FIBROMYALGIA. Leena Mathew, M.D. Director Pain Fellowship Associate Professor Department of Anesthesiology Columbia University

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1 FIBROMYALGIA Leena Mathew, M.D. Director Pain Fellowship Associate Professor Department of Anesthesiology Columbia University

2 disclosures I have no conflicts of interest

3 objectives Be able to accurately diagnose fibromyalgia Understand the pathomechanism of fibromyalgia Identify a multimodal treatment plan for patients with fibromyalgia.

4 prevalence / epidemiology Prevalence 2-8% 4 million fibromyalgia patients 9 1 : 2 1 $5945 annually per person years old

5 history

6 classic criteria % patients / 69% controls Sensitivity 88.4% specificity 81 1%

7 fibromyalgia impact questionnaire ( FIQ) validated 10-item instrument sensitivity 93.1% / specificity 91.7% Assesses impact on function and effect of treatment R. Bennett 2005

8 revised ACR 2010 criteria Eliminated tender point exam widespread pain Index 0-19 Symptom severity score 0-12 Fatigue Cognition Un-refreshed sleep Somatic symptoms WPI 7 and SSS 5 WPI= 3-6 and SSS 9 Sensitivity 86%, specificity 90%

9 revised 2011 ACR criteria Physician estimate of somatic symptoms eliminated and expanded the SSS 0-31 FM symptom scale (FS) 19 pain locations 6 self-reported symptoms- poor sleep, fatigue, poor cognition + headache, depression or abdominal pain FS 13 best meets criteria (sensitivity 96% and specificity 91%)

10 2016 revision Generalized pain in 4 of 5 regions. Symptoms > 3 months. WPI 7 and SSS score 5 or WPI of 4 6 and SSS score 9. Diagnosis of fibromyalgia valid irrespective of other diagnoses

11 symptoms Chronic widespread pain Fatigue Non restorative sleep Mood / cognitive disturbances. Anxiety Depression Sleep Fatigue Pain 40% 50% 90% 90% 100%

12 comorbidities Depression / anxiety Headache / migraines Temporomandibular ds IBS Low back pain Idiopathic paresthesias Fatigue, cognitive ds Allergies Esophageal dysmotility Reactive airway Pelvic pain, cystitis Adapted from Aaron LA et al, Arch Int Med 2000; 160:

13 multidimensional pathology Inflammator y Neurological Genetic Pain matrix 1.Oxidative stress, mitochondrial damage cause a inflammatory state. 2.Inflammatory cytokines upregulated (IL10, IL25, IL36A) 1, Aberrant transmission 2 Serotonin/ NE and EAA 4. epidermal nerve fiber density 5. CSF levels of SP and NG factor and levels of serotonin, GABA, NE % prevalence in 1 relatives vs. 19% in unrelated subjects 2. Multiple genetic polymorphisms effect serotonin, NE dopaminergic system expression 3. Granulocyte-specific genes are down-regulated ( FCER1A, MS4A2, CPA3) 1.Decreased binding of µ- receptors in r-acc 2. Volume change in amygdala, hippocampus, PFC, ACC and insula. 3.Abnormal central pain processing

14 normal abnormal pain processing NK-1 Primary afferent Pain neuron AMPA NMDA receptor Release of EAA/ SP Quiet glia fibromyalgia NK-1 Primary afferent Pain neuron AMPA NMDA receptor Enhanced release EAA /SP Activated glia Adapted from Bradley LA. Pathophysiology of Fibromyalgia. Am J Med 2009

15 genetic signature Genes COMT ADRB2 (β2 adrenergic receptor) HTR2A( serotonin receptor 2A) D4 polymorphism TAAR1 CNR1 RGS4 Mechanism Catecholamine metabolism Altered sympathetic activity Altered serotoninergic function Altered dopaminergic function Modulates dopaminergic receptor Cannabinoid receptor Protein G signaling -X 8.5 risk in 1 relatives -Differential RNA expression of 421 genes identified in 70 patients and 70 controls -Changes in gene expression and concentrations of micrornas -Expression signatures for fibromyalgia with 10 candidate genes sensitivity 95% and specificity 96% Adapted from Ablin JN et al 2015

16 fmri in fibromyalgia Comparison effects of similar pain intensity in patients and controls Arthritis & Rheumatism Volume 46, Issue 5, pages , 8 MAY 2002 DOI: /art

17 fmri in fibromyalgia Comparison effects of similar stimulus pressures in patients and controls Arthritis & Rheumatism Volume 46, Issue 5, pages , 8 MAY 2002 DOI: /art.10225http://onlinelibrary.wiley.com/doi/ /art.10225/full#fig3

18 environmental triggers Infections ( Epstein-Barr virus, Lyme disease, Q fever, hepatitis) Physical trauma (motor vehicle collisions) Psychological trauma ( deployment/ abuse/death / sexual )

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20 therapeutic framework Education Collaboration Treatment Focus on progress

21 interdisciplinary management Grade A evidence : cognitive-behavioral therapy (CBT) Aerobic exercise / PT CAM therapies EMG biofeedback / Neuro-feedback Grade B evidence: Pharmacotherapy Acceptance /commitment group therapy Educational interventions TPI Marijuan a Opioids BDZ Grade C evidence: Mindfulness

22 FDA approved pharmacotherapy Pregablin Milnacipran Duloxetine Binds presynaptic calcium channels decreases glutamate, NE, SP Inhibits NE reuptake Selective inhibition of serotonin and NE reuptake 50 mg bid to 150 mg TID 12.5 mg QD to 50 mg BID 30 mg QD to 60 mg QD Meta-analysis-3 RCT n=1890 reduces pain and improves function 15-wk DBRCT n=1196 patients 27-wk RCT n= 888 patients Improves pain, fatigue and function. DBRCT n=588 patients reduces pain severity and interference with quality of life

23 summary Fibromyalgia is a prototypical centralized pain syndrome There is no agreed-upon FM phenotype or the exact mechanisms driving its multifactorial pathogenesis. Both genetic and environmental triggers involved in development of fibromyalgia with changes in the pain matrix. Management requires an interdisciplinary approach and collaboration.

24 Be able to accurately diagnose fibromyalgia Understand the pathomechanism of fibromyalgia Identify a multimodal treatment plan for patients with fibromyalgia