DW, Pain - Basic Science

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Pain - Basic Science

Implications for Analgesia & Analgesics

http://www.animationfactory.com/en/search/close-up.mc?&oid=5311201&s=1&sc=1&st=12&category_id=E1&q=pain&spage=1&hoid=107376ad3c2888c5cb5f4b0e09dd77bb



Sciops-Medical Division

Definition of pain

www.iasp.org/terms

“Pain is an unpleasant sensory and

emotional experience associated with

actual or potential tissue damage”




Is there a basis for the separation of pain?

A- Chronicity

B- intensity

C- Mechanism of action




A- Chronicity

Acute

Sudden onset

Self-limiting

Generally respondsto drug treatment ormanagement of theunderlying cause

Chronic

Onset not well

defined Persistent or

recurring

Triggered by injuryor disease butpersists even withtreatment

Acute at top of

chronic

(Flare up) Sudden onset

Self-limiting

Generally responds

to drug treatment ormanagement of theunderlying cause




B- Pain Intensity

Mild

Sever

Moderate



Assessing the efficacy of analgesics

Outcome measures used in clinical studies




Assessment of pain in clinical studies

Due to its subjective nature, the assessment of pain in clinical studies ischallenging.

There are several standardized pain assessment instruments:

Pain intensity – Visual Analogue Scale (VAS)

Pain intensity – categorical scale




Pain intensity – Visual Analogue Scale (VAS)

Continuous numerical self-rating pain scale

Patients mark along the line to represent pain intensity

Worst painExperienced

No pain

0 10

VAS score

Joyce C, et al . 1975




Pain intensity – categorical scale

0 = None

1 = Mild

2 = Moderate

3 = Severe

Pain categorized by number or descriptor

Patients select category to represent pain intensity



Feminine pain

Physiological

Psychological

Perception




The Complexity of Feminine Pain …

• Researches over the past twenty years have found significantdifferences between men & women regarding the following aspects

- Physiological response to pain 1

- Psychological perception of pain 2

1.Zubieta et al. 2002; Gear et al. 19962.Campbell, Clauw, & Keefe, 20033.Pain." The Merck Manual of Diagnosis and Therapy,




Why Females are more sensitive?

Nerve receptorsWomen have averaged double the number of nerve receptors

compared with men.

Hormones

Variations in women's Estrogen levels like those that occurthroughout the monthly menstrual cycle, or duringpregnancy regulate the brain's natural ability to suppressbrain. Endorphins ,Enkphalins ).

Testosterone, appears to raise the pain threshold




Incidence of acute pain in the US

CDC. 2004

Migraine/severe

headache

0

5

15

35

30

Neck pain Pain in faceor jaw

Lower backpain

10

20

25

US adults (%)




Prevalence and economic impactof chronic (persistent) pain

Worldwide, 22% of primary care patients suffer from persistent painevery year

75 million US adults experience chronic pain

12.7% of the US work force lose productive time over a 2-weekperiod due to common pain conditions (arthritis, back pain, headacheand other musculoskeletal conditions)

Common pain conditions cost US employers an estimated $61.2billion in lost production time each year

Gureje O, et al . 1998; Schnitzer T. 1998; Stewart W, et al . 2003




Worldwide impact of chronic pain

Gujere O, et al . 1998

Depression Poor health Workimpaired

Activitylimited

Chronic pain

No pain

0

20

30

50

10

Primary care attendees (%)

40




Goals of pain management

• Pain control

• Alter disease course (may not be possible)

• Restore function to affected areas (e.g. joints)• Address psychological factors such as stress and

depression

• Maximize quality of life (QoL)

Adapted from Ashburn MA. 1999




The World Health Organisation (WHO)analgesic ladder

3

2

Simple analgesicse.g. paracetamol , NSAIDs

Weak opiatese.g. codeine or dihydrocodeine +simple analgesics

Strong opiatese.g. morphine or diamorphine+ simple analgesics

I n c r e a s i n g

p a i n

1



Types of analgesics




Types of analgesics

• Simple analgesics (paracetamol)

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Weak opiates

• Strong opiates

• Corticosteroids




History of NSAID to the 21st Century

History: •In 1829, salicin was isolated in a pure form from thewillow bark (spiraer).

•In 1899, introduced into medicine under the name ofaspirin.

•Towards the end of the Nineteenth Century, otherNSAID were discovered.




PG’s pathway




PG has a big role to amplification of inflammation -pain - fever .

1. Anti-inflammatory effects

2. Analgesic effects NSAIDs

supp ress synthes is and

release of PGs by

inhib i t ing Cox enzymes

wh ich in turn block the

sensit izat ion o f pain

receptors.




Biology & Regulation of COX-1& COXII

COX 1 COX 2Constitutive under normal conditions Inducible, COX-2 is typically undetectable

in most tissues under basal conditions, butits expression in many cell types, includingmacrophages, fibroblasts, markedlydepends on stimulation with inflammatorycytokines

COX-1 is expressed in virtually alltissues, most notably:

Platelets ,Endothelial cells ,GIT ,kidney

COX-2 is expressed in a variety tissues in

basal conditions such as:Kidney ,Brain

,Bone &Cartilage

COX-2 is rapidly induced and participatesin pathological and inflammatory tissue

processes.



Sciops-Medical DivisionPlatelet aggregation Cytoprotection Pain and inflammation

Traditional NSAIDsMechanism of action

Thromboxane

synthase

TxA2

AA

Reduction in

platelet aggregation

Reduced

cytoprotection

Reduced

pain and inflammation

Prostaglandin

isomerase

PGI2PGE2

Prostacyclin

synthase

PGH2 PGH2

AA

Prostaglandin

isomerase

Prostacyclin

synthase

Phospholipids

PGH2

Phospholipids Phospholipids

AA

Platelet Inflamed synoviumGI mucosa

COX-2

COX-2

COX-2

COX-1

COX-1

COX-1

COX-1

COX-1

PGI2PGE2

membrane




Risk factors for GI ulcer complications

Corticosteroiduse

Wolfe M, et al. 1999

Warfarin use Aspirin use

Cardiovasculardisease

Increasingage

Risk of ulcercomplication

Higher dosesMore thanone NSAID

Previousulcer or bleed




Strategies to prevent NSAID-associated GI adverseevents

• Administration of concomitant gastroprotectants such as PPIs (e.g. omeprazole; Losec®) prostaglandin analogues (misoprostol) are partiallyeffective but add their own potential side effects1

• Administration of NSAIDs with food reduces gastric irritation

• Enteric-coated tablets release drug in the small intestine, thereby preventingdirect damage to the stomach

1

NICE. 2001




• It has been demonstrated that upper GI ulcers, gross bleeding or

perforation, caused by NSAIDs, appear to occur in approximately 1%

of patients treated for 3-6 months, and in about 2-4% of patients

treated for one year.

FDA



Musculoskeletal diseases




Common musculoskeletal diseases

Osteoarthritis A combination of Predisposing factors &jointBiomechanics(degenerative) which triggers Biochemical(Inflammatory ) changes

Rheumatoid arthritis A chronic, progressive, inflammatory disease of the joints

Ankylosing spondylitis An inflammatory disease of the joints of the back bone

Juvenile arthritis A form of arthritis affecting children

Gout A metabolic disease in which uric acid crystals deposit inthe joints

P l d E i b d f




Prevalence and Economic burden ofmusculoskeletal disease

More than 33 million people in the US (16% of the population) have a form ofarthritis

• 28 million aged 45 years

• prevalence is projected to increase to 18.2%

by 2020 due to aging population

Worldwide it is estimated that 9.6% of men and 18.0%of women aged 60 years have symptomatic OA

1.0 –2.5% of Gross National Product (GNP) is spent

annually on musculoskeletal disorders in the US,Canada, UK, France and Australia

March L, et al. 1997; Woolf A, et al. 2003

Di bilit b d f l k l t l




Disability burden of musculoskeletaldiseases

Ischaemic heart disease

Cerebrovascular disease

Total musculoskeletal disease

OAHIV/AIDS

Chronic obstructivepulmonary disease

Liver cirrhosis

Asthma

RA

0 2 106 84Disability –adjusted life years (millions)

Reginster J, et al. 2002




Rheumatic Disorders Classification

Gout

Tendinitis

Tenosynovitis

Sport Injuries &strains

GoutRheumatoid

Arthritis

AnkylosingSpondylitis

Osteoarthritis

Articulus: Latin word means joint

Bursitis



Normal Joints




Normal Joint




The Articular Cartilage (Hyaline cartilage)

• Avascular ,Aneural

Formed of: Water 69%

Collagen 15%

Proteoglycans 15% Chondrocytes 1%

Matrix

Function: Shock absorbent , distribute load applied on joints

Structure of articular cartilage (hyaline cartilage)




Structure of articular cartilage (hyaline cartilage)

2. Condrocytes :Mature cartilage,cellular manufacturing sites

Fn: Production & MaintenanceOf surrounding matrix

1. Collagen Fibers: sheets of Fibrous proteins ,Fn:provide high tensile strength to theCartilage, resistant to extension

Protect cartilage from swelling pressuregenerated by proteoglycans

3. Proteoglycans: Large ,high molecular weight molecules ,Available in aggregates,Consist of protein core and Carbohydrate Side chain (Chondroitin sulphate and keratin sulphate)

and long central chain of hyaloronic acid, Hygroscopic i.e. attract water to make a hydrated tissuethat resist compression

protein



Osteoarthritis




Prevalence

• Leading cause of chronic disability in elderly

• The most common joint disease.

• 35% of rheumatic consultations

• 30% of women aged between 45-64 years suffer from O.A

• And 70% for patients with age above than 65 years



A Multifactorial Disease

Adapted from The Lancet, Vol 365, Dieppe PA, Lohmander S. Pathogenesis and management ofpain in osteoarthritis, Pages 965-973, Copyright 2005, with permission from Elsevier

1

2

3

O.A is a Combination of predisposing factors & jointbiomechanics leading to biochemical Changes.



Pathogenesis of OA ( Predisposing Factors)

Susceptibility to OA may be increased in part by:

• genetic inheritance (a positive family history increases risk),

• age,

• ethnicity,

• diet and

• female gender

Felson DT (2004a) An update on the pathogenesis and epidemiology of osteoarthritis. Radiologic Clin North Am 42, 1 –9.



Pathogenesis of OA ( Joint Biomechanics)(Mechanical leads to structural changes)

Loading can also be affected by• Obesity & Joint injury (either acutely as in a sporting injury or after

repetitive overuse such as occupational exposure), both of which canincrease the likelihood of development or progression of OA)

Local mechanical factors that facilitate progression

• Malalignment

• Muscle weakness

• Structural integrity (menisical damage of bone marrow lesions)

Felson DT (2004a) An update on the pathogenesis and epidemiology of osteoarthritis. Radiologic Clin North Am 42, 1 –9.



Pathogenesis of OA (Biochemical Changes)

OA results from an imbalance in catabolic and anabolicprocesses that lead to progressive cartilage damage anddestruction.

Initially anabolic process such as proteoglycan synthesismaintain balance with catabolic processes and damage tocartilage is repaired. However with time and age ,anabolicprocesses decline and progressive damage ensues.

Osteoarthritis and Cartilage (2008) 16, 624e630



Often the slow but efficient OA process compensates forthe insults, resulting in an anatomically altered butsymptom free functioning joint (compensated OA)

Sometimes because of severe increased insult or poorrepair response, it fails resulting in progressive tissuedamage and presentation of symptoms due to joint failure.

Pathogenesis of OA (biochemical)





1

12

23

3

44

5



Joint involvement in OA

Solomon L. Clinical features of osteoarthritis. Textbook Rheum 1997;2:1383 –1393.



Knee Osteoarthritis

In the early stages of the disease, pain is the

main symptom, yet in advanced stages,

cartilage degeneration takes place and the

patient also complains from asound

.

Main symptoms:

Localized knee Pain during movement ‘movement related pain’

Resting stiffness

In severe cases, pain is continuous even during rest.

Mechanical pain might also increase with excessive use of

the joint, and this appears at night. 54



Knee joint effusion

Deformities


http://en.wikipedia.org/wiki/Image:Heberden-Arthrose.JPG




Heberden’s nodes :Hard or bony swellings which can develop in thedistal interphalangeal joints (DIP).

Bouchard's nodes: bony growths in the proximal interphalangeal (PIP) joints

http://en.wikipedia.org/wiki/Image:Heberden-Arthrose.JPG




Special Investigations

• Blood tests: Normal

• Radiological features:

• Cartilage loss• Narrowed joint space

• Subchondral sclerosis

• Cysts

• Osteophytes

R di hi F t f th



Radiographic Features of theKnee in OA

Joint space narrowing

Marginal osteophytes

Subchondral cysts

Boney sclerosis

Malalignment

Joint spacenarrowing




Goals of The Treatment

Relief pain, swelling and inflammation.

Inhibit joint degeneration.

Improve quality of life.


Components of Multimodal Osteoarthritis



Components of Multimodal OsteoarthritisTreatment

Non-pharmacological TherapyEducation Physical therapy ExerciseOccupational therapy Weight Control Assistivedevices Nutraceuticals

Pharmacological TherapyNSAIDs Topical

DMAs

Intra-articular Injection

Hyaluronic acidsCorticosteroids

Surgery




Rheumatoid arthritis




What is Rheumatoid Arthritis ( RA )

Systemic multi-organ inflammatory disease Of unknownaetiology.

NORMAL RA




What is rheumatoid arthritis ?

• It is a systemic multi organ inflammatory disease of unknown etiology.

• Associated with characteristics of joint pathology.

• Auto antibodies

• Immunologic hyperactivity

• The cause is unknown ,however the following factors contribute to theetiology:

• Heredity

• Infections

• Rheumatic factor : IgM detected in 85% of R.A patients (seropostive),associated with more severe joint disease and subcutaneous nodes

• Over activity of immune system over individual’s own cells




Risk Factors

• Genetic

• Age ( ↑ with age)

• Sex (> female)

• Obesity

• Joint trauma and injury

• Repetitive occupational joint use

• Physical inactivity

RA - Pathology & Pathogenesis




RA - Pathology & Pathogenesis

• Active chronic inflammation of the synovial membrane

• Synovial membrane proliferation and out-growth

• Erosion of the articular cartilage and sub-chondral bone

• Formation of the characteristic pannus

• First affects the small joints

• Order of involvement : fingers, toes, hands, knees, elbows,

shoulders and hips.



Signs and symptoms of R

Signs

Hand joint deformities suchas Boutonnière and Swan

neck & subcutaneousnodules

Synovium hypertrophy

Bone erosion

Rheumatoid factor present in85% of patients

Symptoms

Joint swelling, warmth andtenderness

Pain and stiffness

Weakness, fatigue

Fever

Depression

Hope R, et al . 1998




RA - Hand Involvement

Subcutaneous NodulesOver Elbow in Rheumatoid Arthritis Severely Affected Hand With

S b t N d l O K kl S N k D f it Of Middl Fi W ti Of




Subcutaneous Nodules Over Knuckle, Swan – Neck Deformity Of Middle Finger, Wasting Of

Hand, and Ulnar Drift of Fingers




RA - Laboratory Findings

• The erythrocyte sedimentation rate (ESR) is elevated

in most patients.

• The presence of RF (85%)

• Antinuclear antibodies (30-40%)




RA – Management Goal

1. Relief of pain

2. Reduction of inflammation

3. Preservation of muscle strength and joint function

4. Return as rapidly as possible to a normal lifestyle




Management

• Pain relief with NSAIDs

• Adequate rest

• Weight reduction

• Immunosuppressive

• Local corticosteroid injections

• Long term corticosteroids (should be preserved for pts with aggressive joint

reaction whose ability to function is threatened)

• Prolonged home exercise program

ff f O f




Differential diagnosis of OA from RA

OA RA

More common inhip and knee

More common inwrist, elbow and shoulder

Joint tenderness Joint warmth and redness

Patient typically >45 yearsat onset

Usually symmetrical joint involvement

Patient typically 25 –55years at onset

Asymmetrical joints

Joint space narrowing



Ankylosing Spondyltis

Classic areas of inflammation in ankylosing




y gspondylitis




Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axialskeleton manifested by back pain and progressive stiffness of the spine.

AS is one of the spondyloarthropathies which show inflammation around theenthesis (the site of ligament insertion into bone) and an association with thehuman leukocyte antigen HLA-B27.

It characteristically affects young adults with a peak age of onset between 20and 40 years. Although classically thought of as a spinal disease, transientacute arthritis of peripheral joints (hips, shoulders, knees) occurs in up to 50 percent of patients




Ankylosing spondylitis

There are three clinical criteria:

• Low back pain

• Morning stiffness of greater than threemonths duration, improving with exercisebut not relieved by rest

• Limitation of motion of the lumbar spine

It can result in the following

• Fused vertebrae

• Rigid spine, and• Flattening of the lower back.

• The joints and ligament becomeinflamed.




Ankylosing Spondylitis {AS}

Investigations:

X-ray findings (bilateral sacrolitis; bamboo spine..)

ESR

HLA-B27

(95% of cases) (human leukocytic antigen) not all

RF -ve

Treatment:

Active mobilisation and spine exercises are very important.

NSAIDs



Non Articular RheumatismSoft Tissue Rheumatism




Non Articular Rheumatic disorders

• Most common Rheumatic disorders where joints aren’taffected .

• Referred to muscular , adipose tissue , tendons , jointcapsules and bursa.

• Both inflammatory & Degenerative processes play role.

• Most prominent symptoms are pain and tenderness.




Non Articular Rheumatic disorders

Disorder Pathology

Bursitis Pleural of bursa is synovial sacs that lies betweentendons ,bones and muscles or tendons and skin

Function is to minimize friction

Inflammation of bursa is associated with swelling ,redness of skin and limitation of movement of nearby joints

Tendonitis /Tenosynovitis

Changes affecting tendons and their sheath due to microtrauma or occupational origin

Synovitis Inflammation in synovial membrane

Periarthritis Inflammation in the tissues surrounding the joints , thebursae is often involved

Myositis Pain , tenderness , due to acute or chronic inflammation

of muscles




Management of Non Articular Rheumatic disorders

Rest

NSAIDS

Local steroids

Physiotherapy



Thank you

DW, Pain - Basic Science

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