How can pain transduction be blocked?
NSAIDS
COX-2 inhibitors
Topical local anaesthetics
How can conduction/transmission of pain signals be blocked?
Epidural block
Regional anaesthesia
How can pain modulation take place at the level of the spinal cord?
Opioids
COX-2 inhibitors
Ketamine
Alpha-2 -Delta ligands
Alpha2 agonists
How can pain perception in the brain be reduced?
Opioids
COX-2 inhibitors
Paracetamol
What are the classes of analgesics based on?
Salicylates (NSAIDs and COX-2 inhibitors these drugs inhibit prostaglandin synthesis)
Opioids (Selective ligands delivery techniques activate inhibitory systems)
What is the most used analgesic in the world?
Paracetamol
What is paracetamol?
A non opioid and non salicylate analgesic
What types of pain is paracetamol used for?
First-line therapy for:
Osteoarthritis
Musculoskeletal pain
Renal disease
Cancer pain
What other effects beside analgesia can paracetamol be used for?
Can be used to lower fever
How does paracetamol work?
Unclear mechanism of action.
Theories include:
Interaction with radical prostanoid intermediate
Inhibits COX-3 in the brain without affecting COX-1, and 2
Interaction with serotonin pathway/cannabinoid receptors
Interaction with NMDA receptor/NO synthetase
What sites is paracetamol inactive at?
Kidney (no renal impairment)
Gut (No risk of peptic ulcers)
Inflammation (Not anti-inflammatory)
What are the adverse effects of using paracetamol?
In clinical doses of 4 - 6 g/day there are no relevant adverse effects compared to the placebo. Toxicity more common in overdose (to the liver) or predisposed individuals
Why is paracetamol highly toxic in higher doses than clinical doses?
In lower doses acetominphen is converted to glucoronides and sulfates which can be excreted by the kidney easily and safely. (glutathione is needed for this)
In higher doses cytochrome P450.2E1 converts paracetamol into NAPQI which is converted to compounds that are hepatotoxic.
If there is too much acetominophen/paracetamol then the excess is converted into NAPQI and the hepatotoxic compounds which need time to be metabolised thus causing liver damage.
Who is at higher risk of liver toxicity?
Overdose
Starvation, malnutrition and low body weight due to low levels of glutathione.
HIV
Alcoholism (but only in overdose.)
Glucose-6-phosphate dehydrogenase deficiency (G6PD) leads to mathaemoglobinaemia and haemolysis
Paracetamol summary:
Good efficacy for mild to moderate pain
Limited component of multimodal analgesia
Available intravenously, orally and rectally (low bioavailability rectally)
Minimal adverse effects in therapeutic doses
Risk of liver failure in overdose
Debated risk to induce asthma/allergy
Recommended as a first line analgesic in many conditions
What is the key target of NSAIDs?
Prostaglandins
What do prostaglandins do?
It sensitizes activation of nociceptors (hyperalgesia)
How do NSAIDs work?
Arachidonic acid forms cyclooxygenase which forms prostaglandins which are important for pain and inflammation.
NSAIDs act on cyclooxygenase nad inhibit its activity thus resulting in less prostaglandin production and less pain.
Why must care be taken with use of NSAIDs?
Prostaglandins are important for normal GI function and Renal function.
Excess use can result in damage to mucosa of gut and ulcer formation.
Excess use can also cause renal toxicity.
What are the 3 important effects of NSAIDs?
They are anti-inflammatory
Analgesic
and anti-pyreti`c
What are the adverse effects of NSAIDs?
Toxicity is dose dependent and effects include:
Intolerability and dyspepsia
GI bleeding
Ulcers
Fluid retention, oedema, hypertension
Renal dysfunction/failure
Heart failure
Contributes to blood loss
Angioedema, bronchospasm
Why were COX-2 inhibitor drugs developed?
NSAIDs have many adverse effects due to action on all cyclooxygenase (both COX-1 and COX-2). COX-2 inhibitors don’t cause adverse effects because COX-1 is the important enzyme for protection of GI, kidneys, and for platelet aggregation and COX-2 acts on inflammation, pain, and fever.
What important structures still require COX-2 for their actions?
Brain
Kidney
Endothelium
Ovary
Uterus
How are COX-2 inhibitors structurally different to NSAIDs?
They are more bulky and that makes them more selective for COX-2 which has a side chain that fits the side pocket of the COX-2 enzyme
Name a famous COX-2 inhibitor?
Celecoxib
What are the normal non-selective NSAIDs?
Salicylates (aspirin)
Arylpropionic acids (ibuprofen, naproxen)
Phenylacetic acids (Diclofenac which has lots of side effects so sparingly used)
Oxicam (piroxicam)
What are the normal COX-2 selective NSAIDs?
Celecoxib
Parecoxib
Etoicoxib
3 other COX-2 inhibitors were banned due to their severe side effects (rofecoxib (associated with hypertension and heart failure), Valdecoxib (skin reaction due to delayed hypersensitivity), and lumiracoxib (associated with liver toxicity)
What is the risk of hospitalisation due to GI bleeds in Celecoxib?
1%
What is the risk of hospitalisation due to piroxicam?
9.8%
What is the purpose of PPIs?
They are proton pump inhibitors that prevent gastric ulcer bleeds in the stomach.
How safe is celecoxib?
The probability of a stomach ulcer using celecoxib is lower than combining most NSAIDs with PPIs.
PPI+celecoxib resulted in no cases of stomach ulceration and bleeding
Given orally does not cause any bronchospasms in patients with aspirin/conventional NSAID sensitivt asthma.
Risk of acute kidney injury is low.
What is the problem with rofecoxib?
Associated with cumulative incidence of confirmed thrombotic events.
FDA statement on “COX-2 Hypothesis”
In various controlled clinical trials, COX-2 selective drugs have been indistinguishable from non-selective NSAIDs in studies of substantial size and duration.
Based upon the available data FDA has concluded that an increase risk of CV events may be a class effects for NSAIDs.
Which NSAID/coxib drugs are safer in terms of GI bleeds and which are safer in terms of CV events?
All coxibs are better for preventing GI bleeds. CV events occur less in most NSAIDs (celecoxib CV event risk is also low)
Conclusion for NSAIDs and Coxibs:
NSAIDs and Coxibs are useful non-opioid analgesics, in particular in painful conditions with inflammation.
Adverse effects limit their safe use particularly in:
Elderly
Patients with GI ulcers
People with CV risk factors
People with renal risk factors
They also shouldn’t be used for extended periods of time
When should COX-2 inhibitors be used instead of non-selective NSAIDs?
Acute pain (rate of ulcers comparable to placebo, less blood loss, less bone healing effects)
Patients with increased risk of GI ulcers
Patients with past history of aspirin induced asthma
In which groups is no real difference seen between COX-2 and non-selective NSAIDs?
Renal adverse effects (evidence points slightly towards coxibs but not conclusive)
CV adverse effects (evidence suggests celecoxib is safe)
What types of conditions can be caused by toxicity with aspirin?
Reyes syndrome
Can cause stomach ulceration by inhibiting prostaglandins and creating acidic environment as well further increasing risk of ulceration
How does aspirin carry out its NSAID actions?
Has a unique mechanism to act on COX with unique activity on platelets and irreversible blockade.
How is aspirin eliminated?
Some renal elimination, urine pH-dependent which is useful in managing overdose
What is reyes syndrome?
Common post-viral infection condition which causes rapidly progressive liver damage as well as encephalopathy.
