2020A09 Outline the effects of opioids injected into the spinal intrathecal space
using both fentanyl and morphine to illustrate your answer.

List:

· Intro: aims

· Kinetics: drug, dose, distribution

· Analgesia

· Resp depression

· Other side effects

Intro:

Aims

· Surgical anaesthesia (synergistic with LA; elevates and prolongs block)

· Post-op analgesia (e.g. intrathecal morphine for Whipple’s procedure)

Mechanism of opioid action

· Activate G_i protein-coupled receptor

· ↓Guanylyl cyclase activity -> ↓cAMP

· Inhibit VDCC

· ↑K⁺ efflux

· Hyperpolarisation, ↓action potential

Pharmaceutics:

Preservative-free

· Must use preservative-free morphine

· No remifentanil (glycine additive is an inhibitory neurotransmitter)

Pharmacokinetics:

Drugs and doses

· Tiny dose because:

o Near effect site

o Low volume of CSF

o Relatively slow reabsorption

· Morphine:

o 0.5mg (range 0.2-1mg)

o IT:IV potency 300:1

· Fentanyl:

o 15mcg (range 10-25mcg)

o IT:IV potency 20:1

· Other:

o Diacetylmorphine

o Pethidine (can be a sole intrathecal agent)

o Sufentanil (local anaesthetic effect at high dose)

If highly lipid soluble (fentanyl)

· Rapid onset (5 mins?)

· Rapid offset (1 hour?)

· ↓ Effect from central spread via CSF due to faster diffusion out of it

· ↑ Effect from systemic absorption

If poorly lipid soluble (morphine)

· Slower onset (4-6 hours)

· Slower offset (12-24 hours

· ↑Effect from central spread via CSF due to slower diffusion out of it

· ↓Effect from systemic absorption

Analgesia:

Spinal cord segments (++++)

· Diffuse across pia mater into dorsal horn (fentanyl fast, morphine slow)

· Height ∝ dose

· Pre-synaptic inhibition of 1° afferent nociceptors especially layer 2 -> ↓Release of excitatory neurotransmitters (glutamate, ACh, substance P)

· Some post-synaptic inhibition

Brain (++)

· Circulate via CSF bulk flow due to arterial pulsation
(morphine yes, fentanyl minimal)

· PAG and RVMM: inhibition of OFF cell -> disinhibition of ON cell -> ↑descending modulation (NAd > 5HT) -> pre-synaptic inhibition

· ? Some post-synaptic inhibition

Systemic (+)

· Absorption via epidural venous plexus

· Very low peak plasma concentration

· Effect on brainstem, spinal cord, GIT, etc

Respiratory depression:

Receptors	· M, D
Location	· Respiratory centre in the medulla
Highly lipid soluble (fentanyl)	· Peak at 30 mins due to systemic absorption
Poorly lipid soluble (morphine)	· Peak at 6-12 hours due to central spread of CSF

Other side effects of neuraxial opioid:

· Nausea, vomiting (chemoreceptor trigger zone mu opioid receptor)

· Urinary retention (spinal cord)

· Itch (unclear cause, reversed by naloxone not antihistamines)

· Foetal bradycardia if in labour (fentanyl > morphine)

Feedback welcome at ketaminenightmares@gmail.com

2020A09 Outline the effects of opioids injected into the spinal intrathecal space using both fentanyl and morphine to illustrate your answer.