Update of Understanding of Fibromyalgia

1. Update of Understanding of Fibromyalgia Dr. Jad OKAIS Hotel Dieu de France November 2009

2. Inflammatory disorders: SA( enthesopathy) Sjogren disease(30% association) Lupus(22% association) RA; PPR;syn. Hyper eosinophilia Infectious diseases: viral infections(Parvo;Hepatitis C,..) post streptococcus rheumatism Metabolic diseases: Hypothyroid VIT- D deficiency multiple calcification Metabolic syndrome ( obesity) Constitutional anomalies : Hyper laxity poly articular dysplesia Diagnostics to roll out

3. Fibromyalgia and Depression Depression Pain

4. Definition of Fibromyalgia • Fibromyalgia syndrome (FMS) is a common rheumatologic condition characterized by chronic widespread pain and reduced pain threshold, with hyperalgesia and allodynia. Associated features include fatigue, depression, anxiety, sleep disturbance, headache, migraine, variable bowel habits, diffuse abdominal pain and urinary frequency Hudson JI, et al. Comorbidity of fibromyalgia with medical and psychiatric disorders. American Journal of Medicine 1992;92:363-367 Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. Journal of Rheumatology 2005;6-21..

5. 1990 ACR fibromyalgia criteria: the core research standard 1. History of widespread pain for at least 3 months in 4 quadrants of the body along with axial skeletal pain 2. Pain at 11 or more of 18 specifically designated muscle-tendon sites called “tender points” . Palpation force of about 4 Kg. 3. Appropriate Rule/outs Note: Tender points are sites that are normally more tender i.e. sensitive to pressure

6. Clinical definition • Descriptive • Based on subjective symptoms • Absence of psychopathological definition reflecting the specificity of this disease

7. Stressors Associated with the onset of Fibromyalgia • Early life stressors • Children with stressors were 1.5- 2 x more likely to have a chronic widespread pain. • Certain catastrophic events • Psychological stress • Triggering events

8. Physical Symptoms Common In Psychiatric Patients Psychiatric Healthy Symptom Patients (%) Subjects (%) Tiredness, lack of energy 85 40 Headache, head pains 64 48 Dizziness or faintness 60 14 Feeling of weakness in parts of body 57 23 Muscle pains, aches, rheumatism 53 27 Stomach pains 51 20 Chest pains 46 14 Data from Kellner R, Sheffield BF. The one-week prevalence of symptoms in neurotic patients and normals. Am J Psychiatry 1973;130:102–105 Hudson JI, et al.: Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 1992, 92:363–367

9. Healthy controls and patients FM without depression : Activations in: In primary somatosensory cortex In secondary somatosensory cortex Anterior insula Patients FM with depression: Activations in Same structures Amygdala More act. In anterior insula Fibromyalgia and depression differ in brain activation patterns

10. Physiopathology • Troubles of nociception (peripheral theory): • Nociceptive Stimuli • Troubles of pain’s Modulation is a central matter: • Reduced pain threshold • Pain’s amplification • Expansion of pain beyond affected organ or dermatome Wolf 1994

11. Trouble of Nociception:peripheral stressors associated with fibromyalgia and chronic widespread pain • Peripheral pain syndromes (RA,SLE,osteoarthritis) • Physical trauma or stress • Infections • Hyperlaxity • Whiplash-associated injuries 1.Clawn et al. J.Clin rheumatology 1995;1:335-42 2. Harkness EF, et al.AR & Rheum. 2004; 50:1665-1664. 3. Albin JN; et al. J Autoimmun 2006,27: 145-152. 4. Nef W, Gerber NJ: Schweiz Med Wochenschr 1998, 128:302–310 5. Elert J, Kendall SA,et al.: J Rheumatol 2001, 28:1361–1368..

12. Peripheral changes at primary afferent neurons • after partial nerve lesion, leading to peripheral sensitization. • Some axons are damaged and degenerate • whereas others are still intact and connected with the peripheral end organ. • The lesion triggers the expression of sodium channels on damaged C-fibers. • Furthermore, products such as nerve growth factor • triggering channel and receptor expression (sodium channels, TRPV1 receptors, adrenoceptors) • on uninjured fibers. Baron R. Nat Clin Pract Neurol 2:95–105. 2006

13. Peripheral injury and chronic pain: . Axons of surviving A-beta fibers sprout new branches and make connection to neurons vacated by the lost C fibers . Nonpainful stimuli become painful. Change from innocuous to noxious sensation is called allodynia = normally non painful stimuli are felt as painful (i.e .light touch of a sun-burned skin) A-beta Pain Signaling neurons C fibers N

14. Neurogenic Inflammation • In neurogenically inflammed tissue in Fibromyalgia, Enthesopathie, irritable bowel syndrome etc biopsy specimens can show: • Vasodilatation and plasma extravasation • Abnormal sprouting of peripheral nerve terminals • Mast cell accumulation • In patients with fibromyalgia, skin tissue RT-PCR positive signals were detected in: • 19/50 for IL-1β • 14/51 for IL-6 • 17/53 for TNF-α • In healthy skin, none of these cytokines were detected 1.Sprott H, et al A&R 1997; 40: 1450-4 2.Salemi S, et al. J Rheumatology 2003; 30:146-50

15. Peripheral sensitization to pain: CGRP Some definitions: Hyperalgesia increased sensitivity to an already painful stimulus Allodynia normally non painful stimuli are felt as painful (i.e .light touch of a sun-burned skin) CGRP

16. Descending inhibition; Diffuse noxious inhibitory control (DNIC) N-METHYL-D-ASPARTAT Aβ - Aδ Afferents (pressure) KETAMIN Wind-up at Widedynamic range -neuron Baron 2004 Wind-up C-fibre nociceptor with resting activity sensitization of the dorsal horn externally applied stimulus evokes hyperalgesia (Aδ) and allodynia (Aβ) due to sensitization

17. Modulating Pain Pathways:unbalance between facilitation and inhibition • Facilitation • Substance P • Glutamate and EAA • Serotonin (5HT 2a,3a) • Neurotensin • Nerve growth factor • Cholecystokinin • Inhibition • Descending anti- • nociceptive pathways • Norepinephrine • Serotonine (5HT 1a,b) • Dopamine • opoids • GABA • Cannabinoids • Adenosine Chronic pain results Increase excitation Decrease inhibition EAA = Excitatory amino acids , GABA = gamma-aminobutyric acid N-methyl-D-aspartate

18. Evolution of Allodynia & Hyperalgesia • Effects of NMDA receptor activation: • Spinal neurons carrying pain signal can be stimulated with less peripheral input • Less glutamate is required to transmit pain signal • More anti-nociceptive input to stop it • Endomorphins and other naturally occuring pain-relievers cannot keep up with the demand and essentially lose their effectiveness N-methyl-D-aspartate Dickerson AH. 1994

19. Serotonin Deficiency • Serotonin • Inhibits release of spinal cord substance P by afferents neurons • Low concentrations of serum tryptophan and serotonin exist in chronic pain patients • Correlates with their number of myofascial tender point • In fibromyalgia, low serotonin manifests specifically in peripheral platelets Russel IJ: Z Rheumatol 1998, 57(Suppl 2):63–68.

20. Serotonin Deficiency • CSF substance P levels in patients with fibromyalgia: • Are 2-3 x than controls • Are not increasing by the induction of noxious stimuli to tender points • SP levels are normal or low in a variety of chronic painful conditions (low back pain, diabetic neuropathy etc.)

21. Expansion of pain beyond affected organ Widespread versus localized

22. Model of central pain sensitization Intense or prolonged impulses from afferents depolarize dorsal horn There is an flux of extracellular Ca into neurons. An exaggerated release of substance P and glutamate leads to neuronal hyperexcitability Amplified pain signal is sent to the brain from the dorsal horn

23. NMDA Receptor Activation • Activation of NMDA receptors: • Cause neural cells to sprout new connective endings • Neural remodeling adds new dimensions to old sensations • Emotional component of pain • May be increased if the new connections channel more of the pain signal to the brain’s reticular activating system • The signal’s pathways into the cerebral cortex is more splayed • Consequently, pain signals is more diffuse and difficult to localize

24. Apoptosis from NMDA Receptor Activation • NMDA receptor activation normal apoptosis trough a series of events involving multiple interdependent events: • Neurotrauma mediates neuronal death • Data suggest that chronic pain follows a similar destructive processus • The requires timely treatment to limit damage that glutamate-mediated excito-toxicity incites. Arundine M. et al. Cell Mol Life Sci. 2004; 61: 657-68

25. Immunology of Pain & Hyperalgesia • Astrocytes and microglia release key mediators of hyperalgesia • NO • NMDA • Cytokines (TNF IL-1..) • NGF Watkins LR, et al. 1999

26. Neural Plasticity & Remodling • The presence of c-fos protein in spinal cord cells: • Marker for neuron activation • C-fos may also indicate central hypersensitization • Alternatively, c-fos-expressing neurons may be inhibitory interneurons activated by noxious stimuli • Protein products of these genes • Function as a transcriptor factors • Trigger long-lasting plastic changes in CNS neurons N-methyl-D-aspartate, alpha-amino-3-hydroxy 5-methyloxzazole-4-proprionate Harris JA 1998

27. Neural Plasticity and Remodeling • With persistent of pain, c-fos protein spreads to progressively higher levels of the spinal cord • Eventually reach the thalamus, at witch pain may be untreatable • Explain why patient with chronic suffering find their pain has spread beyond affected organ or dermatome • That why we can make a false conclusion that the patient’s pain is psychogenic

28. Neurogenic Inflammation evoke the Role of SP • In neurogenically inflammed tissue in Fibromyalgia, Enthesopathie, irritable bowel syndrome etc biopsy specimens can show: • Vasodilatation and plasma extravasation • Abnormal sprouting of peripheral nerve terminals • Mast cell accumulation • Without infiltration of the site by the inflammatory cells Wolf 1994 Weihe 1991

29. Afferents may become Efferent • Neurons can carry signals in afferent or afferent direction • With the prolonged generation of pain signals, a dorsal root reflex can become pathologically established • Afferent cells in the dorsal horn release mediators that cause action potentials to fire antidromically • An antidromic impulse in an axon refers to conduction opposite to the normal Dimitriadou V. et al. neuroscience 1997;77: 829-39

30. Antidromic stimulation NGF Neuron inflammation • The release of SP & NGF into the periphery causes a tissue reaction • Driven by CNS events • Not depending of inflammation’s cells • Substance P causes mast cell degranulation • Vascular endothelial effects : release of bradikinin and production of NO and that lead to vasodilatation of vessels Chronic pain Dimitriadou V. et al. neuroscience 1997;77: 829-39

31. Why stress can generate and increase pain? • Stress influences pain transmission and stress can produce central analgesia • The stress response is primarily mediated trough the HPA axis and the automatic nervous system • Abnormalities of the HPA axis found in pain syndrome • One third of adult fibromyalgia patients are growth hormone deficient HPA: HYPOTHALAMIC-PITUATIRY-ADRENAL

32. Peripheral stressors Exposures syndromes Hyperalgesia/allodynia and/or central sensitization. Long-term neuroplastic changes Chronic pain

33. Mechanistic Classification of Chronic Pain Disorders Peripheral (nociceptive) Neuropathic Central ( non noxious) • Inflammatory or • mechanical damage: • Osteoarthritis • Rheumatoid arthritis • Damage or • entrapment of • peripheral nerve: • Diabetic neuropathy • Post-herpetic neuralgia • Central disturbance • in pain processing: • Fibromyalgia • Irritable bowel syn. • Headache • Idiopathic low • back pain • Temporomandibular • disorder • Others ….

34. Fibromyalgia It’s not a real illness, it’s in the “patient’s head” It’s a real illness, it’s in the’’ patient’s brain’’

35. Supraspinal Opoids SSRIs Serotonine Dopamine Adrenergic agonists Midbrain Opoids Alpha-2adrenergic agonists Tramadol Dorsal horn descending Monoamine reuptake Inhibitors GABA agonists Dorsal horn ascending NMDA antogonists Substance P antogonists NGF antagonists Nitric oxide Peripheral tissue NSAIDS OPOIDS Peripheral nerve Na channels blockers Anti-epileptics