Download Fibromyalgia Syndrome: Pathophysiology and Current

Fibromyalgia Syndrome:
Pathophysiology and
Current Treatments
The George Washington University Medical
Center Department of Rheumatology Series
November 5, 2009
Russell Rothenberg, MD
Bethesda, Maryland
301-571-2273, ext. 118
[email protected]
Case Study Presentation
50 year old female legal secretary who was injured
3 months ago in an automobile accident. She was
rear ended by a teenage driver who was driving
while intoxicated. She suffered an immediate whip
lash injury with marked pain and stiffness in the
neck and right arm. X-ray of C spine showed C5-6
disc space narrowing
PMH- Menopausal in the last year. Migraine
headaches controlled with Imitrex 100 mg prn
Case Study Presentation
The patient was initially treated by her internist with
naproxen and cyclobenzaprine for pain and muscle
spasm, and referred for physical therapy.
She initially had localized pain in the neck, and over
the last month, she developed overwhelming
generalized pain and fatigue. She has been
missing days from work, is not sleeping well, and is
becoming depressed.
Review of PT notes confirm an initial whiplash
injury, and then the development of generalized
myofascial pain
Case Study Presentation
P-58 B/P-102/60 Wt-158 Ht- 5’2” VAS- 8/10
Anxious woman uncomfortable with generalized
pain, physically deconditioned and poor posture
with anterior head position and bilateral TMD, tight
trapezius muscles, decreased ROM C-spine and
occipidynia
18/18 + tender points 3/4 in intensity, hands and
wrists - normal ROM, no swelling, normal grip
strength, and marked myofascial pain in the right
upper arm. Diffuse myofascial pain in the
paraspinal muscles
Case Study Presentation
Cervical spine MRI- degenerative C5-6 disc
disease with moderate disc bulge and
neural foraminal impingement of spinal
nerve C6.
All labs-CBC, CMP, Sed Rate, CRP, T4,
TSH, Magnesium, Iron, TIBC, Vitamin D, B12
were normal
Case Study Presentation
Impression:
– Fibromyalgia Syndrome with Myofascial
Pain
– Cervical Disc Disease
– Temporomandibular Dysfunction (TMD)
– Migraine Headaches
– Sleep Disturbance
– Reactive Depression
Case Study Presentation
Treatment
– The patient responded to a month medical leave
for aggressive PT with a therapist skilled in
treating fibromyalgia, along with TMJ splints
and warm water aquatic exercises
– She was treated with increasing doses of
pregabalin up to 225 mg bid, zolpidem 5 mg and
cyclobenzaprine 10-20 mg qhs along with
tramadol/APAP for brake-through pain.
– She was able to return to work with a telephone
headset and an orthopedic chair with adjustable
arms
History of Fibromyalgia
Dr. Gowers first described fibrositis in 1904
In 1978, Drs. Smythe and Moldofsky published
evidence of fibromyalgia sleep pathology and
central pain sensitization
In 1990, Fibromyalgia Syndrome was first defined
by the American College of Rheumatology which
allowed NIH funding for research
In 1994, Dr. Russell found three fold increases of
substance P in the CSF in fibromyalgia patients
In 2007, the FDA approved pregabalin, in 2008
duloxetine, and in 2009 milnacipran, all specifically
indicated for the treatment of fibromyalgia
Symptoms and Syndromes
Related to Fibromyalgia
Tension/migraine headache
Affective disorders
Temporomandibular
joint syndrome
Memory and cognitive difficulties
ENT complaints (sicca sx, vasomotor
rhinitis,
accommodation problems)
Vestibular complaints
Constitutional symptoms and
syndromes
Multiple chemical sensitivity,
symptoms
Fatigue and Chronic Fatigue
Syndrome (CFS)
Esophageal dysmotility
Sleep disturbances
Idiopathic low back pain
Irritable bowel syndrome
Nondermatomal paresthesias
Aaron et al. Arch Int Med. 2000;160:221-227.
“allergic”
Neurally mediated hypotension, mitral
valve prolapse
Noncardiac chest pain, dyspnea due to
respiratory muscle movement dysfunction
Interstitial cystitis,
female urethral syndrome,
vulvodynia
Evaluation of Fibromyalgia: Comorbid
Medical Disorders
Disorder
Prevalence Rates
(%)
Chronic fatigue syndrome
21-80
Irritable bowel syndrome
32-80
Temporomandibular disorder
75
Tension and migraine headache
10-80
Multiple chemical sensitivities
33-55
Interstitial cystitis
13-21
Chronic pelvic pain
Aaron LA and Buchwald D. Best Pract Res Clin Rheumatol. 2003;17:563-574.
18
Fibromyalgia: Myofascial Pain
Patients get painful palpable “knots” associated
with trigger points (TPs) in their muscles and soft
tissues
TPs can be primary or latent, and are associated
with a referred pain pattern
Biopsies of myofascial tissue show decreased
blood flow and ATP and increased levels of
Substance P and glutamate
Pregabalin can be effective in reducing TPs
TPs can resolve with dry needling and fluoride
spray and stretch techniques
Travell, Janet, Simons, David, Myofascial Pain and Dysfunction, Lippincott Williams &
Wilkins 1983
Fibromyalgia: Fatigue
Fatigue is an important symptom in FM
being present in 90% of patients. It is
often associated with:
–
–
–
–
–
–
Non-restorative sleep
Chronic pain
Exercise deconditioning
Ineffective energy conservation
Ineffective stress coping techniques
Sedative effects of prescribed medications
Fibromyalgia: Abnormal Sleep Studies
Alpha wave intrusion into delta (stage 3 and 4)
sleep or reduced stage 3 and 4 sleep is present
– it is a marker of non-restorative sleep
– these findings are also seen in RA, Sjogren’s,
OA, and with increased sympathetic tone
Sleep studies are indicated only for patients that
have not responded to standard therapy
Sleep apnea and Upper airway resistance
syndrome can contribute to chronic fatigue
Opiates can cause pharyngeal collapse during
sleep
Drewes, AM, Rheumatology, 11/1999: 38, pp1035-8
Avram Gold- 2009 ACR presentation
Fibromyalgia: Mood Disorders
FM patients tend to have dysthymia and
reactive depression, and not major
depression
FM patients have increased anxiety that
correlates with their pain
Giving patients some control of their
condition through education and pain
control, improves physical function and
diminishes mood disorders in many
patients
Katz, W and Rothenberg, R, J of Clinical Rheum, April 2005 Supplement, 11: pp. S1-33
Proposed Etiology of Fibromyalgia
Abnormal sympathetic tone and Autonomic dysfunction
– Nocturnal tachycardia
– Loss of normal circadian rhythm
– Neurally mediated hypotension-abnormal tilt table testing
– HPA axis dysfunction- low AM cortisol, high ACTH
– Irritable bowel and bladder syndromes
– Paresthesias and numbness of extremities
– Dr. Martinez-Lavin (Mexico)- conducted experiments
injecting norepinephrine in FM patients increasing pain
– Dr. Andrew Holman (Reston WA)- presented a study at
2009 ACR using Pindolol- an alpha/beta antagonistshowing significant improvement in FIQ and tender
points/scores in FM patients
• Mease, P. J Rheum, 2005: 32 Supplement 75. pp 6-21
Pathophysiology of Fibromyalgia
Central sensitization of the CNS explains much of
the generalized heightened pain sensitivity of FM
patients
– increased levels of excitatory neurotransmitters
glutamate and substance P
– compared with normal controls, CSF levels of
substance P are 3-fold higher in FM patients
– there are decreased levels of serotonin and
norepinephrine which are needed for pain
modulation
fMRI data provide supporting evidence that FM
involves altered central pain processing
Staud and Rodriguez. Nat Clin Pract Rheumatol. 2006;2:90-98; Henriksson. J Rehabil Med. 2003;41(suppl 41):89-94; Gracely et al. Arthritis Rheum.
2002;46:1333-1343; Giesecke et al. Arthritis Rheum. 2004;50:613-623; Crofford and Clauw et al. Arthritis Rheum. 2002;46:1136-1138; Vaerøy et al.
Pain. 1988;32:21-26; Russell et al. Arthritis Rheum. 1994;37:1593-1601.
Pathophysiology in Fibromyalgia:
Neurotransmitters
Substance P
– Excitatory neurotransmitter which is elevated in CSF
of FM patients compared with controls1,2
– Important in central sensitization along with
pro-nociceptive amino acid glutamate acting at the
alpha-delta and C ascending pain fibers3
Serotonin and Norepinephrine
– Evidence of dysfunction in fibromyalgia4,5
– Serotonin and norepinephrine mediate pain
modulation through the descending inhibitory pain
pathways in the brain and dorsal horn of the spinal
cord6
1. Russell IJ, et al. Arthritis Rheum. 1994;37:1593-1601.
2. Vaerøy H et al., Pain. 1988. 32:21-26.
3. Watkins LR, et al. Brain Res. 1994;664:17-24.
4. Russell IJ, et al. J Rheumatol. 1992;19:104-109.
5. Russell IJ, et al. Arthritis Rheum. 1992;35:550-556.
6. Fields HL, et al. Annu Rev Neurosci. 1991;14:219-245.
Pathophysiology of Fibromyalgia:
“Wind Up”
Drs. Price and Staud have demonstrated that
increasing repetitive nociceptive stimuli will
activate a wide range of dorsal horn neuronal pain
discharges in the CNS called “wind up”
“Wind up” involves recruitment of NMDA pain
receptors in the CNS and neural plasticity of
nociceptive spinal cord pathways in central
sensitization
Exercise can activate endogenous opioids and
reduce “wind up”
Price, D and Staud, R, J Rheumatol 2005:32(75):22-28
Pain Modulation: Serotonin and
Norepinephrine
Pain is associated
with increased excitation and
decreased inhibition of ascending
pain pathways1,2
Descending pathways modulate
ascending signals1,2
Norepinephrine (NE) and serotonin (5HT) are key neurotransmitters in
descending inhibitory pain
pathways1,2
Increasing the availability of NE
and 5-HT may promote pain
inhibition centrally1
Anterior Cingulate Cortex
Thalamus
Hypothalamus
Periacqueductal
Grey (PAG)
Dorsolateral
Pontine
Tegmentum
Amygdala
Rostroventral
Medulla
Pain
Transmission
Neuron
Dorsal
horn
Descending Modulation  PAG indirectly
controls pain transmission in the dorsal horn2
1. Fields HL, et al. Annu Rev Neurosci. 1991;14:219-245.
2. Fields H. Nat. Rev. Neuro. 2004; 5:565-575
3. Fields HL and Basbaum AI. In: Wall PD, Melzack R, eds. Textbook of Pain. 1999:310.
Augmented Pain Processing in
Fibromyalgia
14
Pain Intensity
12
10
8
6
SI
Fibromyalgia
4
Subjective Pain Control
2
Stimulus Pressure Control
0
1.5
2.5
3.5
4.5
Stimulus Intensity (kg/cm2)
SII
SI = contralateral primary somatosensory cortex
SII = secondary somatosensory cortex
Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.
DIAGNOSIS AND MANAGEMENT
OF FIBROMYALGIA
Management of Fibromyalgia (FM)
Nonpharmacologic
Patient education
Low impact aerobic exercise
Balance and strength training
Conservation of energy
Biofeedback
Cognitive behavioral therapy
Nutrition
Acupuncture
Pharmacologic
Antidepressants
Analgesics
Anticonvulsants
Sleep medicines
Muscle relaxants
Goldenberg et al. JAMA. 2004;292:2388-2395; Clauw et al. Best Prac Res Clin Rheumatol. 2003;17:685-701;
Arnold et al. Arthritis Rheum. 2007;56:1336-1344.
Fibromyalgia:
Non-Pharmacologic Treatment
Education
– When patients know and understand their diagnosis,
symptoms can often be reduced by one-third
Physical therapy
– One small retrospective study showed craniosacral
therapy with muscle energy techniques are effective (50%
reduction in pain)
– My experience is that PT (with experienced therapists) can
reduce myofascial pain and improve flexibility, posture
and balance through myofascial release, neuromuscular
re-education, core muscle strengthening and
reconditioning
– PT reports contribute to the documentation of your
patients’ progress
Fibromyalgia:
Non-Pharmacologic Treatment
Exercise - low impact aerobics, postural and
core exercises plus daily stretching (warm
water aquatics, Pilates, Tai Chi and Yoga)
Cognitive behavioral therapy helps anxious FM
patients deal better with pain
Acupuncture- helps some FM patients (2 short
term studies were effective)
Birch, S, et al, Complement Med 2004, Jun:, 10: pp. 468-80
171-9
Li, A, et al, Brain Res 2007; 1186, pp
Fibromyalgia:
Pharmacological Interventions
FDA Approved Medications
– Pregabalin (Lyrica)1- a2 delta ligand- blocks substance P and glutamate
– Duloxetine (Cymbalta)2 SNRI- 0.2:1 serotonin: norepinephrine
– Milnacipran (Savella)4 SNRI- 1:3 serotonin: norepinephrine
– all 3 drugs achieved about 30% reduction of pain/ improved function in 50%
of patients and 50% reduction in pain/ improved function in 30% of patients
Treatments with Demonstrated Efficacy (Non-FDA Approved)
– Cyclic medications3
• Cyclobenzaprine (Flexeril)
• Tricyclic antidepressants- amitriptyline and nortriptyline
– Alpha-2-delta ligands
• Gabapentin5\ (Neurontin)
• Sleep medicine

Sodium oxybate (Xyrem)
1. Please see Pregabalin full Prescribing Information 2007.
2. Please see Duloxetine full Prescribing Information 2008.
3. Arnold LM, et al. Psychosomatics. 2000;41:104-113.
4. Gendreau RM, et al. J Rheumatol. 2005;32(10):1975-1985.
5. Arnold LM, et al. Arthritis Rheum. 2007; 58(4): 1336-1344
6. Arnold LM, et al. Arthritis Res Ther. 2006;8:212.
Sleep Medications
Zolpidem has been shown to be effective in
preserving normal sleep architecture in FM
– It reduces FM fatigue, but not FM pain
Sodium Oxybate- 4.5 and 6 gm- 30% achieved >50%
reduction in pain and 40% achieved >30% reduction
in pain. Similar improvements in FIQ and PGIC.
Moldofsky H, J Rheum, 1996: 23: pp. 529-33
Russell, IJ, et al. 2009 ACR poster
Fibromyalgia:
Medical Management Summary
Think of FM as a multisystem disorder with multiple
pathways creating dysfunction
– Non-restorative sleep
– Myofascial pain
– Neuromuscular dysfunction/deconditioning
– Anxiety and reactive depression
– Abnormal pain processing
• Ascending (Substance P and Glutamine)
• Descending (Serotonin, Norepinephrine and
Endogenous Opioids)
• “Wind up” (NMDA receptors)
– Excess sympathetic tone and Autonomic dysfunction
Fibromyalgia Conclusions
FM patients do not have a progressive disease
FM patients do better with comprehensive care:
–
–
–
–
–
What to expect
What accommodations are needed
Conservation of energy
Exercises and stretches
Medicines and treatments
With empowerment through medical
supervision, patients can improve their
physical ability to function and quality of life