Pain II: NSAIDs - McDougall 2

Question 1

Arthritis

Answer 1

Reduction in quality of life
Disability
Loss of sleep and fatigue
Depression 
Over 100 types of arthritis
4.6 mil Canadians, annual cost of $33 mil
Main concern for patients is pain

Question 2

Eiconsanoids

Answer 2

Prostaglandins and related compounds
1930s: Kuzrok and Lieb found uterine smooth muscle contracts/relazes in presence of semen
Gaddum and von Euler identify that seminal fluid has vasomotor activity: identify as lipid mediator, prostaglandin

Question 3

Prostaglandins

Answer 3

Involved in causing inflammation and pain
Produced by oxygenation of arachidonic acid in cell membranes
Oxygenation occurs by either COX1 or COX2

Question 4

COX1

Answer 4

Constitutively expressed
Found throughout body
Levels are relatively constant
Involved in cell homeostasis

Question 5

COX2

Answer 5

Inducible (i.e. by injury)
Found in inflamed tissues
Present only transiently during inflammation or pain
Short 1/2 life
Promote inflammation and pain

Question 6

COX pathway

Answer 6

Arachidonic acid is oxidized to PGH2 by COX1 or COX2

PGH2 is further broken down

Question 7

Physiological effects of prostaglandins

Answer 7

Vasodilation of vascular smooth muscle, contraction of Gi smooth muscles
Aggregation of platelets
Increase renin release and glomerular filtration rate in kidneys
Peripheral and central sensitization of nervous system

Question 8

Non-steroidal anti-inflammatory drugs (NSAIDs)

Answer 8

Used to treat pain and inflammation

Classic is acetylsalicylic acid: aspirin

Question 9

Aspirin

Answer 9

Acetylsalicylic Acid
Derived from the bark of willow trees
Inhibits COX1 and COX2
Anti platelet activity

Question 10

Other NSAIDs

Answer 10

Ibuprofen, naproxen, diclofenac
All are COX1 and COX2 inhibitors
Similar in pharmacology to aspirin, except not anti-platelet aggregating
Longer half-life and more potent

Question 11

Negative side-effects of NSAIDs

Answer 11

GI damage, renal failure

Question 12

COX2 hypothesis

Answer 12

COX2 inhibitors (COXibs) would reduce inflammation-induced prostaglandin production
Preserve protective effects of COX1 pathway
Preclinical trials: inhibited prostamoid production in inflamed paw and inflamed GI tract, produced level of analgesia comparable to indomethacin, less ulcerogenic than non-selective NSAIDs
Ie. Celebrex

Question 13

VIOXX

Answer 13

Causes increase thrombosis and other cardiovascular complications
Too good at inhibiting COX2
Some byproducts of COX2 catalysis have beneficial effects

Question 14

PGI2

Answer 14

Produced by COX2 catalysis

Causes vasodilation, platelet inhibition and protective of cardomyocytes

Question 15

Recommendations of COX2 use

Answer 15

Select patients with low risk thrombotic events
Prescribe lowest dose required o control symptoms
Add Aspirin and proton pump inhibitor to patients with increased risk of thrombotic event

Question 16

Combining NSAID with opioid combinations

Answer 16

Not possible to keep escalating NSAID dose, therefore used in combination with opioid
Ease of prescribing combination, less propensity for opioid abuse, highly affective analgesia while minimizing side-effects of individual components

Question 17

Topical NSAIDs

Answer 17

Primarily used for arthritis pain
Target pain in the periphery
Minimizing centrally-mediated side effects
Analgesia easily applied to superficial joints
Includes: pennsaid, solar, voltaren, flector (all containing diclofenac in different conc)
Applied either as a patch or gel
May produce local irritation

Question 18

Topical diclofenac

Answer 18

Systemic exposure is 17x lower than oral administration
Average peak plasma is 158x lower than oral agent
Analgesia is comparable to oral agents
Improvement in studies lasting 4-12 weeks
Higher safety margin than oral

Question 19

Acetaminophen (Paracetamol)

Answer 19

Good for rapid relief of acute pain and arthritis pain
NOT COX1 or COX2 inhibitor
Not anti-inflammatory

Question 20

Acetaminophen (Paracetamol) mechanism of action

Answer 20

Deacteylated in liver
Converted into an endocannabinoid in brain
Endocannabinoid can reduce pain at CB1 receptor
Endocannabinoid reinforced descending serotinergic pathway
Spinal release of 5-HT inhibits pain transmission

Question 21

Acetaminophen (Tylenol)

Answer 21

Less affective than other NSAIDs
First line therapy for arthritis pain
Lack side-effects of ASA
Few drug interactions
Adverse effects, but very few, therefore safe up to 6g per day
Overdose causes kidney necrosis and hepatotoxicity
Hepatotoxicity may be potentiated in chronic alcoholics