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Local and Regional

Anesthesia
Updated: Jul 07, 2015 | Author: Robyn Gmyrek, MD; Chief Editor:
Dirk M Elston, MD more...

Overview
Local anesthetics provide a reversible regional loss
of sensation. Local anesthetics reduce pain, thereby
facilitating surgical procedures. Delivery techniques
broaden the clinical applicability of local anesthetics.
These techniques include topical anesthesia,
infiltrative anesthesia, ring blocks, and peripheral
nerve blocks (see the Technique section below for
links to detailed, illustrated articles demonstrating
these techniques).

Local anesthetics are safer than general or systemic

anesthetics; therefore, they are used whenever
possible. In addition, they are relatively easy to
administer and readily available. Local anesthetics
have been undergoing development for centuries,
and, as this article illustrates, research continues to
provide surgeons with pharmacologic variety and to
provide patients with anesthetic agents that have
superior safety and efficacy profiles.

Background
Although the medical world cannot cure every
disease, the control of pain to ensure patient comfort
should be a goal. In 1860, cocaine, the oldest
anesthetic, was extracted from the leaves of the
Erythroxylon coca bush. In 1884, Sigmund Freud and
Karl Koller were the first to use it as an anesthetic
agent during ophthalmologic procedures.

Procaine, a synthetic alternative to cocaine, was not

developed until 1904. Procaine is an ester of para-
aminobenzoic acid (PABA). As procaine is
metabolized, PABA, a known allergen, is released as
a metabolic product. The potential for severe allergic
reactions limits the use of procaine and other ester-
type anesthetic agents. Tetracaine, another ester-
type anesthetic, was introduced in 1930. Tetracaine is
more potent than procaine, and it causes similar
allergic reactions.

In 1943, an alternative class of anesthetics was

discovered when Lofgren developed lidocaine. This
agent is an amide derivative of diethylaminoacetic
acid, not PABA; therefore, it has the benefit of a low
allergic potential. Since then, multiple amide-type
anesthetics have been introduced into clinical use.
Slight chemical alterations to the compounds have
imparted beneficial characteristics, including
increased duration and potency, to each. These
compounds offer the surgeon more choices, and
anesthetics can be appropriately matched to
different procedures.

Pathophysiology
Reviewing the physiology of nerve conduction is
important before any discussion of local anesthetics.
Nerves transmit sensation as a result of the
propagation of electrical impulses; this propagation
is accomplished by alternating the ion gradient
across the nerve cell wall, or axolemma.

In the normal resting state, the nerve has a negative

membrane potential of -70 mV. This resting potential
is determined by the concentration gradients of 2
major ions, Na+ and K+, and the relative membrane
permeability to these ions (also known as leak
currents). The concentration gradients are
maintained by the sodium/potassium ATP pump (in
an energy-dependent process) that transports
sodium ions out of the cell and potassium ions into
the cell. This active transport creates a concentration
gradient that favors the extracellular diffusion of
potassium ions. In addition, because the nerve
membrane is permeable to potassium ions and
impermeable to sodium ions, 95% of the ionic leak in
excitable cells is caused by K+ ions in the form of an
outward flux, accounting for the negative resting
potential. The recently identified 2-pore domain
potassium (K2P) channels are believed to be
responsible for leak K+ currents.

When a nerve is stimulated, depolarization of the

nerve occurs, and impulse propagation progresses.
Initially, sodium ions gradually enter the cell through
the nerve cell membrane. The entry of sodium ions
causes the transmembrane electric potential to
increase from the resting potential. Once the
potential reaches a threshold level of approximately
-55 mV, a rapid influx of sodium ions ensues. Sodium
channels in the membrane become activated, and
sodium ion permeability increases; the nerve
membrane is depolarized to a level of +35 mV or
more.

Once membrane depolarization is complete, the

membrane becomes impermeable to sodium ions
again, and the conductance of potassium ions into
the cell increases. The process restores the excess
of intracellular potassium and extracellular sodium
and reinstates the negative resting membrane
potential. Alterations in the nerve cell membrane
potential are termed the action potential. Leak
currents are present through all the phases of the
action potential, including setting of the resting
membrane potential and repolarization.

Mechanism of action
Local anesthetics inhibit depolarization of the nerve
membrane by interfering with both Na+ and K+
currents. The action potential is not propagated
because the threshold level is never attained.

Although the exact mechanism by which local

anesthetics retard the influx of sodium ions into the
cell is unknown, 2 theories have been proposed. The
membrane expansion theory postulates that the local
anesthetic is absorbed into the cell membrane,
expanding the membrane and leading to narrowing
of the sodium channels. This hypothesis has largely
given way to the specific receptor theory. This theory
proposes that the local anesthetic diffuses across the
cell membrane and binds to a specific receptor at the
opening of the voltage-gated sodium channel. The
local anesthetic affinity to the voltage-gated Na+
channel increases markedly with the excitation rate
of the neuron. This binding leads to alterations in the
structure or function of the channel and inhibits
sodium ion movement. Blockade of leak K+ currents
by local anesthetics is now also believed to
contribute to conduction block by reducing the ability
of the channels to set the membrane potential.

On the basis of their diameter, nerve fibers are

categorized into 3 types. Type A fibers are the
largest and are responsible for conducting pressure
and motor sensations. Type B fibers are myelinated
and moderate in size. Type C fibers, which transmit
pain and temperature sensations, are small and
unmyelinated. As a result, anesthetics block type C
fibers more easily than they do type A fibers.
Therefore, patients who have blocked pain sensation
still feel pressure and have mobility because of the
unblocked type A fibers.

All local anesthetics have a similar chemical

structure, which consists of 3 components: an
aromatic portion, an intermediate chain, and an
amine group (see molecular diagram below). The
aromatic portion, usually composed of a benzene
ring, is lipophilic, whereas the amine portion of the
anesthetic is responsible for its hydrophilic
properties. The degree of lipid solubility of each
anesthetic is an important property because its lipid
solubility enables its diffusion through the highly
lipophilic nerve membrane. The extent of an
anesthetic's lipophilicity is directly related to its
potency.

Molecular diagram.

Local anesthetics are weak bases that require the

addition of hydrochloride salt to be water soluble
and therefore injectable. Salt equilibrates between
an ionized form and a nonionized form in aqueous
solution. Equilibration is crucial because, although
the ionized form is injectable, the nonionized base
has the lipophilic properties responsible for its
diffusion into the nerve cell membrane. The duration
of action of an anesthetic or the period during which
it remains effective is determined by its protein-
binding activity, because the anesthetic receptors
along the nerve cell membrane are proteins.

The intermediate chain, which connects the aromatic

and amine portions, is composed of either an ester
or an amide linkage (see molecular diagram above).
This intermediate chain can be used in classifying
local anesthetics.

Indications
Anesthesia is indicated to reduce pain before
surgical procedures.

Contraindications
Patient allergies may preclude the use of a particular
anesthetic agent (see Complications section below).

Anesthesia
Local anesthetics are classified into 2 groups: the
ester group and the amide group. The classification
is based on the chemical structure of the
intermediate chain. This structural difference affects
the pathway by which local anesthetics are
metabolized and the allergic potential.

Ester anesthetics are listed in the Table below. They

are metabolized by hydrolysis, which depends on the
plasma enzyme pseudocholinesterase. Some
patients have a rare genetic defect in the structure of
this enzyme and may be unable to metabolize ester-
type anesthetics; this inability increases the
possibility of their having toxic reactions and
elevated levels of anesthetics in the blood. In
addition, 1 of the metabolic products generated by
hydrolysis is PABA, which inhibits the action of
sulfonamides and is a known allergen. In patients
with a known allergy to an ester anesthetic, the use
of all other ester-type anesthetic agents should be
avoided.

Amide-type local anesthetics (see Table below) are

metabolized by microsomal enzymes located in the
liver. The specific microsomal enzyme responsible
for the elimination of lidocaine is cytochrome P-450
3A4. Therefore, amide-type anesthetics should be
used with care in patients with severe liver disease
and patients taking medications that interfere with
the metabolism of the anesthetic, and the patients
should be carefully monitored for signs of toxicity.

Cytochrome P-4503A4 is present in the small bowel

and the liver. Commonly used medications known to
inhibit cytochrome P-4503A4 are listed below
(adapted from Klein and Kassarjdian). [1] Specific
potent inhibitors of cytochrome P-4503A4 that have
been associated with clinically relevant interactions
include itraconazole, ketoconazole (azole
antifungals), erythromycin, clarithromycin,
cyclosporin (macrolides), amprenavir, indinavir,
nelfinavir, ritonavir (HIV protease inhibitors),
diltiazem, mibefradil (calcium channel blockers), and
nefazodone. Grapefruit juice is also a potent inhibitor
of P-4503A4 but appears to affect only the enteric
enzyme, which does not play a role in the
metabolism of local anesthetics.

If the enzyme is inhibited because of the concurrent

use of medications, it is unavailable to metabolize
the anesthetic and potentially toxic levels of the
anesthetic can occur. In addition, beta-blockers may
decrease blood flow to the liver; therefore, they may
also decrease the metabolism of amide-type
anesthetics and may cause serum levels of the
anesthetic to increase.

Table. Common Local Anesthetics* (Open Table in a

new window)

Duration Duration
Without With
Anesthetic Epinephrine, Epinephrine,

min min

Esters

Cocaine 45 -

Procaine 15-30 30-90

Chloroprocaine 30-60 -

Tetracaine 120-240 240-480

Amides

Lidocaine 30-120 60-400

Mepivacaine 30-120 30-120

Bupivacaine 120-240 240-480

Etidocaine 200 240-360

Prilocaine 30-120 60-400

*Adapted from Dinehart. [2]

Technique
Specific local anesthetic techniques are described in
detail in the following eMedicine topics:

Anesthesia, Regional, Digital Block

Anesthesia, Topical

Local Anesthetic Agents, Infiltrative

Administration

Nerve Block, Deep Peroneal

Nerve Block, Dorsal Penile

Nerve Block, Dorsal Penile, Neonatal

Nerve Block, Inferior Alveolar

Nerve Block, Infraorbital

Nerve Block, Oral

Nerve Block, Median

Nerve Block, Mental

Nerve Block, Posterior Tibial

Nerve Block, Radial

Nerve Block, Saphenous

Nerve Block, Superficial Peroneal

Nerve Block, Supraorbital

Nerve Block, Sural

Complications
Local effects
Local effects are usually a result of the injection
technique. These effects include pain, ecchymosis,
SECTIONS
hematoma formation, infection, and nerve laceration.
Pain is always felt when a local anesthetic is injected;
however, associated discomfort can be minimized by
using good technique. Several factors, including
needle puncture of the skin, tissue irritation resulting
from the anesthetic, and distention of tissues caused
by infiltration, are responsible for the discomfort
associated with the use of local anesthetics.

Pediatric patients and patients who are extremely

anxious may benefit from pretreatment of the
injection area with a topical anesthetic. [3]
Pretreatment eliminates the initial pain that occurs
when the needle perforates the skin. Small-diameter
needles also decrease the pain associated with
injection. Fortunately, for most dermatologic
procedures, a 30-gauge needle can be used to
infiltrate tissue.

Tissue irritation caused by local anesthetics is related

to the acidity of the infiltrated solution; therefore,
increasing the pH of the mixture can decrease
associated discomfort. The addition of epinephrine
to an anesthetic solution decreases the pH of the
solution, making it more acidic (pH 3.5-4.5) and
leading to a more painful injection. The solution can
be neutralized by the addition of sodium bicarbonate
8.4% to minimize discomfort. For example, sodium
bicarbonate 8.4% can be added to lidocaine with
epinephrine in a 1:10 ratio to achieve a solution pH
similar to that of tissue fluid (pH 7.3-7.4).

Discomfort associated with distension of the tissues

during the injection of local anesthetics is caused by
the rate of injection and the volume of fluid injected.
To limit the pain, the anesthetic should be slowly
administered to allow the stretch receptors time to
accommodate the new volume of fluid. [4] In addition,
the volume of solution injected should be the
smallest volume needed to achieve a loss of
sensation at the surgical site.

Studies have shown that patients receiving

subcutaneous or intradermal injection of local
anesthetics that were warmed to body temperature,
as opposed to room temperature, experienced less
pain during injection. If possible, warming of local
anesthetics should be done prior to administration.
[5]

The formation of ecchymosis or a local hematoma is

a result of the perforation of cutaneous blood
vessels. These complications are encountered more
commonly in areas of high vascularity, including the
mucous membranes, head, and genitalia.
Ecchymosis and hematoma are even more
pronounced when the patient has a bleeding
diathesis or when the patient has been taking aspirin
or other anticoagulants. If ecchymosis occurs, the
patient should simply be reassured. If hematoma
formation occurs, the patient should be evaluated.
The hematoma may require drainage with an 18-
gauge needle, followed by the application of a
pressure dressing.

Infection is an additional local complication of

anesthetic use that usually occurs when proper
sterile technique is not used. Cleansing the skin
surface with alcohol is adequate in otherwise clean
or noninfected areas. If signs of infection are noted,
treatment includes appropriate culture studies and
antimicrobial therapy. If abscess formation occurs,
drainage may also be required.

Nerve laceration, although rare, may occur during

the infiltration of a local anesthetic. This complication
more commonly occurs during the placement of
regional blocks than the placement of other blocks.
Clinical indications of nerve laceration include
paresthesias, shooting or sharp stinging sensations,
and excessive pain during needle insertion.
Paresthesias of the infraorbital nerve are
characterized by sharp or shooting sensations
involving the upper lip, nasal ala, and upper teeth.

If the needle is suspected to have entered or

lacerated a nerve, it should be withdrawn slowly and
deliberately by 1-2 mm, until the paresthesias are no
longer present. The needle should never be
advanced further, moved laterally, or inserted into the
foramen, because these maneuvers further increase
the risk of nerve laceration. Although dysesthesias
may remain for an extended duration, in most
patients, the nerve regenerates and sensation
normalizes over time.

Tendon injury is an inherent aspect of transthecal

digital anesthesia since the needle is pushed
through the tendon. This may cause persistent
discomfort lasting 1-2 days post surgery. Tendon
sheath infection and late occurrence of trigger finger
have also been reported.

Cutaneous adverse effects that have been reported

with the most commonly used topical anesthetic
EMLA include itching, burning, pain, pallor, erythema,
edema, and purpura. Irritant dermatitis, allergic
contact dermatitis, and contact urticaria have also
been reported, but these are very unusual. [6]

Amethocaine may induce an urticarial reaction at the

site of application, and the risk of such a reaction
seems to be significantly higher when amethocaine
is used over the antecubital fossa and in younger
children.

Systemic effects
Systemic effects usually occur when blood
concentrations of local anesthetic increase to toxic
levels. [7] Effects are most often encountered after
the unintentional intravenous injection or
administration of an excessive dose of an anesthetic.
Adding a vasoconstrictor (eg, epinephrine) can
reduce the systemic absorption of an anesthetic.
When using topical anesthetics, strict adherence to
the maximal dose or area recommended is advised;
additionally, great caution must be exercised when
using topical anesthetics on mucosal surfaces
because of the much greater absorption.

Importantly, remember that (1) the metabolism of

ester anesthetics is decreased in patients with
deficient pseudocholinesterase activity and (2) the
metabolism of amide anesthetics in patients who are
taking medications that inhibit the cytochrome P-450
system is decreased. In addition, the potency of an
anesthetic is directly correlated with the potential for
toxicity. Allergic reactions, although systemic, are not
related to serum levels of the anesthetic, but rather,
they are considered idiosyncratic and can occur at
any dose.

Maximal safe doses of lidocaine for local anesthesia

have been determined. For adults, a maximum of 4.5
mg of lidocaine per kilogram of body weight can be
administered, whereas as much as 7 mg/kg can be
used if the lidocaine solution has 1:100,000
epinephrine added as a vasoconstrictor. For children,
lower maximal doses are recommended; only 1.5-2.5
mg/kg of plain lidocaine and 3-4 mg/kg of lidocaine
with epinephrine should be used.

Systemic toxicity resulting from excessive blood

levels of anesthetics is clinically manifested as
adverse reactions in the CNS and cardiovascular
system. The CNS is affected in a predictable and
dose-dependent fashion. As serum levels of
lidocaine increase, effects on the CNS become more
severe.

Any physician who uses local anesthetics must be

aware of the signs and symptoms of systemic
toxicity. At serum lidocaine levels in the range of 1-5
mcg/mL, patients may complain of tinnitus,
lightheadedness, circumoral numbness, diplopia, or a
metallic taste in the mouth. In addition, they may
complain of nausea and/or vomiting, or they may
become more talkative. As serum levels increase to
5-8 mcg/mL, nystagmus, slurred speech, localized
muscle twitching, or fine tremors may be noticed.
Patients also have been noted to have hallucinations
at these levels. If blood lidocaine levels reach 8-12
mcg/mL, focal seizure activity occurs; this can
progress to generalized tonic-clonic seizures.
Respiratory depression occurs at extremely high
blood levels (20-25 mcg/mL) and can progress to
coma.

If signs of CNS toxicity are noted, steps must be

taken to reduce hypoxia and acidosis, because these
states increase the toxicity of local anesthetics. The
patient's airway should be maintained, and
supplemental oxygen provided. If blood levels of
carbon dioxide increase, protein binding of lidocaine
decreases and results in higher levels of free
lidocaine in the blood. Increased respiration and
respiratory alkalosis increase the seizure threshold
and decrease the uptake of the local anesthetic into
the CNS. If convulsions occur, the patient's airway
should be maintained, and supplemental oxygen
administered. If seizure activity is sustained, 5-10 mg
of diazepam should be administered slowly (1-2
mg/min) until the seizures cease.

Compared with the CNS, the cardiovascular system

is less susceptible to the effects of local anesthetics.
Most adverse effects of the cardiovascular system
that occur with the administration of local anesthetics
are a result of the addition of epinephrine rather than
direct effects of the anesthetic. However, high blood
levels of local anesthetics directly reduce cardiac
contractility. In addition to the direct vasodilatory
effects of most local anesthetics, the decrease in
cardiac function can cause hypotension.
Atrioventricular blocks, bradycardia, and ventricular
arrhythmias also are reported; these are more
common in patients with known conduction
disturbances and requiring antiarrhythmic
medications.

The treatment of conduction disturbances should be

appropriately tailored to the type of reaction. The
treatment of hypotension requires the physician to
initiate advanced cardiac life support protocols, that
is, he or she should ensure that the patient has a
patent airway, provide supplemental oxygen, and
elevate the patient's legs. If necessary, intravenous
fluid should be administered, and the use of
vasopressor agents such as ephedrine should be
considered. Ephedrine can be intravenously
administered in 5-mL incremental doses to a total of
15-30 mg, until a blood pressure response is noted.

Lidocaine and the FDA-approved topical anesthetics

EMLA and LMX are pregnancy category B
medications.

Allergic reactions
Allergic reactions to local anesthetics are extremely
rare, especially with amide local anesthetics, and
account for less than 1% of the reactions caused by
local anesthetics. Reactions can be type 1 (ie,
anaphylactic) or type 4 (ie, delayed-type
hypersensitivity) reactions. These reactions are not
dose related, but, rather, they are idiosyncratic. Skin
prick and intradermal test results are negative in the
vast majority of patients, but some authors
recommend testing with the most commonly used
amide local anesthetic (lidocaine).

Type 1 reactions are usually caused by ester-type

anesthetics. The ester group of local anesthetics
have a much greater allergenic potential than that of
the amide group. Pseudocholinesterases, which
produce the highly allergenic metabolic product
PABA, break down ester-type anesthetics. Cross-
reactivity exists among ester anesthetics; therefore,
the use of all anesthetics in this structural group
should be avoided in a patient with an established
sensitivity to one ester-type anesthetic.

No cross-reactivity appears to exist between ester

and amide anesthetics; however, cross-reactivity in
anaphylactic reactions has not been investigated
thoroughly. In addition, reactions to preservatives,
specifically methylparaben and sodium metabisulfate
(found in multiple-dose vials of amide anesthetics),
may cause adverse reactions in a patient who is
allergic to an ester-type anesthetic. Preservative-free
single-dose vials of lidocaine are available for use if
an amide anesthetic is to be used in a patient with a
true hypersensitivity reaction to ester-type
anesthetics.

Clinical signs of type I reactions include pruritus,

urticaria, facial swelling, wheezing, dyspnea,
cyanosis, laryngeal edema, nausea, vomiting, and
abdominal cramping. Epinephrine with a
concentration of 1:1000 should be subcutaneously
administered at a dose of 0.3-0.5 mL. This dose can
be repeated every 20-30 minutes to a maximum of 3
doses. If anaphylaxis ensues, a 5-mL dose of
epinephrine 1:10,000 should be administered
intravenously.

Type IV (ie, delayed-type hypersensitivity) reactions

account for 80% of allergic reactions to local
anesthetics. They are more common with the use of
topical anesthetics and may occur with anesthetics of
the amide and ester subtypes. Clinical manifestations
are similar to those of allergic contact dermatitis and
include erythema, plaques, and pruritus. Patients with
a history of type IV reactions are not at an increased
risk of type I reactions due to amide-type
anesthetics. Contact dermatitis caused by topical
anesthetics should be treated with topical steroid
preparations.

Alternative agents for use as anesthetics in patients

with a known allergy to both ester- and amide-type
local anesthetics include isotonic sodium chloride
solution and injectable antihistamines. An
intradermal injection of 0.9% sodium chloride
solution can provide temporary anesthesia suitable
for shave or punch biopsy. Physical pressure on the
nerve endings resulting from the volume injected is
postulated to be responsible for the anesthetic
effect. Nonbacteriostatic sodium chloride solution
should be used if the patient has an allergy to the
methylparaben preservative in the local anesthetic. A
bacteriostatic solution, which contains benzyl
alcohol, has known anesthetic properties and can be
used for limited procedures such as punch biopsy.

Injectable antihistamines, such as diphenhydramine,

have been administered to patients who are allergic
to local anesthetics. The mechanism of anesthetic
action is unknown. Injectable diphenhydramine is
effective, but it has a short duration of activity, it is
sedating, and its injection is painful. In addition,
tissue necrosis is reported after the local injection of
5% diphenhydramine. If used for injection,
diphenhydramine should be diluted to 1% by mixing 1
vial of 50-mg diphenhydramine with 4 mL of a
bacteriostatic sodium chloride solution.

Reactions to local anesthetic additives

Epinephrine

With the exception of cocaine, local anesthetics

directly cause relaxation of the vascular smooth
muscle, which leads to vasodilation. This effect
increases bleeding at the surgical site.
Vasoconstrictors, such as epinephrine, are often
added to anesthetic solutions to counteract this
effect. The vasoconstrictor effect of epinephrine is
maximal at 7-15 minutes, and this effect is clinically
evident as blanching of the skin. This blanching also
is useful in determining the area that is anesthetized.

Vasoconstriction not only decreases bleeding but

also slows the rate of systemic absorption of the
anesthetic, which allows the body more time to
metabolize the anesthetic and prolongs anesthesia.
Therefore, larger volumes of anesthetic can be