Transcript Chronic pain

Update of Understanding of
Fibromyalgia
Dr. Jad OKAIS
Hotel Dieu de France
November 2009
Diagnostics to roll out
Inflammatory disorders:
SA
Hypothyroid
( enthesopathy)
Sjogren disease
association)
Metabolic diseases:
(30%
Lupus (22% association)
RA; PPR;syn. Hyper
eosinophilia
Infectious diseases:
viral infections (Parvo;Hepatitis
C,..)
post streptococcus rheumatism
VIT- D deficiency
multiple calcification
Metabolic syndrome ( obesity)
Constitutional anomalies :
Hyper laxity
poly articular dysplesia
Fibromyalgia and Depression
Depression
Pain
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..
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
Clinical definition
Descriptive
Based on subjective symptoms
Absence of psychopathological
definition reflecting the specificity of
this disease
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
Physical Symptoms Common
In Psychiatric Patients
Symptom
Tiredness, lack of energy
Headache, head pains
Dizziness or faintness
Feeling of weakness in parts of body
Muscle pains, aches, rheumatism
Stomach pains
Chest pains
Psychiatric
Patients (%)
Healthy
Subjects (%)
85
64
60
57
53
51
46
40
48
14
23
27
20
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
Fibromyalgia and depression
differ in brain activation patterns
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
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
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..
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 Cfibers.
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
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.
A-beta
Pain
Signaling
neurons
C fibers
Change from innocuous to
noxious sensation is called
allodynia = normally non painful stimuli
are felt as painful (i.e .light touch of a sunburned skin)
N
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
Peripheral sensitization to pain:
CGRP
Some definitions:
CGRP
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)
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
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 antinociceptive 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
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
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.
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.)
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 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
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
NO
NMDA
Cytokines (TNF IL-1..)
NGF
Watkins LR, et al. 1999
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-fosexpressing 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
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
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
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
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
NGF
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 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
Peripheral
stressors
Exposures
syndromes
Hyperalgesia/allodynia
and/or central
sensitization.
Long-term neuroplastic changes
Chronic pain
Mechanistic Classification of
Chronic Pain Disorders
Peripheral
(nociceptive)
•Inflammatory or
mechanical damage:
•Osteoarthritis
•Rheumatoid arthritis
Neuropathic
•Damage or
entrapment of
peripheral nerve:
•Diabetic neuropathy
•Post-herpetic neuralgia
Central
( non noxious)
•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’’
Supraspinal
Opoids
SSRIs
Serotonine
Dopamine
Adrenergic agonists
Midbrain
Opoids
Alpha-2adrenergic agonists
Tramadol
Dorsal horn ascending
NMDA antogonists
Substance P antogonists
Peripheral tissue NGF antagonists
NSAIDS OPOIDS Nitric oxide
Peripheral nerve
Na channels blockers
Anti-epileptics
Dorsal horn descending
Monoamine reuptake
Inhibitors
GABA agonists