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CHAPTER 26 Local Anesthetics 471

LIDOCAINE EMLA

Aside from the issue of a high incidence of TNS with spinal The term eutectic is applied to mixtures in which the combination
administration, lidocaine has had an excellent record as an inter- of elements has a lower melting temperature than its component
mediate duration anesthetic and remains the reference standard elements. Lidocaine and prilocaine can combine to form such a
against which most anesthetics are compared. mixture, which is marketed as EMLA (Eutectic Mixture of Local
Anesthetics). This formulation, containing 2.5% lidocaine and
MEPIVACAINE 2.5% prilocaine, permits anesthetic penetration of the keratin-
ized layer of skin, producing localized numbness. It is commonly
used in pediatrics to anesthetize the skin prior to venipuncture for
Although structurally similar to bupivacaine and ropivacaine
(Table 26–1), mepivacaine displays clinical properties that are intravenous catheter placement.
comparable to lidocaine. However, it differs from lidocaine with
respect to vasoactivity, as it has a tendency toward vasoconstriction FUTURE DEVELOPMENTS
rather than vasodilation. This characteristic likely accounts for its
slightly longer duration of action, which has made it a popular Sustained-Release Formulations
choice for major peripheral blocks. Lidocaine has retained its
dominance over mepivacaine for epidural anesthesia, where the The provision of prolonged analgesia or anesthesia, as in the
routine placement of a catheter negates the importance of a longer case of postoperative pain management, has traditionally been
duration. More importantly, mepivacaine is slowly metabolized by accomplished by placement of a catheter to permit continuous
the fetus, making it a poor choice for epidural anesthesia in the administration of anesthetic. More recently, efforts have focused
parturient. When used for spinal anesthesia, mepivacaine has a on drug delivery systems that can slowly release anesthetic, thereby
slightly lower incidence of TNS than lidocaine. providing extended duration without the drawbacks of a catheter.
Sustained-release delivery has the potential added advantage of
PRILOCAINE reducing risk of systemic toxicity. Preliminary work encapsulating
local anesthetic into microspheres, liposomes, and other mic-
Prilocaine has the highest clearance of the amino-amide anes- roparticles has established proof of concept, although significant
thetics, imparting reduced risk of systemic toxicity. Unfor- developmental problems, as well as questions regarding potential
tunately, this is somewhat offset by its propensity to induce tissue toxicity, remain to be resolved.
methemoglobinemia, which results from accumulation of one of
its metabolites, ortho-toluidine, an oxidizing agent. As a spinal Less Toxic Agents; More Selective Agents
anesthetic, prilocaine’s duration of action is slightly longer than It has been clearly demonstrated that anesthetic neurotoxicity does
that of lidocaine, and the limited data suggest it carries a low not result from blockade of the voltage-gated sodium channel.
risk of TNS. It is gaining increasing use for spinal anesthesia in Thus, effect and tissue toxicity are not mediated by a common
Europe, where it has been marketed specifically for this purpose. mechanism, establishing the possibility of developing compounds
No approved formulation exists in the USA, and there is no for- with considerably better therapeutic indexes. In addition, a neo-
mulation that would be appropriate to use for spinal anesthesia saxitoxin, a site 1 sodium channel biotoxin, is currently being
as an off-label indication.
explored as a method to provide prolonged block, with the goal
of obviating the need for catheter placement and continuous
ROPIVACAINE anesthetic infusion.
As previously discussed, the identification and subclassifi-
Ropivacaine is an S(–) enantiomer in a homologous series that cation of families of neuronal sodium channels have spurred
includes bupivacaine and mepivacaine, distinguished by its chiral- research aimed at development of more selective sodium channel
ity and the propyl group off the piperidine ring (Table 26–1). Its blockers. The variable neuronal distribution of these isoforms
perceived reduced cardiotoxicity has led to widespread use for high- and the unique role that some play in pain signaling suggest that
volume peripheral blocks. It is also a popular choice for epidural selective blockade of these channels is feasible and may greatly
infusions for control of labor and postoperative pain. Although improve the therapeutic index of sodium channel modulators.
there is some evidence to suggest that ropivacaine might produce For example, compounds with specificity for the Na v 1.7 and
a more favorable differential block than bupivacaine, the lack of Na 1.8 isoforms have been identified and are currently under
v
equivalent clinical potency adds complexity to such comparisons. clinical development.