Fibromyalgia Syndrome: Fibromyalgia Syndrome: Pathophysiology and Pathophysiology and Current TreatmentsCurrent Treatments

The George Washington University Medical The George Washington University Medical Center Department of Rheumatology Series Center Department of Rheumatology Series

November 5, 2009November 5, 2009

Russell Rothenberg, MDRussell Rothenberg, MDBethesda, Maryland

301-571-2273, ext. 118

RRROTHENBERG@Verizon.net

© Copyright Russell Rothenberg 2009 All Rights Reserved

Case Study PresentationCase Study Presentation50 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 PresentationCase Study PresentationThe 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 PresentationCase Study PresentationP-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 PresentationCase 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 PresentationCase Study PresentationImpression:– Fibromyalgia Syndrome with Myofascial

Pain– Cervical Disc Disease – Temporomandibular Dysfunction (TMD)– Migraine Headaches– Sleep Disturbance– Reactive Depression

Case Study PresentationCase 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 FibromyalgiaHistory of FibromyalgiaDr. Gowers first described fibrositis in 1904In 1978, Drs. Smythe and Moldofsky published evidence of fibromyalgia sleep pathology and central pain sensitizationIn 1990, Fibromyalgia Syndrome was first defined by the American College of Rheumatology which allowed NIH funding for researchIn 1994, Dr. Russell found three fold increases of substance P in the CSF in fibromyalgia patientsIn 2007, the FDA approved pregabalin, in 2008 duloxetine, and in 2009 milnacipran, all specifically indicated for the treatment of fibromyalgia

Symptoms and Syndromes Symptoms and Syndromes Related to FibromyalgiaRelated to Fibromyalgia

Interstitial cystitis, female urethral syndrome, vulvodynia

Tension/migraine headache

Affective disorders

Temporomandibularjoint syndrome

Constitutional symptoms and syndromes

Fatigue and Chronic Fatigue Syndrome (CFS)

Sleep disturbances

Idiopathic low back Idiopathic low back painpain

Irritable bowel Irritable bowel syndromesyndrome

Nondermatomal Nondermatomal paresthesiasparesthesias

Memory and cognitive difficulties

ENT complaints (sicca sx, vasomotor rhinitis, accommodation problems)

Vestibular complaints

Multiple chemical sensitivity, “allergic” symptoms

Esophageal dysmotility

Neurally mediated hypotension, mitral valve prolapse

Noncardiac chest pain, dyspnea due to respiratory muscle movement dysfunction

Aaron et al. Aaron et al. Arch Int Med.Arch Int Med. 2000;160:221-227. 2000;160:221-227.

Evaluation of Fibromyalgia: Comorbid Evaluation of Fibromyalgia: Comorbid Medical DisordersMedical Disorders

Aaron LA and Buchwald D. Best Pract Res Clin Rheumatol. 2003;17:563-574.

18Chronic pelvic pain

13-21Interstitial cystitis

33-55Multiple chemical sensitivities

10-80Tension and migraine headache

75Temporomandibular disorder

32-80Irritable bowel syndrome

21-80Chronic fatigue syndrome

Prevalence Rates (%)

Disorder

18Chronic pelvic pain

13-21Interstitial cystitis

33-55Multiple chemical sensitivities

10-80Tension and migraine headache

75Temporomandibular disorder

32-80Irritable bowel syndrome

21-80Chronic fatigue syndrome

Prevalence Rates (%)

Disorder

Fibromyalgia: Myofascial PainFibromyalgia: Myofascial PainPatients get painful palpable “knots” associated with trigger points (TPs) in their muscles and soft tissuesTPs can be primary or latent, and are associated with a referred pain patternBiopsies of myofascial tissue show decreased blood flow and ATP and increased levels of Substance P and glutamatePregabalin can be effective in reducing TPsTPs can resolve with dry needling and fluoride spray and stretch techniques

Travell, Janet, Simons, David, Myofascial Pain and Dysfunction, Lippincott Williams & Wilkins 1983

Fibromyalgia: FatigueFibromyalgia: 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 StudiesFibromyalgia: Abnormal Sleep StudiesAlpha 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 therapySleep apnea and Upper airway resistance syndrome can contribute to chronic fatigueOpiates can cause pharyngeal collapse during sleep

Drewes, AM, Rheumatology, 11/1999: 38, pp1035-8 Avram Gold- 2009 ACR presentation

Fibromyalgia: Mood DisordersFibromyalgia: Mood DisordersFM patients tend to have dysthymia and reactive depression, and not major depressionFM 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 FibromyalgiaAbnormal 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 antagonist- showing significant improvement in FIQ and tender points/scores in FM patients

• Mease, P. J Rheum, 2005: 32 Supplement 75. pp 6-21

Pathophysiology of FibromyalgiaPathophysiology 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:Pathophysiology in Fibromyalgia:NeurotransmittersNeurotransmitters

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. 4. Russell IJ, et al. J Rheumatol. 1992;19:104-109.2. Vaerøy H et al., Pain. 1988. 32:21-26. 5. Russell IJ, et al. Arthritis Rheum. 1992;35:550-556.3. Watkins LR, et al. Brain Res. 1994;664:17-24. 6. Fields HL, et al. Annu Rev Neurosci. 1991;14:219-245.

Pathophysiology of Fibromyalgia:Pathophysiology of Fibromyalgia:“Wind Up”“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 sensitizationExercise can activate endogenous opioids and reduce “wind up”

Price, D and Staud, R, J Rheumatol 2005:32(75):22-28

1. Fields HL, et al. Annu Rev Neurosci. 1991;14:219-245. 2. Fields H. Nat. Rev. Neuro. 2004; 5:565-5753. Fields HL and Basbaum AI. In: Wall PD, Melzack R, eds. Textbook of Pain. 1999:310.

Pain Modulation: Serotonin and Pain Modulation: Serotonin and NorepinephrineNorepinephrine

Pain is associated with increased excitation and decreased inhibition of ascending pain pathways1,2

Descending pathways modulate ascending signals1,2

Norepinephrine (NE) and serotonin (5-HT) are key neurotransmitters in descending inhibitory pain pathways1,2

Increasing the availability of NE and 5-HT may promote pain inhibition centrally1

Descending Modulation PAG indirectly controls pain transmission in the dorsal horn2

Anterior Cingulate Cortex

Dorsal horn

Amygdala

Pain Transmission

Neuron

Periacqueductal Grey (PAG)

ThalamusHypothalamus

Dorsolateral Pontine

Tegmentum

Rostroventral Medulla

Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.

Augmented Pain Processing in Augmented Pain Processing in FibromyalgiaFibromyalgia

SI

SII

0

2

4

6

8

10

12

14

1.5 2.5 3.5 4.5

Stimulus Intensity (kg/cm2)

Pai

n In

tens

ity

Fibromyalgia

Subjective Pain Control

Stimulus Pressure Control

SI = contralateral primary somatosensory cortexSII = secondary somatosensory cortex

DIAGNOSIS AND MANAGEMENT DIAGNOSIS AND MANAGEMENT OF FIBROMYALGIAOF FIBROMYALGIA

Management of Fibromyalgia (FM)

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.

Nonpharmacologic Pharmacologic

Patient educationLow impact aerobic exerciseBalance and strength trainingConservation of energyBiofeedbackCognitive behavioral therapyNutritionAcupuncture

AntidepressantsAnalgesicsAnticonvulsantsSleep medicinesMuscle relaxants

Fibromyalgia:Fibromyalgia:Non-Pharmacologic TreatmentNon-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:Fibromyalgia:Non-Pharmacologic TreatmentNon-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 painAcupuncture- helps some FM patients (2 short term studies were effective)

Birch, S, et al, Complement Med 2004, Jun:, 10: pp. 468-80 Li, A, et al, Brain Res 2007; 1186, pp 171-9

Fibromyalgia:Fibromyalgia:Pharmacological InterventionsPharmacological InterventionsFDA 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. 4. Gendreau RM, et al. J Rheumatol. 2005;32(10):1975-1985. 2. Please see Duloxetine full Prescribing Information 2008. 5. Arnold LM, et al. Arthritis Rheum. 2007; 58(4): 1336-13443. Arnold LM, et al. Psychosomatics. 2000;41:104-113. 6. Arnold LM, et al. Arthritis Res Ther. 2006;8:212.

Sleep MedicationsZolpidem 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:Fibromyalgia:Medical Management SummaryMedical 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 ConclusionsFibromyalgia Conclusions

FM patients do not have a progressive diseaseFM 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