Advances in Local Anesthesia

Anaesthesia, 2010, 65 (Suppl. 1), pages 22–37 doi:10.1111/j.1365-2044.2009.06201.
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Local anaesthetics and adjuvants – future developments

M. D. Wiles1 and M. H. Nathanson2
1 Lecturer, Division of Anaesthesia and Intensive Care, University of Nottingham, Queen’s Medical Centre, Nottingham,
UK
2 Consultant Anaesthetist, Nottingham University Hospitals NHS Trust, QMC Campus, Nottingham, UK
Summary
The introduction of local anaesthesia some years after the first public demonstration of general
anaesthesia not surprisingly created less excitement and interest amongst both the public and the
medical profession. However, in its own way, a new revolution was happening. Local anaesthesia
produced an increase in the choice of anaesthetic techniques available to practitioners and patients.
In common with general anaesthesia, the choice of agents remained very limited for the first six
decades, and interest in the practice of local, regional or central neuraxial blockade and the
development of new techniques and drugs were hampered by perceived safety issues even as late as
the second half of the 20th century. It is only in the last few years that, with an apparent renaissance
in the use of local anaesthesia, the pace of development has picked up. As the use and range of
techniques has increased, so has interest in solving some of the longstanding problems with the
available drugs.
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Correspondence to: Dr Matt Wiles
E-mail: matt.wiles@nottingham.ac.uk
The first recorded use of a local anaesthetic drug (LA) to selectivity, lesser degrees of motor blockade and lower
provide anaesthesia for surgery was in 1884 when Koller incidences of systemic toxicity continues. This review
used cocaine drops to anaesthetise the conjunctiva. This will examine three areas of research:
led to the widespread clinical use of cocaine, but initial • The development of LAs – some are older agents
enthusiasm was tempered by the reports of toxic effects undergoing a renaissance, some are novel compounds,
and death. With the development of procaine by Einhorn and some are established drugs that have subsequently
in 1904, local anaesthesia saw an increase in popularity been found to have local anaesthetic properties;
but the relatively high incidence of anaphylaxis associated • advances in drug delivery systems;
with the ester LAs such as procaine limited their use. The • the use of adjuncts to LAs.
advent of the amide LAs, first lidocaine in 1943 and then
bupivacaine in 1963, heralded the beginning of modern
Developments in local anaesthetic agents
local and regional anaesthesia. Local anaesthetic drugs are
now widely used throughout anaesthetic practice and ‘Renaissance’ agents
their use continues to increase as attempts are made to Chloroprocaine
provide more ambulatory surgery, to avoid the side effects 2-chloroprocaine is an ester LA with a very short half-life
of systemic analgesics, to avoid some of the risks and a favourable profile for short procedures. It was first
associated with general anaesthesia and to increase used for spinal anaesthesia in 1951 [1], but due to cases of
patients’ safety and satisfaction. neurological damage associated with its epidural use in the
However, anaesthesia still awaits the development of 1980s [2–4] it never gained widespread popularity. With
the ideal LA. Modern LAs are sufficiently effective and the development of preservative-free preparations (earlier
safe for the majority of clinical practice, but the search for solutions contained methylparaben, a preservative,
agents with longer durations of action, better nerve fibre or sodium bisulfite, an anti-oxidant), the use of
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22 Journal compilation 2010 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2010, 65 (Suppl. 1), pages 22–37 M. D. Wiles and M. H. Nathanson Æ Local anaesthetics and adjuvants
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2-chloroprocaine as an intrathecal agent for day-case identical when equal amounts are infused intravenously
surgery is increasing in popularity throughout mainland [18].
Europe, primarily due to concerns about the incidence of The degree of motor block produced by ropivacaine
transient radicular irritation with the use of intrathecal has been compared with bupivacaine and levobupivacaine
lidocaine [5]. Chloroprocaine is not currently available in in numerous studies. A review found that only a minority
the UK. of these were able to demonstrate any decrease in motor
When compared with lidocaine, intrathecal 2-chloro- block with the use of ropivacaine [19]. This is of
procaine has a similar onset time and maximum block particular significance when it is considered that the
height, but is associated with a more rapid resolution of majority of these studies compared identical doses of
sensory block. Day-surgery patients given 2-chloropro- bupivacaine and ropivacaine, as it is has been shown that
caine met discharge criteria earlier [6, 7]. When compared ropivacaine is about 40% less potent than bupivacaine
with low-dose bupivacaine, 2-chloroprocaine was asso- [20–22], and the lesser degree of motor blockade is likely
ciated with faster times to complete block resolution, to to be caused by the lower total mass of drug, rather than
ambulation and to urinary voiding [8]. When compared by a specific drug effect. Levobupivacaine and bupi-
with prilocaine, 2-chloroprocaine was associated with a vacaine appear to be equipotent [23, 24].
faster recovery of motor function and a shorter time to
voiding [9]. The incidence of nerve damage with Butyl amino-benzoate
intrathecal 2-chloroprocaine appears to be very low; a Butyl amino-benzoate (BAB) is an ester LA that, although
case series of 700 patients reported no symptoms sugges- poorly water-soluble, can be prepared as an aqueous
tive of transient radicular irritation [10]. suspension (butamben) for nerve blocks [25] and has
shown promise as a long acting agent. At physiological
Prilocaine pH, BAB is uncharged and hydrophobic, it partitions
Prilocaine is an amide LA that has been used for over into lipid bilayers and is not systemically absorbed. A
50 years. Although primarily used for peripheral nerve single epidural or peripheral nerve block using BAB has
block, intravenous regional anaesthesia and topical provided pain relief for up to 14 weeks, and it has been
anaesthesia (in combination with lidocaine), it has been used successfully in the management of intractable pain
investigated as an intrathecal agent for short duration associated with advanced malignancy [26, 27]. Of
spinal anaesthesia because of its low incidence of particular interest is the low incidence of motor
transient radicular irritation [11–14]. However, the blockade associated with the analgesia [26, 28]. This
duration of sensory and motor block produced by may be attributable to the selective blockade of sodium
intrathecal prilocaine is prolonged when compared with channels [29] or the inactivation of potassium channels
lidocaine [14]. [30] in the dorsal root ganglion. There are concerns
regarding the neurotoxicity of BAB [28], and further
Novel compounds work is required to establish its safety in the management
Chiral compounds of non-palliative pain. The largest single study involved
Ropivacaine and levobupivacaine are two amide LAs that only 75 patients [26] and was undertaken as part of a US
were developed in response to the cardiotoxicity associ- Food and Drug Administration Investigative New Drug
ated with either the accidental administration of intrave- phase 1 study.
nous bupivacaine or the rapid absorption of a large
amount of drug injected into tissues. Each is produced as a Tonicaine and n-butyl tetracaine
pure ‘S’ isomer. Levobupivacaine is the ‘S’ isomer of Tonicaine (N-b-phenylethyl lidocaine) is a novel, per-
bupivacaine and ropivacaine is the ‘S’ isomer of 1-propyl- manently charged, quaternary ammonium derivative of
2¢,6¢-pipecoloxylidide, an amide LA with a similar lidocaine [31]. It produces a block nine times longer than
structure to mepivacaine and bupivacaine. Bupivacaine that seen with lidocaine, with the sensory blockade lasting
has been shown to have a smaller lethal dose than longer than the motor blockade [32]. As tonicaine is a
levobupivacaine or ropivacaine when administered by charged molecule, penetration of neuronal membranes
direct coronary artery injection in pigs [15]. Levobupi- takes longer than with lidocaine and the onset of action is
vacaine has also been shown to be less likely to produce two to three times slower [32, 33]. A similar derivative of
fatal arrhythmias than bupivacaine [16] but neither tetracaine has also been synthesised. N-butyl-tetracaine
levobupivacaine nor ropivacaine are associated with an has produced a reversible sciatic nerve block in rats that
increased likelihood of successful resuscitation in the lasted 2 weeks [34]. There are no studies at present
event of cardiac arrest [17]. The toxicity of levobupiva- involving human subjects and the safety of tonicaine and
caine and ropivacaine in human subjects appears to be n-butyl tetracaine has yet to be established.
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Journal compilation 2010 The Association of Anaesthetists of Great Britain and Ireland 23
M. D. Wiles and M. H. Nathanson Æ Local anaesthetics and adjuvants Anaesthesia, 2010, 65 (Suppl. 1), pages 22–37
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being developed that will also block tetrodotoxin-resis-

tant sodium channels. Ralfinamide and 5-aryl-2-furfurra-
mides are two such agents, both of which have
demonstrated antinociceptive effects in animal studies
[46, 47] and which may be of value as LAs in the future.
ProTx-II is a 30-amino-acid peptide from the venom
of the tarantula Thrixopelma prurien. Like tetrodotoxin it is
a sodium channel inhibitor, but it appears to act
predominately on C nerve fibres, with little effect on
Ab fibres [48]. This selectivity may due to an action upon
a novel binding site that is not occupied by traditional LAs
and may form the basis of the development of new LAs.
The venom of piscovorous marine snails contains an
omega-conotoxin that blocks voltage-sensitive calcium
channels. A synthetic version (zoconotide, previously
known as SNX-111) of the toxin from the species Conus
magus has been manufactured. Zoconotide is a novel
calcium channel blocker that specifically blocks N-type,
Figure 1 Chemical structure of articaine.
neuron-specific, voltage-sensitive calcium channels that
are found at presynaptic primary afferent nerve terminals.
Articaine Animal studies have shown SNX-111 to be an effective
Articaine (4-methyl-3-(2-[propylamino]-propionamido)- analgesic for both acute and chronic pain and it can be
2-thiophenecarboxylic acid) is a unique ester LA that administered via the intrathecal or perineural route [49–
contains additional ester and thiophene rings [35] (Fig. 1). 51]. Unlike opioid analgesics, no tolerance developed
It has been widely used in dental surgery as it has a rapid after seven days of infusion and SNX-111 was estimated
onset, a short duration of action and achieves good to be 1000 times more potent than intrathecal morphine
periosteal penetration with a low incidence of systemic [50]. Human studies are ongoing, but zoconotide has
toxicity [36]. However, it has not been shown to offer been used successfully as a continuous intrathecal infusion
any clinically useful advantage over lidocaine in dental in patients with refractory chronic pain, both as mono-
practice [35]. Articaine has also been used intrathecally for therapy and in conjunction with intrathecal morphine
day surgery. When compared with low-dose bupivacaine, [52, 53]. Side effects include nausea, dizziness, headache,
articaine had a shorter duration of motor and sensory confusion, somnolence, memory impairment and small
blockade, and discharge criteria were met more rapidly increases in creatine kinase [52].
[37]. There appears to be no clinically significant
difference between lidocaine and articaine when used Drugs with local anaesthetic properties
for spinal [38, 39], epidural [40] or brachial plexus Sameridine and pethidine
regional anaesthesia [41]. Articaine provides superior Sameridine and pethidine are compounds with local
akinesia and a more rapid onset of anaesthesia than a anaesthetic and opioid actions. Both have been used
lidocaine and bupivacaine mixture when used in a sub- successfully as intrathecal agents in human studies,
Tenon’s block for cataract surgery [42, 43]. As the predominately in Asia and North America. The duration
majority of the studies involving articaine had a small of sensory blockade is similar to that of lidocaine, but
number of participants (with the exception of studies of analgesia is more prolonged and without side effects such
dental surgery), it is difficult to recommend its use in as respiratory depression [54, 55]. Pethidine has been
preference to lidocaine, especially as concerns exist associated with a higher incidence of nausea and vom-
relating to its potential for neurotoxicity [44]. iting, especially when used in obstetric patients [56, 57].
Tramadol may also have local anaesthetic properties (see
Animal toxins below).
Tetrodotoxin is the naturally occurring toxin of the puffer
fish (fugu) that specifically blocks sodium channels, but in Antidepressants
a different manner to LAs such as lidocaine. When Tricyclic antidepressants share a number of properties,
combined with adrenaline, it has been shown to produce both physical and pharmacological, with LAs. Both have a
prolonged sciatic nerve block in rats, but its use is limited hydrophobic portion connected to an amine. They share
by its considerable systemic toxicity [45]. Other agents are a common mechanism of action with both blocking
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neuronal sodium channels in a use-dependent manner

[58], although tricyclic antidepressants also affect numer-
ous other neurotransmitters including serotonin, gluta-
mate, adenosine and acetylcholine [59]. Tricyclic
antidepressants have been shown to produce a longer
neuronal block than bupivacaine in rat sciatic nerve
blocks [60], although neurotoxicity [61–63] and myo-
toxicity [64] have been seen due to a very narrow
therapeutic range. In sheep, intrathecal amitriptyline has
been shown to produce differential nerve blockade with
sparing of motor fibres [65]. Human studies are limited. A
phase 1 study examining the use of amitriptyline for ulnar
nerve blockade showed no difference in the quality of
analgesia or in the duration of block when compared with
bupivacaine. Transdermal amitriptyline has been shown
to produce topical analgesia for several hours, but no
comparison was made with other topical local anaesthetic
creams [66]. Doxepin has been shown to be an effective
topical analgesic for oral mucositis in a non-randomised,
unblinded trial [67]. Further work is required to establish Figure 2 Electron micrograph of a liposome (courtesy of Flynn
the efficacy and safety of tricyclic antidepressants before Pharma Ltd).
their use as LAs can be recommended.
and mepivacaine occurs more slowly than with standard

Advances in drug delivery systems
preparations of either drug, resulting in a prolonged
Liposomal delivery systems analgesic effect without an increase in the time to onset of
Liposomal delivery systems have been developed in an analgesia [69–71]. The intravenous dose of bupivacaine
attempt to prolong the duration of action of administered required to cause cardiac and central nervous system
LAs without the need for adjuvant drugs, nerve sheath toxicity is also greater for a liposomal preparation,
catheters or pumps. Liposomes are microscopic lipid suggesting that they may have an additional safety benefit
vesicles ranging in size from 0.02 to 40 lm. They are [72].
created from amphipathic lipid molecules that have a Liposomal encapsulated LAs have been used in patients
polar, hydrophilic head and a hydrophobic, hydrocarbon by the topical [73, 74], subcutaneous [75] and epidural
tail. When these are placed in an aqueous suspension a [76, 77] routes. There are no large, randomised control
vesicle is formed, with a central aqueous compartment trials comparing liposomal LAs with standard formula-
surrounded by a lipid bilayer. This may be only a single tions. A liposomal formulation of bupivacaine placed
lipid bilayer (unilamellar) or there may be multiple intraderamlly produced a more prolonged period of
concentric lipid bilayers (multilamellar). It is also possible anaesthesia compared with standard bupivacaine (19 h vs
to create multivesicular preparations (Fig. 2). The central 1 h), although pinprick testing was the sole test of
aqueous compartment can then contain a water-soluble analgesia [75]. Liposomal bupivacaine given epidurally has
drug or lipid soluble drugs can be carried within the lipid been shown to provide longer postoperative analgesia
bilayer. The permeability of the lipid bilayer varies after abdominal surgery (mean (SD) = 3.2 (0.4) h with
according to its structure and physiochemical properties plain bupivacaine and 6.25 (1.13) h with the liposomal
[68] and can be modified to allow drug diffusion from the preparation), with the additional benefit of no lower limb
central compartment to occur more slowly, creating a motor blockade and an identical onset time [76]. These
slow-release preparation of the drug. findings require confirmation in larger, randomised
Liposomes are attractive as a delivery system for LAs as control trials. The safety of liposomal preparations is yet
they are able to provide a reservoir of drug. The to be fully established. There are concerns regarding the
liposomes are large enough to prevent redistribution potential neurotoxicity of the liposomes themselves or of
from the site of injection whilst having a low risk of compounds produced during their metabolism [68].
systemic toxicity as only a fraction of the drug is bio- There is also a risk from the potential for liposomal
available. Work in animal models has shown that the breakdown, resulting in the rapid release of large amounts
release of liposomally encapsulated lidocaine, bupivacaine of free drug.
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Multivesicular liposomal preparations of morphine when intermediate-acting LAs such as mepivacaine and
have been developed for epidural use. Due to the gradual lidocaine were used. The addition of clonidine to longer-
release mechanism, this technology can allow larger acting LAs such as bupivacaine did not increase the
epidural doses to be given, providing analgesia for a duration of the sensory block. It could not be established
greater period of time. Improved pain scores and whether the benefits seen with clonidine were mediated by
decreased opioid consumption have been demonstrated a local or a systemic effect. With doses of < 150 lg there
for up to 48 h after lower abdominal surgery [78], hip was a low incidence of side effects such as hypotension,
arthroplasty [79] and caesarean section [80]. Some studies bradycardia, dry mouth and sedation.
have shown an increase in opioid-related side effects [78, Dexmedetomidine is a highly selective alpha-2 adre-
79], and in one study a patient’s death was attributed to noreceptor agonist that has an alpha-2 to alpha-1
the administration of liposomal morphine [78]. When selectivity ratio seven times greater than that of clonidine
epidurally delivered liposomal morphine is compared [88]. A study comparing intrathecal dexmedetomidine
with equivalent doses of standard morphine, no improve- with intrathecal clonidine in patients undergoing tran-
ment in pain scores or decrease in postoperative opioid surethral urological surgery found that dexmedetomidine
consumption was shown [78, 80]. offered no additional benefit in terms of duration of
sensory blockade or postoperative analgesia requirements
Microspheres and cyclodextrins [89]. Dexmedetomidine does seem to provide prolonged
Microspheres and cyclodextrins have also been used for postoperative analgesia when used as an additive to an LA
drug delivery systems as an alternative to liposomes. in total intravenous anaesthesia [90, 91]. Further work is
Microspheres are larger molecules than liposomes (10 to necessary to quantify whether dexmedetomidine offers a
150 lm diameter) and are constructed from biodegrad- significant clinical benefit over clonidine as neurotoxicity
able polymers. Cyclodextrins are cyclic oligosaccharides has been observed in rabbits receiving epidural dexmede-
with a hydrophobic internal cavity similar to liposomes. tomidine [92].
Bupivacaine has been incorporated into both systems and
used in animals [81–83], but work on humans is very Adrenaline
limited. Bupivacaine encapsulated in microspheres has Adrenaline has been used as an adjunct to LAs for more
provided sensory anaesthesia for up to 96 h when used than a century on the basis that adrenaline-induced
subcutaneously and for intercostal nerve blockade [84, vasoconstriction decreases tissue blood flow and results in
85]. slower clearance of drug from the target site [93].
Theoretically this should produce prolonged anaesthesia
and lower systemic absorption of injected LA. In addition,
Adjuvants to local anaesthetics
adrenaline appears to have an analgesic effect in its own
Alpha-2 adrenoreceptor agonists right by directly stimulating alpha-2 adrenoreceptors and
Clonidine is an alpha-2 adrenoreceptor agonist com- thereby decreasing presynaptic neurotransmitter release
monly used to prolong the duration of action of LAs. A from C- and Ad-fibres in the substantia gelatinosa of the
systematic review of the intrathecal use of clonidine as an dorsal horn.
adjunct to an LA [86] found that it prolonged the Adrenaline has been used epidurally in concentrations
duration of the sensory blockade by approximately 1 h ranging between 1.66 and 5 lg.ml)1. The addition of
and the time to first analgesic request by around 100 min. adrenaline to thoracic epidural infusions of LA and
The time to establish the block was unchanged, but the fentanyl has been shown to improve the quality of
duration of motor blockade was prolonged. The addition analgesia produced without an increase in side effects
of clonidine resulted in a greater incidence of hypoten- [94–96]. With lumbar epidurals there are conflicting
sion. The optimal dose for intrathecal use could not be reports, with some showing no benefit from the addition
established, but there was a linear relationship between of adrenalie [97–99] and others showing improvements in
clonidine doses of between 15 and 150 lg and the time to analgesia [100, 101]. This difference may be due to the
regression of the sensory block. The clinical significance fact that lumbar epidural catheters are sited further from
of theses changes is open to question, and further work is the spinal cord dorsal horn cells, thereby decreasing the
needed to establish whether intrathecal clonidine offers an analgesic effect of alpha-2 adrenoreceptor stimulation.
advantage over an increased dose of LA alone. The intrathecal use of adrenaline as an adjunct in
A systematic review of the evidence for the use of subarachnoid or combined spinal-epidural anaesthesia
clonidine as an adjunct in peripheral nerve blocks was (dose range 12.5–120 lg) remains contentious, with
largely inconclusive [87]. Clonidine appeared to be of some some studies suggesting a prolongation of analgesia
benefit for peribulbar and single-shot axillary blocks, or [102, 103] whilst others show no benefit [104]. A single
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study has suggested that adrenaline may prolong the cal tramadol 25 mg to be no better than placebo in
analgesic effect of intrathecal morphine [105]. urological surgery [125] but superior to sufentanil for
There have been concerns about the risk of spinal cord labour analgesia [126]. There are concerns over the
ischaemia with the use of epidural and intrathecal neurotoxic potential of intrathecal tramadol, both in
adrenaline, but recent large human surveys have failed animal models [127] and from a case report [128].
to identify adrenaline as a clear risk factor for neuraxial
injury [106]. Midazolam
There is no convincing evidence that the addition of A high concentration of type-II benzodiazepine receptors
adrenaline to LAs for peripheral nerve blocks provides any is found in the substantia gelatinosa of the human spinal
analgesic benefit in terms of prolongation of sensory cord, leading to the hypothesis that they may have a role
blockade [107–109]. Adrenaline has no effect upon the in sensory pathways [129]. Midazolam acts by facilitating
systemic absorption of ropivacaine [110] but does the action of the inhibitory neurotransmitter c-aminobu-
decrease systemic levels of prilocaine, bupivacaine and tyric acid (GABA). It may also have a central antinoci-
lidocaine [111, 112]. ceptive effect via the activation of spinal d opioid
receptors [130]. When used intrathecally, midazolam 1–
Tramadol 2 mg has been shown to potentiate the analgesic effects of
Tramadol is a synthetic 4-phenyl-piperidine analogue of intrathecal bupivacaine for 2–6 h [131, 132] and intra-
codeine and acts as an analgesic via an affinity for thecal fentanyl by 50 min [133]. A recent meta-analysis
l-opioid receptors, by alpha-2 adrenoreceptor agonistic that included 672 patients concluded that intrathecal
and serotoninergic effects and by inhibiting the re-uptake midazolam delayed the time to request rescue analgesia
of noradrenaline and 5-hydroxytryptamine. Work in without any increase in the duration of motor blockade
animals has suggested that it may also act directly on spinal [134]. Similar improvements in pain scores were seen
receptors [113] in a similar manner to opioids. Recent with the addition of midazolam to bupivacaine for adult
studies have now shown that intradermal tramadol has a epidurals (0.83–1.66 mg.h)1) and paediatric caudal epid-
local anaesthetic effect equivalent to that of prilocaine urals (0.25–0.5 lg.kg)1) [135, 136], although there was
[114, 115]. Tramadol has been studied as adjunct to LAs an increased incidence of sedation [135, 137].
in the hope that it may have an effect similar to other When used in conjunction with bupivacaine for a
alpha-2 adrenoreceptor agonists such as clonidine. The supraclavicular nerve block, midazolam 50 lg.kg)1 was
results have been variable. When used as an adjunct to associated with improved postoperative pain scores and
mepivacaine in brachial plexus blockade, tramadol pro- decreased analgesic requirements for up to 24 h [138].
longed the motor and sensory blockade and decreased Intra-articular midazolam (50–75 lg.kg)1) provided 4 h
postoperative analgesic requirements [116, 117]. The of additional analgesia after arthroscopy [139]. Some
addition of tramadol to bupivacaine for psoas compart- animal studies have raised concerns about neurotoxicity,
ment blockade was not associated with a change in the but a study of 1100 patients found that 2 mg of intrathecal
duration of anaesthesia or a decrease in postoperative midazolam did not increase the occurrence of symptoms
opioid requirements [118]. suggestive of neurological damage when compared with
A number of studies has examined the efficacy of conventional therapies [140].
epidurally delivered tramadol, with doses ranging from 40
to 200 mg (1.5–2.0 mg.kg)1). There have been conflict- Adenosine
ing reports in children undergoing caudal epidurals, with Adenosine exerts an analgesic effect via spinal adenosine
some showing no benefit and others a decrease in A1 receptors, many of which are located in the substantia
postoperative analgesia requirements [119–122]. The gelatinosa of the dorsal horn of the spinal cord [141].
systemic absorption of tramadol from caudal epidural Adenosine also appears to act as an endogenous anti-
administration is extensive, producing similar tissue levels inflammatory agent [142]. There is no evidence of
to those of intravenous administration [123]. It may be neurotoxicity in animal studies [143], and adenosine
that epidural tramadol acts only as a depot for later appears to have little effect upon systemic haemodynamics
systemic absorption and that this is the sole analgesic in clinical studies, although short-lived side effects
mechanism of action. Studies involving adults are more including fainting, palpitations, headache, transient atrio-
limited, but boluses of tramadol 100 mg given epidurally ventricular block and severe bronchospasm have all been
have been shown to provide superior analgesia when reported [144]. When administered intravenously, aden-
compared with boluses of bupivacaine 25 mg [124]. Data osine (25 lg.kg)1.min)1) was as effective as remifentanil
on the use of intrathecal tramadol are limited. Studies for intra-operative analgesia and was associated with
involving small number of patients have shown intrathe- decreased opioid requirements in the early postoperative
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period [145]. This has led to studies examining adenosine significant side effects far outweighed the small improve-
as an adjunct to LAs in both peripheral nerve blocks and ments in analgesia, and its use could not be recommended
spinal anaesthesia. In two studies of patients undergoing [161].
hysterectomy, the use of intrathecal adenosine 0.5– Neostigmine (60–500 lg) has been used as an adjunct
1.0 mg made no difference to pain scores or postoperative for epidural use and has produced improved postoperative
analgesic consumption [146, 147]. When used as an analgesia with a low incidence of nausea and vomiting,
adjunct to brachial plexus blockade, the addition of but with an increase in sedation [162–165]. Neostigmine
adenosine 10 mg to a prilocaine and lidocaine mixture (2–4 lg.kg)1) also prolongs analgesia when used in caudal
made no difference to the onset or offset of sensory epidural anaesthesia in children [136, 166–168]. The use
blockade, and did not extend the duration of analgesia of neostigmine in peripheral blocks has been studied with
[148]. conflicting reports, both in terms of analgesic benefit and
the incidence of side effects. Three studies have examined
Dextrans the addition of neostigmine 500 lg to either mepivacaine
Dextrans are complex, branched polysaccharides consist- or lidocaine for axillary brachial plexus block. Only one
ing of chains of individual glucose units, and are showed improved postoperative analgesia [169], with the
synthesised from sucrose by the action of certain lactic- others showing no prolongation of sensory blockade [170,
acid bacteria. The addition of dextran as an adjunct to LAs 171]. One of the studies reported a 30% incidence of side
was first studied in 1960 in an attempt to prolong the effects, which were predominately gastrointestinal in
duration of action of the sensory blockade. Since that nature [170].
time there have been conflicting results from numerous
other studies, with some demonstrating a prolongation of Neuromuscular blocking drugs
analgesia [149, 150], while others have been unable to Neuromuscular blocking drugs have been used as adjuncts
show any conclusive benefit [151, 152]. The mechanism to LAs in peribulbar blocks and in intravenous regional
of action is unclear, but it is hypothesised that dextrans anaesthesia. Vecuronium 0.5 mg has been shown to
may form water-soluble complexes with LAs that remain provide superior ocular and eyelid akinesia than placebo
at the site of injection longer than the unbound drug, due when added to a mixture of lidocaine with adrenaline,
to an increase in viscosity with reduced diffusion of the bupivacaine and hyaluronidase [172]. The addition of
complex [153]. Alternatively, the addition of dextran atracurium 5 mg to a lidocaine and bupivacaine mixture
alters the pH of the injected LA solution, and this resulted in more rapid ocular akinesia but no difference in
alkalinisation may contribute to the prolongation of the frequency of complete akinesia [173]. The addition of
action [154]. Dextrans have been shown to decrease the atracurium (2 mg) and cisatracurium (0.01 mg.kg)1) to
systemic absorption of lidocaine, offering benefits in lidocaine and prilocaine for intravenous regional anaes-
decreasing the incidence of toxicity [155]. No large scale thesia is associated with superior intra-operative analgesia
trials have been performed to investigate whether the use and easier forearm fracture reduction with no adverse side
of dextrans as adjuvants offers any significant clinical effects [174–176]. However, the addition of mivacurium
advantages in terms of prolongation of analgesia or 0.6 mg to prilocaine resulted in all patients complaining
superiority to vasoconstrictors for reducing systemic of symptoms consistent with LA toxicity and all experi-
absorption of LAs. enced prolonged motor blockade [177].
Neostigmine N-methyl D-asparate (NMDA) receptor antagonists

Cholinesterase inhibitors exert a dose-dependent antino- N-methyl-D-aspartate receptors are increasingly impli-
ciceptive effect by the activation of intrinsic ascending cated in the induction and maintenance of central
and descending cerebral cholinergic pathways via musca- sensitisation during pain states. They may also be
rinic, but not nictotinic, receptors [156, 157]. Intrathecal involved in peripheral pain sensitisation and visceral pain.
neostigmine (50–200 lg) has been shown to be as As a result, NMDA receptor antagonists have been
effective as intrathecal morphine for postoperative anal- investigated as analgesics and as adjuncts to LAs.
gesia after gynaecological surgery [158, 159] and prolongs
postoperative analgesia after lower limb orthopaedic Ketamine
surgery [160]. Its usefulness is limited by numerous side Ketamine acts as a non-competitive antagonist of the
effects including sweating, evacuation of bowels and NMDA receptor through interaction with the phencyc-
severe nausea and vomiting, which have proved to be lidine receptor. It also has effects on sodium and calcium
resistant to pharmacologic treatment [158]. A recent channels, and nicotinic, muscarinic and opioid receptors
meta-analysis concluded that the high incidence of [178]. A recent review attempted a meta-analysis on the
2010 The Authors

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numerous studies examining the use of epidural ketamine Opioids

in adults. Twelve studies were examined that involved Intrathecal and epidural opioids were first administered to
585 patients. Due a large variation in treatment regimens, human subjects in 1979 [200, 201], and since that time
a meta-analysis was deemed inappropriate, but seven they have been proven to provide effective and prolonged
studies concluded that epidural ketamine decreased analgesia [202]. Systematic reviews have shown a pro-
postoperative pain, while five found no evidence of longed analgesic effect with intrathecal morphine in
benefit [179]. When used in caudal epidurals in children, lower limb joint arthroplasty [203, 204] and caesarean
numerous studies have demonstrated a prolongation of section [205]. A single bolus of intrathecal opioid also
postoperative analgesia with ketamine 0.5 mg.kg)1 added decreases pain after thoracotomy for up to 24 h [206].
to LAs (including bupivacaine, ropivacaine and lido- Similar benefits have been shown with the epidural
caine), without an increase in side effects [180–186]. The administration of opioids, although after joint arthroplasty
analgesic action appears to be mediated by a direct the analgesic effect is limited to 6 h [207]. A systematic
neuraxial effect rather than by systemic absorption [184]. review of post-thoracotomy analgesia concluded that a
The intrathecal use of ketamine is limited to studies of thoracic epidural infusion of LA with an opioid provided
small numbers of patients with cancer pain [187–189]. A the most consistently effective analgesia [206]. This
trial investigating intrathecal ketamine as the sole anaes- improvement in analgesia has to be balanced against the
thetic agent for urological surgery was terminated early high incidence of undesirable side effects that include
due to a high incidence of severe psychomimetic side respiratory depression (which may occur several hours
effects and inadequate intra-operative analgesia [190]. after initial administration), nausea, vomiting, pruritus and
When used as an adjunct to ropivacaine in a brachial urinary retention [208]. As described above, liposomally
plexus block, ketamine provided no analgesic benefit and encapsulated preparations of morphine are now available
was associated with a high incidence of adverse effects that can provide analgesia for up to 48 h after adminis-
[191]. No significant benefits were demonstrated from tration.
the addition of ketamine to bupivacaine for inguinal field A review article examining the efficacy of adding
block [192]. opioids to LAs for brachial plexus blocks considered ten
trials involving 413 patients. The opioids included
Magnesium morphine, fentanyl, sufentanil, alfentanil, butorphanol
At resting membrane potential, NMDA receptor channels and buprenorphine. Overall, six were supportive and four
are blocked by extracellular magnesium ions in a non- negative. The authors concluded that there was little
competitive manner [193]. Intrathecal magnesium 50 mg evidence for any analgesic benefit of using opioid
has been shown to prolong the analgesic effect of analgesics in brachial plexus block over systemic admin-
intrathecal fentanyl for labour analgesia [194] and lower istration [209].
limb surgery [195], although the latter study did demon-
strate a slower onset of motor and sensory blockade with Non-steroidal anti-inflammatory drugs (NSAIDs)
the use of magnesium. When used as adjunct to Non-steroidal anti-inflammatory drugs have been used as
bupivacaine and sufentanil in patients undergoing lower adjuncts in intravenous regional anaesthesia. When
limb arthroplasty, intrathecal magnesium 94.5 mg de- lornoxicam 8 mg was used in conjunction with lidocaine,
creased postoperative analgesia requirements by almost the onset time for motor and sensory blocks was
50% [196]. The use of intrathecal magnesium has not decreased and an improvement in postoperative analgesia
been associated with any increase in side effects or adverse was noted [210]. Similar benefits in postoperative anal-
events. When given as an adjunct to bupivacaine and gesia have been demonstrated with ketorolac (20–60 mg)
fentanyl by the epidural route, magnesium has been [211, 212], tenoxicam (20 mg) [213] and lysine acetyl-
shown to decrease pain scores and analgesic requirements salicylate (90 mg) [214]. Animal studies examining the
for up to 72 h after surgery without any side effects [197]. possibility of using intrathecal NSAIDs as analgesics are
Interestingly, the benefit of magnesium was only evident ongoing [215].
if administration was commenced before the start of the
surgical procedure. This may be due to a pre-emptive Steroids
analgesic action, a phenomenon that has been demon- The duration of analgesia produced by axillary and
strated with other NMDA receptor antagonists [198]. supraclavicular nerve blocks of the brachial plexus can be
The optimal dose for either epidural or intrathecal use prolonged with the addition of dexamethasone 8 mg
remains to be established. Animal experiments suggest [216, 217]. A similar benefit may be seen with the
that there is no role for the use of magnesium as an addition of methylprednisolone [218], but there are
adjunct to peripheral nerve blocks [199]. concerns that the prolonged analgesia may in part be
2010 The Authors

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due to the preservative benzyl alcohol, which has 2 Reisner LS, Hochman BN, Plumer MH. Persistent
neurotoxic properties [219]. Intra-operative and postop- neurologic deficit and adhesive arachnoiditis following
erative analgesia with intravenous regional anaesthesia intrathecal 2-chloroprocaine injection. Anesthesia &
using lidocaine is also improved by the addition of Analgesia 1980; 59: 452–4.
3 Ravindran RS, Bond VK, Tasch MD, Gupta CD, Luerssen
dexamethasone 8 mg [212, 220].
TG. Prolonged neural blockade following regional anal-
gesia with 2-chloroprocaine. Anesthesia & Analgesia 1980;
Conclusions 59: 447–51.
4 Moore DC, Spierdijk J, vanKleef JD, Coleman RL, Love
The LAs currently available in the UK are satisfactory for GF. Chloroprocaine neurotoxicity: four additional cases.
the vast majority of indications. Although safety, partic- Anesthesia & Analgesia 1982; 61: 155–9.
ularly in the context of accidental intravascular injection, 5 Pollock JE, Neal JM, Stephenson CA, Wiley CE. Pro-
remains a concern, the newer chiral compounds provide spective study of the incidence of transient radicular irri-
an increased safety margin. However, the use of lipid tation in patients undergoing spinal anesthesia.
rescue, discussed elsewhere in this supplement, is of Anesthesiology 1996; 84: 1361–7.
greater significance. Two main pharmacological desires – 6 Kouri ME, Kopacz DJ. Spinal 2-chloroprocaine: a com-
parison with lidocaine in volunteers. Anesthesia & Analgesia
that are paradoxically opposing – remain to be filled. One
2004; 98: 75–80.
is for a short-acting agent suitable for intrathecal use for
7 Casati A, Fanelli G, Danelli G, et al. Spinal anesthesia with
day surgery. 2-Chloroprocaine seems ideal, and its lidocaine or preservative-free 2-Chlorprocaine for outpa-
introduction in to the UK would seem overdue. The tient knee arthroscopy: a prospective, randomized,
other desire is for the ability to prolong blockade and, if double-blind comparison. Anesthesia & Analgesia 2007;
possible, to extend only the sensory component. To some 104: 959–64.
extent at least this can be met by the use of catheter 8 Yoos JR, Kopacz DJ. Spinal 2-chloroprocaine: a compar-
techniques – also discussed elsewhere in this supplement. ison with small-dose bupivacaine in volunteers. Anesthesia
However, these are not suitable for all indications and the & Analgesia 2005; 100: 566–72.
most fruitful area of current research would appear to be 9 Hendriks MP, de Weert CJM, Snoeck MMJ, Hu HP,
the use of liposomally encapsulated LAs and opioids. Pluim MAL, Gielen MJM. Plain articaine or prilocaine for
spinal anaesthesia in day-case knee arthroscopy: a double-
These delivery systems should provide the clinician with
blind randomized trial. British Journal of Anaesthesia 2009;
both an extended range and a choice in the degree of
102: 259–63.
prolongation of the action of each agent. 10 Palas TAR. Four years’ experience with 1% chloroprocaine
The use of adjuvants with LAs has been practised for for spinal anesthesia in ambulatory anesthesia. Regional
many years and remains the subject of much interest. Anesthesia and Pain Medicine 2005; 30: 13.
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lower incidence with prilocaine and bupivacaine than with
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ficial use is the NMDA receptor antagonists and further
13 Martinez-Bourio R, Arzuaga M, Quintana JM, et al.
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Conflicts of interest prilocaine. Anesthesiology 1998; 88: 624–8.
14 Ostgaard G, Hallaraker O, Ulveseth OK, Flaatten H. A
Dr Wiles and Dr Nathanson have received honoraria randomised study of lidocaine and prilocaine for spinal
from AstraZeneca for membership of advisory boards anaesthesia. Acta Anaesthesiologica Scandinavica 2000; 44:
relating to ropivacaine and bupivacaine; Dr Nathanson 436–40.
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Anaesthesia, 2010, 65 (Suppl. 1), pages 22–37 doi:10.1111/j.1365-2044.2009.06201.

Local anaesthetics and adjuvants – future developments

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being developed that will also block tetrodotoxin-resis-

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neuronal sodium channels in a use-dependent manner

and mepivacaine occurs more slowly than with standard

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Neostigmine N-methyl D-asparate (NMDA) receptor antagonists

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numerous studies examining the use of epidural ketamine Opioids

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