FRCA Notes

Adjuncts for Neuraxial Anaesthesia in Obstetrics

This page complements the pages on spinal anaesthesia for LSCS and the epidural top-up.

Curriculum

"Knowledge of drugs used for regional anaesthesia including doses and toxicity" (Primary FRCA syllabus)

"The choice of local anaesthetic agents, opioids, and other additives and techniques of administration" (Final FRCA syllabus)

Examiner feedback

Intrathecal opioids were the topic of an SAQ in 2019 with a pass rate of 57%.

Most sections were answered well, but the mechanism of action of intrathecal opioids was poorly understood, leading the examiners to quip candidates "consistently neglected" pharmacology knowledge

Resources

  • Neuraxial adjuncts are drugs given alongside local anaesthetic (LA) in epidurals and spinals, or occasionally intravenously, with the aim of reducing the dose of LA required (and its adverse effects) without compromising the quality of analgesia or anaesthesia

Why use adjuncts?

  • LA is the primary component of neuraxial mixtures, but its adverse effects are dose dependent:
    • Hypotension
    • Motor block (and an associated ↑ risk of instrumental delivery)
    • LA systemic toxicity
  • Simply reducing the LA dose risks inadequate anaesthesia and breakthrough pain
  • Adjuncts aim to allow a lower LA dose whilst maintaining (or improving) block quality, speed of onset and duration

The ideal neuraxial adjunct


Pharmaceutical Clinical
Preservative-free solution Reduces effective dose of LA
Proven mechanism of action Effective for both labour analgesia and caesarean section
Compatible with LA and other adjuncts Prolongs analgesia without prolonging motor block
Predictable pharmacokinetics Analgesia without excessive sedation
Effective via epidural and intrathecal routes Minimal systemic adverse effects; not neurotoxic

Licensing and neurotoxicity

  • Many commonly used adjuncts are not licensed for neuraxial use i.e. their use is off-label
  • Neurotoxicity may be direct, or indirect through ischaemia secondary to vasoconstriction
  • Any drug given neuraxially must be preservative-free, as many preservatives are themselves neurotoxic
  • Conversely, by reducing the LA dose, adjuncts may reduce the risk of LA-induced neurotoxicity

Mechanism of action

  • Act predominantly at MOP (μ) receptors in the substantia gelatinosa (lamina II) of the dorsal horn
  • G-protein coupled receptors (Gi/o) which, when activated:
    • Presynaptically: inhibit voltage-gated Ca2+ channels, reducing release of excitatory neurotransmitters (glutamate, substance P) from primary afferents
    • Postsynaptically: open K+ channels, hyperpolarising the second order neurone so it is less likely to reach threshold
    • Both reduce transmission of nociceptive signals
  • Epidural opioids must first diffuse across the dura into CSF; they are also absorbed into epidural fat and the venous plexus, hence higher epidural doses are needed
  • Intrathecal opioids act directly at the dorsal horn, so much lower doses suffice

Benefits when added to LA

  • Faster onset
  • Improved quality of analgesia/anaesthesia, particularly visceral pain
  • Longer duration
  • LA-sparing; in labour this means less motor block, less breakthrough pain and fewer instrumental deliveries

Lipophilic vs hydrophilic opioids


Lipophilic (fentanyl, sufentanil, diamorphine) Hydrophilic (morphine)
Onset Fast Slow (45 - 75min)
Duration Short (2 - 4h); diamorphine is the exception (12 - 24h) as it is converted to morphine Long (12 - 24h)
Intra-operative analgesia Yes No; mainly post-operative
Clearance from CSF Rapid; uptake into fat and plasma Slow; remains in CSF
Cephalad spread Limited Marked, towards the respiratory centres of the brainstem
Risk of respiratory depression Lower Higher, and may be delayed

Epidural use

  • Labour:
    • LA combined with a short-acting lipophilic opioid is the gold standard for labour analgesia
    • Fentanyl 1 - 3μg/ml or sufentanil 0.3 - 0.75μg/ml in the epidural LA solution
    • Main adverse effect is pruritus
    • Morphine is not recommended: slow onset and accumulation risk maternal and neonatal respiratory depression
    • Remifentanil and tramadol are not recommended for neuraxial use (the latter due to high rates of nausea and vomiting)

  • Caesarean section (top-up):
    • Fentanyl 50 - 100μg added to the top-up speeds onset and improves intra-operative analgesia
    • After delivery: diamorphine 2.5 - 3mg or morphine 2 - 3mg for post-operative analgesia
    • Higher doses increase side-effects without significant additional analgesic benefit

Intrathecal use

  • Fentanyl 15 - 20μg or sufentanil 2 - 2.5μg improve intra-operative anaesthesia and reduce LA requirements
  • Long-acting opioid for post-caesarean analgesia:
    • Diamorphine 300μg was the UK standard, but supply has been unreliable
    • In its absence, morphine 100μg plus fentanyl 15μg gives similar efficacy and side-effect profile (BJA, 2021)
    • Morphine 50 - 100μg represents the best balance between efficacy and adverse effects; higher doses add side-effects but little analgesia

Adverse effects

  • All are dose dependent

  • Pruritus:
    • The most common; up to 90% with intrathecal opioids
    • Around 50% with intrathecal morphine 100μg

  • Nausea and vomiting: around 10% with intrathecal morphine 100μg
  • Urinary retention

  • Respiratory depression:
    • Around 0.06% with intrathecal morphine; almost non-existent with intrathecal diamorphine
    • Risk factors include obesity and concurrent sedative drugs
    • Hydrophilic opioids may cause delayed respiratory depression, hence the need for post-operative respiratory monitoring

  • Fetal heart rate abnormalities (labour CSE):
    • Associated with higher intrathecal doses (fentanyl >25μg or sufentanil >5μg)
    • Thought to be due to uterine hypertonicity from a rapid fall in circulating adrenaline (relative to noradrenaline) as analgesia takes effect
    • Usually self-limiting and rarely requires emergency delivery

  • Hypothermia:
    • Spinal anaesthesia itself causes hypothermia through redistribution of heat, impaired vasoconstriction and shivering, and loss of thermal input from blocked skin
    • A small RCT found that adding intrathecal morphine 150μg increased the maximum temperature drop compared with bupivacaine alone, with one patient reaching 34.3°C (Anaesthesia, 2006)
    • Proposed mechanism: cephalad spread of morphine in CSF to the hypothalamic thermoregulatory centre
    • Temperature should be monitored and active warming used

Mechanism of action

  • α and β adrenoceptor agonist with direct and indirect actions:
    • Direct: stimulation of α2 adrenoceptors in the dorsal horn, improving the quality of the block
    • Indirect: vasoconstriction of the epidural venous plexus, slowing systemic absorption of LA
  • The latter reduces peak LA plasma concentration (and so risk of toxicity) and prolongs duration of the block

Clinical use

  • Commonly used in the UK with 2% lidocaine for epidural top-up for caesarean section
  • Typically 5μg/ml (1:200,000) e.g. 100μg in 20ml
  • Also used as part of an epidural test dose (10 - 15μg) to detect intravascular catheter placement

Advantages Disadvantages
Improved quality of block Prolongs motor block
Longer duration of block Animal studies show reduced endoneurial blood flow and ↑ neurotoxicity
↓ peak LA plasma concentration and risk of toxicity Additional drawing up adds time in an emergency


Mechanism of action

  • LAs are weak bases; only the unionised fraction can cross the lipid neuronal membrane to reach its site of action on the internal side of the Na+ channel
  • Adding bicarbonate raises the pH of the solution closer to the pKa of the LA, increasing the unionised fraction
  • This speeds the onset of the block

Clinical use

  • 8.4% sodium bicarbonate 1ml per 10ml of 2% lidocaine i.e. 2ml in 20ml
  • Reduces time to surgical anaesthesia by around 2 - 5min
  • Used in UK top-up mixtures, although not available as a dedicated preservative-free neuraxial preparation, so not used in some countries

Cautions

  • Not suitable for use with (levo)bupivacaine or ropivacaine as it causes precipitation

Mechanism of action

  • Imidazoline derivatives:
    • Clonidine α2:α1 selectivity 220:1
    • Dexmedetomidine α2:α1 selectivity 1620:1 i.e. around eight times more α2 selective
  • Neuraxial effect is thought to be largely independent of α2 receptors: they block hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels
  • This keeps the neurone hyperpolarised and inhibits conduction in Aδ and C fibres

Clonidine

  • Epidural:
    • Improves and prolongs labour analgesia, reduces LA dose and provides mild anxiolysis
    • Bolus 50 - 100μg, or infusion 1 - 1.5μg/ml in epidural LA solution
    • Mainly used for difficult to manage labour pain e.g. occipitoposterior position or breakthrough pain, where a single bolus of 75μg may help
    • Neurotoxicity appears negligible
  • Intrathecal: not recommended due to significant maternal hypotension, sedation and fetal acidosis

Dexmedetomidine

  • Epidural: 0.3 - 0.6μg/ml in LA solution at 10ml/h lowers pain scores and total LA dose, with slightly ↑ sedation
  • Intrathecal (5 - 10μg in studies):
    • Prolongs post-operative analgesia and reduces shivering at caesarean section
    • No apparent effect on uteroplacental circulation or neonatal outcome
    • Further research on neurotoxicity needed before it can be recommended

Adverse effects

  • Hypotension; MAP may fall >15mmHg more than with LA alone
  • Bradycardia; typically within 15 - 30min of an epidural dose
  • Bradycardia with dexmedetomidine is relatively atropine resistant, needing higher doses to treat
  • Sedation

Dexamethasone

  • Long-acting synthetic glucocorticoid, 25 times more potent than cortisol
  • Mechanism incompletely understood; may ↑ expression of inhibitory K+ channels in C fibres, reducing their excitability, alongside systemic anti-inflammatory effects
  • Prolongs sensory block, ↑ time to rescue analgesia and reduces shivering, without worsening hypotension
  • IV and intrathecal routes produce similar benefits, so IV dexamethasone is preferred: 0.1mg/kg (range 4 - 16mg)

Neostigmine

  • Reversible acetylcholinesterase inhibitor; ↑ acetylcholine acts at spinal muscarinic and nicotinic receptors to produce analgesia
  • Epidural:
    • Improves analgesia and reduces LA requirements
    • 500 - 750μg, alone or with clonidine 75μg, can rescue inadequate analgesia via an otherwise well-functioning catheter
    • Appears safe from a neurotoxicity perspective
  • Intrathecal: not recommended due to bradycardia, nausea and vomiting, anxiety and agitation

Ketamine

  • Non-competitive NMDA receptor antagonist acting on second order neurones in the dorsal horn
  • Faster onset and longer duration of block; synergistic with bupivacaine
  • Not recommended: limited obstetric evidence, potential neurotoxicity from the preservative benzalkonium chloride, sedation, headache and psychotomimetic effects

Magnesium sulphate

  • NMDA receptor antagonist; blocks the receptor's ion channel and so prevents Ca2+ influx into neurones
  • Prolongs time to rescue analgesia (around 109min epidurally; around 39min intrathecally)
  • Not recommended until concerns about nausea, vomiting and neurotoxicity are excluded


Drug Epidural Intrathecal Main adverse effects
Fentanyl 1 - 3μg/ml in LA (labour); 50 - 100μg bolus (top-up) 15 - 20μg Pruritus
Sufentanil 0.3 - 0.75μg/ml in LA 2 - 2.5μg Pruritus
Diamorphine 2.5 - 3mg bolus after delivery 300μg Pruritus; nausea and vomiting; respiratory depression
Morphine 2 - 3mg bolus after delivery 50 - 100μg Pruritus; nausea and vomiting; respiratory depression
Clonidine 50 - 100μg bolus; 1 - 1.5μg/ml infusion Not recommended Hypotension; bradycardia
Dexmedetomidine 0.3 - 0.6μg/ml infusion 5 - 10μg (research use) Hypotension; bradycardia
Neostigmine 500 - 750μg bolus Not recommended Bradycardia; nausea and vomiting; sedation


Labour analgesia

  • Low concentration LA plus a lipophilic opioid (e.g. 0.1% bupivacaine with fentanyl 2μg/ml)
  • Other adjuncts are not for routine use

Spinal for caesarean section

  • 0.5% hyperbaric bupivacaine 10 - 12.5mg
  • Plus diamorphine 300μg, or morphine 100μg with fentanyl 15μg
  • Consider IV dexamethasone (also useful as an antiemetic)
  • See spinal anaesthesia for LSCS

Epidural top-up for caesarean section

  • A typical UK 'fizzy' mixture: 2% lidocaine 20ml with adrenaline 100μg and 8.4% bicarbonate 2ml
  • Plus fentanyl 50 - 100μg for intra-operative analgesia
  • Diamorphine or morphine after delivery for post-operative analgesia
  • See epidural top-up