Adjuvants in central neuraxial

blockade
Dr ABHISHEK / DR ANIL
 Rationale
• To allow lower doses of each agent and to
preserve analgesia

• The incidence and severity of side effects can

be diminished by combining different classes
of drugs, thereby decreasing the dose of each
component.
 Modulation of nociception

Schematic representation of the organization of several dorsal horn

systems that contributes to the processing of nociceptive information
• Acute postoperative pain is a complex physiologic reaction to
tissue injury.

• knowledge of nociception in the dorsal horn of the spinal cord

is important to understand the mechanism of action of
adjuvants drugs for regional anaesthesia.

• Many pharmacological processes underlie nociceptive

transmission in the spinal cord.

• The dorsal horn is the site of termination of primary afferents

and there is a complex interaction among afferent fibres, local
intrinsic spinal neurons and the endings of descending fibres
from the brain.

• A number of peptides, catecholamines and indoleamines act

as neurotransmitters at the dorsal horn.
• Modulation within the spinal cord results from the action
of neurotransmitter substances in the dorsal horn or from
spinal reflexes that convey efferent impulses back to the
peripheral nociceptive field.

• Adjuvant drugs used with local anaesthetics may interact

with others exerting an antinociceptive effect, such as
alpha 2- adrenergic drugs (clonidine) and adrenaline.

• Also in clinical use are anti-cholinergic agents

(neostigmine), NMDA receptor antagonists (ketamine), and
N-specific calcium-channel blockers (ziconotide).

• As can be anticipated, all these drugs will show a variety of

side effects apart from their dominant antinociceptive
effect.
 LOCAL ANAESTHETICS
• Local anaesthetics are esters or amides, the term
describing the chemical link between the aromatic
moiety and the hydrocarbon chain. Local anaesthetics
block the generation and propagation of action
potentials in excitable nerve tissues, primarily by
impairing the function of voltaged sodium (Na+)
channels in the axonal membrane.

• The sodium channel itself is a specific receptor for local

anaesthetic molecules. Local anaesthetics can cause a
differential blockade, i.e. selective block of small fibers,
by use of low concentrations.
• This results in clinically important zones of
differential blockade involving somatic sensory
fibers and preganglionic sympathetic fibers.

• The clinically important properties of local

anaesthetic agents include speed of onset,
potency and duration of action and blockade of
sensory of sensory and motor nerves.
 CLONIDINE
• Clonidine is a selective α2 adrenergic agonist with some α1 agonist
properties.

• Such drugs induce antinociception by activating the descending

noradrenergic inhibitory system and by inhibiting synaptic transmission
within the dorsal horn of the spinal cord via activation of spinal cholinergic
neurons.

• Activating the α2 adrenoceptor triggers an inwardly rectifying potassium

conductance in dorsal horn neurons, causing hyperpolarization, reduced
excitability and analgesia.

• Spinal clonidine produces analgesia by mimicking the effect of

norepinephrine on wide dynamic range neurons. This inhibition is also
observed in the intermediolateral cell column, the origin of sympathetic
vasoactive neurons, and causes a decrease in sympathetic outflow.
 CENTRAL NEURAL BLOCKADE
• Clonidine acts synergistically with local anaesthetics because
of its action of opening potassium channels.

• The duration of both sensory and motor blockade from

spinally and epidurally applied local anaesthetics is
prolonged.

• Co-administration of clonidine and local anaesthetics

intrathecally prolongs analgesic and motor block duration,
and the quality of the block is enhanced compared to
intrathecal local anaesthetic alone.

• This is a dose dependent phenomenon with a maximum

effect after 75-100 μg. The type of local anaesthetic does not
seem to be important.
• The antinociceptive interaction of intrathecal clonidine
and lidocaine was demonstrated in a rat model.

• isobolographic analysis showed a synergistic effect.

• Arterial hypotension is the most commonly reported

side effect of neuraxial use of clonidine; it is mostly due
to direct inhibition of sympathetic outflow of
preganglionic neurons in the spinal cord. Other side
effects include sedation and a reduction of the heart
rate.
• PERIPHERAL BLOCKADE
• Clonidine prolongs the action of local anaesthetic
peripheral blocks into the post-operative period.

• Its effect is dose-related and the minimum effective

doses, which significantly prolong analgesia and
anaesthesia are respectively 0.1 and 0.5 mcg/kg after
brachial plexus block with mepivacaine.

• Clonidine opens the potassium channels, resulting in

membrane hyperpolarization, a state that is
unresponsive to excitatory input.
 KETAMINE
• Ketamine is a phencyclidine derivate and is commercially available
as a racemic mixture of the two enantiomers S(+) ketamine and R(-)
ketamine. Ketamine is a N-methyl-D-aspartate (NMDA) receptor
antagonist.

• The activation by excitatory amino acids (glutamate) of spinal

dorsal horn NMDA receptors is believed to play an important role in
the development of neuropathic pain, or more accurately, central
sensitization.

• Ketamine is a non-competitive antagonist of the NMDA receptor

calcium pore, and blocks the open calcium channel on the NMDA
receptor complex, thus inhibiting excitatory transmission by
decreasing depolarisation.
• Through this mechanism, ketamine prevents the
development of, or alleviates, established
neuropathic pain arising from dorsal horn wind-
up phenomenon. S(+)-ketamine, the left-handed
optical isomer of racemic ketamine, has a
fourfold higher affinity for NMDA receptors than
right-handed R(-)-ketamine.

• Ketamine is also known to produce both sensory

and motor block, but the mechanism of action is
not clear.
 CENTRAL NEURAL BLOCKADE
• Concern has been expressed about neurotoxicity after neuraxial use
of ketamine, because spinal myelopathy has been reported with
intrathecal injection of large doses. However in animals and
humans there is no evidence for neurological injury after repeated
intrathecal injection of preservative-free ketamine.

• Conflicting results have been reported when epidural

administration of ketamine is used for pain management. One
study found a reduction in the onset time of sensory block
following epidural administration of 25 mg ketamine with
bupivacaine compared to bupivacaine alone.

• However postoperative analgesic duration was comparable

between the groups. Others found that the combination of epidural
S(+)-ketamine and ropivacaine increased postoperative pain relief
compared to ropivacaine alone.
• Potential complementary antinociceptive actions of
the two drugs may play a role. However, intrathecal
ketamine added to a small dose of spinal bupivacaine
did not provide extended postoperative analgesia or
decrease the postoperative analgesic requirements.

• Further, ketamine is associated with side effects like

sedation, dizziness, nystagmus, ‘strange feelings’,
postoperative nausea and vomiting when used as a
sole agent or as an adjuvant to bupivacaine.
 NEOSTIGMINE
• The cholinergic system is thought to modulate pain perception and
transmission by a spinal mechanism.

• Acetylcholine is one of more than 25 neurotransmitters that participate in

spinal cord modulation of pain processing. Intrathecal neostigmine
provides antinociception by inhibiting breakdown of acetylcholine.

• This acts on cholinergic neurones within the spinal cord; the increased
concentration of acetylcholine in the spinal fluid stimulates spinal
muscarinic and nicotinic receptors; it is mainly the former that play a part
in producing analgesia.

• This analgesia is not associated with respiratory depression, but there is a

significant incidence of nausea, vomiting and, more rarely, anxiety.
• CENTRAL NEURAL BLOCKADE
• Epidural neostigmine 1 to 4 μg added to a local anaesthetic
solution produced a dose-independent analgesic effect in
patients after minor orthopaedic procedures.

• Addition of 50 μg neostigmine to a spinal bupivacaine

solution prolonged the duration of sensory and motor
block.

• Smaller doses of neostigmine (6.25 and 12.5 μg) do not

significantly enhance sensory or motor block, but do
increase the incidence of nausea and vomiting, which limits
clinical usefulness.
 ADENOSINE
• Adenosine receptors are expressed on the
surface of nearly all cells. Five classes of
adenosine receptors have been identified of
which A1 and A2 and agonists of both receptor
subtypes have been identified as being
analgesic.The A1 and A2 receptors are present
centrally and peripherally, with agonists of the A1
receptor being antinociceptive and agonists of
the A2 receptor algogenic (i.e., activation results
in pain).
• CENTRAL NEURAL BLOCKADE
• In volunteers, the efficacy in reducing areas of
experimental hypersensitivity was the same following
an intrathecal dose of 0.5 or 2 mg adenosine, but side
effects were commoner with the larger dose.

• The diagnostic and potential therapeutic role for

intrathecal adenosine in acute and chronic pain states
is at present under investigation. Intrathecal adenosine
decreases the spontaneous and evoked pain intensity
in patients with neuropathic pain involving
hyperalgesia-dysesthesia-allodynia.
 ADRENALINE
• Vasoconstrictor drugs, in particular adrenaline, are
commonly used as adjuvants in solutions of local
anaesthetics to slow the systemic absorption, leading to
increased neuronal uptake of local anaesthetics.

• As a consequence the depth and duration of neural

blockade are increased. In clinical practice, local
anaesthetic solutions usually contain adrenaline at a
concentration of 5 μg/ml (1:200.000). The prolongation
of the duration of action of neural blockade varies with
the specific local anaesthetic and its concentration.
• CENTRAL NEURAL BLOCKADE
• Prolongation of sensory analgesia has been
shown to be more pronounced with the
epidurally administered shorter acting local
anaesthetic agents like lignocaine and
prilocaine.

• On the other hand, addition of adrenaline to

either bupivacaine or etidocaine solutions
appears to increase the intensity of motor
blockade.
• Adrenaline addition is more effective with low
concentrations of local anaesthetic. With spinal
anaesthesia, the increase in duration of neural
blockade might be related to vasoconstriction of the
vessels supplying the dura mater and spinal cord,
leading to slower systemic vascular absorption and
increased neuronal uptake of the local anaesthetic, or
to a direct α-adrenergic effect of the vasoconstrictor
on the spinal cord.

• The greatest increase in duration is seen when

adrenaline is added to amethocaine solutions; added
to lignocaine and bupivacaine, it has substantially less,
if any, effect on duration. The most profound effect of
adding adrenaline to the spinal solution occurs in the
lumbosacral region.
 OPIOIDS
• Neuraxially administered opioids produce
significant dose-dependent analgesia through
opioid receptors in the substantia gelatinosa.
They have two well-established actions on
neurons. Firstly, they inhibit a voltagesensitive
calcium channel on presynaptic nerve terminals.
This action inhibits release of neurotransmittors,
including substance P and glutamate, active in
spinal nociceptive transmission. Secondly, opioids
can hyperpolarize, and thus inhibit, postsynaptic
neurons by opening potassium channels.
• The analgesic effects of opioids are based on interference at
different opioid receptors (principally mu receptors) in the spinal
cord after epidural or intrathecal administration. Since the dura
mater is not a lipid membrane, the rate of diffusion from epidural
into intrathecal space is inversely proportional to molecular size,
and high lipophilicity actually increases the uptake into epidural fat
and blood vessels.

• Analgesia is dose related: the epidural dose is 5 to 10 times the

subarachnoid dose.

• In animal studies, isobolographic analysis reveals synergistic

antinociception of co-administrated morphine and local
anaesthetics.
• CENTRAL NEURAL BLOCKADE
• The primary differences among opioids used for analgesia
relate to their onset of action, duration of actionand
propensity to produce side-effects. For analgesia, fentanyl
and sufentanil are the most popular opioids combined with
local anaesthetics. Combination therapy is mostly used for
postoperative and labour pain.

• Although the interaction between epidural local

anaesthetics and opioids is highly synergistic in animals, a
clearbenefit from this interaction in humans has been
surprisingly difficult to demonstrate. Studies strongly
suggest that the mode of action for epidurally administered
lipid-soluble opioids is uptake into the systemic circulation
with subsequent distribution to brain uptake receptors.
• There is no evidence of a selective spinal site of action. In contrast,
the potent analgesia produced by modest doses of the hydrophilic
drug morphine is largely the result of redistribution from the
epidural space to spinal cord opioid receptors.

• The dose required for intrathecal administration of opioids is 10-20

times smaller than that required for epidural administration.

• Combination therapy reduces dose requirements for either the

local anaesthetic or the opioid compared to their administration as
single drugs, [28] and improves the control of incident (i.e.,
movement-related) pain. Compared to epidural administration
there is a greater risk of adverse effects, including late-onset
respiratory depression.
 CONCLUSION
• Antinociceptive drugs have been combined with local
anaesthetics in several settings in an attempt to reduce the
latter’s side effects, or to intensify or prolong their effect.
Different groups of drugs, each acting by a unique
mechanism, have been shown to block nociceptive afferent
transmission in the spinal cord.

• None of the neuraxially administered local anesthetics and

antinociceptive drugs produce analgesia without side
effects. Balanced neuraxial analgesia using a combination
of low doses of drugs, with separate but synergistic
mechanism of analgesia may produce the best results.
• References
• Euroanaesthesia 2003 - Glasgow
Thank you