Fibromyalgia Syndrome: Pathophysiology and Current Treatments Suburban Hospital Grand Rounds January 23, 2009 Russell Rothenberg, MD Bethesda, Maryland , ext. 118 © Copyright Russell Rothenberg 2009 All Rights Reserved

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 jaw pain, tight trapezius muscles, decreased ROM C-spine and occipidynia 18/18 + tender points 3/4 in intensity, peripheral joints all normal, normal grip strength, marked myofascial pain in the right upper arm. Diffuse myofascial pain in the paraspinal muscles

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 Discussion Points How would you approach this case? What would your initial work up include? What treatment recommendations would you make?

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, T4, TSH, Sed Rate, CRP, Iron, TIBC, Vitamin 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 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, and in 2008, the FDA approved duloxetine, the first two drugs specifically indicated for the treatment of fibromyalgia

Symptoms and Syndromes Related to Fibromyalgia Interstitial cystitis, female urethral syndrome, vulvodynia Tension/migraine headache Affective disorders Temporomandibular joint syndrome Constitutional symptoms and syndromes Fatigue and Chronic Fatigue Syndrome (CFS) Sleep disturbances Idiopathic low back pain Irritable bowel syndrome Nondermatomal paresthesias 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. Arch Int Med. 2000;160:

Evaluation of Fibromyalgia: Comorbid Medical Disorders Aaron LA and Buchwald D. Best Pract Res Clin Rheumatol. 2003;17:

Fibromyalgia: Myofascial Pain Myofascial pain is a major cause of disability in many FM patients Patients get painful palpable “knots” associated with trigger points in their muscles and soft tissues Trigger points 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 Trigger points 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 abnormal findings are also seen in RA, OA, Sjogren’s, etc. Sleep studies are indicated only for patients that have not responded to standard therapy Zolpidem has been shown to be effective in preserving normal sleep architecture in FM –It reduces FM fatigue, but not FM pain Drewes, AM, Rheumatology, 11/1999: 38, pp Moldofsky H, J Rheum, 1996: 23: pp

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, 4/2005 Supplement, 11: pp. S1-33

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: ; Giesecke et al. Arthritis Rheum. 2004;50: ; Crofford and Clauw et al. Arthritis Rheum. 2002;46: ; Vaerøy et al. Pain. 1988;32:21-26; Russell et al. Arthritis Rheum. 1994;37:

Pathophysiology in Fibromyalgia: Neurotransmitters Substance P –Excitatory neurotransmitter which is elevated in CSF of FM patients compared with controls 1,2 –Important in central sensitization along with pro-nociceptive amino acid glutamate acting at the alpha-delta and C ascending pain fibers 3 Serotonin and Norepinephrine –Evidence of dysfunction in fibromyalgia 4,5 –Serotonin and norepinephrine mediate pain modulation through the descending inhibitory pain pathways in the brain and dorsal horn of the spinal cord 6 1.Russell IJ, et al. Arthritis Rheum. 1994;37: Russell IJ, et al. J Rheumatol. 1992;19: Vaerøy H et al., Pain : Russell IJ, et al. Arthritis Rheum. 1992;35: Watkins LR, et al. Brain Res. 1994;664: Fields HL, et al. Annu Rev Neurosci. 1991;14:

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

1. Fields HL, et al. Annu Rev Neurosci. 1991;14: Fields H. Nat. Rev. Neuro. 2004; 5: Fields HL and Basbaum AI. In: Wall PD, Melzack R, eds. Textbook of Pain. 1999:310. Pain Modulation: Serotonin and Norepinephrine Pain is associated with increased excitation and decreased inhibition of ascending pain pathways 1,2 Descending pathways modulate ascending signals 1,2 Norepinephrine (NE) and serotonin (5- HT) are key neurotransmitters in descending inhibitory pain pathways 1,2 Increasing the availability of NE and 5-HT may promote pain inhibition centrally 1

Gracely RH, et al. Arthritis Rheum. 2002;46: Augmented Pain Processing in Fibromyalgia

Pathophysiology of Fibromyalgia: Autonomic Nervous System Dysfunction Pathophysiology of Fibromyalgia: Autonomic Nervous System Dysfunction FM patients have increased: –Neurally mediated hypotension and reduced heart rate variability (abnormal tilt table testing) –Irritable bowel and bladder symptoms –HPA axis dysfunction (low AM cortisol, inappropriately high ACTH) –Vascular headaches –Paresthesias of arms and legs may be related to the increased sympathetic tone Mease P, J Rheumatol 2005: 32 (Suppl) 75 pp. 6-21

DIAGNOSIS AND MANAGEMENT OF FIBROMYALGIA

Management of Fibromyalgia (FM) Goldenberg et al. JAMA. 2004;292: ; Clauw et al. Best Prac Res Clin Rheumatol. 2003;17: ; Arnold et al. Arthritis Rheum. 2007;56: Nonpharmacologic Pharmacologic Patient education Low impact aerobic exercise Balance and strength training Conservation of energy Biofeedback Cognitive behavioral therapy Nutrition Acupuncture Antidepressants Analgesics Anticonvulsants Sleep medicines Muscle relaxants

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 plus stretching (warm water aerobics, Pilates, Curves™) 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 Li, A, et al, Brain Res 2007; 1186, pp 171-9

Fibromyalgia: Pharmacological Interventions FDA Approved Medications –Pregabalin (Lyrica) 1 –Duloxetine (Cymbalta) 2 Treatments with Demonstrated Efficacy (Non-FDA Approved) –Cyclic medications 3 Cyclobenzaprine Tricyclic antidepressants –Selective serotonin and norepinephrine reuptake inhibitors Milnacipran 4 –Alpha-2-delta ligands Gabapentin 5\ - Other therapies that are clinically helpful, but not studied as well, are sleep medicines, muscle relaxants, and pain medicines for breakthrough pain. 1. Please see Pregabalin full Prescribing Information Gendreau RM, et al. J Rheumatol. 2005;32(10): Please see Duloxetine full Prescribing Information Arnold LM, et al. Arthritis Rheum. 2007; 58(4): Arnold LM, et al. Psychosomatics. 2000;41: Arnold LM, et al. Arthritis Res Ther. 2006;8:212.

Fibromyalgia: Medical Management Summary Think of FM as a multisystem disorder with multiple neuro-pathways creating dysfunction –Non-restorative sleep –Myofascial pain and muscular deconditioning –Anxiety and reactive depression –Abnormal central and peripheral pain processing Ascending (Substance P and Glutamine) Descending (Serotonin, Norepinephrine and Endogenous Opioids) “Wind up” (NMDA receptors) –Autonomic Nervous System 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 medical supervision, patients can improve their physical ability to function and quality of life