The role of the central nervous system in thegeneration and maintenance of chronic pain

in rheumatoid arthritis, osteoarthritis andfibromyalgia

Yvonne C Lee1*, Nicholas J Nassikas1 and Daniel J Clauw2

Review:

Article Reviewed by:Danial Mehranfard

Advisor:Prof.Dr. Emre Hamurtekin

Pharmacology GroupMarch 8th 2017

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.

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

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.

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.

Basic biology of pain in healthy individuals

Acute pain:1. Last from seconds to weeks or months2. Sudden in onset3. Direct result of noxious stimulus

Chronic pain:1. At least 3 months2. Maybe persist because:

1. the initially stimulus is still present

2. OR because changes to nervous system have been occurred

Pain categorization :

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

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

Types of nociceptor

s

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.

Chronic painMechanism

Mec

hani

sms o

f chr

onic

pain

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

AllodyniaPan in response to

normally NONPAINFUL stimuli

Abnormalities in CPP

Descending Facilitatory

Inhibitory Pain Pathway

Central Sensitization

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.

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

Descending analgesic pathways are typically Tonically active inhibit the upward

transmission of pain signals,

involve enhanced activity down the descending

facilitatory pain pathwaysOther descending pain-processing mechanisms

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 occurs 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.

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 ofGlutamate and substance P at the level of the

spinal cord.

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

NMDA Mechanism

NMDA receptor activation calcium influx Stimulating calcium/calmodulin-dependent kinases

Extracellular signal-regulated kinases

AND

modulate CNS plasticity

hyperalgesia and allodynia

characterize central sensitization

Experimentally Central sensitization characterized by

Repeated Stimulation

Diffuse pain sensitivityIncreased pain severity

During and after repeated stimuli

Individuals with Central sensitization

Low Thermal and Mechanical Threshold

So

Painful after-Sensation

Persist after stimulus is withdrawn;

Also pain rating for the last

stimulus is HIGHER

NMDA receptor antagonists

DextrametraphonInhibit

temporal stimulation Ketamine

Rheumatic Diseases OutlineWhich we’re going to learn more about it in the present review

1.FIBROMYALGIA

2.OSTEOARTHRITIS

3.RHEUMATOID ARTHRITIS

1. FIBROMYALGIA Fibromyalgia is the prototypical non-inflammatory chronic pain

syndrome.

They have LOWER pain Threshold than normal healthy controls

Lab Result Differences in Fibromyalgia patients:

Serotonin (Serum Level) L-Tryptophan 5-Hydroxyindoleacetic acid 3-Methoxy-4-Hydroxyphen-

Ethylene

LOWERIn compare of healthy controls

Activity of Endogenous Opioidergic System

HIGHERIn compare of healthy controls

These defects in inhibitory pain responses may be due to

Cerebral spinal fluid

blunted activity of the descending serotonergic–

noradrenergicsystem

Fibromyalgia patients are more sensitive to variety of stimuli

Due to enhances Neuronal activity

INSULA

Posterior

Anterior

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

Gracely and colleagues

Fibromyalgia patientsVs

Controls

RESEARCH 1 studies of fMRI in fibromyalgia

Exhibit enhanced activation

1. Contralateral primary somatosensory cortex (SI)

2. Inferior parietal lobe3. Insula4. Anterior cingulate cortex5. Posterior cingulate cortex6. Ipsilateral secondary somatosensory

cortex (SII) Cortex7. 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

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

Napadow and colleagues

Default mode network

RESEARCH 3

I. medial frontal gyriII. hippocampusIII. lateral temporal cortexIV. posterior cingulate cortex V. precuneusVI. 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

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.

Pain intensity and severity poorly correlates

with peripheral joint damage

and strongly associated

With Radiographic damage

Little is known about OA causes.

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

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

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

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.

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.

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

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

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.

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. SNRIs3. The α2δ

Ligands

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*.

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.

In clinical PracticeTCA’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

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

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

Duloxetine60-120mg/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

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

Pregabalin

ExaminationsA 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

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.