2020A Question 09
Outline the effects of opioids injected into the spinal intrathecal space using both fentanyl and morphine to illustrate your answer.
Examiner Report
An understanding of the benefits and risks of the common anaesthetic practice of injecting the opioid drugs fentanyl and morphine into the intrathecal space is a fundamental piece of knowledge for an anaesthetist. This clinical practice beautifully demonstrates the necessity to grasp particular pharmacokinetic and pharmacodynamic principles pertinent to use of these drugs in order to be a safe and effective practitioner.
In order to score a passing mark for this question candidates needed to demonstrate a knowledge of both the desirable and undesirable clinical effects of intrathecal injection of opioids, some pharmacodynamic reasons for these effects (anatomical locations, receptors and cellular effects of the drugs), the pharmacokinetic differences between fentanyl and morphine which explain their different desirable and undesirable clinical effects.
Many candidates failed because they entirely missed or gave cursory and inadequate attention to one or more of these areas.
Better answers gave more detailed explanations of particular supraspinal and spinal nociception pathways and centres, explained in detail the reasons for the four most important side effects of spinal opioids (nausea and vomiting, urinary retention, pruritus and respiratory depression), and offered detail in differentiating between both the pharmacokinetic and pharmacodynamic effects of the two drugs in question.
Common errors included attribution of pruritus to a systemic histamine effect, an attribution of the analgesic effects of fentanyl to systemic absorption, an assertion that intrathecal opioids cause significant motor, sensory or sympathetic blockade, and incorrect descriptions of significant cardiovascular side effects of intrathecal opioids.
Model Answer
Structure:
- Introduction
- Kinetics: Drug, dose, distribution
- Analgesia
- Resp depression
- Other side effects
Introduction
| Factor | Detail |
|---|---|
| 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 Gi 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
| Domain | Detail |
|---|---|
| Drugs and doses | - Tiny dose because: - Near effect site - Low volume of CSF - Relatively slow reabsorption - Morphine: - 0.5mg (range 0.2-1mg) - IT:IV potency 300:1 - Fentanyl: - 15μg (range 10-25μg) - IT:IV potency 20:1 - Other: - Diacetylmorphine - Pethidine (can be a sole intrathecal agent) - 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
| Term | Detail |
|---|---|
| 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 - 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
| Factor | Detail |
|---|---|
| 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
- 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)