Pain II - NSAIDs Flashcards
What are the mediators involved in central sensitization?
Pre-synaptic augmentation
- vasoactive intestinal polypeptide (VIP)
- Glutamate
- Substance P
Post-synaptic facilitation
True or false, there have been no new pain specific drugs for over 100 years.
True
What is the #1 cause of pain and disability?
Musculoskeletal disorders (eg. arthritis)
What are eicosanoids?
Any of a class of compounds (as the prostaglandins, leukotrienes, and thromboxanes) derived from polyunsaturated fatty acids (as arachidonic acid) and involved in cellular activity (lipid mediators).
What are prostaglandins?
Eicosanoids. Found that it causes vasomotor activity in the prostate and uterus.
Most importantly, they are involved in causing inflammation and pain. They are produced by oxygenation of arachidonic acid in cell membranes.
Oxygenation of arachidonic acid occurs by what two enzymes?
Either cyclooxygenase 1 (COX1) or cyclooxygenase 2 (COX2).
The oxygenation of arachidonic acid in cell membranes produces prostaglandins, which can cause inflammation and pain.
What are the differences between the COX isoforms (COX1 and COX2)?
COX1
- Constitutively expressed
- Throughout body
- Consistent levels
- Homeostasis (platelets, cytoprotection, renal perfusion etc.)
COX2
- Inducible (eg. by injury)
- Found in inflamed tissue
- Present transiently
- Short half life
- Promotes inflammation and pain
What is the physiological effect of prostaglandins on:
- Smooth muscle
- Platelets
- Kidney
- Nervous system
Smooth muscle: vasodilation and GI contraction
Platelets: Aggregation
Kidney: Increased renin release and increased glomerular filtration rate
Nervous system: Peripheral sensitization and central sensitization
What are NSAIDs? Give an example of a classic NSAID?
Non-steroidal anti-inflammatory drugs
- Used to treat pain and drugs
- A classic NSAID is acetylsalicylic acid (ASA, Aspirin)
- Derived from the bark of the willow tree. Inhibits both COX1 and COX2.
In addition to acetylsalicylic acid, list three other NSAIDs
- Ibuprofen
- Naproxen
- Diclofenac
All are COX1 and COX2 inhibitors. They have similar pharmacology to ASA (ie. analgesic and anti-inflammatory, but NOT anti-platelet aggregation). Another difference from ASA is their longer half life and increased potency.
List two negative side-effects of NSAIDs after prolonged use
- GI damage
- Renal failure
Could selective COX inhibitors reduce inflammation and pain, but maintain protective effects of constitutive COX responses (to prevent GI/renal damage)?
For pain, you would want to inhibit COX2, because it is inducible for pathological responses.
COX2 hypothesis: COX2 inhibitors (Coxibs) would reduce inflammation-induced prostaglandin production and preserve protective effects of COX1 pathway.
Celebrex is a Coxib in preclinical studies. It produced a level of analgesia comparable to indomethacin and was less ulcerogenic than non-selective NSAIDs
Recall the VIOXX story. Why did it fail?
The FDA approves VIOXX (a selective NSAID, Coxib) as arthritis treatment. It’s effective but caused thrombosis and other CV complications (4x more likely to have heart attack). It is withdrawn and there was a class action settlement in Canada.
It was too effective at inhibiting COX2 and some products of COX2 catalysis have beneficial effects (eg. PGI2, which has a role in vasodilation, platelet inhibition and cardiomyocyte protection).
What are three recommendations for COX2 NSAID use?
- Select patients at low risk of thrombic events
- Prescribe lowest dose required to control symptoms.
- Add aspirin (81 mg) and a proton pump inhibitor to patients with increased risk of thrombotic events.
Why are NSAIDs used with opioids?
It’s not possible to keep escalating NSAID dose due to negative effects, therefore opioids supplement analgesia. This causes highly effective analgesia while minimising side effects of individual components.
