Analgesic ladder and pain management

Question 1

Outline the analgesic ladder

Answer 1

Mild pain (0-3): Non-opiate analgesic +/- adjuvant Moderate pain (3-6): Mild-opiate analgesic +/- non-opiate and adjuvant Severe pain (7-10): Strong opiate analgesic +/- non-opiate and adjuvant

Question 2

Name the non-opioid analgesics

Answer 2

Paracetamol, NSAIDs (inc. aspirin) and COXIBs

Question 3

Paracetamol: MOA, effects, side effects, overdose

Answer 3

MOA: Inhibition of COX within the CNS, not completely understood

Effects: Antipyretic and analgesic

Side-effects: Few and uncommon. Do not see disruption to gastric mucosa as seen from NSAIDs

Overdose: Saturation of normal metabolic pathway –> alternative pathway with conjugation to glutathione –> Glutathione depleted leads to accumulation of the toxic metabolism –> Necrosis of the liver and kidney tubules

Question 4

NSAIDs: MOA, examples, effects, side effects

Answer 4

MOA: Irreversible inhibition of COX-2, decreasing prostaglandin production

Examples: Ibuprofen, naproxen, diclofenac, aspirin (CVD use, inhibition of COX/thromboxane synthesis leads to anti-platelet action)

Effects: Anti-inflammatory, anti-pyretic and analgesic

Side-effects: Peptic ulcer due to inhibition of COX-1 (loss of protective prostaglandins); kidney damage (decreased blood flow - vasoconstriction is seen due to the loss of vasodilatory PGE/PGI, reduces GFR)

Question 5

COXIBs: MOA, examples, effects, side effects

Answer 5

MOA: Selective inhibition of COX-2

Examples: Celecoxib

Effects: Analgesic

Side-effects: No gastric side effects as seen for NSAIDs; pro-thrombotic (CV risk, increased BP)

Question 6

NSAIDs vs COXIBs

Answer 6

NSAIDs: Higher GI risk (dose dependent, + PPI decreases this), some CV risk COXIBs: Low GI risk, High CV risk (risk of thrombotic effects)

Question 7

MOA of opioid analgesics

Answer 7

• Act within the periphery and CNS
• Act on opioid receptors (particularly mew)
• Act upon G(i) PCRs, decreases cAMP, affects phosphorylation pathways, impacts cell function
• ALSO, acts upon K⁺ and Ca²⁺ channels, creates hyperpolarisation, increases threshold, decreases pain.

Question 8

Opioids: Adverse effects

Answer 8

Euphoria Respiratory depression: Due to decreases sensitivity to CO2 Constipation: Due to decreased GI mobility and increased tone Pupil constriction Nausea Itching Increased intra-biliary pressure

Question 9

Name weak opiates

Answer 9

Codeine, tramadol

Question 10

Codeine: Dose, side-effects, pharmacokinetics

Answer 10

Dose: Has a ceiling dose (no further effects past this dose)

Side-effects: General opioid side effects

Pharmacokinetics: Prodrug - metabolised to active form (morphine) in the liver by CytP2D6.

• Genetic variabilty: 10 % of Caucasians lack this enzyme

Question 11

Tramadol: MOA, side effects, pharmacokinetics, contraindications

Answer 11

MOA: DUAL ACTION - also has some ability to decrease ACh reuptake

Side-effects: Less respiratory depression and constipation

Pharmacokinetics: Metabolised to active form by CytP2D6

Contraindications: Epilepsy, renal impairment, use alongside any drugs that lower the seizure threshold

Question 12

Naloxone

Answer 12

Opioid antagonist. Has affinity for all 3 opioid receptors. Can aid constipation

Question 13

Describe the actions of COX1 and COX2

Answer 13

Question 14

Describe the effects of COX inhibition

Answer 14