Pain, Inflammation and Healing - Basic Science Core

Immuno Exam 1

Nociceptive Pain

• When the nociceptors become irritated – this typically results from ongoing injury or Inflammation of somatic (e.g. – joint, muscle, skin) or visceral tissue (e.g. – GI tract); examples include:

  • Arthritis

  • Sports injuries (strains, sprains, tears, fractures)

  • Burns

  • Gastritis

  • Post-operative pain

Spinothalamic System Parts (2)

1) LATERAL SPINOTHALAMIC TRACT

2) ANTERIOR SPINOTHALAMIC TRACT

LATERAL Spinothalamic Tract

• Conveys sensory impulses for pain & temperature

• Sensory from the brain to the distal to move in response to pain

ANTERIOR Spinothalamic Tract

For light touch

Ascended from distal to the brain

Describe Nociceptive Pain

• Sharp,

• Aching

• Stinging

• Throbbing that is easily localized

• Nociceptive pain is typically time-limited (with arthritis being the exception)

How to treat Nociceptive pain

• Generally responds “well” to various drug therapies, namely opioid and non- opioid analgesics.

Neuropathic Pain

• The peripheral or central nervous systems are malfunctioning

• Cause by damage of the brain, spinal cord or peripheral nerves

• Pain Symtoms

  • burning

  • tingling

  • numbness

  • shooting

  • stabbing

  • electric-like feelings

  • Allodynia

  • Hyperalgesia

Neuropathic pain is very “stubborn”, as it does not usually respond as well as nociceptive pain to opioid or non-opioid analgesics.

Hyperalgesia

An extreme, abnormal increase in sensitivity to pain.

• It occurs when your body's pain receptors or nerves become overly sensitive, meaning a mild hurt feels much worse than it should

Allodynia

• a medical condition where you feel pain from things that do not normally hurt, such as a light touch, a gentle breeze, or soft clothing. It is a sign of sensitive nerves, not a disease itself.

Neuropathic Pain Examples (3)

• Diabetic neuropathy

• Trigeminal neuralgia

• Post-herpetic neuralgia

Analgesics

• Medications that relieve pain

Types of Analgesics (3)

1) Non-Opioid Analgesics

2) Opioid Analgesics

3) Adjuvant Analgesics or Co-Analgesics

Non-Opioid Analgesics (4)

• Aspirin (ASA; salicylates)

• Non-steroidal anti-inflammatory drugs (NSAIDs)

• Corticosteroids (Glucocorticoids, “Steroids”)

• Acetaminophen (APAP; Tylenol)

_______

• Biggest number of drugs.

Opioid Analgesics

• “Opioids”

• “Narcotics”

Adjuvant Analgesics or Co-Analgesics

• Drugs that are usually given for reasons other than pain but that sometimes relieve pain

Pain Scales (3 Steps)

Developed by the World Health Organization (WHO) - Three Steps:

1) Mild Pain

• 1-3 / 10 Step 1

2) Mild to Moderate Pain

• 4-6 / 10 Step 2

3) Moderate to Severe Pain

• 7-10 / 10 Step 3

Mild Pain Treatment

• Mild pain be treated with non-opioid medications such as aspirin,

  acetaminophen or other NSAID

• 1 to 3

Moderate Pain Treatment

• Moderate pain be treated with a “weaker” opioid (e.g., codeine, hydrocodone, oxycodone or propoxyphene) and a non-opioid

• 4 to 6

Severe Pain Treatment

• Severe pain be treated with a “stronger” opioid (e.g., morphine or hydromorphone) and a non-opioid

• 7 to 10

Most of the time what is pain?

• Inflammation

Is Acute inflammation positive?

• Yes

- 1) inflammation provides a cellular environment to healing

- 2) healing and repair of tissue will not occur unless inflammation occurs first

The five principal effects of acute inflammation:

• 1) Redness - caused by vessel dilation

• 2) Heat - caused by increased blood flow

• 3) Swelling - due to extravascular accumulation of fluid

• 4) Pain - due to chemical mediators & tissue distortion

• 5) Loss of function - movement of inflamed area is consciously inhibited by pain, plus severe swelling can immobilize tissue

Acute Inflammation Cascade: (7)

Tissue injured →

Vasodilation →

Increased capillary permeability →

Formation of exudate containing fluid, proteins & ions → Blood flow slows →

WBCs transmigrate across capillary wall to the site of injury →

WBCs engulf microbes, tissue debris, etc. →

WBCs kill and destroy microbes, tissue debris, etc.

What Controls the Acute Inflammation Cascade:

CHEMICAL MEDIATORS & MOLECULES

Types of Chemical Medicators (2)

• Exogenous mediators -- come from the injurous agent

• Endogenous mediators – come from us

Five Endogenous Mediators

1) Histamine

2) Arachidonic Acid Metabolites (e.g. – prostaglandins, leukotrienes)

3) Cytokines

4) Kinins

5) Serotonin

Histamine

• Released by basophils and mast cells

• Causes vasodilation, increasing the blood flow to the site of injury

• Increases vascular permeability

• Promotes production of mucus

• Recruits WBCs to the injured area

_

• Triggers the release of cytokines, further amplifying the inflammatory response

Serotonin

• Released from platelets

_

• Attracts neutrophils to sites of injury to initiate and exacerbate the inflammatory response

• Can promote the production of cytokines

Cytokines

• Released from various WBCs

_

• Include several different types of chemicals:

  • Leukotrienes or interleukins (e.g., IL-17, IL-23)

  • Tumor necrosis factors (e.g., TNF-)

  • Chemokines

• Signal and recruit other WBCs (major amplifiers of inflammation) –

  allows WBCs to communicate with each other

• “Balance” the inflammatory response – some cytokines promote

  inflammation (pro-inflammatory), while others help to dampen it

  down (anti-inflammatory)

• Can promote vasodilation, but to a lesser extent than other chemical mediators

Prostaglandins

• Released from injured cells

• Cause significant amounts of vasodilation and capillary permeability

• Significant contributor to sensation of pain

• Attract neutrophils to site of injury

• Can also cause fever

Kinins

• Released from injured cells

• Major one is BRADYKININ

• Promote vasodilation and capillary permeability

• Stimulate the release of cytokines and prostaglandins

• Promote migration of neutrophils to the site of injury

• Significant contributor to sensation of pain

Outcomes of Acute Inflammation: (3)

• Resolution

• Tissue destruction and persistent acute inflammation

• Progression to chronic inflammation

Primary Goals of Treating Inflammation (2)

1) The relief of pain, which is often the presenting symptom and the major continuing complaint of the patient

2) The slowing or arrest of tissue-damaging processes

Nonsteroidal anti-inflammatory drugs (NSAIDs) – How Do They Work?

• By interfering with the cyclooxygenase pathway

• Stops both COX 1 & Cox 2

• THUS prevents the amount of Prostaglandins made

The Cyclooxygenase Pathway

• The normal process begins with arachidonic

  acid, a dietary unsaturated fatty acid obtained

  from animal fats.

• This acid is converted by the

  enzyme cyclooxygenase (COX) to synthesize

  different prostaglandins.

• The prostaglandins go on to stimulate many other regulatory functions and reactionary responses in the body

Types of Cyclooxygenase (COX)

1) Cox-1

2) Cox-2

COX-1

• is stimulated continuously by normal body physiology.

• The COX-1 enzyme is constitutive (Concetraion is stable)

• It is present in most tissues and converts arachidonic acid into prostaglandins.

• These prostaglandins in turn stimulate normal body functions

COX-2

The COX-2 enzyme is induced (not normally present in cells but its expression can be increased dramatically.

• COX-2 is involved in producing prostaglandins for an inflammatory response.

Which COX variant is the only one we want to target?

COX-2

Main Difference between COX-1 & COX-2?

So, in summary:

• COX-1 is stimulated continually

• COX-2 is stimulated only as a part of an immune system response.

Action of NSAIDs on Cyclooxygenase

• Most NSAIDs are non-selective and work by temporarily blocking the attachment site for arachidonic acid on the BOTH FORMS of cyclooxygenase enzyme

• ASPRIN → The only exception irreversibly acetylates cyclooxygenase (takes longer to wear of)

Non-Selective NSAIDs (4 Endings)

1) Ibuprofen

2) Naproxen

3) Ketoprofen

4) Diclofenac

5) Sulindac

6) Etodolac

7) Oxicam Derivatives Rx

-profen (2)

• 1) Ibuprofen

  • OTC & RX

• 2) Ketoprofen

  • Rx only

Naproxen

• OTC & RX

• Non-Selective NSAIDs

-ac (3)

• Diclofenac

• Sulindac

• Etodolac

Oxicam Derivatives Rx

• Piroxicam

• Meloxicam

Non-Selective NSAIDs – both OTC & Rx

Corticosteroids

• Corticosteroids are more potent and efficacious anti-inflammatories compared to NSAIDs

• They inhibits the release of prostaglandins and leukotrienes via inhibition of phospholipase A2

• Also have immunosuppressive effects

Example of a Corticosteroid we make in our body

• CORTISOL

• we can’t live without it

How to administer Corticosteroids? (6)

1) Oral (for rheumatoid arthritis, gout, lupus, inflammatory

bowel disease, to prevent organ transplant rejection, etc.)

2) Topical (for skin disorders, insect bites, etc.)

3) Ophthalamic (for eye inflammation)

4) Intranasal (for allergic rhinitis)

5) Inhalational (for asthma)

6) Injectable (into joint cavities for osteoarthritis, etc.)

Side Effects of Oral Corticosteroids

• Due to higher doses & prolonged time

• Sodium & water retention and subsequent hypertension

• Fat deposition in face, neck, shoulders and abdomen

• Thinning of the skin and easy brusability

• Adrenocortical suppression / atrophy of the adrenal glands

• Immunosuppression

• Hyperglycemia

• Decreased bone mineral density

• Slowed / delayed linear growth in children

The two most common oral corticosteroids are:

1) PREDNISONE

2) PREDNISOLONE

Cushing’s Syndrome

• A side effect of taking synthetic glucocorticoids (oral corticosteroid)

Intranasal Corticosteroids Name (2 Endings)

Budesonide

Ciclesonide

Flunisolide

Triamcinolone acetonide

Fluticasone propionate

Mometasone furoate

Beclomethasone dipropionate

Inhaled Corticosteroids

• Budesonide (Pulmicort)

• Ciclesonide (Alvesco)

• Flunisolide (Aerospan)

• Beclomethasone (QVAR)

• Fluticasone (Flovent, Arnuity Ellipta)

• Mometasone (Azmanex)

Acetaminophen (APAP)

• Excellent analgesic/antipyretic (Fever & Pain)

• Weak anti-inflammatory activity, as it does not affect COX-1 or COX-2 peripherally

• Recent evidence suggests that acetaminophen inhibits central nervous system COX enzymes, and hence can relieve pain and fever (but again, NOT peripheral inflammation

How to Get Morphine

• Poppy Seed → OOze white gum

• If you let it sit it becomes crude opium.

• In Crude opium

  • morphine → is present in a concentration of about 10%

Three Main Opioid Receptors

• Mu (μ)

• Kappa (κ)

• Delta (δ)

Which receptor is the benchmark see if an opioid is effect?

• Mu (μ)

Endogenous opioids

• The body generates internal opioids

1) endorphins

2) enkephalins

3) dynorphins

What do Opioids Do?

• Opioids bind to opioid receptors in the CNS to inhibit or modify the transmission of pain signals from the periphery to the spinal cord and to the brain.

• Thus Opioids do not help they body except limit the feeling of pain!

Examples of STRONG Opioids

1) Morphine

2) Hydromorphone

3) Fentanyl

4) Meperidine

5) Oxycodone

6) Methadone

Moderate Opioid Agonists (3)

Codeine

Hydrocodone

Dihydrocodeine

Opioid Cocktails

• Use two drugs like opioids and ibuprofen

  • This is to lower the amount of opioid per dose

  • Less addictive but still VERY ADDICTIVE