CPT16 - Opioids

Question 1

5 features of the neurological mechanisms behind pain

Tissue Damage
Substantia Gelatinosa
Peripheral Modulation of Pain
Periaqueductal Grey Matter
Central Modulation of Pain

Answer 1

1. ) Tissue Damage - produces pain
   - stimulatory A-delta and C fibres sent to the DH
   - inhibitory fibres sent to the substantia gelatinosa
   - DH -> thalamus -> cortex+periaqueductal grey matter
2. ) Substantia Gelatinosa - dampens down pain
   - found in the apex of dorsal grey column
   - sends inhibitory fibres to the dorsal horn
   - this ↓pain sent from the spinal cord to the cortex
3. ) Peripheral Modulation of Pain - mechanoreceptors
   - sends A-ß fibres to stimulate the substantia gelatinosa
   - this promotes inhibition of the DH –> ↓pain
4. ) Periaqueductal Grey Matter - when activated:
   - stimulates the substantia gelatinosa via serotonin, 5-HT
   - this promotes inhibition of the DH –> ↓pain
5. ) Central Modulation of Pain - higher cortical function
   - cortex stimulates the periaqueductal grey matter
   - this promotes inhibition of the DH –> ↓pain

Question 2

4 features of morphine as a strong agonist

Administration x3
Pharmacodynamics x4
Mechanism
Side Effects x4

Answer 2

1. ) Administration - oral, IV, SC, IM, rectal (PR)
   - only given orally or PR for long term use
   - gut absorption is erratic and only 40% bioavailability
2. ) Pharmacodynamics
   - distribution: lipophilic so rapidly enters all tissues including foetal but struggles to cross the BBB
   - metabolism: w/ glucuronic acid –> M6G + M3G
   - elimination: renal (caution w/ AKI and CKD)
3. ) Mechanism - strong affinity to µ-receptor
   - minimal affinity to k and delta receptor
   - causes analgesia and euphoria
4. ) Side Effects
   - respiratory depression: medulla ↓responsive to CO2
   - nausea/vomiting: stimulates CTZ in the medulla
   - constipation: ↓motility, ↑sphincter tone (docusate sodium can be prescribed with it to reduce its effects)
   - histamine release: vasodilation, asthma attack, pruritus

Question 3

4 features of fentanyl as a strong agonist

Administration x4
Pharmacodynamics x6
Mechanism
Side Effects x3

Answer 3

1.) Administration - IV, epidural, intrathecal (CSF), nasal

2. ) Pharmacodynamics
   - distribution: highly lipophilic, highly protein bound, and can cross the BBB
   - metabolism: by the liver via CYP3A4
   - elimination: short half-life (6mins) and renal excretion
3. ) Mechanism - strong affinity for the µ-receptor
   - has 100x potency compared to morphine
   - analgesia and anaesthetic
4. ) Side Effects - less than morphine due to less histamine release, less sedation, and less constipation
   - respiratory depression, constipation, vomiting

Question 4

4 features of codeine as a moderate agonist (weak opiate)

Administration x2
Pharmacodynamics x2
Mechanism
Side Effects x2

Answer 4

1.) Administration - oral or SC

2. ) Pharmacodynamics
   - metabolism: turned into morphine via CYP2D6 and then glucoronidation of morphine
   - elimination: same as morphine
3. ) Mechanism - same as morphine
   - approx 1/10th the potency of morphine
   - mild/moderate analgesia and cough depressant
   - variable expression of CYP2D6 means variable efficacy
4. ) Side Effects
   - respiratory depression (worse in children)
   - constipation (can be co-prescribed w/ laxatives)

Question 5

4 features of buprenorphine as a mixed agonist-antagonist

Administration x3
Pharmacodynamics x4
Mechansim
Side Effects x4

Answer 5

1.) Administration - transdermal (main), buccal, sublingual

2. ) Pharmacodynamics
   - distribution: very lipophilic, enters all tissues (inc CNS)
   - metabolism: liver via CYP3A4 then glucoronidation
   - elimination: long half-life (37hrs), biliary excretion means its safe in patients w/ renal impairment
3. ) Mechansim - µ-receptor, compared to morphine:
   - higher affinity (so lower Kd) means a longer duration of action since it is not easily displaced
   - partial agonist so lower efficacy (lower Emax)
   - antagonist at kappa receptors
4. ) Side Effects - less severe
   - respiratory depression, nausea, dizziness, low BP

Question 6

4 features of naloxone as a antagonist

Administration x4
Pharmacodynamics x4
Mechanism
Side Effects x2

Answer 6

1. ) Administration - IV (main), IM, intranasal, oral
   - rapid onset of action but very low oral bioavailability (2%) due to extensive first pass effect
2. ) Pharmacodynamics
   - distribution: very lipophilic, enters all tissues (inc CNS)
   - metabolism: liver turns it into naloxone-3-glucuronide
   - elimination: short half-life (30-60mins), renal excretion
3. ) Mechanism - affinity µ>delta>kappa
   - competitive antagonism of opioids
   - used to reverse OD
   - ↑affinity than morphine but less than buprenorphine
4. ) Side Effects
   - withdrawal symptoms: short half-life means patients will crash again as naloxone wears off
   - slow infusion: gives time for other drugs to metabolise

Question 7

Process of opioid tolerance

Arrestin
cAMP Production

Answer 7

1. ) Arrestin - uncouples G-proteins
   - occurs due to repeated exposure to opioids
   - this prevents opioids mechanism of action
2. ) cAMP Production - when the opioid is removed
   - ↑neuronal excitability –> withdrawal symptoms
   - larger doses of opioids needed for the same effect

Question 8

5 scenarios where you need to be cautious when prescribing opioids

Answer 8

1.) Respiratory Disease - due to respiratory depression

2. ) Renal Impairment - most are excreted by the kidneys
   - dosage may need to be adjusted
   - buprenorphine is excreted via the biliary tract so must be careful in patients w/ biliary tract obstruction
3. ) Pregnancy - opioids are highly lipophilic and can often cross the placenta and enter the fetus
   - the fetus may then suffer from respiratory depression and can also get withdrawal symptms
4. ) Asthmatics - histamine release can cause bronchoconstriction and mucus release
   - this can trigger an asthma attack

5.) Manual Labourers/Drivers - sedative effects

Question 9

5 contraindications to prescribing opioids

Answer 9

1. ) Hepatic Failure
2. ) Acute Respiratory Distress
3. ) Raised ICP, head injuries, comatose patients