Intraoral topical anesthesia J OHN G. M EECHAN Local anesthesia is the mainstay of pain control during intraoral operative procedures. A number of advances have occurred in relation to drugs and delivery systems since cocaine was isolated as the active anesthetic component of cocoa leaves by Albert Niemann in the middle of the 19th century (18, 104). Although the main role for local anesthetic drugs in the mouth is by injection they can also be applied topically. Topical intraoral application can be used to reduce the discomfort of intraoral local anesthetic injections; to provide anesthesia for intra- oral operative procedures; to provide symptomatic relief from the pain of superficial mucosal lesions (such as ulcers); or to treat toothache and post- extraction pain. The earliest recorded anesthetic effect of isolated cocaine was topical anesthesia of the tongue, reported by Niemann in 1860 (18). We have come full circle in that the latest local anesthetic formulation designed specifically for periodontal treatments (Oraqix Ò ) is a topical application (45). This paper will consider the use and effectiveness of topical anes- thesia in the mouth before local anesthetic injections, as the sole means of anesthesia for intraoral proce- dures, and as a treatment for toothache and post- operative pain. Pharmacology of local anesthetic drugs Those local anesthetics that are injected for the control of pain during intraoral operative procedures are classified by their chemical structure into esters and amides. Ester local anesthetics, such as procaine, are no longer in routine use as injectable agents because of the superior qualities of the amide type; however, esters such as benzocaine and amethocaine (tetracaine) are employed topically. Ester and amide anesthetics differ in two important respects. First, in their potential to produce allergic reactions; second, in the way they are metabolized. Ester allergy has been recognized for some time (114). One study reported that the ester agent ben- zocaine produced contact sensitivity in 5% of a sample of 1200 eczematous patients (134). On the other hand, allergy to amides is thought to be rare (30, 38) and many so-called allergic reactions are probably toxic or vaso-vagal (30). This is supported by the fact that a number of patients reported to be allergic do not suffer reactions when challenged with the supposed antigen (32). Nevertheless, a number of allergic reactions to the amide lidocaine have been reported (30, 58, 74, 87, 118, 127, 132). These have ranged from mucosal reactions after topical use (58) to anaphylaxis (74, 85). Cross reactivity between dif- ferent amide agents has been reported (30) and it is pertinent to point out that other components of dental local anesthetic carpules, such as preserva- tives, reducing agents and latex, could cause allergy (5, 91). Fortunately most modern local anesthetics are preservative-free and latex-free carpules are available. Ester local anesthetics are metabolized in the plasma by pseudocholinesterases and thus have a relatively short plasma half-life. Amide metabolism is more complex and takes place mainly in the liver, but not all amides are metabolized in an identical fash- ion. The metabolism of the archetypal amide lido- caine is shown in Fig. 1. Variations to the plan shown in Fig. 1 are experienced by prilocaine and articaine. Prilocaine undergoes some biotransformation in the lungs (9, 13). Articaine, although an amide, under- goes initial metabolism in plasma by a pseudocho- linesterase (120). These differences in metabolism explain why prilocaine and articaine are available in higher concentrations than lidocaine for injection in dentistry. Although the higher concentrations may be more effective (82) there is some concern over problems of localized toxicity (nerve damage such as 56 Periodontology 2000, Vol. 46, 2008, 56–79 Printed in Singapore. All rights reserved Ó 2008 The Author. Journal compilation Ó 2008 Blackwell Munksgaard PERIODONTOLOGY 2000
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Intraoral topical anesthesia
JO H N G. ME E C H A N
Local anesthesia is the mainstay of pain control
during intraoral operative procedures. A number of
advances have occurred in relation to drugs and
delivery systems since cocaine was isolated as the
active anesthetic component of cocoa leaves by
Albert Niemann in the middle of the 19th century (18,
104). Although the main role for local anesthetic
drugs in the mouth is by injection they can also be
applied topically. Topical intraoral application can
be used to reduce the discomfort of intraoral local
anesthetic injections; to provide anesthesia for intra-
oral operative procedures; to provide symptomatic
relief from the pain of superficial mucosal lesions
(such as ulcers); or to treat toothache and post-
extraction pain.
The earliest recorded anesthetic effect of isolated
cocaine was topical anesthesia of the tongue,
reported by Niemann in 1860 (18). We have come full
circle in that the latest local anesthetic formulation
designed specifically for periodontal treatments
(Oraqix�) is a topical application (45). This paper will
consider the use and effectiveness of topical anes-
thesia in the mouth before local anesthetic injections,
as the sole means of anesthesia for intraoral proce-
dures, and as a treatment for toothache and post-
operative pain.
Pharmacology of local anestheticdrugs
Those local anesthetics that are injected for the
control of pain during intraoral operative procedures
are classified by their chemical structure into esters
and amides. Ester local anesthetics, such as procaine,
are no longer in routine use as injectable agents
because of the superior qualities of the amide type;
however, esters such as benzocaine and amethocaine
(tetracaine) are employed topically. Ester and amide
anesthetics differ in two important respects. First, in
their potential to produce allergic reactions; second,
in the way they are metabolized.
Ester allergy has been recognized for some time
(114). One study reported that the ester agent ben-
zocaine produced contact sensitivity in 5% of a
sample of 1200 eczematous patients (134). On the
other hand, allergy to amides is thought to be rare
(30, 38) and many so-called allergic reactions are
probably toxic or vaso-vagal (30). This is supported
by the fact that a number of patients reported to be
allergic do not suffer reactions when challenged with
the supposed antigen (32). Nevertheless, a number of
allergic reactions to the amide lidocaine have been
reported (30, 58, 74, 87, 118, 127, 132). These have
ranged from mucosal reactions after topical use (58)
to anaphylaxis (74, 85). Cross reactivity between dif-
ferent amide agents has been reported (30) and it is
pertinent to point out that other components of
dental local anesthetic carpules, such as preserva-
tives, reducing agents and latex, could cause allergy
(5, 91). Fortunately most modern local anesthetics
are preservative-free and latex-free carpules are
available.
Ester local anesthetics are metabolized in the
plasma by pseudocholinesterases and thus have a
relatively short plasma half-life. Amide metabolism is
more complex and takes place mainly in the liver, but
not all amides are metabolized in an identical fash-
ion. The metabolism of the archetypal amide lido-
caine is shown in Fig. 1. Variations to the plan shown
in Fig. 1 are experienced by prilocaine and articaine.
Prilocaine undergoes some biotransformation in the
lungs (9, 13). Articaine, although an amide, under-
goes initial metabolism in plasma by a pseudocho-
linesterase (120). These differences in metabolism
explain why prilocaine and articaine are available in
higher concentrations than lidocaine for injection in
dentistry. Although the higher concentrations may
be more effective (82) there is some concern over
problems of localized toxicity (nerve damage such as
56
Periodontology 2000, Vol. 46, 2008, 56–79
Printed in Singapore. All rights reserved
� 2008 The Author.
Journal compilation � 2008 Blackwell Munksgaard
PERIODONTOLOGY 2000
paresthesia) when injected around nerve trunks (59,
72).
It is important to understand the mechanism of
action of clinically useful local anesthetics. Notwith-
standing their chemical differences, ester and amide
local anesthetics have the same mode of action; they
influence the voltage-gated sodium channel. The
structure of the voltage-dependent sodium channel is
well characterized (25, 26); it is a complex structure
composed of three subunits named a, b1, and b2. The
b units are concerned with modulation of channel
gating and are important in intercellular interactions
(25) while the pore itself is contained in the a unit.
Simplified diagrammatic representations of the asubunit and its configurational changes from rest
through activation to inactivation are shown in
Fig. 2A–C. The a unit comprises four very similar
protein domains (I–IV), each of which has six helical
segments (S1–S6) that traverse the width of the cell
membrane. S1–S3 are negatively charged, S4 is posi-
tively charged, mainly arising from arginine and
lysine residues (146). Activation of the channel occurs
when the S4 segment moves outwards in a spiral path
to open up the channel. A loop between domains III
and IV acts as the inactivation gate (25), demon-
strated by the fact that antibodies directed against
this loop block inactivation (146). The S6 segment is
the proposed site of local anesthetic binding (see
below). When binding occurs, a physical blockade to
sodium entry is created. In simple terms local anes-
thetics act as chemical roadblocks to the entry of
sodium into the nerve cell, although they also prevent
leakage of potassium. By blocking sodium entry, local
anesthetics inhibit nerve cell depolarization and thus
prevent the propagation of nerve cell impulses along
the nerve.
There are two theories of local anesthetic action.
These are the membrane expansion theory and the
specific binding theory. The membrane expansion
theory dictates that the incorporation of the local
anesthetic into the nerve cell membrane causes a
degree of expansion of the membrane and this
physical distortion prevents sodium entry. There may
be some effect of this non-specific action but the
specific binding theory (71) is the method that is
generally accepted as the main mode of action; in
this model the local anesthetic binds to a receptor on
the sodium channel. Good support for this theory is
provided by the fact that different racemic forms of
the same molecule show different pharmacological
activities (146) and that binding ability is directly
related to anesthetic potency (88). Two critical amino
acid residues for local anesthetic binding (Phe 1764
and Tyr 1771) have been located on the S6 segment of
domain 4 in the a subunit (25). Access to the binding
site is from within the cell (25) and entry into the cell
requires a lipophilic uncharged moiety to enter the
nerve cell. Access to the binding site is easiest when
the nerve cell is in the inactivated configuration (63,
146). It has been suggested that the binding of local
anesthetic molecules is 17 times lower for resting
channels than for inactivated channels (146). The
more regularly a nerve fires the more times it adopts
the inactivated form so rapidly firing neurons are the
most susceptible to the action of local anesthetics.
This gives rise to the phenomenon known as use-
HN 2
HC 3
HC 3
C2H5
C2H5NHC 2C
O
HN
HC 3
HC 3
H
C2H5
NHC 2C
O
HN
HC 3
HC 3
HC 3
HC 3
OH
noitalyklaed-N
sisylordyH
noitalyxordyH
eniacodiL
edidilyxenicylglyhteonoM
enidilyx-6,2
enidilyx-6,2-yxordyh-4HN 2
Fig. 1. The metabolism of lidocaine.
57
Intraoral topical anesthesia
dependent (or frequency-dependent) block. This act
of binding maintains the sodium channel in the
configuration that it adopts during the refractory
phase of the nerve firing cycle (Fig. 2C). In this for-
mation any further stimulation will not result in
depolarization. Specific binding is achieved by
charged molecules, so the anesthetic must be in the
charged form to be active.
The ability of local anesthetics to exist as both
charged and uncharged portions is possible because
they are weak bases. The portion that is present as an
uncharged base is governed by the pH of the medium
and the pKa of the molecule. The uncharged part
traverses the nerve cell membrane and re-equilib-
rates to release the charged portion within the cell
and this gains access to the binding site.
Sodium channels are not all identical in structure.
At present, nine different voltage-gated sodium
channels have been identified (24). These are sus-
ceptible to different pharmacological actions and
this, together with the fact that drug-binding sites are
being characterized (41), suggests that it should be
possible to develop drugs that are highly specific, for
example it should be possible to increase affinity for
peripheral nerves rather than cardiac tissue. In this
way, local anesthetic drugs with less cardiotoxicity
(see below) could be developed. The heterogeneity of
sodium channels means that there is a variation in
the efficacy of local anesthetics and is one explana-
tion as to why the presence of inflammation, which
encourages the development of neural tissue into
areas of inflammation, reduces the effectiveness of
local anesthetics as these new nociceptors have
sodium channels that are less sensitive to the action
of local anesthetics (63).
Adverse effects of local anesthetics
The problem of allergy was discussed above. Other
unwanted effects are toxicity and drug interactions.
The topic of drug interactions is covered in the paper
by Hersh & Moore in this volume (69). Toxicity may
be systemic or localized. Localized toxicity presents
as nerve damage. This adverse effect of local anes-
3
21
4 5
6
3
2 1
4 5
6
I
I I
I I I
V I
I
II
III
VI
3
21
45
6
I
II
III
VI
A
B
C
Fig. 2. (A) The resting state of the a unit of the sodium
channel showing the pore surrounded by the four
domains each containing six protein segments that tra-
verse the membrane. The entry of the S4 segments into
the channel prevents sodium entry and thus maintains
the resting potential. (B) The channel during the activa-
tion phase when the obstruction to sodium entry has been
removed by movement of the S4 segments into the body of
the membrane. (C) The inactivated configuration when a
loop between domains III and IV blocks sodium entry.
This is the configuration that is maintained with local
anesthetic binding.
58
Meechan
thetics on nerves is concentration-dependent and
has been demonstrated in vivo with differing con-
centrations of lidocaine (79). This has clinical impli-
cations because there is some evidence that more
concentrated solutions, such as 4% articaine and 4%
prilocaine, cause a greater prevalence of long-lasting
paresthesia, especially of the lingual nerve. (59, 72).
Some have criticized these findings (99), noting that
large-scale studies have shown no difference in the
production of paresthesias following the intraoral
injection of 2% lidocaine and 4% articaine (100). The
jury is still out on this debate and undoubtedly more
work will be performed in this important area.
Local anesthetics are not specific in their action.
They will affect tissues other than peripheral sensory
nerves, thus adverse effects in other areas can ensue.
Toxic effects of local anesthetics occur mainly in the
central nervous and cardiovascular systems. The
central nervous system is particularly sensitive to
local anesthetics; plasma concentrations that do not
affect transmission in peripheral nerves can affect
the central nervous system. A study that investigated
the levels of lidocaine required to produce central
nervous system toxicity in humans concluded that
the critical plasma level was 5 lg ⁄ ml (40). At low
doses the toxic effect is excitatory as a result of the
anesthetic blocking inhibitory activity; at higher
doses the effect is depressant, for example uncon-
sciousness. Fatalities as a result of local anesthetic
overdose are a result of the effect on the central
nervous system, namely respiratory arrest (92). Any
effect on the central nervous system will be deter-
mined by a number of factors, such as the concurrent
use of other central nervous active agents, for
example the convulsive threshold of lidocaine is
raised by concurrent use of diazepam (31).
The effects of local anesthetics on the cardiovas-
cular system can be direct or indirect. The latter
occurs as a result of inhibition of the autonomic
fibers that regulate cardiovascular function. Early
signs of cardiovascular toxicity are a slowing of the
pulse. Further inhibition of conduction leads to
varying degrees of block, arrhythmias, and ventricu-
lar fibrillation (90).
Toxicity is avoided by using sensible doses and
ensuring that intravascular injection is avoided. The
maximum doses of the local anesthetics used for
injection in dentistry are shown in Table 1. These
doses are those recommended when vasoconstrictor-
free solutions are used. Although the addition of a
vasoconstrictor, such as epinephrine, will reduce
systemic uptake of local anesthetics, the downside is
that epinephrine has been shown to reduce the
concentration of lidocaine needed to produce central
nervous system effects (145, 154). Thus the doses
given in Table 1 are suggested as a wise maximum. As
a working rule of thumb one-tenth of a cartridge per
kilogram of patient body weight approximates to the
safe maximum dose for most formulations. The
treatment of local anesthetic overdose is outlined in
Table 2.
Methemoglobinemia
Methemoglobinemia is an unwanted effect of a
number of local anesthetics, but is mainly associated
with prilocaine and benzocaine (2, 62). Methemo-
globinemia can cause cyanosis. It is a consequence of
the oxidation of hemoglobin from the ferrous to the
ferric state, leading to an inability to transport
oxygen. Kreutz & Kinni (89) reported a case of met-
hemoglobinemia in a healthy adult who received
632 mg of prilocaine with epinephrine. Crawford (29)
Table 1. Maximum recommended doses for theinjectable local anesthetics used in dentistry
Drug and
concentration
Recommended
maximum dose
(mg ⁄ kg)
(Ceiling in mg)
Amount (mg)
in 1.8-ml
(2.2-ml)
carpule
0.5% Bupivacaine 1.3 (90) 9 (11)
1.5% Etidocaine 8.0 (400) 27 (33)
2% Lidocaine 4.4 (300) 36 (44)
3% Lidocaine 4.4 (300) 54 (66)
2% Mepivacaine 4.4 (300) 36 (44)
3% Mepivacaine 4.4 (300) 54 (66)
3% Prilocaine 6.0 (400) 54 (66)
4% Prilocaine 6.0 (400) 72 (88)
4% Articaine 7.0 (500) 72 (88)
Table 2. Management of local anesthetic overdose
• Stop the procedure
• Reassure the patient
• Lie the patient flat
• Monitor and record vital signs
• Administer oxygen
• Give intravenous fluids
• Give intravenous anticonvulsants
• Perform basic life support
59
Intraoral topical anesthesia
reported that the injection of the maximum recom-
mended dose of prilocaine (400 mg) resulted in <1%
of the total hemoglobin being converted to methe-
moglobin at 90 minutes post injection; this is
considered a physiological level (95). Methemoglo-
binemia has been reported after topical application
of prilocaine and benzocaine (see below); the man-
agement of methemoglobinemia is the intravenous
infusion of methylene blue at a dose of 1–2 mg ⁄ kg
over a 5- to 10-minute period (62).
Pharmacology of topicalapplication of local anesthetics
When applied topically, anesthetic agents must cross
tissue barriers to get to their site of action. To achieve
suitable amounts of drug at the site of action it is
necessary to use concentrations that are higher than
those normally injected. This has an impact on the
production of systemic toxicity, as rapid and exten-
sive absorption can occur. Animal experiments have
demonstrated the transfer of lidocaine and prilocaine
across oral mucosa within 2.5 minutes of application
(11).
Not all local anesthetics are active when applied to
surface tissues, procaine for example does not
achieve topical anesthesia at clinically acceptable
concentrations (4, 11, 12). Both amide and ester local
anesthetic agents can be active when applied topi-
cally. In addition non-ester, non-amide agents are
used as topical anesthetics, for example dyclonine is
a ketone. The agents that are most effective topically
are those that are potentially most toxic systemically
(4), this limits the choice.
The duration of anesthesia following topical
application is less than that of the same dose depos-
ited intracutaneously. Adriani et al. (4) reported
that the duration of action of 1% tetracaine was
53 minutes after topical application compared with
120 minutes after subcutaneous injection.
Factors affecting efficacy
A number of in vitro and in vivo studies in both
animals and humans have shown that a variety of
factors influence the action of topical anesthetics.
The drug
Adriani et al. (4) studied a number of different topical
anesthetics in human volunteers. They used electrical
stimulation as the test method. These workers
reported that the longest-acting drugs were those
with the slowest onset. When different drugs were
combined (lidocaine and tetracaine) the duration of
anesthesia was determined by the longer-lasting
drug, and no benefit was derived. This finding is in
contrast to later work, which has shown increasing
efficacy with certain combinations such as lidocaine
and prilocaine (see below). In order of decreasing
duration the clinically useful drugs tested were
amethocaine, cocaine, dibucaine, dyclonine, and
lidocaine.
Concentration
The study of Adriani et al. (4) showed that although
the onset and duration of local anesthetic action were
concentration-dependent, there was a ceiling dose
above which these factors did not vary. An in vivo
study in dogs (11) showed that the plasma level
of lidocaine, not surprisingly, was raised with
increasing concentration of the topical agent. When
a concentration of 12.5% was applied to lingual
mucosa the average rate of transfer into plasma
was 0.0017 mg% ⁄ minute; this increased to
0.007 mg% ⁄ minute when the concentration was
doubled.
A dose response has been shown by a number of
workers. Giddon et al. (54) used electrical stimulation
of the attached gingiva in the maxillary premolar
region of human volunteers to assess the efficacy of
different concentrations of lidocaine in film strips in
a placebo-controlled single-blinded study. They
found a positive dose response for both depth and
duration of anesthesia. Hersh et al. (67) compared
the efficacies of intraoral patches containing 10%
and 20% lidocaine or placebo placed on the man-
dibular buccal gingiva in human volunteers and
noted that the more concentrated material was
significantly more effective than placebo after a 2.5-
minute application. The 10% patch took 5 minutes to
achieve a similar result. They demonstrated a positive
dose response throughout the 45 minutes of that
trial.
pH
As it is the un-ionized form of the drug that diffuses
across tissues to get to the site of action and local
anesthetics are weak bases, then an increase in pH
should increase the rate of diffusion by increasing
the amount of un-ionized base. In an in vitro exper-
iment using dogs (11) the rate of transfer of 1%
60
Meechan
lidocaine across the oral mucosa increased from
0.05 mg ⁄ 5 minutes at pH 5.9 to 0.07 mg ⁄ 5 minutes
at pH 8.6. Similar results were reported for prilocaine.
Additives
Adriani et al. (4) reported that the addition of
catecholamine and peptide vasoconstrictors did
not influence the activity of topical anesthetics.
The addition of 1:10,000 epinephrine or vasopres-
sin did not affect the duration, onset or depth of
topical anesthesia provided by cocaine or tetra-
caine.
The addition of detergents has been shown to both
increase and decrease the onset of anesthesia when
combined with topical anesthetics. Some studies
have shown a decrease in onset time (4), while others
(11) demonstrated that detergents inhibited onset.
Bergman et al. (11) noted that the effect of the
detergent cetylpyridinium chloride was concentra-
tion-dependent. At low concentrations of cetylpy-
ridinium chloride (0.1%) the anesthetic action was
enhanced and with higher concentrations (1%)
anesthesia was inhibited. Other workers (83) have
noted benefits by adding absorption-enhancing
agents to topical anesthetic formulations; they found
that the addition of the glycyrrhiza derivative
glycerrhetinic acid monohemiphthalate disodium
increased the efficacy of 10% lidocaine in reducing
the discomfort of skin pin-prick sensation in humans.
A later study (136) showed that this enhanced lido-
caine preparation was as effective as EMLA (eutectic
mixture of local anesthetics; see below) in reducing
skin pin-prick pain in humans.
Duration of application
The duration of application of the anesthetic influ-
ences the amount of penetration. This has been
shown in a volunteer study (12) using needle inser-
tion into skin in which workers measured the depth
of penetration of an 18-gauge needle through skin at
which pain was reported following the application of
a mixture of lidocaine and prilocaine (EMLA) or
placebo. They noted that increasing the time of
application increased the depth at which pain per-
ception began. Another human study (67) using an
intraoral application of 10% or 20% lidocaine in a
bioadhesive patch showed increasing relief from pin-
prick pain with increased time of application. The
authors of that study suggested that the duration of
residual anesthesia was dependent upon the duration
of application.
Site
Studies in human volunteers (4) have shown that the
site of intraoral application governs the onset time
and duration of anesthetic action after topical
application. Anesthesia to electrical stimulation was
apparent on the tongue after a 30-second application.
This was not improved by extending the time of
application up to 3 minutes. Duration of intraoral
anesthesia increased from tip of tongue to lip to
palate, although these were all less than the duration
after conjunctival application.
One aspect that makes intraoral sites vary in their
susceptibility to topical anesthetics is the degree of
keratinization of the mucosa. The palatal mucosa is
much more keratinized than the buccal sulcus.
Regimens that produce anesthesia of buccal sulcus
mucosa have no effect on the palate (74, 76). It is
not only the extent of keratinization that governs
efficacy. One study has shown that the mandibular
buccal sulcus is more rapidly anesthetized following
topical application compared with the equivalent
zone in the maxilla (67). The results of a retro-
spective study of 703 dental patients receiving
maxillary infiltration injections with or without 20%
benzocaine topical anesthetic applied for 1 minute
suggested that the topical anesthetic was effective in
reducing the discomfort of needle penetration in the
maxillary lateral incisor region, but had no influence
in this regard in the maxillary molar buccal sulcus
(119).
Formulations
There are a number of different formulations of
topical anesthetic for intraoral use. The anesthetic
may be present: as a water-soluble salt; dissolved in
organic solvents; as an oil–water emulsion; as a
eutectic mixture; incorporated into patches and
controlled-release devices; or incorporated into
liposomes.
The type of preparation affects it efficacy. A human
volunteer study showed that less lidocaine needed to
be incorporated into a film-strip compared with the
doses in a spray or ointment to achieve a similar
anesthetic effect on attached gingiva (54). In addi-
tion, incorporation into film strips increased the
duration of topical anesthetic action when compared
with ointments and sprays (54).
As mentioned above, local anesthetics achieve their
effect by binding to specific receptors in the sodium
channel in nerve cells. This requires the agent to be in
a charged form; however, it is the uncharged (base)
61
Intraoral topical anesthesia
form that gains access to the inside of the nerve cell
(the site from which the anesthetic gains access to its
site of action). Water possesses the good penetrative
properties that are important in the diffusion of
topical preparations; however, the uncharged local
anesthetic molecule is poorly soluble in water. This is
overcome by using oil–water emulsions, which
effectively increase the concentration of base in the
water. The anesthetic is dissolved in oil and then
emulsified in an aqueous vehicle. The maximum
concentration of lidocaine that can be obtained in oil
droplets is 20%; however, when lidocaine and prilo-
caine are combined they produce a eutectic form that
achieves an anesthetic concentration of 80%. This is
known as EMLA (eutectic mixture of local anesthet-
ics) (37).
When applied as ointments or creams the local
anesthetic is released from all surfaces of the applied
load. The amount entering the mucosa is therefore
uncontrolled. To overcome this, controlled release
devices (16) have been designed to discharge the
agent from one surface at a predetermined rate.
These devices have been used intraorally in a number
of studies (15, 67, 144).
Another method used to increase penetration after
application of topical anesthetics is incorporation of
the drug into liposomes (93). These are artificial
membranes consisting of uni- or multilamellar
concentric bilayers that are formed when phospho-
lipids are suspended in aqueous solution (10). Thus
they are similar in composition to biological mem-
branes. Liposome structure can be varied, depend-
ing upon the function required, by altering the
number of layers. They can be used to deliver
both water and lipid-soluble drugs. Delivery of a
hydrophobic drug is best served by a unilamellar
structure; a multilamellar construction with more
aqueous phases is better for the incorporation of
hydrophilic drugs. In addition to offering increased
penetration, other advantages of liposomes include
decreasing the effective dose, prolonging the action
of drugs as they protect the drug from metabolism
(34, 138) and decreased systemic toxicity (14). They
have been investigated in medicine both as inject-
able forms (34) and as topical applications to skin
(112) and cornea (137). They have been investigated
intraorally as a means of delivering corticosteroids
in animal models (64).
The use of liposomes to deliver local anesthetics
has been investigated by a number of authors. The
increased efficacy afforded by liposomes has been
demonstrated in skin where a standard application of
amethocaine has been shown to be ineffective
whereas the drug incorporated into liposomes pro-
vided anesthesia (53). Similarly, lidocaine (17, 23) and
amethocaine (75) incorporated into liposomes pro-
duce anesthesia of the skin that is as effective as
EMLA (see below). The use of liposomes for the
delivery of local anesthetics intraorally has been
reported in two studies. One (155) compared lipo-
somes containing 5% amethocaine with 20% ben-
zocaine in a double-blind split-mouth trial as a
means of disguising intraoral local anesthetic injec-
tion pain. These workers reported that the liposome
formulation significantly reduced the discomfort of
needle penetration and infiltration of anesthesia. The
other study (42) compared 1% ropivacaine incorpo-
rated into liposomes with plain 1% ropivacaine,
EMLA and 20% benzocaine in combating intraoral
pin-prick discomfort. The liposome preparation
produced longer-lasting anesthesia than the plain
ropivacaine and 20% benzocaine and was similar in
effect to EMLA.
Iontophoresis and phonophoresis
Another method of directing the diffusion of anes-
thetics after topical application is the use of ionto-
phoresis (50). Iontophoresis employs an electrical
charge to increase transportation of ionized mate-
rials across membranes. Local anesthetics such as
lidocaine have a positive charge so penetration into
tissue can be encouraged using iontophoresis. The
method has been employed in dentistry and medi-
cine to improve topical anesthesia, for example
iontophoretically applied 4% lidocaine was more
effective than topical lidocaine in reducing the
discomfort of venous cannulation and the injection
of propofol in the dorsum of the hand (135). The
extent of local anesthetic entry has been shown to
be directly related to the voltage in an animal
model (61). Such a phenomenon, using cocaine for
pulpal anesthesia, was described in the late 19th
century (115). Gangarosa (49) used iontophoresis
with lidocaine and epinephrine when extracting
deciduous teeth (see below). Won et al. (152)
reported the use of iontophoresis to deliver 4%
lidocaine with 1:50,000 epinephrine for soft tissue
anesthesia of buccal and lingual mandibular
mucosa in a human study with five volunteers.
They reported duration of anesthesia ranging from
25 to 55 minutes. Another method that could be
used to increase penetration is phonophoresis. This
uses high-frequency radio waves and has been
suggested as a possible method of increasing the
efficacy of topical applications (98).
62
Meechan
The use of topical anesthetics toreduce the discomfort of intraorallocal anesthetic injections
The use of topical anesthetics before injections is
common in dentistry. A recent study of over 500 UK
general dental practitioners reported that 95% of
them used topical anesthesia before injections, 28%
of the total sample used this pretreatment before all
injections (28). Lidocaine and benzocaine were the
scale scores for injection compared with placebo. The
rather long application time in this study was chosen
by the authors because periods shorter than this
failed to show any efficacy. They note that this is an
unreasonable time clinically.
One study (155) compared the effectiveness of the
topical application of liposomes incorporating 5%
amethocaine with 20% benzocaine gel in reducing
both needle penetration and injection discomfort
during administration of 4% prilocaine at un-named
contralateral sites intraorally. These authors noted
that the liposome regimen was more effective in
reducing discomfort.
Carr & Horton (21) compared the discomfort of the
injection of 2% lidocaine with 1:100,000 epinephrine
following the 15-minute application of a patch con-
taining 20% lidocaine or placebo in the gingiva in the
maxillary premolar–molar region with both 25- and
27-gauge needles. The active patch was more effec-
tive than placebo in reducing injection discomfort.
All of the studies mentioned above have investi-
gated the use of topical anesthetics before infiltration
anesthesia. Two studies have investigated the use
of topical anesthetics before inferior alveolar nerve
64
Meechan
block injections, which necessitate deeper needle
penetration. Meechan et al. (109) found that 20%
benzocaine applied for two minutes was no better
than no mucosal preparation before inferior alveolar
nerve block injections with 2% lidocaine and 1:80,000
epinephrine using a 27-gauge needle in an adult
population before mandibular extractions. The data
from a retrospective study of 1635 dental patients
who received inferior alveolar nerve blocks (27-gauge
needle) with or without 20% benzocaine topical
anesthetic for one minute (119) suggested that the
topical anesthetic had no effect on needle insertion
discomfort.
Comparison of positive and negative response
studies
The results of the needle penetration and injection
studies described above are summarized in Tables 3
and 4, which separate them into those showing
positive and no difference from placebo. When the
Tables are compared some differences are apparent.
Negative findings are more common when the palate
Table 3. Studies showing no difference between effects of topical anesthetic and placebo in reducing needlepenetration or local anesthetic injection discomfort
is the site of application and wider gauge needles
seem to be associated with greater failure of topical
anesthesia. Also most of the successful applications
had at least a 2-minute application. The exceptions
are the studies of Yaacob et al. (153), Carr & Horton
(20) and part of the investigation of Hutchins et al.
(76). The first of these studies (153) reported a 30-
second application of lidocaine to be effective in the
palate. The design of that investigation was not ideal
as the operator was not blinded and the active side
was injected first. It is known that the first of a pair of
injections is likely to be less painful (102) and thus
this would have contributed to the effect. Carr &
Horton (20) noted that a 30-second application of
benzocaine was better than placebo in the mandib-
ular mucosa but did not find that a similar regimen
was effective in the maxillary buccal sulcus; a later
study (21), which doubled the application time to
1 minute, failed to produce anesthesia better than
placebo in either arch. The study of Hutchins et al.
(76) investigated a number of methods of reducing
injection discomfort and part of their data suggested
that a 1-minute application of 20% benzocaine was
better than placebo in disguising injection pain in the
buccal sulcus, but not in the palate. These workers
injected less anesthetic than was used for the other
injection studies that showed a positive response (21,
47) and the authors were unsure of the clinical rele-
vance of their results. It seems therefore that appli-
cation times of at least 2 minutes are required before
needle penetration or injection. Indeed for an effect
on injection discomfort very long application times of
lidocaine (15–20 minutes) appear to be required. The
efficacies of different topical anesthetics are sum-
marized in Table 5 and show that some novel prep-
arations (EMLA, see below; and use of liposomes)
may be effective in reducing injection discomfort and
can be of use on the palate.
It is surprising that the gauge of needle affects the
efficacy of topical anesthetics as it has been reported
that needles of those gauges used in dentistry (25–
30 g) do not differ in the discomfort they produce
when inserted into oral mucosa (48).
EMLA
The above studies investigated topical anesthetics
designed for intraoral use. A number of investigators
have studied EMLA intraorally. EMLA is an acronym
for eutectic mixture of local anesthetics and is a 5%
mixture of prilocaine and lidocaine. This formulation
was developed in the late 1970s and early 1980s (81)
and has been used to anesthetize skin before a
number of procedures such as venepuncture and
minor operations (80, 101). It is one of the most
commonly used topical anesthetics in dermatological
practice (44). In dentistry it has been used on skin
before venepuncture for sedation and has been
reported as the sole means of anesthesia before
temporomandibular joint arthrocentesis (70). It is not
licensed for use intraorally but has shown interesting
properties when used in the mouth.
Table 5. Studies showing significant differences between different topical anesthetic agents in reducing needle pene-tration or local anesthetic injection discomfort. The lower agent of each pair in the left-hand column was more effective