Update of Understanding of Fibromyalgia

Dr. Jad OKAISHotel Dieu de France

November 2009

Diagnostics to roll out 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 calcificationMetabolic syndrome ( obesity)

Constitutional anomalies :

Hyper laxity

poly articular dysplesia

Fibromyalgia and Depression

Pain Depression

Definition of FibromyalgiaFibromyalgia 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;92:363-367Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. Journal of Rheumatology 2005;6-21..

1990 ACR fibromyalgia criteria:

the core research standard 1. History of widespread pain 1. History of widespread pain

for at least 3 months in 4 for at least 3 months in 4 quadrants of the body quadrants of the body along with axial skeletal along with axial skeletal painpain

2. Pain at 11 or more of 18 2. Pain at 11 or more of 18 specifically designated specifically designated muscle-tendon sites called muscle-tendon sites called “tender points” . Palpation “tender points” . Palpation force of about 4 Kg.force of about 4 Kg.

3. Appropriate Rule/outs 3. Appropriate Rule/outs

Note: Tender points are sites that are normally more Note: Tender points are sites that are normally more tender i.e. sensitive to pressuretender i.e. sensitive to pressure

Clinical definition DescriptiveBased on subjective symptomsAbsence of psychopathological definition reflecting the specificity of this disease

Stressors Associated with the onset of Fibromyalgia

Early life stressorsChildren with stressors were 1.5- 2 x more likely to have a chronic widespread pain.

Certain catastrophic eventsPsychological stressTriggering events

Physical Symptoms Common In Psychiatric

Patients

Data from Kellner R, Sheffield BF. The one-week prevalence of symptoms in neurotic patients and normals. Am J Psychiatry 1973;130:102–105

Psychiatric Healthy Symptom Patients (%) Subjects (%)

Tiredness, lack of energy 85 40Headache, head pains 64 48Dizziness or faintness 60 14Feeling of weakness in parts of body 57 23Muscle pains, aches, rheumatism 53 27Stomach pains 51 20Chest pains 46 14

Hudson JI, et al.: Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med 1992, 92:363–367

Fibromyalgia and depression differ in brain activation

patternsHealthy controls and patients FM without depression :

Activations in:In primary somatosensory cortexIn secondary somatosensory cortexAnterior insula

Patients FM with depression:

Activations inSame structuresAmygdalaMore act. In anterior insula

Physiopathology Troubles of nociception (peripheral theory):

Nociceptive Stimuli

Troubles of pain’s Modulation is a central matter:

Reduced pain thresholdPain’s amplificationExpansion of pain beyond affected organ or dermatome

Wolf 1994

Trouble of Nociception:peripheral stressors associated with fibromyalgia and chronic widespread

pain

Peripheral pain syndromes (RA,SLE,osteoarthritis)

Physical trauma or stressInfectionsHyperlaxity Whiplash-associated injuries

1.Clawn et al. J.Clin rheumatology 1995;1:335-422. 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, 128:302–3105. Elert J, Kendall SA,et al.: J Rheumatol 2001, 28:1361–1368..

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.

Ralf Baron (2006) Mechanisms of Disease: neuropathic pain—a clinical perspective.Nat Clin Pract Neurol 2: 95–105 doi:10.1038/ncpneuro0113

Figure 2 Mechanisms of peripheral and central sensitization in neuropathic pain

Baron R. Nat Clin Pract Neurol 2: 95–105. 2006

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

C fibersPain

Signalingneurons

N

Neurogenic Inflammation In neurogenically inflammed tissue in Fibromyalgia, Enthesopathie, irritable bowel syndrome etc biopsy specimens can show:

Vasodilatation and plasma extravasationAbnormal sprouting of peripheral nerve terminalsMast cell accumulation

In patients with fibromyalgia, skin tissue RT-PCR positive signals were detected in:

19/50 for IL-1β14/51 for IL-617/53 for TNF-αIn healthy skin, none of these cytokines were detected

1.Sprott H, et al A&R 1997; 40: 1450-42.Salemi S, et al. J Rheumatology 2003; 30:146-50

CGRP

CGRP

Peripheral sensitization to pain:

Some definitions:Hyperalgesia increased sensitivity to an already painful stimulusAllodynia normally non painful stimuli are felt as painful (i.e .light touch of a sun-burned skin)

sensitization of the dorsal horn

Aβ - Aδ Afferents(pressure)

C-fibre nociceptor with resting activity

Wind-up at Widedynamic range -neuron

Descending inhibition; Diffuse noxious inhibitory control (DNIC) N-METHYL-D-ASPARTAT

Wind-up

externally applied stimulus evokes hyperalgesia (Aδ) and allodynia (Aβ) due to sensitization

KETAMIN

Baron 2004

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

EAA = Excitatory amino acids , GABA = gamma-aminobutyric acid

Chronic pain resultsIncrease excitation Decrease inhibition

N-methyl-D-aspartate

Evolution of Allodynia & Hyperalgesia

Effects of NMDA receptor activation:Spinal neurons carrying pain signal can be stimulated with less peripheral inputLess glutamate is required to transmit pain signalMore anti-nociceptive input to stop it

Endomorphins and other naturally occuring pain-relievers cannot keep up with the demand and essentially lose their effectiveness

Dickerson AH. 1994N-methyl-D-aspartate

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 pointIn fibromyalgia, low serotonin manifests specifically in peripheral platelets

Russel IJ: Z Rheumatol 1998, 57(Suppl 2):63–68.

Serotonin Deficiency CSF substance P levels in patients with fibromyalgia:

Are 2-3 x than controlsAre 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.)

Expansion of pain beyond affected organ

Widespread versus localized

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

NMDA Receptor ActivationActivation of NMDA receptors:

Cause neural cells to sprout new connective endingsNeural remodeling adds new dimensions to old sensations

Emotional component of painMay be increased if the new connections channel more of the pain signal to the brain’s reticular activating systemThe signal’s pathways into the cerebral cortex is more splayedConsequently, pain signals is more diffuse and difficult to localize

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

Immunology of Pain & Hyperalgesia

Astrocytes and microglia release key mediators of hyperalgesia

NONMDACytokines (TNF IL-1..)NGF

Watkins LR, et al. 1999

Neural Plasticity & RemodlingThe presence of c-fos protein in spinal cord cells:

Marker for neuron activationC-fos may also indicate central hypersensitizationAlternatively, c-fos-expressing neurons may be inhibitory interneurons activated by noxious stimuli

Protein products of these genes

Function as a transcriptor factorsTrigger long-lasting plastic changes in CNS neurons

Harris JA 1998N-methyl-D-aspartate, alpha-amino-3-hydroxy 5-methyloxzazole-4-proprionate

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 dermatomeThat why we can make a false conclusion that the patient’s pain is psychogenic

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 extravasationAbnormal sprouting of peripheral nerve terminalsMast cell accumulationWithout infiltration of the site by the inflammatory cells

Wolf 1994Weihe 1991

Afferents may become Efferent

Neurons can carry signals in afferent or afferent directionWith the prolonged generation of pain signals, a dorsal root reflex can become pathologically establishedAfferent cells in the dorsal horn release mediators that cause action potentials to fire antidromicallyAn antidromic impulse in an axon refers to conduction opposite to the normal

Dimitriadou V. et al. neuroscience 1997;77: 829-39

Neuron inflammationThe release of SP & NGF into the periphery causes a tissue reaction

Driven by CNS eventsNot depending of inflammation’s cellsSubstance P causes mast cell degranulationVascular endothelial effects : release of bradikinin and production of NO and that lead to vasodilatation of vessels

Antidromic

stim

ulation

NGF

Chronic pain

Dimitriadou V. et al. neuroscience 1997;77: 829-39

Why stress can generate and increase pain?

Stress influences pain transmission and stress can produce central analgesiaThe stress response is primarily mediated trough the HPA axis and the automatic nervous systemAbnormalities of the HPA axis found in pain syndrome

One third of adult fibromyalgia patients are growth hormone deficient

HPA: HYPOTHALAMIC-PITUATIRY-ADRENAL

Peripheral stressors

Exposures syndromes

Hyperalgesia/allodynia and/or central sensitization.

Long-term neuroplastic changes

Chronic pain

Mechanistic Classification of Chronic Pain Disorders

Peripheral (nociceptive)

Neuropathic Central

( non noxious)

•Inflammatory ormechanical damage:

•Osteoarthritis•Rheumatoid arthritis

•Damage or entrapment ofperipheral nerve:

•Diabetic neuropathy•Post-herpetic neuralgia

•Central disturbance in pain processing:

•Fibromyalgia •Irritable bowel syn.•Headache•Idiopathic low back pain•Temporomandibular disorder•Others ….

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’’

Peripheral tissueNSAIDS OPOIDS

Peripheral nerveNa channels blockers

Anti-epileptics

Dorsal horn descendingMonoamine reuptake

InhibitorsGABA agonists

Dorsal horn ascendingNMDA antogonists

Substance P antogonistsNGF antagonists

Nitric oxide

Midbrain Opoids

Alpha-2adrenergic agonistsTramadol

Supraspinal OpoidsSSRIs

Serotonine Dopamine

Adrenergic agonists