NEURAXIAL ADJUVANTS

Adjuvants are drugs that increase the efficacy or potency of other drugs when given
concurrently. Neuraxial adjuvants are used to improve or prolong analgesia and decrease the
adverse effects associated with high doses of a single local anaesthetic agent. In addition to
their dose sparing effects, neuraxial adjuvants are also utilised to increase the speed of onset
of neural blockade (reduce latency), improve the quality and prolong the duration of neural
blockade.

Neuraxial

adjuvants

include

opioids,

sodium

bicarbonate

(NaHCO3),

vasoconstrictors, alpha-2 adrenoceptor agonists, cholinergic agonists, N-methyl-d-aspartate

(NMDA) antagonists and -aminobutyric acid (GABA) receptor agonists.
OPIOIDS
Mechanism of Action
Opioids act as agonists at opioid receptors which are widespread throughout the body
including the brain (cerebral cortex, thalamus, hypothalamus, amygdala, basal ganglia,
brainstem, reticular activating system), spinal cord and non neural tissues such as the
gastrointestinal tract. There are four main classes of opioid receptors; mu, kappa, delta and
nociceptin, all of which are G-protein coupled inhibitory receptors. Each opioid has different
affinities for these classes of receptors, and each class is associated with specific therapeutic
and adverse effects.
Analgesia from neuraxial opioid administration is primarily mediated by binding pre and
postsynaptic mu-opioid receptors in the substantia gelatinosa of the dorsal horn of the spinal
cord. Activation of presynaptic receptors on primary afferent neurons carrying nociceptive
information results in decreased conductance through voltage gated calcium channels and
reduced calcium influx with subsequent decreased neurotransmitter release. This reduces
signalling between primary and secondary afferent neurons in the dorsal horn. Binding of
postsynaptic opioid receptors on secondary afferent neurons results in hyperpolarisation and
decreased propagation of action potentials.
Intrathecal opioids
Intrathecal opioids potentially act as ligands on opioid receptors in three different areas to
produce analgesia:
1. They have direct access to the dorsal horn of the spinal cord (their main site of action).
2. They are transported supra-spinally by bulk CSF flow where they modulate descending
inhibitory pain pathways.
3. A small amount of opioid diffuses into the epidural space with subsequent systemic
absorption resulting in centrally mediated analgesia (minor effect).

Intrathecal opioids undergo minimal metabolism within the CSF. The onset and duration of
analgesia and the degree of cephalad spread are dependent on lipid solubility. Highly lipid
soluble (lipophilic) opioids such as fentanyl and sufentanil diffuse into the spinal cord and
bind dorsal horn receptors rapidly. This produces a rapid onset of analgesia with minimal
cephalad spread and subsequently a low risk of delayed respiratory depression, however the
duration of analgesia is relatively short. Morphine is poorly lipid soluble (hydrophilic) and is
much slower to bind dorsal horn receptors resulting in a slower onset but more prolonged
duration of analgesia, increased cephalad spread and subsequently an increased risk of
delayed respiratory depression.
Epidural opioids
After epidural administration, variable quantities (depending on which opioid is used) will
diffuse across the dura and arachnoid mater into the subarachnoid space to bind opioid
receptors in the dorsal horn of the spinal cord. Lipid solubility is the most important factor
affecting the rate of diffusion and the subsequent onset and duration of analgesia. Lipophilic
opioids such as fentanyl and sufentanil diffuse rapidly across the dura into the CSF compared
to hydrophilic opioids such as morphine. Lipophilic opioids produce rapid onset of analgesia
which is of short overall duration. After epidural delivery, CSF opioid levels peak at 6
minutes for sufentanil, 20 minutes for fentanyl and 1-4 hours for morphine.
The epidural space is extremely vascular and there is extensive absorption of opioids via the
epidural venous plexus into the systemic circulation. Systemic opioids reach the CNS and
bind receptors in areas of the brain that modulate pain perception and response. Epidural
administration of sufentanil, fentanyl and morphine produces plasma levels of opioid similar
to those seen after intramuscular injection of similar doses. Centrally mediated analgesia after
systemic absorption is an important mechanism of analgesia for epidural opioids. Lipophilic
opioids such as sufentanil and fentanyl are absorbed the most rapidly, and are therefore more
likely to cause early respiratory depression. After epidural delivery, plasma levels peak at less
than 5 minutes for sufentanil, 5-10 minutes for fentanyl and 10-15 minutes for morphine.
Dose
The appropriate dose depends on the type of opioid (potency, efficacy, lipid solubility),
indication for use, addition of other adjuvants, patient factors and route of administration.
Intrathecal drugs have direct access to the central nervous system (CNS) and need relatively
small doses for analgesic effect compared to epidural dosing. Intrathecal doses are usually
approximately 1/10th of the epidural dose.

Tabel 1. Indicative doses of neuraxial opioids

DRUG

Fentanyl
Sufentanil
Morphine
Diamorphine
Pethidine

INTRATHECAL

EPIDURAL

DOSE

LOADING

10-25g
2.5-10g
50-300g
300-400g
Not recommended

DOSE
50-100g
10-50g
2-5mg
2-3mg
25-50mg

Morphine
Morphine is a hydrophilic phenanthrene derivative and is approximately 100 times less potent
then fentanyl. Its onset is slow compared to the lipophilic opioids (15 minutes intrathecal, 30
minutes epidural), and it has a significantly longer duration of action (approximately 12-24
hours). Its terminal elimination half life is approximately 170 minutes. Intrathecal morphine
is slow to bind dorsal horn receptors in the spinal cord due to its poor lipid solubility and free
opioid in the CSF may migrate supra-spinally resulting in delayed respiratory depression.
Neuraxial morphine has been shown to be as effective as fentanyl at improving the quality of
analgesia for labour pain, caesarean delivery, and more effective than a single dose of
fentanyl at providing postoperative pain relief. Unfortunately both intrathecal and epidural
morphine are associated with a higher incidence of nausea, vomiting, pruritus, urinary
retention, sedation and delayed respiratory depression when compared to fentanyl. In the
setting of post caesarean analgesia, both single dose intrathecal and epidural morphine have
been shown to have a ceiling analgesic effect; at doses greater then 100g (intrathecal) and
3.75mg (epidural) there is minimal additional analgesic benefit, but increased incidence of
adverse effects (particularly pruritus). Anaesthetists must be cautious in utilising only
preservative free morphine for neuraxial anaesthesia and analgesia.
Morphine
Morphine is a hydrophilic phenanthrene derivative and is approximately 100 times less potent
then fentanyl. Its onset is slow compared to the lipophilic opioids (15 minutes intrathecal, 30
minutes epidural), and it has a significantly longer duration of action (approximately 12-24
hours). Its terminal elimination half life is approximately 170 minutes. Intrathecal morphine
is slow to bind dorsal horn receptors in the spinal cord due to its poor lipid solubility and free
opioid in the CSF may migrate supra-spinally resulting in delayed respiratory depression.
Neuraxial morphine has been shown to be as effective as fentanyl at improving the quality of

analgesia for labour pain, caesarean delivery, and more effective than a single dose of
fentanyl at providing postoperative pain relief. Unfortunately both intrathecal and epidural
morphine are associated with a higher incidence of nausea, vomiting, pruritus, urinary
retention, sedation and delayed respiratory depression when compared to fentanyl. In the
setting of post caesarean analgesia, both single dose intrathecal and epidural morphine have
been shown to have a ceiling analgesic effect; at doses greater then 100g (intrathecal) and
3.75mg (epidural) there is minimal additional analgesic benefit, but increased incidence of
adverse effects (particularly pruritus). Anaesthetists must be cautious in utilising only
preservative free morphine for neuraxial anaesthesia and analgesia.
Side Effects
Adverse effects from neuraxially administered opioids are potentially due to the cephalad
spread of opioid in the CSF or via systemic absorption from the epidural space which can
lead to similar adverse effects observed following parenteral administration. Intrathecal and
hydrophilic opioids are more likely to cause adverse effects secondary to cephalad migration,
while epidural and lipophilic opioids are more likely to cause central effects after systemic
absorption. Most side effects are dose related and are due to opioid receptor interactions,
however some are unrelated. The classical side effects of neuraxial opioids include:
Pruritus
Pruritus is the most common adverse effect of neuraxial opioids. It occurs within the first few
hours and is usually localised to the face, neck and thorax. The mechanism for pruritus is not
fully understood but is thought to be mediated by cephalad migration of opioid which binds
to opioid receptors in the trigeminal nucleus. It is more common when poorly lipid soluble
agents are used (for example there is a 70% incidence of pruritus with intrathecal morphine
compared to 10% for fentanyl). Histamine-1 receptor antagonists may be helpful even though
the pruritus is not mediated by histamine release. Opioid receptor antagonists such as
naloxone are most effective at managing pruritus but may diminish analgesic effects.
Nausea and vomiting
The incidence of nausea and vomiting associated with neuraxial opioids is reported as being
between 20-50%. It is more common in females and with intrathecal morphine. It is thought
to be mediated by cephalad migration of the opioid to the chemoreceptor trigger zone where
the opioids can act as a partial dopamine-2 receptor agonist.
Urinary retention

The incidence of urinary retention is approximately 30-40%. It is more common in young

men and with intrathecal morphine. It is mediated by opioid receptors in the sacral spinal
cord. This inhibits sacral parasympathetic outflow that leads to detrusor relaxation.
Respiratory Depression
Respiratory depression is potentially the most serious adverse effect caused by neuraxial
opioids. The incidence after neuraxial administration is similar to that of parenterally
administered opioids. Factors increasing the risk of respiratory depression include high opioid
dose, elderly patients, concomitant use of sedative and analgesic drugs, lack of opioid
tolerance and the presence of comorbid factors (for example sleep apnoea and pulmonary
disease). Treatment with opioid antagonists such as naloxone may be required in some cases.
Early respiratory depression generally develops within 2 hours of epidural administration of
lipophilic opioids such as sufentanil and fentanyl. It is due to systemic absorption from the
epidural space, and is less common after intrathecal administration and hydrophilic opioids
such as morphine.
Delayed respiratory depression usually develops between 6-12 hours after intrathecal
administration of poorly lipid soluble opioids such as morphine. It is due to cephalad
migration of the opioid in the CSF which reaches opioid receptors in the respiratory centre. It
is uncommon with lipophilic opioids because they rapidly penetrate the spinal cord, leaving
minimal free opioid in the CSF.
Other
Other adverse effects include sedation, CNS excitation, viral reactivation (herpes simplex
labialis virus), gastro-intestinal dysfunction, sexual dysfunction, ocular dysfunction and
thermoregulatory dysfunction.