The role of the central nervous system in thegeneration and maintenance of chronic painin rheumatoid arthritis, osteoarthritis andfibromyalgia

1. The role of the central nervous system in the
generation and maintenance of chronic pain
in rheumatoid arthritis, osteoarthritis and
fibromyalgia
Yvonne C Lee1*, Nicholas J Nassikas1 and Daniel J Clauw2
Review:
Article Reviewed by:
Danial Mehranfard
Advisor:
Prof.Dr. Emre Hamurtekin
Pharmacology Group
March 8th 2017

2. Abstract and Overview
 What is the key component of most rheumatologic diseases ?
 In the fibromyalgia, the importance of central nervous
system pain mechanisms is well documented.
 A few studies have also noted alterations in CPP(central
pain-processing) in osteoarthritis & also suggest that
CPP defects may alter the pain response in rheumatoid
arthritis patients.
Pain is a key component of most rheumatologic diseases.

3. What is the importance ?
 BUT When central pain is identified;
different classes of analgesics for example:
 serotonin–norepinephrine reuptake inhibitors,
 α2δ ligands
may be more eff effective
 Classically in such a rheumatological diseases we try to
treat peripheral or nociceptive pain with medications
such as :
 Nonsteroidal anti inflammatory Drugs
 Opioids

4. Importance of chronic pain in the rheumatic diseases
 Rheumatologists often consider pain a peripheral entity, but
there is great discordance b/w pain severity and purported
peripheral causes of pain.
• Most researches has been conducted up on the
Fibromyalgia and few researches on OA and RA.

5.  These studies have highlighted the
role of central pain processing
mechanisms :
Loss of Descending Analgesic Activity
• Condition of nervous system that is associated with
development and maintenance of chronic pain.
Central Sensitization
• The nervous system goes through Wide up and
gets regulated in a persistent state of reactivity.

6. Basic biology of pain in healthy individuals
 Acute pain:
1. Last from seconds to weeks or months
2. Sudden in onset
3. Direct result of noxious stimulus
 Chronic pain:
1. At least 3 months
2. Maybe persist because:
1. the initially stimulus is still present
2. OR because changes to nervous
system have been occurred
Pain categorization :

7. Acute pain
 develops when a stimulus, such as pressure, heat or inflammation, is presented to the body.
Stimuli
Transfer To
CNS; by:
Fibers
extend; Into:
Dorsal Horn
of Spinal
cord

8. Specialized receptors Include:
 Low threshold receptors Respond to Non-Noxious
level of stimuli
 High threshold receptors Respond to Noxious stimuli
(NOCICEPTORS)
 Nociceptor:
Is a sensory nerve cell that responds to damaging or potentially damaging stimuli
by sending signals to spinal cord and brain
This process called NOCICEPTIN
Usually cause the sensation of pain in sentient beings

9. Types of
nociceptors
Aδ afferent
Type I
Higher Heat
Threshold
Transmit
Mechanical
Stimuli
Type II
Higher
Mechanical
Threshold
Transmit noxious
heat stimuli
C afferent
Detect Mechanical
and Heat stimulus
as well as Chemical
stimulus
nociceptors
 Compared with
pain mediated by
Aδ fibers, pain
mediated by
unmyelinated C
fibers tends to be
poorly localized.

10. Chronic painMechanism
Mechanismsofchronicpain
can
Peripheral pain
Mechanism
Peripheral sensitization
Play important role in OA
& RA
Central Pain
Mechanism
Operate at the level of
CNS; Individuals with
augmented central pain
process
Diffuse Hyperalgesia
INCREASED pain in
response to normally
painful stimuli
Allodynia
Pan in response to
normally NONPAINFUL
stimuli

11. Abnormalities in
CPP
Descending
Facilitatory
Inhibitory Pain
Pathway
Central
Sensitization

12. Descending Analgesic Pathway
 Serotonergic-Noradrenergic Pathway
 Opioidergic Pathway
 Serotonin
 Norepinephrine
 Endogenous Opioids
Best characterized ones
Lead to release of
Inhibits release of excitatory neurotransmittersSuch as GLUTAMATE
 These pathways are activated in response to
noxious stimuli, leading to a widespread
decrease in pain sensitivity after exposure to
an acutely painful stimulus.
In Chronic Pain In chronic pain syndromes,
descending analgesic activity is often
impaired or absent.

13.  Experimentally, diffuse noxious
inhibitory control is commonly
assessed by exposing subjects to two
types of stimuli:
The conditioning stimulus
The test stimulus
an acute noxious stimulus that activates descending
analgesic pathways, leading to a diff use decrease in pain
sensitivity throughout the body
ice-cold water, contact heat and tourniquet ischemia
is a painful stimulus that is applied at baseline and
during/after exposure to the conditioning stimulus.
For example:
is the difference between the pain rating of the test stimulus before exposure to
the conditioning stimulus and the pain rating of the test stimulus after exposure to
the conditioning stimulus.
magnitude of the descending
analgesic response

14. Descending analgesic
pathways are typically Tonically active inhibit the upward
transmission of pain signals,
involve enhanced activity down
the descending facilitatory pain
pathways
Other descending pain-
processing mechanisms

15. Descending pain pathways
and central sensitization.
 Descending analgesic
pathways include the
serotonin–norepinephrine
and Opioidergic
descending pathways,
which dampen pain
sensitivity response. Loss
of descending analgesia
leads to hyperalgesia and
allodynia.
 Central sensitization
through the action of
glutamate on the N-
methyl-D-aspartate
(NMDA) receptor, resulting
in an increase in
intracellular calcium levels
and kinase activation,
leading to hyperalgesia
and allodynia.

16. central sensitization
 Central sensitization is a condition of the nervous system that is associated with the development and
maintenance of chronic pain. When central sensitization occurs, the nervous system goes through a process
called “wind-up” and gets regulated in a persistent state of high reactivity. (Apr 27, 2012)
 SENSITIZATION
(Maybe used in two ways)
Def.
To describe general abnormalities in
central pain processing
describe a specific defect in central pain
processing associated with activation of
N-methyl-d-aspartate (NMDA) receptor
channels
Central augmentation
central sensitization
occurs largely as a
result of enhanced
release of
Glutamate and substance P at the level of the spinal
cord.

17. GLUTAMATE (Is the major excitatory neurotransmitter in the nervous system)
 Acts on 3 Receptors
1) α-amino-3-hydroxy-5-methyl-4-
isoxazeloproprionic acid
receptor
2) NMDA receptor
3) G-protein-coupled metabotropic family of
receptors
responsible for the baseline
response to noxious stimuli
enhances and extends the pain
response

18. NMDA Mechanism
NMDA receptor activation calcium influx Stimulating calcium/calmodulin-
dependent kinases
Extracellular signal-regulated kinases
AND
modulate CNS plasticityhyperalgesia and allodynia
characterize central sensitization

19.  Experimentally Central sensitization
characterized by
 Repeated Stimulation
Diffuse pain sensitivity
Increased pain severity
During and after
repeated stimuli
Individuals with Central sensitizationLow Thermal and Mechanical Threshold
So
Painful after-Sensation
Persist after stimulus is
withdrawn;
Also
pain rating for the last stimulus
is HIGHER

20. NMDA receptor antagonists
 Dextrametraphon
Inhibit
temporal stimulation
 Ketamine

21. Rheumatic Diseases
Outline
Which we’re going to learn more about it in the present review
1.FIBROMYALGIA
2.OSTEOARTHRITIS
3.RHEUMATOID ARTHRITIS

22. 1. FIBROMYALGIA
 Fibromyalgia is the prototypical non-inflammatory chronic pain syndrome.
 They have
LOWER pain
Threshold
than normal
healthy
controls

23. Lab Result Differences in Fibromyalgia patients:
 Serotonin (Serum Level)
 L-Tryptophan
 5-Hydroxyindoleacetic acid
 3-Methoxy-4-Hydroxyphen-Ethylene
LOWER
In compare of healthy controls
 Activity of Endogenous
Opioidergic System
HIGHER
In compare of healthy controls
These defects in inhibitory
pain
responses may be due to
Cerebral spinal
fluid
blunted activity of the descending
serotonergic–noradrenergic
system

24. Fibromyalgia patients are more sensitive to variety of
stimuli
Due to enhances Neuronal activity
INSULA
PosteriorAnterior
Affective/emotional
modulation of pain
processing Higher level of GLUTAMATE
Sensory/discriminative processing of pain
Changes of Glutamate are related with changes in PAIN
and TENDERNESS after acupuncture
At least a component of fibromyalgia is a result of
Sensory Amplification rather than just affective
processing

25. Gracely and colleagues
 Fibromyalgia patients
Vs
Controls
RESEARCH 1 studies of fMRI in fibromyalgia
Exhibit enhanced activation
1. Contralateral primary somatosensory cortex
(SI)
2. Inferior parietal lobe
3. Insula
4. Anterior cingulate cortex
5. Posterior cingulate cortex
6. Ipsilateral secondary somatosensory cortex
(SII) Cortex
7. Bilateral superior temporal gyrus
8. Cerebellum
When exposed to experimental pain of
same magnetite
fibromyalgia patients exhibited activation in the same
neural structures as controls

26. Cook and colleagues
 Heat stimuli response
Fibromyalgia patients
Healthy Controls
NO neuronal activation in
Periaqueductal Gray region
Significant neuronal activation in
Periaqueductal Gray region
Periaqueductal Gray region is involved in descending
pain modulation
RESEARCH 2

27. Napadow and colleagues
 Default mode network
RESEARCH 3
I. medial frontal gyri
II. hippocampus
III. lateral temporal cortex
IV. posterior cingulate cortex
V. precuneus
VI. inferior parietal lobe
Consists of
connectivity between the default mode network and the
insula was positively correlated with
clinical pain severity
potential modulator of spontaneous
clinical pain in fibromyalgia patients

28. 2. OSTEOARTHRITIS
 OA is a common degenerative joint disease, characterized by damage to cartilage and
bone, which affects approximately 27 million people in the United States.

29.  Pain intensity and severity poorly correlates
with peripheral joint damage
and strongly associated
With Radiographic damage

30. Examinations
 O’Driscolla
and
Jayson
 Kosek
And
Ordeberg
Low pressure pain threshold at the forehead A clinically nonpainful site
Increased sensitivity to pressure, ischemia and innocuous
warm stimuli at the affected hip and at the contralateral hip
Diffuse process extending beyond
just the affected joint

31. Imamura and Colleague
 Wide distribution
of
pain sensitivity
1) Subcutaneous Hyperalgesia to pressure stimuli at 7 Dermatome
2) Myotomal Hyperalgesia at 9 lower extremity muscle group
3) Sclerotomal Hyperalgesia at 8 sites across the lower back and leg
RESULT
 Chronic pain state
Peripheral mechanism more impt. in
Central mechanism more impt. in
EARLY stages
LATE stages

32. Knee Replacement Surgery
 Significant Clinical relief 6-14 months pain free
Exhibit significant increase in pain
thresholds compare with pre surgery
Post surgery pain threshold were
similar to healthy controls

33. 3. RHEUMATOID ARTHRITIS
 Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects
joints. It typically results in warm, swollen, and painful joints. In contrast to fibromyalgia
and OA, RA is characterized by systemic inflammation.

34.  RA patients have lower pressure pain thresholds (higher pain sensitivity) than healthy controls at joint and
non-joint sites.
 The Magnitude of descending analgesic activity in RA patients is less than healthy controls.

35. Examination
 Wandler and Colleagues
 Morris and Colleagues
Used Electro
encephalopathy
RA patients had Enhanced Cortical
response to repeated noxious stimulation
CASPACIN induced large area of hyperalgesia among
RA patients
Area of enhanced hyperalgesia may correspond to the
enlargement of Spinal Cord Neuron Receptive Fields
Characterized of CENTRAL SENSITIZATION
Structure in MEDIAL PAIN SYSTEM my modulate
pain processing in RA

36. Jones and Derhyshire
 Using POSITRON EMISSION TOMOGRAPHY
regional cerebral blood flow in
1. dorsolateral prefrontal cortex
2. anterior cingulate cortex (ACC)
3. cingulofrontal transition cortex
LOWER in RA patients compared with healthy controls
exposed to heat pain

37. C-REACTIVE PROTEN (CRP)
 C-REACTIVE PROTEN (CRP) levels were
inversely associated with pain THRESHOLD
at joint sites but NOT at non-joint sites.
 C-reactive protein measures general levels of
inflammation in your body. High levels of CRP are
caused by infections and many long-term diseases.

38. MECHANISM BASED TREATMENT
 Pain is multifunction the origin
 Anti depressants
 Anti convulsants
Successful treatment require
combination of medications with
different mechanism of actions
Here we focus more on
the treatment of
UNDERLYING disease
process
Target Central
Pain-Processing
mechanism
Here we are gonna
discuss about 1. TCA
2. SNRIs
3. The α2δ Ligands

39. 1. Tricyclic antidepressant
• Amitriptyline
• Dothiepin
• Imipramine
Most commonly used
MOA Inhibiting SEROTONIN and NOREPINEPHRINE reuptake.
 blocking the (SERT) and the (NET)
* Micó J, Ardid D, Berrocoso E, Eschalier A (2006). "Antidepressants and pain". Trends Pharmacol Sci. 27 (7): 348–54.
doi:10.1016/j.tips.2006.05.004. PMID 16762426
 The TCAs show efficacy in the clinical treatment of a number of different types of
chronic pain, notably neuralgia or neuropathic pain and fibromyalgia*.

40. Examinations
Amitriptyline
 Ten randomized, double-
blinded, placebo-
controlled trials in
Fibromyalgia
25mg/day 6-8 weeks
Poor to moderate
evidence of efficacy
 66 OA, RA mixed
population
and
Ankylosing Spondylitis
Examine efficacy of Imipramine Showing significant pain relief
 NO studies specifically carried out on the OA until the publishing date of this article.

41. In clinical Practice
TCA’s are often problematic
In addition to inhibiting Serotonin and NE reuptake
They also block
Side effects such as
 Sedation
• Dry mouth
 Blurred vision
 Dizziness
Particularly problematic in RA population
Because many of them also have SJOGREN’S Syndrome
• Cholinergic receptor
• Histamine receptor
• alpha-adrenergic receptor
Side effects

42.  They have similar Noradrenergic/Serotonergic reuptake
RATIOS compared with TCA’s
 In contrast to TCA’s, SNRIs are selective
• Duloxetine
• Milnacipran
2. Serotonin–norepinephrine reuptake inhibitor
MOA

43. Examinations
 40 Healthy individuals
 231 KNEE OA patients,
during 13 weeks
Low descending
analgesic activity
Duloxetine
60 mg/day
Increase in descending analgesic activityFrom 0.15 to 19.35 in 1 week
With
Duloxetine
60-120mg/day
Reduced mean 24 hours score
FDA approved for FIBROMYALGIA treatment
• Duloxetine
• Milnacipran
Pain relieving effect has been
seen in
both depressed and Non-
depressed patients

44. The α2δ Ligands
• Gabapentin
• Pregabalin
The α2δ Ligands are Anti convulsants
used to treat hronic pain conditions such
as
Postherpetic Neuroglia
Diabetic Neuropathy
Bind to α2δ subunit of Ca2+ Channels
Inhibiting the release of
Neuro transmitters
 Glutamate
 Noradrenaline
 Serotonin
 Substance P
MOA
These compounds working individuals with Central
sensitization, as well as decreased
Descending analgesic activity due to low serotonergic-
Noradrenergic Activity

45.  Pregabalin
Examinations
A Cochrane systematic review including1,376 fibromyalgia patients
300-450 mg/day
relative benefit between 1.5 (95%
confidence interval 1.2 to 1.9) and
1.7 (95% confidence interval 1.4 to
2.1) for a 50% decrease in pain
Improves in pain severity
in Fibromyalgia patients
although some patients will experience
moderate pain relief from Pregabalin, few
will experience a large effect
 No studies has been carried out on pain relief by
The α2δ Ligands in OA and RA patients until
publishing date of present article

46. Conclusions
 Central pain mechanisms play important roles in
widespread pain syndromes, including fibromyalgia. Th e
role of these mechanisms in rheumatologic diseases such
as OA and RA is not well understood.
 Larger studies about disease characteristics are necessary
to better understand the impact of central pain
mechanisms in OA and RA.
 If central pain mechanisms do play a significant role in
pain processing among OA and RA patients, drugs such
as SNRIs and α2δ ligands that target central pain
mechanisms may be attractive adjunctive treatments to
manage pain in patients with rheumatologic disease.