Professional Documents
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Printed in Singapore. All rights reserved Journal compilation 2008 Blackwell Munksgaard
PERIODONTOLOGY 2000
Local anesthesia is the mainstay of pain control their potential to produce allergic reactions; second,
during intraoral operative procedures. A number of in the way they are metabolized.
advances have occurred in relation to drugs and Ester allergy has been recognized for some time
delivery systems since cocaine was isolated as the (114). One study reported that the ester agent ben-
active anesthetic component of cocoa leaves by zocaine produced contact sensitivity in 5% of a
Albert Niemann in the middle of the 19th century (18, sample of 1200 eczematous patients (134). On the
104). Although the main role for local anesthetic other hand, allergy to amides is thought to be rare
drugs in the mouth is by injection they can also be (30, 38) and many so-called allergic reactions are
applied topically. Topical intraoral application can probably toxic or vaso-vagal (30). This is supported
be used to reduce the discomfort of intraoral local by the fact that a number of patients reported to be
anesthetic injections; to provide anesthesia for intra- allergic do not suffer reactions when challenged with
oral operative procedures; to provide symptomatic the supposed antigen (32). Nevertheless, a number of
relief from the pain of superficial mucosal lesions allergic reactions to the amide lidocaine have been
(such as ulcers); or to treat toothache and post- reported (30, 58, 74, 87, 118, 127, 132). These have
extraction pain. ranged from mucosal reactions after topical use (58)
The earliest recorded anesthetic effect of isolated to anaphylaxis (74, 85). Cross reactivity between dif-
cocaine was topical anesthesia of the tongue, ferent amide agents has been reported (30) and it is
reported by Niemann in 1860 (18). We have come full pertinent to point out that other components of
circle in that the latest local anesthetic formulation dental local anesthetic carpules, such as preserva-
designed specifically for periodontal treatments tives, reducing agents and latex, could cause allergy
(Oraqix) is a topical application (45). This paper will (5, 91). Fortunately most modern local anesthetics
consider the use and effectiveness of topical anes- are preservative-free and latex-free carpules are
thesia in the mouth before local anesthetic injections, available.
as the sole means of anesthesia for intraoral proce- Ester local anesthetics are metabolized in the
dures, and as a treatment for toothache and post- plasma by pseudocholinesterases and thus have a
operative pain. 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-
Pharmacology of local anesthetic ion. The metabolism of the archetypal amide lido-
drugs caine is shown in Fig. 1. Variations to the plan shown
in Fig. 1 are experienced by prilocaine and articaine.
Those local anesthetics that are injected for the Prilocaine undergoes some biotransformation in the
control of pain during intraoral operative procedures lungs (9, 13). Articaine, although an amide, under-
are classified by their chemical structure into esters goes initial metabolism in plasma by a pseudocho-
and amides. Ester local anesthetics, such as procaine, linesterase (120). These differences in metabolism
are no longer in routine use as injectable agents explain why prilocaine and articaine are available in
because of the superior qualities of the amide type; higher concentrations than lidocaine for injection in
however, esters such as benzocaine and amethocaine dentistry. Although the higher concentrations may
(tetracaine) are employed topically. Ester and amide be more effective (82) there is some concern over
anesthetics differ in two important respects. First, in problems of localized toxicity (nerve damage such as
56
Intraoral topical anesthesia
CH3
C2H5
NH C CH2 N Lidocaine
C2H5
O
CH3 N-dealkylation
CH3
C2H5
NH C CH2 N Monoethylglycinexylidide
H
O
CH3
Hydrolysis
CH3
NH2 2,6-xylidine
CH3 CH3
Hydroxylation
HO NH2
4-hydroxy-2,6-xylidine
CH3
Fig. 1. The metabolism of lidocaine.
paresthesia) when injected around nerve trunks (59, anesthetics inhibit nerve cell depolarization and thus
72). prevent the propagation of nerve cell impulses along
It is important to understand the mechanism of the nerve.
action of clinically useful local anesthetics. Notwith- There are two theories of local anesthetic action.
standing their chemical differences, ester and amide These are the membrane expansion theory and the
local anesthetics have the same mode of action; they specific binding theory. The membrane expansion
influence the voltage-gated sodium channel. The theory dictates that the incorporation of the local
structure of the voltage-dependent sodium channel is anesthetic into the nerve cell membrane causes a
well characterized (25, 26); it is a complex structure degree of expansion of the membrane and this
composed of three subunits named a, b1, and b2. The physical distortion prevents sodium entry. There may
b units are concerned with modulation of channel be some effect of this non-specific action but the
gating and are important in intercellular interactions specific binding theory (71) is the method that is
(25) while the pore itself is contained in the a unit. generally accepted as the main mode of action; in
Simplified diagrammatic representations of the a this model the local anesthetic binds to a receptor on
subunit and its configurational changes from rest the sodium channel. Good support for this theory is
through activation to inactivation are shown in provided by the fact that different racemic forms of
Fig. 2AC. The a unit comprises four very similar the same molecule show different pharmacological
protein domains (IIV), each of which has six helical activities (146) and that binding ability is directly
segments (S1S6) that traverse the width of the cell related to anesthetic potency (88). Two critical amino
membrane. S1S3 are negatively charged, S4 is posi- acid residues for local anesthetic binding (Phe 1764
tively charged, mainly arising from arginine and and Tyr 1771) have been located on the S6 segment of
lysine residues (146). Activation of the channel occurs domain 4 in the a subunit (25). Access to the binding
when the S4 segment moves outwards in a spiral path site is from within the cell (25) and entry into the cell
to open up the channel. A loop between domains III requires a lipophilic uncharged moiety to enter the
and IV acts as the inactivation gate (25), demon- nerve cell. Access to the binding site is easiest when
strated by the fact that antibodies directed against the nerve cell is in the inactivated configuration (63,
this loop block inactivation (146). The S6 segment is 146). It has been suggested that the binding of local
the proposed site of local anesthetic binding (see anesthetic molecules is 17 times lower for resting
below). When binding occurs, a physical blockade to channels than for inactivated channels (146). The
sodium entry is created. In simple terms local anes- more regularly a nerve fires the more times it adopts
thetics act as chemical roadblocks to the entry of the inactivated form so rapidly firing neurons are the
sodium into the nerve cell, although they also prevent most susceptible to the action of local anesthetics.
leakage of potassium. By blocking sodium entry, local This gives rise to the phenomenon known as use-
57
Meechan
58
Intraoral topical anesthesia
59
Meechan
reported that the injection of the maximum recom- stimulation as the test method. These workers
mended dose of prilocaine (400 mg) resulted in <1% reported that the longest-acting drugs were those
of the total hemoglobin being converted to methe- with the slowest onset. When different drugs were
moglobin at 90 minutes post injection; this is combined (lidocaine and tetracaine) the duration of
considered a physiological level (95). Methemoglo- anesthesia was determined by the longer-lasting
binemia has been reported after topical application drug, and no benefit was derived. This finding is in
of prilocaine and benzocaine (see below); the man- contrast to later work, which has shown increasing
agement of methemoglobinemia is the intravenous efficacy with certain combinations such as lidocaine
infusion of methylene blue at a dose of 12 mg kg and prilocaine (see below). In order of decreasing
over a 5- to 10-minute period (62). duration the clinically useful drugs tested were
amethocaine, cocaine, dibucaine, dyclonine, and
lidocaine.
Pharmacology of topical
application of local anesthetics Concentration
When applied topically, anesthetic agents must cross The study of Adriani et al. (4) showed that although
tissue barriers to get to their site of action. To achieve the onset and duration of local anesthetic action were
suitable amounts of drug at the site of action it is concentration-dependent, there was a ceiling dose
necessary to use concentrations that are higher than above which these factors did not vary. An in vivo
those normally injected. This has an impact on the study in dogs (11) showed that the plasma level
production of systemic toxicity, as rapid and exten- of lidocaine, not surprisingly, was raised with
sive absorption can occur. Animal experiments have increasing concentration of the topical agent. When
demonstrated the transfer of lidocaine and prilocaine a concentration of 12.5% was applied to lingual
across oral mucosa within 2.5 minutes of application mucosa the average rate of transfer into plasma
(11). was 0.0017 mg% minute; this increased to
Not all local anesthetics are active when applied to 0.007 mg% minute when the concentration was
surface tissues, procaine for example does not doubled.
achieve topical anesthesia at clinically acceptable A dose response has been shown by a number of
concentrations (4, 11, 12). Both amide and ester local workers. Giddon et al. (54) used electrical stimulation
anesthetic agents can be active when applied topi- of the attached gingiva in the maxillary premolar
cally. In addition non-ester, non-amide agents are region of human volunteers to assess the efficacy of
used as topical anesthetics, for example dyclonine is different concentrations of lidocaine in film strips in
a ketone. The agents that are most effective topically a placebo-controlled single-blinded study. They
are those that are potentially most toxic systemically found a positive dose response for both depth and
(4), this limits the choice. duration of anesthesia. Hersh et al. (67) compared
The duration of anesthesia following topical the efficacies of intraoral patches containing 10%
application is less than that of the same dose depos- and 20% lidocaine or placebo placed on the man-
ited intracutaneously. Adriani et al. (4) reported dibular buccal gingiva in human volunteers and
that the duration of action of 1% tetracaine was noted that the more concentrated material was
53 minutes after topical application compared with significantly more effective than placebo after a 2.5-
120 minutes after subcutaneous injection. 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
Factors affecting efficacy trial.
60
Intraoral topical anesthesia
61
Meechan
form that gains access to the inside of the nerve cell whereas the drug incorporated into liposomes pro-
(the site from which the anesthetic gains access to its vided anesthesia (53). Similarly, lidocaine (17, 23) and
site of action). Water possesses the good penetrative amethocaine (75) incorporated into liposomes pro-
properties that are important in the diffusion of duce anesthesia of the skin that is as effective as
topical preparations; however, the uncharged local EMLA (see below). The use of liposomes for the
anesthetic molecule is poorly soluble in water. This is delivery of local anesthetics intraorally has been
overcome by using oilwater emulsions, which reported in two studies. One (155) compared lipo-
effectively increase the concentration of base in the somes containing 5% amethocaine with 20% ben-
water. The anesthetic is dissolved in oil and then zocaine in a double-blind split-mouth trial as a
emulsified in an aqueous vehicle. The maximum means of disguising intraoral local anesthetic injec-
concentration of lidocaine that can be obtained in oil tion pain. These workers reported that the liposome
droplets is 20%; however, when lidocaine and prilo- formulation significantly reduced the discomfort of
caine are combined they produce a eutectic form that needle penetration and infiltration of anesthesia. The
achieves an anesthetic concentration of 80%. This is other study (42) compared 1% ropivacaine incorpo-
known as EMLA (eutectic mixture of local anesthet- rated into liposomes with plain 1% ropivacaine,
ics) (37). EMLA and 20% benzocaine in combating intraoral
When applied as ointments or creams the local pin-prick discomfort. The liposome preparation
anesthetic is released from all surfaces of the applied produced longer-lasting anesthesia than the plain
load. The amount entering the mucosa is therefore ropivacaine and 20% benzocaine and was similar in
uncontrolled. To overcome this, controlled release effect to EMLA.
devices (16) have been designed to discharge the
agent from one surface at a predetermined rate.
Iontophoresis and phonophoresis
These devices have been used intraorally in a number
of studies (15, 67, 144). Another method of directing the diffusion of anes-
Another method used to increase penetration after thetics after topical application is the use of ionto-
application of topical anesthetics is incorporation of phoresis (50). Iontophoresis employs an electrical
the drug into liposomes (93). These are artificial charge to increase transportation of ionized mate-
membranes consisting of uni- or multilamellar rials across membranes. Local anesthetics such as
concentric bilayers that are formed when phospho- lidocaine have a positive charge so penetration into
lipids are suspended in aqueous solution (10). Thus tissue can be encouraged using iontophoresis. The
they are similar in composition to biological mem- method has been employed in dentistry and medi-
branes. Liposome structure can be varied, depend- cine to improve topical anesthesia, for example
ing upon the function required, by altering the iontophoretically applied 4% lidocaine was more
number of layers. They can be used to deliver effective than topical lidocaine in reducing the
both water and lipid-soluble drugs. Delivery of a discomfort of venous cannulation and the injection
hydrophobic drug is best served by a unilamellar of propofol in the dorsum of the hand (135). The
structure; a multilamellar construction with more extent of local anesthetic entry has been shown to
aqueous phases is better for the incorporation of be directly related to the voltage in an animal
hydrophilic drugs. In addition to offering increased model (61). Such a phenomenon, using cocaine for
penetration, other advantages of liposomes include pulpal anesthesia, was described in the late 19th
decreasing the effective dose, prolonging the action century (115). Gangarosa (49) used iontophoresis
of drugs as they protect the drug from metabolism with lidocaine and epinephrine when extracting
(34, 138) and decreased systemic toxicity (14). They deciduous teeth (see below). Won et al. (152)
have been investigated in medicine both as inject- reported the use of iontophoresis to deliver 4%
able forms (34) and as topical applications to skin lidocaine with 1:50,000 epinephrine for soft tissue
(112) and cornea (137). They have been investigated anesthesia of buccal and lingual mandibular
intraorally as a means of delivering corticosteroids mucosa in a human study with five volunteers.
in animal models (64). They reported duration of anesthesia ranging from
The use of liposomes to deliver local anesthetics 25 to 55 minutes. Another method that could be
has been investigated by a number of authors. The used to increase penetration is phonophoresis. This
increased efficacy afforded by liposomes has been uses high-frequency radio waves and has been
demonstrated in skin where a standard application of suggested as a possible method of increasing the
amethocaine has been shown to be ineffective efficacy of topical applications (98).
62
Intraoral topical anesthesia
63
Meechan
A double-blind randomized placebo-controlled Another investigation (76) studied the topical app-
trial with 40 subjects (20) investigated the efficacies lication of 20% benzocaine and placebo for 1 minute
of a 20% lidocaine patch applied for 15 minutes and for reducing the discomfort of buccal and palatal
the 30-second application of a benzocaine gel in injections of 2% lidocaine with 1:100,000 epinephrine
reducing 25-gauge needle stick pain in the buccal using 27-gauge needles in volunteers. The results
gingiva in the bicuspid-molar region of either jaw. showed that the topical anesthetic reduced injection
The needle was inserted to periosteum. When com- discomfort on the buccal side but not palatally.
paring five-point verbal pain and visual analog scale Keller (84) investigated a 45-second application of
scores the lidocaine patch was superior to placebo in the same topical anesthetics used in the study of Gill
reducing needle-stick pain in both jaws; benzocaine & Orr (55) (described above) before the injection of
was significantly better than placebo in the mandible 0.3 ml lidocaine with epinephrine close to the greater
but not in the maxilla. The lidocaine patch was sig- palatine foramen with a 25-gauge needle. The results
nificantly more effective than the benzocaine gel at of this study on 60 patients showed no significant
reducing needle-stick discomfort in both jaws. In a difference in reported pain between treatments with
further double-blind placebo-controlled studies the 20% benzocaine, 18% aminobenzoate with 0.1%
same workers (21) increased the application time of benzalkonium, and placebo.
the benzocaine gel to 1 minute and compared this Kincheloe et al. (86) investigated the effects of a
with the 15-minute application of the 20% lidocaine topical local anesthetic agent (material and concen-
patch using a verbal rating score. As in the study tration not reported) and placebo on pain perception
above, the lidocaine patch was superior to placebo on mucosa and injection of 2% mepivacaine with a
and benzocaine gels in countering the pain of 25- 27-gauge needle. They reported no difference in injec-
gauge needle insertion to the periosteum; however, tion experience between active agent and placebo.
the benzocaine did not differ significantly from pla- Fukuyama et al. (47) investigated the abilities of
cebo in this trial. These workers (21) also compared 20% benzocaine and 60% lidocaine applied topically
the discomfort of 25-gauge and 27-gauge needle stick for 20 minutes in reducing the discomfort of the
in the maxillary premolarmolar region following the injection of 0.9 ml 2% lidocaine with 1:80,000 epi-
15-minute application of a patch containing 20% nephrine in the maxillary anterior labial gingivae. The
lidocaine or placebo. There was no difference in benzocaine was no better than placebo; however, the
needle-stick discomfort between gauges; however the 60% lidocaine formulation decreased visual analogue
active patch was more effective than placebo in scale scores for injection compared with placebo. The
reducing discomfort. rather long application time in this study was chosen
Zed et al. (155) reported that 5% amethocaine in by the authors because periods shorter than this
liposomes was more effective than 20% benzocaine failed to show any efficacy. They note that this is an
in reducing the discomfort of needle penetration unreasonable time clinically.
before local anesthetic injections but needle gauge One study (155) compared the effectiveness of the
and time of application were not reported. topical application of liposomes incorporating 5%
Nakanishi et al. (116) reported that a 4-minute amethocaine with 20% benzocaine gel in reducing
application of 20% benzocaine was significantly both needle penetration and injection discomfort
more effective than placebo in reducing the dis- during administration of 4% prilocaine at un-named
comfort of 30-gauge needle penetration in the contralateral sites intraorally. These authors noted
mandibular buccal sulcus in the canine region in a that the liposome regimen was more effective in
blinded parallel study. A similar study using 27-gauge reducing discomfort.
needles inserted in the pterygotemporal depression Carr & Horton (21) compared the discomfort of the
to mimic regional block anesthesia showed no dif- injection of 2% lidocaine with 1:100,000 epinephrine
ference between placebo and 20% benzocaine after a following the 15-minute application of a patch con-
4-minute application (116). taining 20% lidocaine or placebo in the gingiva in the
maxillary premolarmolar region with both 25- and
27-gauge needles. The active patch was more effec-
Injection studies
tive than placebo in reducing injection discomfort.
Pollack (124) studied the effects of a 15-second applica- All of the studies mentioned above have investi-
tion of a topical anesthetic or placebo before injection gated the use of topical anesthetics before infiltration
in 500 patients and showed no difference in reaction anesthesia. Two studies have investigated the use
to the local anesthetic delivery between treatments. of topical anesthetics before inferior alveolar nerve
64
Intraoral topical anesthesia
block injections, which necessitate deeper needle topical anesthetic had no effect on needle insertion
penetration. Meechan et al. (109) found that 20% discomfort.
benzocaine applied for two minutes was no better
Comparison of positive and negative response
than no mucosal preparation before inferior alveolar
studies
nerve block injections with 2% lidocaine and 1:80,000
epinephrine using a 27-gauge needle in an adult The results of the needle penetration and injection
population before mandibular extractions. The data studies described above are summarized in Tables 3
from a retrospective study of 1635 dental patients and 4, which separate them into those showing
who received inferior alveolar nerve blocks (27-gauge positive and no difference from placebo. When the
needle) with or without 20% benzocaine topical Tables are compared some differences are apparent.
anesthetic for one minute (119) suggested that the Negative findings are more common when the palate
Table 3. Studies showing no difference between effects of topical anesthetic and placebo in reducing needle
penetration or local anesthetic injection discomfort
Agents Duration Site Test Reference
20% Benzocaine, 30 seconds Palate 25-g needle penetration (54)
5% Lidocaine
20% Benzocaine 30 seconds Maxillary buccal 25-g needle penetration (20)
20% Benzocaine 45 seconds Palate Injection with 25-g needle (84)
20% Benzocaine 1 minute Palate Injection with 27-g needle (76)
20% Benzocaine 1 minute Maxillary and mandibular buccal 25-g needle penetration (20)
20% Benzocaine 3 minutes Maxillary buccal 25-g needle penetration (86)
20% Benzocaine 3 minutes Maxillary buccal 25-g needle penetration (102)
20% Benzocaine 4 minutes Pterygotemporal depression 27-g needle penetration (116)
20% Benzocaine 20 minutes Maxillary buccal 30-g needle penetration (47)
20% Benzocaine 20 minutes Maxillary buccal Injection with 30-g needle (47)
Table 4. Studies showing positive effects of topical anesthetic over placebo in reducing needle penetration or
local anesthetic injection discomfort
Agents Duration Site Test Reference
5% Lidocaine 30 seconds Palate 27-g needle penetration (153)
20% Benzocaine 30 seconds Mandibular buccal 25-g needle penetration (20)
20% Benzocaine 1 minute Maxillary buccal injection with 27-g needle (76)
5% Lidocaine 2 minutes Maxillary buccal 27-g needle penetration (150)
5% Lidocaine 2 minutes Mandibular buccal 27-g needle penetration (73)
5% Lidocaine, 3 minutes Maxillary buccal 27-g needle penetration (133)
20% Benzocaine
20% Benzocaine 4 minutes Mandibular buccal 30-g needle penetration (116)
10% Lidocaine, 15 minutes Maxillary and mandibular buccal 25-g needle penetration (67)
20% Lidocaine
20% Lidocaine 15 minutes Maxillary and mandibular buccal 25-g needle penetration (20, 21)
20% Lidocaine 15 minutes Maxillary buccal Injection with 2527-g needle (21)
60% Lidocaine 20 minutes Maxillary buccal Injection with 30-g needle (47)
65
Meechan
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
Agents Duration Site Test Reference
20% Benzocaine, 2 minutes Maxillary buccal 30-g needle insertion (42)
1% Ropivacaine in liposomes
20% Benzocaine, 2 minutes Maxillary buccal 30-g needle insertion (42)
1% Ropivacaine in liposomes
5% Lidocaine 5 minutes Periodontal ligament Intraligamentary injection (110)
EMLA with 30-g needle
20% Benzocaine 10 minutes Palate 27-g needle insertion (6)
EMLA
10% Lidocaine, 15 minutes Mandibular buccal 25-g needle insertion (67)
20% Lidocaine
20% Benzocaine gel, 20 minutes Maxillary buccal Maxillary infiltration (47)
60% Lidocaine gel with 30-g needle
20% Benzocaine gel, not reported Not reported Intraoral injection (155)
5% Amethocaine in liposomes
is the site of application and wider gauge needles on injection discomfort very long application times of
seem to be associated with greater failure of topical lidocaine (1520 minutes) appear to be required. The
anesthesia. Also most of the successful applications efficacies of different topical anesthetics are sum-
had at least a 2-minute application. The exceptions marized in Table 5 and show that some novel prep-
are the studies of Yaacob et al. (153), Carr & Horton arations (EMLA, see below; and use of liposomes)
(20) and part of the investigation of Hutchins et al. may be effective in reducing injection discomfort and
(76). The first of these studies (153) reported a 30- can be of use on the palate.
second application of lidocaine to be effective in the It is surprising that the gauge of needle affects the
palate. The design of that investigation was not ideal efficacy of topical anesthetics as it has been reported
as the operator was not blinded and the active side that needles of those gauges used in dentistry (25
was injected first. It is known that the first of a pair of 30 g) do not differ in the discomfort they produce
injections is likely to be less painful (102) and thus when inserted into oral mucosa (48).
this would have contributed to the effect. Carr &
Horton (20) noted that a 30-second application of
EMLA
benzocaine was better than placebo in the mandib-
ular mucosa but did not find that a similar regimen The above studies investigated topical anesthetics
was effective in the maxillary buccal sulcus; a later designed for intraoral use. A number of investigators
study (21), which doubled the application time to have studied EMLA intraorally. EMLA is an acronym
1 minute, failed to produce anesthesia better than for eutectic mixture of local anesthetics and is a 5%
placebo in either arch. The study of Hutchins et al. mixture of prilocaine and lidocaine. This formulation
(76) investigated a number of methods of reducing was developed in the late 1970s and early 1980s (81)
injection discomfort and part of their data suggested and has been used to anesthetize skin before a
that a 1-minute application of 20% benzocaine was number of procedures such as venepuncture and
better than placebo in disguising injection pain in the minor operations (80, 101). It is one of the most
buccal sulcus, but not in the palate. These workers commonly used topical anesthetics in dermatological
injected less anesthetic than was used for the other practice (44). In dentistry it has been used on skin
injection studies that showed a positive response (21, before venepuncture for sedation and has been
47) and the authors were unsure of the clinical rele- reported as the sole means of anesthesia before
vance of their results. It seems therefore that appli- temporomandibular joint arthrocentesis (70). It is not
cation times of at least 2 minutes are required before licensed for use intraorally but has shown interesting
needle penetration or injection. Indeed for an effect properties when used in the mouth.
66
Intraoral topical anesthesia
67
Meechan
Table 6. Studies showing positive effects of EMLA over placebo in reducing needle penetration or local anesthetic
injection discomfort
Agent Duration Site Test Reference
EMLA 2 minutes Maxillary buccal 27-g needle penetration (148)
EMLA 5 minutes Palate and mandibular buccal 27-g needle penetration (73)
EMLA 5 minutes Palate 27-g needle penetration (142)
EMLA 5 minutes Palate Injection with 27-g needle (111)
68
Intraoral topical anesthesia
One study (139) compared the 5-minute applica- lary anterior gingiva in children. They reported that
tion of a patch containing 20% lidocaine with the the mean onset times were 75 seconds for benzo-
1-minute application of 20% benzocaine gel before caine, 105 seconds for lidocaine, and 138 seconds for
application of rubber dams in children aged EMLA. McMillan et al. (106) compared the effects on
617 years using an unblinded split-mouth design. the pain-pressure threshold (105) and sensitivity to
These workers found no difference in efficacy pin-pricking of EMLA and 5% lidocaine applied
between treatments but concluded that the patch topically on the buccal attached gingiva in the
was not suitable for children because of the lack of maxillary premolar region for 10 minutes. The pain
adhesion and the length of time of application. In pressure threshold was measured using an algometer
that study, patch adhesion was <30% but was age- with a 4-mm ball-ended tip (106). EMLA was superior
related, especially for girls where the increase in to 5% lidocaine in increasing the painpressure
adhesion was 9 percentage points per year of age. threshold and in producing anesthesia to pin-prick.
The effects on painpressure threshold suggested
that EMLA was superior to lidocaine in penetrating
EMLA the buccal cortical bone. EMLA produced anesthesia
to pin-prick in all 10 volunteers in that trial but
Experimental
lidocaine was successful in only eight.
Svensson et al. (141) used argon laser stimulation of Roghani et al. (130) also looked at the effects of
the lower labial gingiva to compare the efficacy and topical anesthetics on the load required on the gin-
duration of effect of lidocaine and EMLA. They giva to produce discomfort in a double-blind study
measured pain and sensory thresholds following a that compared placebo, 1% dyclonine, 10% cocaine
2-minute application of 2% lidocaine gel and 2-, 5- 20% benzocaine, 10% lidocaine, and EMLA on the
and 15-minute applications of 1 g EMLA. The latter maxillary anterior gingiva. These workers used a
formulation was significantly more effective than 18 mm ball-ended tip connected to a measuring
lidocaine alone in increasing sensory and pain device and reported that a 3-minute application of
thresholds. The greatest increase in pain threshold EMLA was more effective than the other topical
was noted immediately after removal of the topical agents and placebo in raising the painpressure
anesthetic for all treatments. Sensory and pain threshold. In the study of Franz-Montana et al. (42),
thresholds were elevated for all regimens up to the median duration of gingival anesthesia provided
25 minutes after removal. The duration of EMLA after a 2-minute application of EMLA in 30 volunteers
application did not affect the intensity of the anes- was around 14 minutes.
thetic effect on the gingiva. The authors concluded The results presented above suggested that EMLA
that a 2-minute application on the gingiva produced might be useful as a topical anesthetic for minor
analgesia for 10 minutes. operative procedures on the gingiva and it has been
Contrary to the results described above, Haasio investigated in this regard in the clinical studies
et al. (60) found no difference in the analgesic effects described below.
of EMLA and lidocaine on buccal gingival mucosa on
Clinical
the upper jaw in 10 volunteers. They recorded both
sensory and pain thresholds using electrical stimu- The effects on the discomfort of scaling of 5-minute
lation. The application and amounts of anesthetic applications of EMLA or placebo to the gingival
differed between this trial and that described above margins in patients with mild chronic periodontitis
(141). In this study, 4 g of EMLA was applied over have been compared in a double-blind, randomized,
four sites on the buccal gingiva with a toothbrush and split-mouth study (143). EMLA reduced the pain and
the lidocaine formulation was a 10% spray, which unpleasantness of scaling in both jaws when com-
was applied to four sites on the upper gingivae (total pared to placebo. The influence on pain was more
200 mg lidocaine). The maximum analgesic effect marked than the effect on unpleasantness. In another
occurred at a mean time of 13 minutes for EMLA and double-blind, split-mouth volunteer study (36) a 5-
at 14 minutes for lidocaine. Normal sensation had minute application of EMLA allowed a significantly
returned in most cases by 30 minutes for each greater depth of pain-free probe penetration into the
treatment. gingival crevice compared to similar treatment with
Nayak & Sudha (117) looked at the anesthetic onset 5% lidocaine. The use of a 4-minute application of
times of EMLA, 18% benzocaine, and 5% lidocaine in 4 g EMLA to the gingivae using a toothbrush as a
providing anesthesia to blunt probing of the maxil- means of pain control for the removal of arch-bars
69
Meechan
used in intermaxillary fixation was investigated in a was no difference reported in duration of anes-
double-blind, placebo-controlled trial in 45 dentate thesia to probing between 30-second, 2-minute
patients (123). Pin-prick sensation was significantly and 5-minute applications (mean duration was
reduced in the EMLA group 5 minutes after tooth 1820 minutes); however, the authors of that study
brushing with the topical compared to the placebo, noted that this does not reflect anesthesia for scaling
before removal of the arch-bars. Following removal of or root planing.
the arch-bars (mean time 19 minutes after tooth A placebo-controlled study with 130 patients (35)
brushing) there was no difference between treat- looked at the discomfort of periodontal debride-
ments in response to pin-pricking of the gingiva. ment after a 30-second application of Oraqix into
Significantly more patients with EMLA reported no periodontal pockets. In that investigation, median
pain compared to those who received placebo during pain scores measured by visual analogue scale were
removal of the arch-bars. low but those recorded after active treatment were
There is a case report (107) of the use of a 15- significantly lower than placebo (5 and 13 mm
minute application of EMLA as the only means of respectively). Verbal rating scores using a five-point
pain control for the surgical removal of intraoral soft scale did not differ between treatments in that study;
tissue from the palate in a patient with a needle 78% reporting no or mild pain with active treatment
phobia. and 76% with placebo. Another investigation (78)
used a similar design to that described above (35) but
varied the application time of Oraqix between
Oraqix
30 seconds and 2 minutes. Significant differences
Those studies discussed above, which showed that were apparent in visual analogue scale scores be-
EMLA was superior to 5% lidocaine, led to the tween placebo and active treatment and in this study.
development of a topical preparation of lidocaine Differences in the five-point verbal rating score were
and prilocaine dedicated for intraoral use. This also apparent with 90% of patients in the active
material, known as Oraqix, is supplied as a group and 64% in the placebo group reporting no or
thermosetting agent. Oraqix contains 25 mg g mild pain. Rescue anesthesia was required by 11% of
lidocaine and 25 mg g prilocaine. The material is the active and 17% of the placebo groups. No data
liquid at room temperature but when injected into correlating the time of application and efficacy were
the gingival crevice it forms an elastic gel (46). reported. The data from this study suggested that the
Interestingly, although Oraqix was specifically for- effect of Oraqix was more pronounced in subjects
mulated for intraoral use, subjects who have re- with more severe periodontal disease. Following on
ceived both Oraqix and EMLA in the mouth have from that finding, another study (96) looked at the
reported that the latter was superior with regard to effect of Oraqix in patients who reported moderate to
taste and smell (6). severe pain on periodontal probing (i.e. >30 mm on
Oraqix has been investigated as a means of a visual analogue scale [27]). In this study with 85
reducing the discomfort of intraoral injections (6), patients Oraqix was placed in the periodontal pocket
where it has been shown to be more effective than for 3045 seconds. The results showed that visual
20% benzocaine gel in reducing the pain of palatal analogue scale scores and verbal rating scores were
infiltrations in a human volunteer study. The indi- less when the active treatment was compared to
cation for the use of Oraqix however, is for the relief placebo; 70% of those receiving Oraqix reporting no
of discomfort during periodontal treatments. It has or mild pain after scaling and root planing, compared
been evaluated in a number of studies as the sole with 48% for placebo. None of the 43 patients in the
agent for anesthesia during periodontal treatments Oraqix group reported severe pain whereas four of 42
(35, 46, 78, 96, 147). When applied to periodontal patients in the placebo group reported severe or very
pockets, onset of action is rapid with an anesthetic severe pain. Five per cent of the active and 17% of the
effect obvious at 30 seconds (46). An open-label placebo patients required rescue anesthesia. Unlike
investigation into the efficacy of Oraqix in reducing the previous study, the results of this investigation
the discomfort of scaling and root planing in 30 did not show any relationship between the extent
patients showed that pain reduction (as measured by of disease and the efficacy of Oraqix. The data from
a visual analogue scale) was significantly greater after the three double-blind placebo-controlled studies
a 30-second compared with a 2-minute application of described above (35, 78, 96) were pooled and
the gel, although there was no difference between a re-analysed by considering percentage changes
30-second and a 5-minute application (46). There between active and placebo treatments (97) and the
70
Intraoral topical anesthesia
authors concluded that the active treatments reduced attached gingiva in the maxillary premolar region
discomfort during scaling and root planing by a produced significant elevations in pain threshold
factor of 50%. compared to base-line in first premolars and when
One open labeled, cross-over, multi-center study compared to those teeth adjacent to placebo patches.
of 170 subjects investigated patients responses to No teeth in either the test or control group showed
Oraqix and conventional infiltration anesthesia for total anesthesia. Franz-Montan et al. (42) showed
scaling and root planning (147). Evaluations were that a 2-minute treatment of 20% benzocaine or 1%
performed immediately following and 4 hours after ropivacaine (plain and in liposomes) to the maxillary
treatment. Efficacy of anesthesia, as determined by buccal gingiva in the canine region in human vol-
both operator and patient, was greater follow- unteers did not alter canine pulp responses during
ing injection compared to application of the gel; the 20 minutes following application. The application
however, the majority of patients (70%) preferred of a drop of 50% lidocaine solution onto exposed
anesthesia with Oraqix. This was despite the fact that human dentin reduced the response to air blasting
one in five patients did not receive adequate pain and probing in an uncontrolled study with six vol-
control after application of the gel. The principal unteers (7), while an anecdotal report (33) claimed
reason for the preference was less numbness after great success when 20% benzocaine was used as a
treatment; 63% of subjects were bothered to a sig- topical application to the dental pulp during endo-
nificant degree by the postoperative feeling after the dontic treatment.
injection compared to 44% after Oraqix. The main The application of patches containing 20 mg lido-
reason chosen by those preferring injection (22%) caine to the buccal and palatal lingual gingiva has
was greater comfort during treatment. In none of been investigated as a means of pain control for
these studies (35, 46, 78, 96) were there differences in dental extractions (144). Both children and adults
adverse effects between active and placebo treat- were included in this study of 49 extractions in 40
ments and those reported could have been caused by patients. The extraction was performed when the
the operative treatments provided. gingivae could be detached from the tooth without
An interesting finding with Oraqix is the report pain. The mean times to extraction were app-
that onset of anesthesia is rapid and seems to diminish roximately 19 and 13 minutes for the maxilla and
very quickly. There is evidence that a 30-second mandible respectively. Successful anesthesia was
application is more effective than a 2-minute treat- achieved in 81% of teeth. Gangarosa (49) used ion-
ment (46). This is in contrast to the other work tophoresis for 10 minutes to apply 2% lidocaine with
described above, which has shown that the efficacy of 1:50,000 epinephrine for the extraction of deciduous
intraoral topical anesthesia increases with time of teeth. The method was successful in 12 out of 13
application (67). This could be the result of wash away teeth, which were extracted without discomfort.
and might vary between methods of application, for
EMLA
example if a patch is used loss of active agent into the
mouth (rather than into the tissues) may be reduced. The effectiveness of a 5-minute application over the
When performing procedures such as scaling it is apical areas of maxillary deciduous teeth has been
useful to have anesthesia of the tooth as well as the investigated in a double-blind placebo-controlled
soft tissues. It is thus valid to ask the question do trial (108). The results showed no difference in
topical local anesthetics produce pulpal anesthesia? response to electrical pulp testing between treat-
This is addressed below. ments. The same investigators studied the efficacy of
EMLA to eliminate the discomfort of restorative
dentistry on deciduous teeth. They found that 80% of
Studies into use of topical anesthetics to
the children studied required supplementary local
provide anesthesia for procedures on
anesthesia to allow treatment to be completed pain-
teeth
lessly (108). Another investigation (151) compared the
A number of workers have investigated changes in application of EMLA, 10% lidocaine, and placebo on
pulpal response to electrical testing after the appli- the response of maxillary central incisors to electrical
cation of topical anesthetics. pulp testing. Twelve of the 13 volunteers who received
EMLA showed no response to electrical pulp testing
Conventional agents
between 15 and 30 minutes of application; however,
Brook et al. (15) reported that the 30-minute appli- some of the lidocaine-treated and placebo-treated
cation of a patch containing 50 mg lidocaine to the cases also showed failure to respond under maximum
71
Meechan
stimulation from the pulp tester. Another human relief scores) the only significant difference they
volunteer study (42) showed that the 2-minute noted was an increase in the percentage of patients
application of EMLA to the maxillary buccal gingiva in with meaningful pain relief at 30 minutes with the
the canine region did not affect canine pulp responses benzocaine patch. The median time to first notice-
during the 20 minutes after placement. able pain relief with the active patch was between 5
The effectiveness of 1 g topical EMLA as an alter- and 6 minutes. In a later study, these workers (68)
native to infiltration anesthesia as pain control for reported a greater number of responders (that is
restorative procedures was investigated in an patients who reported a significant pain reduction)
uncontrolled pilot study in 12 patients (149). The following the application of 20% benzocaine gel
authors reported that 75% of subjects obtained compared to placebo for the treatment of toothache.
adequate analgesia. They concluded that this method The median onset for meaningful pain relief was
provided some, but not complete, anesthesia to allow 8.3 minutes.
restorative dentistry to be performed. Three investigations (8, 52, 57) have looked at the
use of topical bupivacaine as a means of reduc-
ing post-operative discomfort in children following
Topical anesthetic relief of toothache
dental extractions. In one study (57) dental rolls
and post-operative pain
soaked with 7 ml of 0.25% bupivacaine with
The earliest reference to local anesthetic action of 1:200,000 epinephrine placed over the extraction sites
cocoa leaves was an intraoral effect recorded in 1653 were more effective than saline-soaked rolls in
when Bernabe Cobo reported that chewing cocoa relieving discomfort following extractions under
leaves eased the pain of toothache (18). This may or general anesthesia in children aged between 7 and
may not have been a topical effect. Over-the-counter 15 years. The swabs were placed after the children
medications containing topical anesthetics such as awoke from the general anesthetic. The other two
benzocaine have been available for over 80 years. studies (8, 52) showed that no difference in pain relief
More recent studies have investigated the use of was obtained when swabs with 0.25% bupivacaine
topically applied anesthetics for the symptomatic and epinephrine or placebo (saline or distilled water)
treatment of toothache (51, 66, 68, 140). It has been were inserted over the extraction sites in children
pointed out that significant soft tissue anesthesia immediately following extractions, while the child
(including periosteum) may influence the relief of was still anesthetized. The mean time of application
toothache and that penetration through to bone and of the agent was 8 minutes in the former study (8).
to the pulpal supply is not essential to produce some
relief, as a result of convergence of trigeminal fibers
Plasma levels following intraoral topical
at the brainstem (66).
anesthetic application
Sveen et al. (140) noted that a 7.5% benzocaine gel
produced better pain relief than placebo when Anesthetic applied topically is absorbed and will
applied to the gingivae adjacent to painful teeth in a eventually enter the bloodstream. This is important
double-blind trial with 49 patients. Pain relief because improper use could lead to toxicity, either as
occurred within 34 minutes. The treatment was not a result of topical application alone or in combina-
entirely successful, with 83% of the active treatments tion with any injected anesthetic (see above). It has
producing relief. A similar study investigated higher been claimed that toxic reactions are more common
concentrations of benzocaine in gels (10% and 20%) after topical application compared to other methods
and found these to be better than placebo in of local anesthetic delivery (3). When considering
decreasing the intensity of toothache (51). Hersh toxic reactions the amount of drug is important. The
et al. (66) also used benzocaine but this time concentration of drug in topical preparations is
included in an adhesive patch (12 mg benzocaine) as greater than that used for injectable formulations. An
opposed to a gel. They investigated the efficacy of this animal study (3) demonstrated that entry of local
patch in a double-blind, placebo-controlled trial in 60 anesthetics into the circulation was quicker after
patients with toothache. Patches were applied at the topical administration to the pharynx compared to
mucogingival junction of the affected tooth and subcutaneous injection. Topical administration
remained in place for an hour. These workers achieved much higher peak levels than slow intra-
reported a large placebo response in this investiga- venous infusion of the same dose. The authors of that
tion and although the active patch was superior in all study concluded that, although the peak plasma level
their outcome measures (pain intensity and pain was around a third of that obtained after intravenous
72
Intraoral topical anesthesia
injection, the profile of entry into the bloodstream rapid metabolism of the latter. Haasio et al. (60)
following topical administration simulated that after found that the highest lidocaine concentration was
rapid intravenous injection. Certainly toxic reactions, 0.47 lg ml at 5 minutes and the highest prilocaine
including fatalities, to topically applied local anes- concentration was 0.21 lg ml at 10 minutes follow-
thetics have occurred (3, 77). ing the application of 4 g EMLA intraorally. These
authors noted that absorption was more rapid after
Lidocaine EMLA compared to a 10% lidocaine spray, but the
only significant difference was a higher mean plasma
Hersh et al. (67) found that plasma lidocaine levels
concentration of lidocaine at 30 minutes in the 10%
rose steadily after the use of patches containing
lidocaine spray group where the mean plasma lido-
either 10 or 20 mg of the local anesthetic during the
caine concentration was 0.35 lg ml compared with
15 minutes of patch application and then remained
0.14 lg ml in the EMLA group. The highest lidocaine
steady over a period of 30 minutes from the
concentration in the EMLA group was 0.47 lg ml at
15-minute sample. The average peak plasma levels
5 minutes compared to 0.66 lg ml in the lidocaine
obtained were 0.016 lg ml for the 10% patch and
group at 20 minutes.
0.022 lg ml for the 20% patch. These levels are an
The plasma concentrations of lidocaine and prilo-
order of magnitude less than those achieved after the
caine following the 30-minute application of 8 g of
intraoral injection of 2% lidocaine solutions (19, 56).
EMLA to the buccal mucosa were measured in 12
Brook et al. (15) reported peak lidocaine levels
volunteers by Vickers et al. (149). Peak plasma levels
4560 minutes after a 30-minute application of a
occurred 40 minutes after initial application for both
patch containing 50 mg lidocaine on the buccal
anesthetics; the mean peak level for lidocaine was
gingivae opposite the premolar teeth in either jaw.
0.221 lg ml and for prilocaine was 0.131 lg ml. The
The mean peak level was around 0.030 lg ml and
maximum concentrations noted in any one subject
the highest concentration recorded was 0.095 lg ml.
were 0.418 lg ml (lidocaine) and 0.223 lg ml
Haasio et al. (60) reported a mean plasma level
(prilocaine).
0.35 lg ml for lidocaine 30 minutes after the in-
traoral delivery of a large dose (200 mg) of lidocaine Oraqix
as a 10% lidocaine spray. The highest concentration
Plasma levels of lidocaine and prilocaine following
noted was 0.66 lg ml at 20 minutes.
application of Oraqix have been reported in two
Leopold et al. (94) investigated lidocaine levels in
studies. In one study (45), doses of 0.93.5 g Oraqix
children after the intraoral application of patches
were applied to periodontal pockets in 10 patients.
containing 20% lidocaine. A 5-minute application
Blood samples were taken 10, 20, 30, 40, 60, 75, and
in the maxillary buccal gingiva was used. The
90 minutes after application of Oraqix. Peak plasma
maximum level of lidocaine recorded in plasma
levels occurred between 20 and 40 minutes after
was 0.128 lg ml (mean 0.082 lg ml). The average
application. The highest concentration of lidocaine
time to peak plasma concentration was 9 minutes
reported was 0.266 lg ml (at 40 minutes) with a
with a range of 115 minutes. These workers point
median of 0.169 lg ml (at 30 minutes). The great-
out that although these levels are well below the
est plasma level of prilocaine was 0.118 lg ml
toxic concentration they are around four times
(at 30 minutes) with a median of 0.077 lg ml
higher than those reported with the same material
(at 30 minutes). In another study (65), plasma levels
in adults (0.022 lg ml see study of Hersh et al. [67]
of lidocaine and prilocaine were measured following
above).
longer applications of a larger dose of Oraqix. In this
study a median of 8.6 g (maximum 8.7 g) of Oraqix
EMLA
was applied over periods up to 3.4 hours and blood
Plasma levels of lidocaine and prilocaine have been samples were taken in a 10-hour period post-appli-
investigated after the 4-minute application of 4 g cation. Peak plasma levels of the anesthetics were
EMLA (100 mg lidocaine and 100 mg prilocaine) with achieved 3.7 hours after the start of application for
a toothbrush to the gingiva (60, 123). Pere et al. (123) lidocaine and 3.3 hours for prilocaine. The greatest
reported that the highest plasma level for lidocaine level of lidocaine was 0.55 lg ml and of prilocaine
was 0.26 lg ml at 15 minutes and for prilocaine it was 0.18 lg ml. Methemoglobin levels were mea-
was 0.09 lg ml at 30 minutes after the start of the sured in this study; the greatest level noted was
application. The plasma levels of lidocaine were 1.73% with a median of 1.23%, occurring 14 hours
greater than those of prilocaine because of the more after application. This represented a rise from the
73
Meechan
Table 7. Results of studies measuring plasma levels of anesthetic agents following topical intraoral and buccal
infiltration administration
Dose of anesthetic [formulation] Average (maximum) peak plasma level (lg ml) Reference
23 mg Lidocaine [10% patch] 0.016 (67)
46 mg Lidocaine [20% patch] 0.022 (67)
46 mg Lidocaine [20% patch]* 0.082 (0.128)* (94*)
50 mg Lidocaine [patch] 0.03 (0.095) (15)
200 mg Lidocaine [10% spray] 0.35 (0.66) (60)
4 g EMLA Lidocaine 0.21 (0.26), Prilocaine 0.05 (0.09) (123)
4 g EMLA Lidocaine 0.18 (0.47), Prilocaine 0.1 (0.21) (60)
8 g EMLA Lidocaine 0.22 (0.42), Prilocaine 0.13 (0.22) (149)
Up to 3.5 g Oraqix Lidocaine 0.169 (0.266), Prilocaine 0.077 (0.118) (45)
8.6 g Oraqix Lidocaine 0.28 (0.55), Prilocaine 0.11 (0.18) (65)
36 mg Lidocaine [2% Lidocaine 0.31 (56)
as a buccal infiltration]
36 mg Lidocaine [2% Lidocaine 0.22 (56)
with 1:100,000 epinephrine
as a buccal infiltration]
*A study in children.
pre-application median of 0.77% but was still within have also been reported to produce allergies after
normal limits (<2%). topical use in the oro-facial region (126). Neverthe-
Table 7 summarizes the results of the studies that less, reports of damage to mucosa are not common
have measured plasma levels of anesthetics following and any adverse effects appear to be reversible (67).
intraoral topical application and also shows the An exception is the misuse of the anesthetic agent
results obtained in one study (56) that investigated cocaine. This drug can cause ulceration and gingival
plasma levels of anesthetics after buccal infiltration necrosis following topical application as a result of
anesthesia. It can be seen from Table 7 that, although vasoconstriction (121, 128). A histological study in
conventional intraoral topical agents produce levels hamsters showed that the application of 5% lido-
of anesthetic in plasma that are an order of magni- caine for periods up to 24 hours to the oral mucosa
tude below those obtained after injection, large doses revealed no signs of any inflammatory response or
of some topical anesthetics achieve plasma levels tissue edema (22) while in humans, the application
similar to those obtained after conventional buccal of 10% or 20% lidocaine patches did not differ from
infiltration. It is therefore essential when considering the use of placebo patches with regard to adverse
maximum doses that both topical and any injected effects on the mucosa (67). There were no adverse
material are considered. local effects reported following a 30-minute appli-
cation of 8 g EMLA to buccal mucosa in humans
(149).
Adverse effects of topical Pashley & Parsons (122) described a case of severe
anesthetics pain following application of 5% lidocaine ointment
adjacent to teeth with exposed dentine. They sug-
The topical application of anesthetics seems to gested that this was the result of an osmotic effect on
produce few problems locally. The problems of dentinal tubules caused by the hypertonic topical
allergy, especially with ester-type local anesthetics, preparation.
were mentioned earlier and must always be borne in It was mentioned above that one of the adverse
mind, especially as the ester benzocaine is a popular effects of some local anesthetics is methemoglobi-
topical agent. Non-ester agents, such as dyclonine, nemia and that the drugs most likely to cause this
74
Intraoral topical anesthesia
problem are benzocaine and prilocaine. There are 2. Adriani J. Reactions to local anesthetics. JAMA 1966: 196:
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3. Adriani J, Campbell D. Fatalities following topical appli-
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cation of local anesthetics to mucous membranes. JAMA
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incidence of methemoglobinemia following topical parative potency and effectiveness of topical anesthetics
application before bronchoscopy is 1:7000 (62). It in man. Clin Pharmacol Ther 1963: 5: 4962.
5. Aldrete JA, Johnson DA. Evaluation of intracutaneous
should be pointed out that the doses used on the
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in the mouth, but the fact that methemoglobinemia 6. Al-Melh MA, Andersson L. Comparison of topical anes-
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There has been a case of methemoglobinemia anesthesia of dentine in man. J Dent Res 1996: 75: 270
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281283.
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9. Arthur GR, Scott DHT, Boyes RN, Scott DB. Pharmaco-
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