Non-Opioid Analgesics

Question 1

How can pain transduction be blocked?

Answer 1

NSAIDS

COX-2 inhibitors

Topical local anaesthetics

Question 2

How can conduction/transmission of pain signals be blocked?

Answer 2

Epidural block

Regional anaesthesia

Question 3

How can pain modulation take place at the level of the spinal cord?

Answer 3

Opioids

COX-2 inhibitors

Ketamine

Alpha-2 -Delta ligands

Alpha2 agonists

Question 4

How can pain perception in the brain be reduced?

Answer 4

Opioids

COX-2 inhibitors

Paracetamol

Question 5

What are the classes of analgesics based on?

Answer 5

Salicylates (NSAIDs and COX-2 inhibitors these drugs inhibit prostaglandin synthesis)

Opioids (Selective ligands delivery techniques activate inhibitory systems)

Question 6

What is the most used analgesic in the world?

Answer 6

Paracetamol

Question 7

What is paracetamol?

Answer 7

A non opioid and non salicylate analgesic

Question 8

What types of pain is paracetamol used for?

Answer 8

First-line therapy for:

Osteoarthritis

Musculoskeletal pain

Renal disease

Cancer pain

Question 9

What other effects beside analgesia can paracetamol be used for?

Answer 9

Can be used to lower fever

Question 10

How does paracetamol work?

Answer 10

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

Question 11

What sites is paracetamol inactive at?

Answer 11

Kidney (no renal impairment)

Gut (No risk of peptic ulcers)

Inflammation (Not anti-inflammatory)

Question 12

What are the adverse effects of using paracetamol?

Answer 12

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

Question 13

Why is paracetamol highly toxic in higher doses than clinical doses?

Answer 13

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.

Question 14

Who is at higher risk of liver toxicity?

Answer 14

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

Question 15

Paracetamol summary:

Answer 15

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

Question 16

What is the key target of NSAIDs?

Answer 16

Prostaglandins

Question 17

What do prostaglandins do?

Answer 17

It sensitizes activation of nociceptors (hyperalgesia)

Question 18

How do NSAIDs work?

Answer 18

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.

Question 19

Why must care be taken with use of NSAIDs?

Answer 19

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.

Question 20

What are the 3 important effects of NSAIDs?

Answer 20

They are anti-inflammatory

Analgesic

and anti-pyreti`c

Question 21

What are the adverse effects of NSAIDs?

Answer 21

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

Question 22

Why were COX-2 inhibitor drugs developed?

Answer 22

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.

Question 23

What important structures still require COX-2 for their actions?

Answer 23

Brain

Kidney

Endothelium

Ovary

Uterus

Question 24

How are COX-2 inhibitors structurally different to NSAIDs?

Answer 24

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

Question 25

Name a famous COX-2 inhibitor?

Answer 25

Celecoxib

Question 26

What are the normal non-selective NSAIDs?

Answer 26

Salicylates (aspirin) Arylpropionic acids (ibuprofen, naproxen) Phenylacetic acids (Diclofenac which has lots of side effects so sparingly used) Oxicam (piroxicam)

Question 27

What are the normal COX-2 selective NSAIDs?

Answer 27

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)

Question 28

What is the risk of hospitalisation due to GI bleeds in Celecoxib?

Answer 28

1%

Question 29

What is the risk of hospitalisation due to piroxicam?

Answer 29

9.8%

Question 30

What is the purpose of PPIs?

Answer 30

They are proton pump inhibitors that prevent gastric ulcer bleeds in the stomach.

Question 31

How safe is celecoxib?

Answer 31

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.

Question 32

What is the problem with rofecoxib?

Answer 32

Associated with cumulative incidence of confirmed thrombotic events.

Question 33

FDA statement on "COX-2 Hypothesis"

Answer 33

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.

Question 34

Which NSAID/coxib drugs are safer in terms of GI bleeds and which are safer in terms of CV events?

Answer 34

All coxibs are better for preventing GI bleeds. CV events occur less in most NSAIDs (celecoxib CV event risk is also low)

Question 35

Conclusion for NSAIDs and Coxibs:

Answer 35

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

Question 36

When should COX-2 inhibitors be used instead of non-selective NSAIDs?

Answer 36

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

Question 37

In which groups is no real difference seen between COX-2 and non-selective NSAIDs?

Answer 37

Renal adverse effects (evidence points slightly towards coxibs but not conclusive) CV adverse effects (evidence suggests celecoxib is safe)

Question 38

What types of conditions can be caused by toxicity with aspirin?

Answer 38

Reyes syndrome Can cause stomach ulceration by inhibiting prostaglandins and creating acidic environment as well further increasing risk of ulceration

Question 39

How does aspirin carry out its NSAID actions?

Answer 39

Has a unique mechanism to act on COX with unique activity on platelets and irreversible blockade.

Question 40

How is aspirin eliminated?

Answer 40

Some renal elimination, urine pH-dependent which is useful in managing overdose

Question 41

What is reyes syndrome?

Answer 41

Common post-viral infection condition which causes rapidly progressive liver damage as well as encephalopathy.