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Home , Fibromyalgia, Peripheral neuropathy

A Major Cause of Disability Pathogenesis, Diagnosis and and Morbidity Therapeutic Options • 25.3% of patients • 31% of patients received disability employed prior to payments; (Wolfe, onset of their fm Kevin V. Hackshaw, M.D. 1996) reported loss of employment due to Associate Professor of Medicine • 27.8% of patients were their disease Division of Immunology/ seeking/receiving (Thorson, 1998) Fellowship Director - Rheumatology disability; The Ohio State University (Robinson, 2007; J ) Columbus, Ohio

Fibromyalgia Associated Conditions • • • A chronic musculoskeletal pain amplification syndrome • Muscular Rheumatism • Psychogenic Rheumatism • • Tension Rheumatism • Wide spread muscular aching • Fibrositis/ Myofibrositis • • Sleep disturbance • Shell Shock • Temperature intolerance • Post Traumatic Syndrome • • Chemical Hypersensitivity Syndrome • Sick Building Syndrome

1 Demographics “Pain” • Female > Male (5:1) * • Age Onset: 9 – 60 • An unpleasant sensory and emotional • Most commonly between 40 and 60 experience associated with actual or • All Races potential tissue damage • Between 3 – 7% of the U.S. population is affected • Inciting events: Trauma (**), , MVA with whiplash, Head or

Pain Mechanisms

• Nociceptive transmission: arising from or degeneration of joints and Pain Mechanisms soft tissue • Examples: Rheumatoid and

2 Pain Mechanisms Peripheral and Spinal • Neuropathic transmission: arising from a Pain Mechanisms primary in the peripheral or central • Central endings - gray matter • Hyperresponsiveness to subthreshold stimuli • Modulating factors {5HT – High presynaptic levels inhibit NT release, low levels enhance NT • Examples: , Diabetic release} , Post herpetic neuralgia, Fibromyalgia (?) • Neurotransmitters 9 Substance P (NK1 receptors; long acting) 9 Nociceptive 9 Glutamate (NMDA receptors; short acting) 9 Inflammatory 9 Excitatory Amino Acids 9 Neuropathic 9 Vasoactive intestinal peptide (visceral organs) 9 CGRP 9 Maladaptive

Peripheral and Spinal Pain Mechanisms

• Nociceptive afferents 9 A delta myelinated (fast transmission ) 9 C unmyelinated (slow transmission)

3 Descending Controls Mechanisms of

• Modulation of nociceptive processing and pain • Spontaneous discharges either peripherally or 9 Perceptual correlates centrally ¾ Placebo effect • Localized demyelination, DRG abnormalities or aberrant Sodium or Calcium channels may ¾ Hypnosis and suggestion contribute ¾ Combat, athletics • Aberrant expression of neurotransmitters in periphery or centrally leads to “Sensitization” ¾ Ritual analgesia • Results is more ectopic firing ¾ Pharmacological analgesia

Pain Processing Areas in the Brain

Somatosensory Cortex

Insular Cortex Anterior Cingulate Cortex Thalamus

Amygdala

4 Fibromyalgia Spectrum

• Seek Medical Care • Don’t seek medical care • Multiple tender points • Multiple tender points Clinical Presentation • * • * • High frequency of recent stressful experiences

Rheumatic Symptoms • • Hyperalgesia 9 A non-noxious 9 An exagerrated • General aches/ stimulus elicits response to a pain painful stimulus • Articular pains without joint swelling • Morning stiffness about 1 hour • Subjective morning swelling

5 Non-Rheumatic Symptoms Diagnostic Criteria

• Anxiety • * Widespread subjective aching for more than 3 • Sleep disturbances months • Headaches • *Pain in >11 of 18 tender points * • • Subjective stiffness of more than 3 months • Irritable bladder • Pain in all 4 quadrants of body • PMS • “Normal Labs” to include ESR, TSH, ANA, • Numbness D Level, etc. • • Concurrent chronic fatigue, emotional distress, poor sleep, morning stiffness *specific • Mottled skin appearance diagnostic criteria • Temperature instability

Fibromyalgia Tender Points

Other Considerations…

6 Pain Catastrophizing -1 Pain Catastrophizing -3

• Individuals who catastrophize have difficulty • Describing pain as “awful, horrible or shifting their focus of attention away from painful unbearable” or threatening stimuli • Early studies suggested these maladaptive • They attach more threat or harm to non-painful responses mirrored responses in depressed stimuli (Crombez 1998, 2002) individuals • Catastrophizing is also associated with affective • Later studies have found catastrophizing to be pain ratings leading to higher evaluations of the significantly associated with pain related experience of pain (Geisser 1994) disability independent of depression or negative affect (Keefe 1989, Geiser 1994, 2003)

Pain Catastrophizing -2 Waddell Signs • Tenderness • Independent of influence of depression: 9 Superficial - skin is tender to light pinch over a wide area of lumbar skin nonanatomic - deep tenderness • Associated with brain areas associated with over a wide area, not localized to one structure anticipation of pain: medial frontal cortex, cerebellum; • Simulation Tests - give the impression that an examination is being done, when in fact it is • Attention to pain : Dorsal ACC, Dorsal prefrontal not cortex; 9 Axial loading - vertical loading over the • Emotional aspects of pain: Claustrum, closely standing patient’s skull by the examiner’s connected to amygdala and motor control hands rotation - turn standing patient to one side by rotating lower extremities (not spine)

7 Waddell Signs • Distraction Tests - reevaluating a positive finding while the patient’s attention is not focused on the test 9 Indirect observation - can patient move the body part without pain when not being directly examined? 9 Straight leg raise - if positive when examined supine, do "flip test" (sitting SLR) Pathogenesis • Regional Disturbances - widespread divergence from accepted neuroanatomy 9 - "cogwheeling" or many muscle groups that cannot be explained neuroanatomically 9 Sensory - "stocking" distribution of sensory changes • Overreaction 9 Disproportionate verbalization, facial expression, muscle tension and , collapsing, sweating

Phasic intrusion patterns correlate with clinical symptoms in fibromyalgia • 25% of RA with FM • 30% of SLE with FM • 50% of SS with FM • 20 -80% of DM with FM • MS with FM

8 Family and Genetic Studies Genetic influences on pain sensitivity may in part mediate • Odds ratio for a family member of a patient with FM to also have FM is 8.5 the relation between (Arnold, 2004) and the • FM family members have increased pain development of widespread pain sensitivity as measured by total myalgic score

Women with abnormal pain sensitivity or chronic widespread pain show a functional polymorphism in the promoter region of the transporter gene 5-HTT.

9 Correlation between levels of CSF Substance P in CSF BDNF and Glutamate in FM Patients

• No significant relationship with depression (Russell , 1994) • No difference in CSF SP levels between individuals with major depression and normal controls (Deuschle, 2005) • CSF SP levels are unchanged by treatment / response (Deuschle, 2005)

NGF and BDNF in NGF is elevated in CSF CSF of FM of Primary Fibromyalgia

Table - CSF Levels of NGF and BDNF (Mean +/- 2 SD) in Patient Groups and Controls CM PATIENTS PFMS CONTROLS • Primary FM: 41.8 +/- 12.7 pg/ml NGF (pg/mL) 46.7 4.6 47.2 5.3 13.7 2.7 BDNF (pg/mL) 39.4 6.7 40.4 4.6 11.3 3.4 • Secondary FM: 8.9 +/- 4.4 pg/ml Glutamate (mol/L) 2.18 0.4 2.36 0.3 1.37 0.3 * * • Other : 16.2 +/- 8.4 pg/ml

Abbreviations: CM, chronic migraine; PFMS, primary fibromyalgia syndrome; NGF, growth factor; BDNF, brain-derived neurotrophic factor. * = Statistically Significant

Sarchielli et al., 2007

Giovengo et al., 1999

10 Changing Glutamate Question? Levels in Insula “Does the pattern of brain activation in FM patients match that produced by equally low correlate with stimulus pressures in normal volunteers, or does it match that produced by equally subjectively Fibromyalgia Pain painful stimuli (produced by significantly greater stimulus pressures) in the normal volunteer H-MRS (proton magnetic group?” A match of equal subjective pain intensities is consistent with a pathologic resonance spectroscopy) increase in pain sensitivity in patients.

(Gracely et al., 2008)

FM patients report pain at Functional Imaging normally painless pressures Techniques • PET Scanning • Functional MRI • Studies by K. Casey, Peyron • Pain is associated with activation in the Secondary Somatosensory(SII), Insular Region, Anterior Cingulate Cortex (ACC), contra lateral thalamus and primary somatosensory cortex (SI) • Activation is characterized by an increase in Regional Cerebral Blood Flow

Gracely et al, 2002

11 Treatment

Normally painless pressures activate fm brains uniquely Treatment Options (after exercise program has been established *)

• Class • Study Results • 1-Tricyclic • 1-8 and 12 week trials: Some +, Most - • 2- • 2-All - except • 3-SNRI’s * • 3-All + • 4-SSRI’s • 4-All – • 5- (A2D) * • 5-All + • 6-Other anticonvulsants • 6-Most have not been (Na channel) tested • * FDA approved • * FDA approved

Gracely et al, 2002

12 Treatment Regimens Summary • 50 qhs • 12.5 x 1 wk mg day 1 • The pathogenesis of FM has more in common with neuropathic pain spectrum disorders than • 50 bid wk 2 • 12.5 mg bid days 2 the typical inflammatory or degenerative and 3 musculoskeletal pain disorders • 50/100 wk 3; etc. • 25 bid days 4 – 7 • Treatments should be directed towards CNS • 30 mg mechanisms qAM wk 1 • 50 bid thereafter • FM and classical neuropathic pain syndromes • 60 qAM thereafter • Treat symptom respond similarly to drugs of several different chemical classes with different MOA consistent domains for most with shared pathogenic mechanisms patients; ie., sleep, fatigue, pain, etc.

Other Treatment References Considerations • Brain 127: 835 – 843, 2004 • Cognitive Behavioral Therapy • Arth Rheum 46: 1333 – 1343, 2004 • Local Trigger Point Injections • J Rheum 26: 1564 – 1569, 1999 • Topical • J Pain 8: 737 – 745, 2007 • Muscle Relaxants / Anti inflammatories • Arth Rheum 58: 903 – 907, 2008 • NMDA Antagonists () – C-fiber • J Pain 5: 323 – 332, 2005 second pain (Windup) dependent on NMDA • Brain Res 1041: 38 – 47, 2005 mechanisms – not effective • Spine 5: 117 – 125, 1980

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