DW, Pain - Basic Science

Pain - Basic Science
Implications for Analgesia & Analgesics
Definition of pain
Pain is an unpleasant sensory and
emotional experience associated with

actual or potential tissue damage
Sciops-Medical Division
www.iasp.org/terms
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 responds to drug treatment or management of the underlying cause
Chronic
Onset not well defined Persistent or recurring Triggered by injury or disease but persists even with treatment
Acute at top of chronic (Flare up)

Sudden onset
Self-limiting Generally responds to drug treatment or management of the underlying cause
B- Pain Intensity
Mild
Moderate
Sever
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 is
challenging.
There are several standardized pain assessment instruments:

Pain intensity Visual Analogue Scale (VAS) Pain intensity categorical scale
Pain intensity Visual Analogue Scale (VAS)

Worst pain Experienced
No pain
10
VAS score
Continuous numerical self-rating pain scale Patients mark along the line to represent pain intensity
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 significant differences between men & women regarding the following aspects
- Physiological response to pain
- Psychological perception of pain 2
1.Zubieta et al. 2002; Gear et al. 1996 2.Campbell, Clauw, & Keefe, 2003 3.Pain." The Merck Manual of Diagnosis and Therapy,
Why Females are more sensitive?

Nerve receptors
Women have averaged double the number of nerve receptors compared with men.
Hormones Variations in women's Estrogen levels like those that occur throughout the monthly menstrual cycle, or during pregnancy regulate the brain's natural ability to suppress brain. Endorphins ,Enkphalins ).
Testosterone, appears to raise the pain threshold
Types of acute and chronic pain

Acute
Headache/migraine Postoperative pain Dysmenorrhoea Pain following dental surgery Gout
Chronic
Osteoarthritis (OA) Rheumatoid arthritis (RA) Ankylosing spondylitis (AS) Lower back pain Cancer pain
Sciencephoto.com
Incidence of acute pain in the US

US adults (%) 35 30 25 20 15 10 5 0 Migraine/ severe headache Neck pain Lower back pain Pain in face or jaw
CDC. 2004
Prevalence and economic impact of chronic (persistent) pain

Worldwide, 22% of primary care patients suffer from persistent pain
every year
75 million US adults experience chronic pain 12.7% of the US work force lose productive time over a 2-week
period due to common pain conditions (arthritis, back pain, headache and other musculoskeletal conditions)
Common pain conditions cost US employers an estimated $61.2

billion in lost production time each year
Gureje O, et al. 1998; Schnitzer T. 1998; Stewart W, et al. 2003

Worldwide impact of chronic pain

Primary care attendees (%) 50 40 30 20 10 0 Chronic pain No pain
Depression
Poor health
Work impaired
Activity limited
Gujere O, et al. 1998
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
Increasing pain
3 2
Simple analgesics
e.g. paracetamol , NSAIDs
Strong opiates
e.g. morphine or diamorphine + simple analgesics
Weak opiates
e.g. codeine or dihydrocodeine + simple analgesics
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 the willow bark (spiraer). In 1899, introduced into medicine under the name of aspirin. Towards the end of the Nineteenth Century, other NSAID were discovered.
PGs pathway
PG has a big role to amplification of inflammation pain - fever .

1. Anti-inflammatory effects 2. Analgesic effects NSAIDs
suppress synthesis and release of PGs by
inhibiting Cox enzymes

which in turn block the sensitization of pain receptors.
Biology & Regulation of COX-1& COXII

COX 1
Constitutive under normal conditions
COX 2
Inducible, COX-2 is typically undetectable in most tissues under basal conditions, but its expression in many cell types, including macrophages, fibroblasts, markedly depends on stimulation with inflammatory cytokines
COX-1 is expressed in virtually all tissues, 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 participates in pathological and inflammatory tissue processes.
Traditional NSAIDs Mechanism of action

Platelet
Phospholipids
AA
COX-1 COX-1
GI mucosa
Phospholipids
AA
COX-1 COX-1
Inflamed synovium
Phospholipids membrane
AA
COX-1 COX-2 COX-2 COX-2
PGH2
Thromboxane synthase
PGH2
Prostacyclin synthase
Prostaglandin isomerase
PGH2
Prostacyclin synthase
Prostaglandin isomerase
TxA2
PGE2
PGI2
PGE2
PGI2
Reduction in Platelet aggregation Sciops-Medical Division platelet aggregation
Reduced Cytoprotection cytoprotection
Reduced Pain and inflammation pain and inflammation
Risk factors for GI ulcer complications

Increasing age
Aspirin use
Warfarin use
More than one NSAID
Risk of ulcer complication
Higher doses
Cardiovascular disease Corticosteroid use

Previous ulcer or bleed
Wolfe M, et al. 1999
Strategies to prevent NSAID-associated GI adverse events
Administration of concomitant gastroprotectants such as PPIs (e.g.

omeprazole; Losec) prostaglandin analogues (misoprostol) are partially effective 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 preventing
direct damage to the stomach
1NICE.
2001
FDA
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.
Musculoskeletal diseases
Common musculoskeletal diseases

Osteoarthritis A combination of Predisposing factors &joint Biomechanics(degenerative) which triggers Biochemical (Inflammatory ) changes A chronic, progressive, inflammatory disease of the joints An inflammatory disease of the joints of the back bone A form of arthritis affecting children A metabolic disease in which uric acid crystals deposit in the joints
Rheumatoid arthritis Ankylosing spondylitis Juvenile arthritis Gout
Prevalence and Economic burden of musculoskeletal disease

More than 33 million people in the US (16% of the population) have a form of arthritis
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 1.02.5% 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
Disability burden of musculoskeletal diseases

Ischaemic heart disease
Cerebrovascular disease Total musculoskeletal disease OA HIV/AIDS Chronic obstructive pulmonary disease Liver cirrhosis Asthma RA 0
2 4 6 8 10 Disabilityadjusted life years (millions)

Reginster J, et al. 2002
Rheumatic Disorders Classification
Gout
Tendinitis Rheumatoid Arthritis Osteoarthritis Gout Tenosynovitis Ankylosing Spondylitis Sport Injuries & strains Bursitis
Articulus: Latin word means joint

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)

1. Collagen Fibers: sheets of Fibrous proteins , Fn:provide high tensile strength to the Cartilage, resistant to extension Protect cartilage from swelling pressure generated by proteoglycans 2. Condrocytes :Mature cartilage, cellular manufacturing sites Fn: Production & Maintenance Of surrounding matrix
protein
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 tissue Sciops-Medical Division that resist compression
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
O.A is a Combination of predisposing factors & joint biomechanics leading to biochemical Changes.
1 2 3
Adapted from The Lancet, Vol 365, Dieppe PA, Lohmander S. Pathogenesis and management of pain in osteoarthritis, Pages 965-973, Copyright 2005, with permission from Elsevier
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, 19.
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 can increase 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, 19.
Pathogenesis of OA (Biochemical Changes)

OA results from an imbalance in catabolic and anabolic
processes that lead to progressive cartilage damage and destruction.
Initially anabolic process such as proteoglycan synthesis

maintain balance with catabolic processes and damage to cartilage is repaired. However with time and age ,anabolic processes decline and progressive damage ensues.
Osteoarthritis and Cartilage (2008) 16, 624e630
Pathogenesis of OA (biochemical)
Often the slow but efficient OA process compensates for
the insults, resulting in an anatomically altered but symptom free functioning joint (compensated OA)
Sometimes because of severe increased insult or poor

repair response, it fails resulting in progressive tissue damage and presentation of symptoms due to joint failure.
4 3 3 2
Joint involvement in OA
Solomon L. Clinical features of osteoarthritis. Textbook Rheum 1997;2:13831393.
Clinical Manifestations
Pain and Stiffness
Tenderness and swelling

Crepitus ; irregular joint Functional impairment
Crepitus :Crackling or popping sounds created when two rough surfaces in the human body come into contact
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 a sound.
Main symptoms:
Localized knee
Pain during movement movement related pain
Resting stiffness excessive use of

54
In severe cases, pain is continuous even during rest. Mechanical pain might also increase with the joint, and this appears at night.
Deformities
Knee joint effusion
Heberdens nodes :Hard or bony swellings which can develop in the distal interphalangeal joints (DIP). Bouchard's nodes: bony growths in the proximal interphalangeal (PIP) joints
Special Investigations
Blood tests: Normal
Radiological features:
Cartilage loss Narrowed joint space Subchondral sclerosis Cysts Osteophytes
Radiographic Features of the Knee in OA

Joint space narrowing Marginal osteophytes Subchondral cysts Boney sclerosis Malalignment
Joint space narrowing
Goals of The Treatment

Relief pain, swelling and inflammation.
Inhibit joint degeneration. Improve quality of life.
Components of Multimodal Osteoarthritis Treatment
Surgery
Intra-articular Injection Hyaluronic acids Corticosteroids Pharmacological Therapy

NSAIDs Topical DMAs
Non-pharmacological Therapy
Education Physical therapy Occupational therapy Weight Control devices Nutraceuticals Exercise Assistive
Rheumatoid arthritis
What is Rheumatoid Arthritis ( RA )

Systemic multi-organ inflammatory disease Of unknown aetiology. 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 the etiology: 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 individuals own cells
Risk Factors
Genetic Age ( with age) Sex (> female)
Obesity
Joint trauma and injury
Repetitive occupational joint use Physical inactivity
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. Sciops-Medical Division
Signs and symptoms of RA

Signs
Hand joint deformities such as Boutonnire and Swan neck & subcutaneous nodules Synovium hypertrophy Bone erosion Rheumatoid factor present in 85% of patients
Symptoms
Joint swelling, warmth and tenderness
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 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.
2. 3. 4.
Relief of pain
Reduction of inflammation Preservation of muscle strength and joint function 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
Differential diagnosis of OA from RA

OA
Patient typically >45 years at onset Asymmetrical joints Joint space narrowing More common in hip and knee Joint tenderness
RA
Patient typically 2555 years at onset More common in wrist, elbow and shoulder
Usually symmetrical joint involvement

Joint warmth and redness
Ankylosing Spondyltis
Classic areas of inflammation in ankylosing spondylitis
Ankylosing Spondylitis
Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton manifested by back pain and progressive stiffness of the spine. AS is one of the spondyloarthropathies which show inflammation around the enthesis (the site of ligament insertion into bone) and an association with the human leukocyte antigen HLA-B27. It characteristically affects young adults with a peak age of onset between 20 and 40 years. Although classically thought of as a spinal disease, transient acute 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 three months duration, improving with exercise but 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 become inflamed.
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 Rheumatism Soft Tissue Rheumatism
Non Articular Rheumatic disorders

Most common Rheumatic disorders where joints arent
affected .
Referred to muscular , adipose tissue , tendons , joint

capsules and bursa.
Both inflammatory & Degenerative processes play role.
Most prominent symptoms are pain and tenderness.

Non Articular Rheumatic disorders

Disorder
Bursitis
Pathology
Pleural of bursa is synovial sacs that lies between tendons ,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 Changes affecting tendons and their sheath due to micro trauma or occupational origin Inflammation in synovial membrane Inflammation in the tissues surrounding the joints , the bursae is often involved Pain , tenderness , due to acute or chronic inflammation of muscles
Tendonitis / Tenosynovitis Synovitis Periarthritis
Myositis
Management of Non Articular Rheumatic disorders

Rest NSAIDS
Local steroids
Physiotherapy
Thank you

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Pain - Basic Science

Implications for Analgesia & Analgesics

Pain is an unpleasant sensory and

emotional experience associated with

Is there a basis for the separation of pain?

Acute at top of chronic (Flare up)

Assessing the efficacy of analgesics

Assessment of pain in clinical studies

There are several standardized pain assessment instruments:

Pain intensity Visual Analogue Scale (VAS)

Joyce C, et al. 1975

Pain intensity categorical scale

0 = None 1 = Mild 2 = Moderate 3 = Severe

Pain categorized by number or descriptor

The Complexity of Feminine Pain

- Physiological response to pain

- Psychological perception of pain 2

Why Females are more sensitive?

Types of acute and chronic pain

Incidence of acute pain in the US

Prevalence and economic impact of chronic (persistent) pain

Common pain conditions cost US employers an estimated $61.2

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

Worldwide impact of chronic pain

Gujere O, et al. 1998

Goals of pain management

Maximize quality of life (QoL)

Adapted from Ashburn MA. 1999

The World Health Organisation (WHO) analgesic ladder

Nonsteroidal anti-inflammatory drugs (NSAIDs)

History of NSAID to the 21st Century

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

suppress synthesis and release of PGs by

inhibiting Cox enzymes

Biology & Regulation of COX-1& COXII

COX-1 is expressed in virtually all tissues, most notably:

Traditional NSAIDs Mechanism of action

Reduction in Platelet aggregation Sciops-Medical Division platelet aggregation

Reduced Cytoprotection cytoprotection

Reduced Pain and inflammation pain and inflammation

Risk factors for GI ulcer complications

More than one NSAID

Risk of ulcer complication

Cardiovascular disease Corticosteroid use

Previous ulcer or bleed

Wolfe M, et al. 1999

Strategies to prevent NSAID-associated GI adverse events

Administration of concomitant gastroprotectants such as PPIs (e.g.

Common musculoskeletal diseases

Rheumatoid arthritis Ankylosing spondylitis Juvenile arthritis Gout

Prevalence and Economic burden of musculoskeletal disease

prevalence is projected to increase to 18.2% by 2020 due to aging population

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

Disability burden of musculoskeletal diseases

2 4 6 8 10 Disabilityadjusted life years (millions)

Rheumatic Disorders Classification

Articulus: Latin word means joint

The Articular Cartilage (Hyaline cartilage)

Function: Shock absorbent , distribute load applied on joints

Structure of articular cartilage (hyaline cartilage)

The most common joint disease.

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

Pathogenesis of OA ( Predisposing Factors)