patient, Family Education
►
Primary care or specialist setting.
►
Core set of information should always be provided.
►
Pathophysiology best based on biopsychological
illness model.
►
Anticipate common patient questions and concerns.
►
Recognize the wealth of patient misinformation.
►
Encourage patient participation.
Who Should Treat Fibromyalgia?
►
More than 50% of visits are to primary care physicians
►
Currently, 16% of FM visits are to rheumatologists
►
The American College of Rheumatology suggest that
rheumatologists serve as consultants (tertiary care)
►
Other specialists should include mental health
professionals, physiatrists and pain management
experts
Multidisciplinary FM Treatment
►
Physical medicine/rehabilitation
●
●
●
●
●
►
Avoiding inactivity
Analgesic advice and non-pharmacologic
treatment (trigger point injections)
Cardiovascular fitness
Stretching, strengthening
OT, work rehab, ergonomics
Mental health professional
●
●
●
Psychopharmacology
Counseling
CBT
Fibromyalgia Controversies
►
Does the diagnostic label promote
helplessness and disability?
● Only one controlled study; it didn’t
● Diagnosis should be reassuring and
end doctor shopping
● Only if diagnosis is coupled with
education
Fibromyalgia Controversies
►
Does the diagnosis promote litigation?
● Not because of the diagnosis but
rather medico-legal misconceptions
● This can lead to symptom
amplification and rehabilitation
difficulties
● Problems with “causation”
● Use headache or fatigue models
Positive Impact of Fibromyalgia Diagnosis in
Clinical Practice
•Total Rate of Diagnostic Tests
Performed on FM Cases and on Matched Controls (N=2,260)
Rate per 100 person-years
20
0
95% CI
Case
Control
15
0
100
50
The vertical line at 0
indicates the date of
fibromyalgia diagnosis
0
-10
-5
0
Years relative to index date
5
Decrease in diagnostic testing and visit rates following diagnosis
Hughes G, et al. Arthritis Rheum. 2006;54:177-183.
Initial Medication and Non-pharmacologic
Treatment of Fibromyalgia
As a first-line approach for patients with moderate to severe pain, trial with
evidence-based medications for example: Trial with low-dose tricyclic
antidepressants, SSRI, SNRI, antiseizure medication
Provide additional treatment for comorbid conditions
Stress management techniques
Encourage exercise according
to fitness level
Modified From Arnold LM. Arthritis Res Ther 2006;8:212.
Further Medication and Non-pharmacologic Treatment
of Fibromyalgia: Often with Specialists’ Input
Polypharmacy; for example, trial of SSRI in AM and tricyclic in PM, SNRI in AM
and anti-seizure drug in PM
Trial of additional analgesics such as tramadol
Structured rehabilitation program;
Formal mental health program, such as
CBT for patients with prominent psychosocial stressors,
and/or difficulty coping, and/or difficulty functioning
Comprehensive pain
management program
Modified from Arnold LM. Arthritis Res Ther 2006;8:212.
Explaining the Typical
Outcome in Fibromyalgia
►
►
►
►
►
►
►
FM does not herald the onset of a systemic disease
There is no progressive, structural or organ damage
Most patients in specialty practice have chronic,
persistent symptoms
Primary care patients more commonly report complete
remission of symptoms
Most patients continue to work, but 10-15% are disabled
There is often adverse impact on work and leisure
activities
Most patients quality of life improves with medical
management
Granges G, Zilko P, Littlejohn GO.Fibromyalgia syndrome: assessment of the severity of the
condition 2 years after diagnosis. J Rheumatol 21:523-529, 1994
Felson DT, Goldenberg DL. The natural history of fibromyalgia. Arthritis Rheum. 1986;29:1522-1526.
Interdisciplinary Pain Management
Integrated Coordinated
Nurses
Pain Specialist
Psychiatrist
Neurologist
Primary
Clinician
Physiatrist
Rheumatologist
Pharmacist
Social Worker
Psychologist
Anesthesiologist
Physician Assistant
Occupational Therapist
Physical Therapist