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As dentists generally find it difficult to insert an intravenous line, an option is intramuscular administration. The
drug can be injected into the deltoid muscle (shoulder),
gluteus muscle (upper lateral quadrant so as not to inject
the sciatic nerve or the vessels of the leg), or the vastus lateralis muscle of the leg (medial-
lateral area of the thigh).
Convulsions were previously treated with barbiturates;
however, these can lead to respiratory depression, thus aggravating the situation (Goodson and Moore1983). Convulsions
were later treated with diazepam (2 ml with 10 mg), a benzodiazepine that is as efficacious but does not lead to respiratory
depression. Today, the preferred drug is another benzodiazepine, midazolam, because of the advantages set out above.
Recovery andDischarge
If the signs and symptoms are mild and the patient does
not experience convulsions and recovers well in a few minutes, then dental treatment can continue.
If, on the other hand, the clinical manifestations are very
severe and recovery is slow, he/she should be sent home
accompanied by a relative. In cases of doubt, a detailed
report of the incident should be made and the patient
should see his/her doctor for a check- up.
If the patient requires a benzodiazepine (midazolam or
diazepam) for the convulsions, the patient loses consciousness, or it is necessary to call the emergency services
because of severe cardiovascular depression, then he/she
should be taken to a hospital for observation during the
recovery phase. A detailed report of the incident should be
made (e.g. time of onset, anesthetic solution and quantity
injected, technique used, patient’s reaction, onset of reaction, signs, and symptoms, patient’s progress, etc.).
It is important to remember that severe systemic intoxication by local anesthetics in clinical practice may be fatal in
4% of cases. Consequently, advanced life support and intravenous lipid emulsion are necessary (Gitman etal.2019).
Prevention
The main measures for preventing local anesthetic- induced
toxicity were addressed at the start of the chapter and
include the following: (i) aspirate before injection, (ii)
inject slowly, and (iii) do not exceed the maximum dental
dose for body weight.
Toxic Methemoglobinemia
tissue. Each molecule of Hb has four iron atoms, each of
which binds to an O
++
form (Fe
or Fe2+) for gas exchange with tissue to take
molecule. Iron has to be in its ferrous
2
place. However, the ferrous form is unstable, and small
+++
amounts transfer to the ferric form (Fe
which O
binds so firmly that it cannot be released, with
2
or Fe3+), in
the result that gas exchange does not take place. Hb with
3+
iron in the Fe
form is known as methemoglobin (MHb)
(Curry 1982; Rodriguez et al. 1994; Coleman and
Coleman 1996) or, albeit more rarely, hemoglobin (Hi)
(Olson and McEvoy1981).
Erythrocytes can reduce MHb to Hb via two pathways
(Curry 1982; Rodriguez et al. 1994; Coleman and
Coleman1996):
● The nicotinamide- adenine- dinucleotide methemoglobin
reductase (NADH-
cytochrome b
depends on cytochrome b
MHb- reductase) system or NADH-
- reductase or diaphorase because it
5
(Olson and McEvoy 1981;
5
Jackobson and Nilsson1985; Coleman and Coleman1996;
Aalfs etal.2000). This system is responsible for recycling
95% of MHb to Hb.
● The nicotine-adenine-dinucleotide-phosphate-methe-
moglobin reductase (NADPH-
which requires the enzyme glucose-
MHb- reductase) system,
6- phosphatedehydrogenase (G- 6- P- D) and is responsible for reducing
the remaining 5% of MHb to Hb.
Under normal conditions, less than 1–2% of Hb is in the
form of MHb (Hjelm and Holmdahl 1964; Lund and
Cwick1965; Curry1982; Anderson etal.1988; Rodriguez
et al.1994; Wilburn-
goo and Lloyd 1999), although this
may increase for two reasons:
1) Hereditary abnormalities:
● Hemoglobin M. Altered Hb that is a poor transporter
(Anderson etal.1988).
of O
2
● NADH- MHb- reductase deficiency caused by an alter-
ation in chromosome 22 (Aalfs etal.2000).
● NADPH- MHb- reductase deficiency.
● G- 6- P- D deficiency.
2) Acquired (toxic) factors. Around 100 chemical com-
pounds and medications can produce MHb (Coleman
and Coleman 1996), including two local anesthetics,
prilocaine and benzocaine (Coleman and Coleman1996;
Wilburn- goo and Lloyd1999), therefore the condition is
also called acquired or toxic methemoglobinemia. It is
interesting to note that of 100 scientific reports on toxic
methemoglobinemia in the twentieth century, nine
were dental cases (Wilburn- goo and Lloyd1999).
Hemoglobin (Hb) is a stable, tetrameric iron- containing
protein that is found in red cells (erythrocytes) and that
binds reversibly to oxygen (O
), which is released in body
2
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The earliest sign of toxic methemoglobinemia is cyanosis
or a bluish color to the skin, nails, and lips (Lund and
Cwick 1965). The toxicity stems from the fact that toxic
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methemoglobinemia can reduce the capacity to transport
oxygen to the tissues, leading, in extreme cases, to death
byhypoxia.
Local Anesthetics Involved
A review of 242 cases of local anesthetic- induced toxic
MHb collected between 1947 and 2007 revealed that 65%
were caused by benzocaine and 30% by prilocaine; both
anesthetics were clearly the most frequently involved
(Guay2009).
Benzocaine
Benzocaine is a rapid and safe topical anesthetic, which,
because it is scarcely water soluble, is absorbed poorly.
However, cases of benzocaine-
induced toxic methemoglobinemia have been appearing since the middle of the
twentieth century (Ocklitz1949; Bernstein1950). In 1979,
the United States Food and Drug Administration (FDA)
reported this complication to be rare, with one case for
every 140
000 applications of topical anesthetic (Wilburngoo and Lloyd1999). However, the number of cases published gradually increased, even in dental practice (Townes
et al. 1977; Potter and Hillman 1979; Klein et al. 1983;
Anderson etal.1988).
Although benzocaine is not normally absorbed, it can
enter the bloodstream through the gastrointestinal tract
(Berstein1950; Townes etal.1977; Potter and Hillman1979;
Rodriguez etal.1994) or via eroded and inflamed skin or
mucosa (Severinghaus etal.1991; Rodríguez etal.1994).
The mechanism underlying toxic methemoglobinemia is
not well known (Rodriguez etal.1994), although the condition seems to involve a metabolite resulting from oxidation of benzocaine (Coleman and Coleman 1996),
especially nitrobenzene- like (Singh and Al2019).
There is no official figure for the maximum dose of benzocaine (Beutlich 1991); however, several authors agree
that there is a clear risk of toxic methemoglobinemia with
doses greater than 15–25
mg/kg (Potter and Hillman1979;
Rodriguez et al. 1994). This criterion is increasingly
accepted (Klein et al. 1983; Severinghaus et al. 1991;
Wilburn- goo and Lloyd1999). In addition, the risk is elevated in small children (Townes et al. 1977; Kellet and
Copeland 1983; Severinghaus et al. 1991), especially in
those under one year old. In fact, one review of 44 cases
showed that almost half involved children in this age group
(Rodriguez etal.1994). It is important to remember that
the concentration of benzocaine in topical anesthetic is
very high (20%).
In conclusion, we can say that benzocaine should be
avoided in children aged less than 2 years (Singh and
Al2019) and that doses of more than 15–25 mg/kg should
be avoided, given their association with toxic methemoglobinemia, but it is not possible to predict who will be at
risk. Finally, after the 242 cases review, in susceptible individuals, there is no “therapeutic window” between the
doses required to produce a therapeutic effect and those
producing toxicity (Guay2009).
Prilocaine
Since the first reports of cases of methemoglobinemia
caused by prilocaine (Daly etal.1964; Scott etal.1964), a
direct association has been established between the amount
of anesthetic administered and the level of MHb (Onji and
Tyuma 1965; Hjelm and Holmdahl 1964; Lund and
Cwick 1965; Spoerel et al. 1967), although considerable
individual variations have been reported (Spoerel
etal.1967).
MHb reaches peak values at 1.5–4
hours after administration of prilocaine (Onji and Tyuma 1965; Lund and
Cwick 1965; Spoerel et al. 1967) and tends to disappear
spontaneously at 8–14
et al. 1967), although occasionally it can last 5–72
hours (Daly et al. 1964; Spoerel
hours
depending on the level reached in blood (Lund and
Cwick1965; Kreutz and Kini1983).
The cause of methemoglobinemia is not prilocaine (Scott
etal.1964), but its metabolite orthotoluidine (o-
methylaniline (Onji and Tyuma 1965; Lund and
or 2-
toluidine)
Cwick1965; Spoerel etal.1967). Another metabolite of prilocaine 4- hydroxy- o- toluidine has been shown to cause
methemoglobinemia (Frayling etal.1990).
Clinical research has shown that onset of cyanosis is
usually at 400
and that it tends to become generalized at ≥900
mg (Daly etal.1964; Lund and Cwick1965)
mg of
injected prilocaine (Scott etal.1964; Lund and Cwick1965).
Thus, the absolute maximum recommended adult (≥70 kg)
dose in medical practice is 600
mg (8.5 mg/kg) (Lund and
Cwick1965; Spoerel etal.1967). According to the prudent
1984 recommendation of the Council on Dental
Therapeutics of the American Dental Association, the
maximum recommended adult dose in dental practice is
400 mg (5.7 mg/kg) (American Dental Association1984).
It is interesting to note that most cases of cyanosis in
dental practice occurred when the maximum medical dose
(8.5 mg/kg) was exceeded (Anonymous 1994; Hardwick
and Beaudreau 1995) or when the dose was close to the
limit (Kreutz and Kini1983; Duncan and Kobrinsky1983;
Johnson1994). However, there is one report of a child with
idiopathic toxic methemoglobinemia induced by low- dose
prilocaine (Ludwig1981).
Other Anesthetics
Table23.8 shows local anesthetics for which studies have
found no association with toxic methemoglobinemia after
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452
Table23.8 Local anesthetics andstudies showing that they do
not produce toxic methemoglobinemia.
Anesthetic Reference
Lidocaine Onji and Tyuma (1965)
Hjelm and Holmdahl (1964)
Lund and Cwick (1965)
Muschaweck and Rippel (1974)
Weiss etal. (1987)
Articaine Muschaweck and Rippel (1974)
Rupieper etal. (1978)
Rupieper and Stocker (1981)
Bupivacaine Rupieper and Stocker (1981)
Etidocaine Lund etal. (1973)
Rupieper and Stocker (1981)
Procaine Hjelm and Holmdahl (1964)
intravenous administration or other types of parenteral
administration. The main anesthetics involved are lidocaine, articaine, bupivacaine, etidocaine, and procaine.
However, the review of 242 cases includes 12 (5%) that
are associated with lidocaine, although lidocaine was the
trigger in only three of these cases since the remaining cases
involved other drugs (oxidative drugs) that were administered concomitantly (nitrate therapy, benzocaine, dapsone,
phenazopyridine, phenacetin, etc.) (Deas1956; Burne and
Doughty 1964; O’Donohue et al. 1980; Olson and
McEvoy1981; Hall etal.2004), therefore the literature suggests a less clear association with lidocaine (Guay2009).
The review addresses tetracaine in an even more limited
fashion (Guay2009) since there was only one case in which
the anesthetic was the only trigger (Levergne etal.2006).
Consequently, the association is even weaker.
Nevertheless, it seems prudent to avoid both lidocaine
and tetracaine in patients taking other oxidative drugs and
especially in patients with congenital methemoglobinemia
(Guay2009).
Aggravating Factors
Patients with diseases or abnormalities that alter or hamper transport of oxygen to tissues are more vulnerable to
prilocaine- and benzocaine- induced toxic methemoglobinemia. These conditions include the following.
1) Cardiovascular disease
● Any heart disease (e.g. heart failure, coronary artery
disease, arrhythmias, etc.) because these reduce the
flow of blood to the liver, where local anesthetics are
metabolized (Spoerel et al. 1967; Wilburn- goo and
Lloyd 1999), or reduce transport of oxygen to tissue (Olson and McEvoy 1981; Duncan and
Kobrinsky1983; Rodriguez etal.1994).
● Anemia (abnormalities of and/or reductions in red
cells). Patients with anemia have less healthy hemoglobin in circulation, and the reduced hemoglobin
caused by methemoglobinemia aggravates the situation (Lund and Cwick1965; Spoerel etal.1967; Olson
and McEvoy 1981; Duncan and Kobrinsky 1983;
Severinghaus etal.1991; Anonymous1994; Rodriguez
etal.1994; Wilburn-
● Insufficient blood supply to the brain or periphery
goo and Lloyd1999).
since transport of oxygen to the brain is more seriously compromised (Spoerel etal.1967).
2) Severe respiratory diseases
In patients with severe respiratory diseases, oxygen
exchange in the lungs decreases and toxic methemoglobinemia aggravates this situation (Anonymous1994;
Wilburn- goo and Lloyd1999).
3) Extreme age groups (children aged less than 1 year and
elderly patients)
● Newborns, infants, and, to a lesser extent, children
aged less than 1
year have a greater proportion of
MHb in blood owing to the immaturity of their enzymatic system (Kunzer and Schneider1953; Ross and
Desforges1959; Ross1963), seen mainly in the form
of reduced activity of the methemoglobinemia reductase system (Ross1963; Lo and Agar1986). This situation is more severe during the first months of life
(Kunzer and Schneider etal.1953), although it is considered to involve a certain degree of risk until the
patient is 1
year old (Severinghaus etal.1991; Kellet
and Copeland1983; Rodriguez etal.1994).
● Elderly patients are more vulnerable to toxic methe-
moglobinemia because many have diseases that
impair oxygen transport (i.e. cardiovascular disease,
respiratory disease, anemia) and are on medication,
some of which exerts oxidative action on hemoglobin
(Wilburn- goo and Lloyd1999).
4) Hereditary methemoglobinemia
A few hundred cases have been reported of patients
with genetic diseases that involve abnormalities of
hemoglobin or of its metabolic pathways (Olson and
McEvoy1981; Curry1982; Coleman and Coleman1996;
Wilburn-
goo and Lloyd1999). Most cases are diagnosed
by pediatricians during the patient’s first year of life
(Wilburn- goo and Lloyd1999).
Clinical Manifestations
Onset of symptoms is late, generally within 2–4 hours after
administration of the anesthetic, and usually coincides
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with the peaks of MHb (Malamed2004; Esteban- Sanchez
etal.2013). Anesthetics are metabolized during this interval, which is when toxic metabolites are generated.
Furthermore, clinical manifestations are associated with
the amount of MHb, that is, the greater the amount of
MHb, the greater the severity, as follows:
● MHb 10–15%. Onset of cyanosis (Curry1982; Kreutz and
Kini 1983; Anderson et al. 1988; Wilburn-
goo and
Lloyd1999), which is characterized by the following:
○ Bluish- colored or brown- gray- bluish- colored skin
(Lund and Cwick1965; Townes etal.1977; Curry1982;
Coleman and Coleman 1996; Wilburn-
goo and
Lloyd1999), although the condition is best observed in
the nails (nail bed), lips, and oral mucosa. In persons
with black skin, cyanosis is also detected in the nail
bed and oral mucosa (Wilburn- goo and Lloyd1999).
○ Blood is dark in color (chocolate brown) (Daly
et al. 1964; Olson and McEvoy 1981; Kreutz and
Kini1983; Anderson etal.1988; Rodriguez etal.1994;
Coleman and Coleman1996).
○ The patient’s urine is dark (Curry1982).
● MHb 30–40%. Symptoms of hypoxia (Spoerel etal.1967;
Curry 1982; Duncan and Kobrinsky 1983; Kellet and
Copeland 1983; Anderson et al. 1988; Rodriguez
etal.1994; Coleman and Coleman1996), which involve
the following:
○ Sensation of weakness, fatigue, and dizziness.
○ Headache (cephalea).
○ Difficulty breathing, sensation of breathlessness
(dyspnea).
○ On occasion, nausea, and even vomiting.
○ Physical examination reveals increased heart rate
(tachycardia).
● MHb 55–60%. Onset of CNS depression (Curry 1982;
Duncan and Kobrinsky 1983; Rodriguez et al. 1994;
Anonymous1994; Coleman and Coleman1996):
○ Signs of lethargy and stupor that progress to loss of
consciousness and coma.
○ The cardiovascular examination reveals arrhythmia,
reduced heart rate (bradycardia), and progress to heart
failure.
● MHb 70%. Death by hypoxia- induced heart failure
(Curry1982; Anderson etal.1988; Rodriguez etal.1994;
Coleman and Coleman1996).
(Wilburn-
goo and Lloyd1999): (i) the amount of MHb in
blood depends on the amount of benzocaine or prilocaine
administered and absorbed, and (ii) the risk the patient is
at owing to his/her general health (e.g. cardiovascular disease, respiratory disease, extreme age groups).
Management by theDentist
If the first signs of cyanosis appear at the dentist’s office
(unusual because they usually appear hours after administration of the anesthetic), then the steps to be taken are
asfollows:
● Remove topical anesthetic from the mouth (Benzocaine,
EMLA, Oraqix) or stop administering injectable prilocaine (Potter and Hillman 1979; Curry1982; Anderson
etal.1988).
● Administer 100% oxygen through a facemask to
facilitate the transport of O
to tissue (Olson and
2
McEvoy 1981; Jakobson and Nelson 1985; Hardwick
and Beaudreau1995; Coleman and Coleman 1996). It
should be noted that cyanosis does not resolve despite
administration of oxygen (Jakobson and Nelson1985).
● Send the patient to the emergency department for obser-
vation and determination of MHb in blood (Wilburn-
goo
and Lloyd1999). If the situation worsens, call the emergency services (911 in the United States, 112 in the
European Union, and 999in the UK).
At the medical center, the first step is to evaluate the
patient’s situation and determine the level of MHb in
blood. The appropriate measures can then be taken. Data
from modern pulse oximeters are not valid as they cannot
detect methemoglobin and will often read out a false reading of 85% or 86% saturation (Pogrel etal.2014). In severe
cases, the patient receives a very slow (5 minutes) intravenous injection of methylene blue (methylthioninium
chloride) (Curry1982), which boosts the NADPH- MHbreductase system and resolves cyanosis in 15–60 minutes
(Wendel1939; Ludwig1981; Klein1983; Klein etal.1983;
Kreutz and Kini1983; Curry1982; Rodriguez etal.1994;
Hardwick and Beaudreau1995).
Allergy
Some authors have reported that the signs of cyanosis
first appear when MHb levels are 5–6% (Hjelm and
Holmdahl1964; Jakobson and Nelson1985), although in
healthy patients, malaise starts at 10–15% (Coleman and
Coleman1996).
Finally, it is important to bear in mind that the severity
of symptoms depends on two factors simultaneously
Allergies to local anesthetic solutions are adverse drug
reactions triggered by an immune mechanism
(Becker1995). They account for fewer than 1% of all general complications in the dentist’s office (Table 23.9),
although many patients report any adverse effect as being
allergic (Batinac etal.2013). Table23.10 shows some of the
basic terms used in allergology. The substances that trigger
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454
Table23.9 Allergic reactions asa percentage ofgeneral
complications inthe dentist’s office.
No. of
emergencies
Reference Origin
Fast etal.
(1986)
Malamed
(1993)
Chapman
(1997)
Girdler and
Smith (1999)
Table23.10 Basic allergy terminology.
Anaphylactic
reaction or
anaphylaxis
Anaphylactoid
reaction
Allergicreaction
Reagin Mainly, but not exclusively,
Atopy Hereditary predisposition to production
Sensitization Process by which a person who does not
Hypersensitivity Exaggerated response of a target organ
Idiosyncrasy Exaggerated nonimmune response not
Intolerance Exaggerated nonimmune response due
Skin tests Prick test, intradermal test, patch test,
United
States
United
States
Australia 2743 15 0.3
United
Kingdom
like
studied
16 773 10 0.8
835 10 1.3
13
814 15 0.9
Severe systemic reaction (lifethreatening) caused by an IgE- mediated
immunological reaction
Severe systemic reaction (lifethreatening) allergic type caused by a
nonimmune mechanism or a reaction
that has not been shown to be allergic
Reaction similar to allergic reactions
but caused by a nonimmune
mechanism
immunoglobulin E (IgE)
high levels of IgE to common allergens
react to an allergen comes to react to an
allergen
to specific stimuli (allergens) or
nonspecific stimuli (physical exercise)
due to pharmacologic effect
to a pharmacologic effect
subcutaneous test
Years of
study
Mean 0.8
Allergic
reactions
(%)
≈ 1
response by themselves, but combine with a host protein
to form new compounds that have sufficient antigenic
capacity to trigger the allergic response (Giovannitti and
Bennett 1979). Local anesthetics or products derived
from their metabolism act as haptens (Giovannitti and
Bennett1979; Schatz1984; Schatz and Fung1986).
As adverse drug reactions, allergic reactions have a series
of specific characteristics:
1) Previous contact with the drug and a latency (or incuba-
tion) period are necessary for the immune system to
become sensitized.
2) They are dose- independent. The allergic reaction starts
with very low doses of allergen. In contrast, toxicity is
directly associated with dose (dose–response relationship). Although there is a certain association between
dose and response in allergic reactions, the response is
always disproportionate to the dose.
3) Once a patient has had allergy to a drug, then the patient
is allergic for an indefinite period, given that the immune
system has memory, therefore the drug is absolutely
contraindicated (De Nova etal.1996).
Allergic reactions can be classified into four types, as
established by Gell and Coombs in 1963 (Coombs and
Gell1968):
● Type I or humoral or anaphylactic reaction or immediate
type, which is mediated by immunoglobulin E (IgE) and
includes anaphylaxis, bronchial asthma, and urticaria.
● Type II or cytotoxic reaction, such as autoimmune hemo-
lytic anemia and fetal erythroblastosis.
● Type III or immune complex reaction, such as Arthus
reaction and serum sickness.
● Type IV or delayed- type immune reaction, which is cell-
mediated and includes contact dermatitis.
Local anesthetic solutions cause type I and IV allergic
reactions (Germishuys and Anderson1982; Canfield and
Gage1987; Assem and Punnia-
Moorthy 1988; Doyle and
Goepferd 1989; Ball 1999; Wilson et al. 2000; Fuzier
etal.2009; Batinac etal.2013) and very rarely type III reactions (Lederman etal.1980), although it is not always clear
that a reaction is type III (see Chapter22, “Localized LateOnset Skin Lesion”).
an allergic hypersensitivity reaction are known as allergens
and may be of two types:
● Antigens, which are high- molecular- weight polysaccha-
rides or proteins that stimulate the immune system
directly to trigger an allergic reaction.
● Haptens (incomplete antigens), which are low- molecular-
weight compounds that do not stimulate an immune
● Type I or humoral reaction. This IgE- mediated antigen–
antibody reaction develops as a systemic reaction that
manifests in a few minutes, although it often takes longer
(generally less than 1 hour to a few hours) if the hapten is
a metabolite resulting from the breakdown of a local
anesthetic compound and takes time to catabolize. This
type of reaction accounts for 20% of all allergies to local
anesthetics.
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● Type IV or delayed- type immune reaction. This T
lymphocyte-
mediated reaction occurs at the contact site,
although it may have systemic effects, as is the case with
type I reactions (Campbell etal.2001). It manifests after
hours or days (generally more than 6
hours or 1 or 2 days)
and is the most frequent reaction (80%) to local anesthetic
solutions (Aldrete and Jonhson 1970; Larson 1977;
Giovannitti and Bennett 1979; Johnson and
DeStigter1983; Ball1999).
Finally, the most common causes of allergy in the den-
tist’s office are (in order of frequency) latex, penicillin, nonsteroidal anti-
inflammatory drugs (NSAIDs), and, albeit
much more rarely, local anesthetics (Greenwood 2008).
Therefore, allergy to local anesthetics is very rare.
Allergy tothe Components ofLocal
Anesthetic Solution
As we saw in Chapter 7, local anesthetic solutions have
various components, and a patient may become sensitized
to each of them. We analyze these components below.
Local Anesthetic
As we saw in Chapter5, the intermediate chain determines
the type of biotransformation and catabolism of anesthetics, therefore, there are two groups that have clearly different allergic manifestations.
Esters
Esters, or amino- esters, are anesthetics that are metabolized rapidly through hydrolysis by plasma cholinesterases
or pseudocholinesterases and form compounds such as
para-
aminobenzoic acid (PABA). This compound has
marked sensitizing potency (Giovannitti and Bennett1979)
and was reported in 1920in the first cases of allergic dermatitis in dentists (Guptill 1920; Klauder1922). Allergic
reactions to the ester group are frequent and take the form
of cross- reactions between the different ester anesthetics
(Adler and Simon 1949; Aldrete and Jonhson 1970;
Giovannitti and Bennett1979; Johnson and DeStigter1983;
Schatz1984; Adriani etal.1986).
The frequency of allergic reactions to ester drugs has
fallen dramatically since 1950 for various reasons (Adriani
etal.1986): (i) they have been replaced by new injectable
amide anesthetics and are currently used only as topical
anesthetics (benzocaine and tetracaine) and (ii) the use of
gloves by dental staff prevents direct contact with drugs and
the subsequent risk of sensitization. However, benzocaine
is still used in some sunscreens (Bruze etal.1990) and can
therefore sensitize the patient before the dental topical
anesthetic is administered (Kaidbey and Allen1981).
Amides
Amide or amino- amide anesthetics are the most widely
used type today. The frequency of allergy to these drugs is
unknown, although it seems to be very low, accounting for
approximately <1% of all adverse reactions caused by local
anesthetics (Verrill 1975; Giovannitti and Bennett 1979).
This frequency is widely accepted (deShazo and
Nelson1979; Schatz1984; Schatz and Fung1986; Schwartz
and Sher1985; Chandler etal. 1987; Wilson etal. 2000).
Table23.11 shows the results of various series that only
examined suspected cases of allergic reaction to local anesthetics from the amide group and in which only 5% of cases
were true allergies.
Although some people are allergic to various amide
anesthetics, allergy to this group is quite rare (Table23.12),
and in many cases, the patient has multiple allergies to
other compounds. Allergy to amides is very rare because
the chemical structure of the anesthetics in the group
Table23.11 Studies ofallergy tests incases ofsuspected
allergy tolocal anesthetic inwhich allergy is confirmed.
No. of
suspicious
Reference
Incaudo etal. (1978) 70 2 2.8
deShazo and Nelson
(1979)
Babajews and Ivanyi
(1982)
Adriani etal. (1986) 450 41 9.1
Chandler etal. (1987) 58 0 0
Ruzicka etal. (1987) 104 9 8.6
Assem Punnia-
Moorthy (1988)
Hodgson etal. (1993) 90 22 25
De Nova etal. (1996) 20 1 5
Fisher and Bowey
(1997)
Wildsmit etal. (1998) 25 2 8
Ball (1999) 702 73 10.4
Ball (1999) 217 27 12.4
Rood (2000) 44 0 0
Rood (2000) 97 0 0
Nettis etal. (2001) 105 0 0
Malamed (2004) 210 0 0
Jacobsen etal. (2005) 48 3 6.3
Harboe etal. (2010) 135 2 1.5
Batinac etal. (2013) 331 3 0.9
cases studied
90 1 1.1
37 3 8.1
22 4 18
205 8 3.9
No. of
allergic
cases proven
Mean 6.1 ≈ 5
Allergic
cases
proven (%)
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Table23.12 Cases ofpatients withallergy toseveral local
anesthetics simultaneously (multiple allergies).
Anesthetics causing allergy
Group Reference
Ester Adler and Simon (1949) Procaine, tetracaine
Sidon and Aldrete (1971) Procaine, tetracaine
Johnson and DeStigter
(1983)
Amide Waldman and Binkley
(1967)
Brown etal. (1981) Lidocaine, prilocaine,
Hodgson etal. (1993) Lidocaine, prilocaine,
Warrington and
McPhillips (1997)
Fuzier etal. (2009) Lidocaine, mepivacaine
in the same patient
Procaine, tetracaine
Lidocaine, prilocaine
bupivacaine
mepivacaine
Lidocaine, prilocaine,
bupivacaine, articaine
differs from one drug to another (Aldrete and Jonhson1970),
therefore cross-
reactions are rare and it is always easy to
find alternatives within the group (Ball 1999; Batinac
etal.2013).
Of note, there are no cross-
reactions between local anesthetics from the ester and amide groups, since these are different chemical families (Incaudo etal.1978; Schatz1984),
therefore a patient who is allergic to an ester anesthetic can
receive an amide anesthetic. Table 23.13 summarizes
proven cases of allergy to various local anesthetics.
Vasoconstrictor
Vasoconstrictors are addressed in Chapter10 under absolute
contraindications. Epinephrine and norepinephrine are natural neurotransmitters and hormones, with the result that
there are no cases of allergy to their base forms since this
would be incompatible with life. However, the exogenous
vasoconstrictors in local anesthetics take the form of bitartrates or hydrochlorides. Two cases of allergy to epinephrine
have been reported (Kohase and Umino2004).
Felypressin (octapressin) and levonordefrin are artificial
vasoconstrictors, therefore they may cause allergic sensitization. In fact, there has been one case of allergy to levonordefrin (Germishuys and Anderson1982).
Although the cases reported may lead us to consider
these drugs to be absolutely contraindicated, we must
remember that the reactions are extremely rare, with only
three cases reported after many years using the drugs
(more than a century in some cases).
Antioxidants (Sulfites)
Sulfites are addressed in Chapter7, under the composition
of local anesthetic solutions, and in Chapter 10, under
Table23.13 Cases ofallergy toa local anesthetic, mainly
indentistry.
Group Local anesthetic Reference
Esters Procaine Guptil (1920)
Klauder (1922)
Adler and Simon (1949)
Rickles (1953)
Benzocaine Magnuson etal. (1970)
Kaidbey and Allen (1981)
Wildsmith etal. (1998)
Tetracaine Adler and Simon (1949)
Aldrete and Jonhson (1970)
Sidon and Aldrete (1971)
Johnson and DeStigter (1983)
Amides Lidocaine Waldman and Binkley (1967)
Wellis (1969)
Walker (1971)
Rood (1973)
Ravindranathan (1975)
Burguess (1987)
De Nova etal. (1996)
Ball (1999)
Al-
Dosary etal. (2014)
Articaine MacColl and Young (1989)
Malanin and Kalimo (1995)
Davila- Fernández etal. (2012)
Mepivacaine Seskin (1978)
deShazo and Nelson (1979)
Johnson and DeStigter (1983)
Sambrook etal. (2011)
Prilocaine Waldman and Binkley (1967)
Yeoman (1982)
Bupivacaine Brown etal. (1981)
Wildsmith etal. (1998)
absolute contraindications of sympathomimetic vasoconstrictors. The main sulfites are sodium or potassium
bisulfite or metabisulfite, which are added to local anesthetic solutions with sympathomimetic vasoconstrictors
(epinephrine, norepinephrine, and levonordefrin) to
lengthen their self- life. The antioxidant captures the oxygen before it inactivates the vasoconstrictor (Milano
etal. 1982; Klein1983; Huang and Fraser1984; Schwartz
and Sher1985; Seng and Gay1986).
Sulfites are also added in the form of antimicrobials,
reducing agents, and bleaches to foods such as fruit, vegetables, salads, mushrooms, pasta, wine, and beer, as well as
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to other medications (Bush etal.1986; Seng and Gay1986;
Simon1986; Ban etal.2014). Consequently, allergic sensitization may occur before local anesthetic solutions are
administered, although the FDA considers sulfites a safe
additive (Bush etal.1986; Seng and Gay1986; Simon1986)
because they rarely produce allergic reactions (Bush
etal.1986). However, there have been rare cases of intolerance to dental local anesthetic solution with sympathomimetic vasoconstrictors caused by sulfites (Huang and
Fraser1984; Schwartz and Sher1985; Schwartz etal.1989;
Dooms-
Goossens etal.1989; Campbell etal.2001).
It is important to point out that sensitization to sulfites is
difficult to evaluate using skin tests (Bush etal.1986), and
it may be necessary to use oral tests (Bush et al. 1986;
Simon1986; Ban etal.2014) or challenge tests (Schwartz
and Sher1985; Schwartz etal.1989). In the case of severe
allergy to dental local anesthetic (Schwartz and Sher1985)
or in cases of unexplainable asthmatic reactions that are
very resistant to treatment, we must evaluate the possibility of sensitization to sulfites, which may even be in antiasthma medications (Bush et al.1986). There have been
proposals to replace sulfites with other antioxidants in
these cases (Seng and Gay1986), although the alternatives
are less effective, more costly, and risky (Bush etal.1986).
At present, there are no antioxidants other than sulfites in
local dental anesthetic solutions with sympathomimetic
vasoconstrictors, therefore these solutions are absolutely
contraindicated in patients with reaction to sulfites.
Preservative (Methylparaben)
Parabens were addressed in Chapter 7. They have been
used to keep local dental anesthetic cartridges free from
contamination by bacteria (Latronica et al. 1969;
Larson1977; Luebke and Walker1978), owing to their considerable bacteriostatic and fungistatic effects (Schorr1968;
Latronica etal.1969; Nagel etal.1977; Larson1977; Luebke
and Walker 1978). In addition, they are effective at low
doses (Larson 1977; Luebke and Walker1978) and have
low toxicity (Luebke and Walker1978). The most widely
used preservative in dentistry is methylparaben or
4- (hydroxymethyl) benzoate.
Parabens are also used as additives in skin creams, ointments, lotions, toothpastes, cosmetics, and some foods
(Schorr1968; Nagel etal.1977; Larson1977; Luebke and
Walker 1978; Lederman et al. 1980; Giovannitti and
Bennett1979), therefore they can cause allergic sensitization before anesthetic solutions are applied.
The main problem with these compounds is that they are
the acid alkyl ester for aminobenzoate (Latronica etal.1969;
Nagel et al. 1977; Larson1977; Luebke and Walker1978;
Giovannitti and Bennett1979) and their chemical structure
is similar and shared with ester- type anesthetics, therefore
allergic reactions to anesthetic solutions caused by these
compounds are common (Aldrete and Jonhson 1969;
Latronica etal.1969; Luebke and Walker1978; Giovannitti
and Bennett1979; Johnson and DeStigter1983), as is crosssensitivity with ester- type local anesthetics (Aldrete and
Jonhson1969; Latronica etal.1969; Larson 1977; Luebke
and Walker1978). Consequently, in 1984, the FDA banned
these compounds in dental local anesthetic cartridges.
Since then, they have been removed almost everywhere,
with a dramatic reduction in associated adverse reactions
(Malamed2004; Pogrel etal.2014).
Confusion withOther Reactions
Administration of local anesthetic may be followed by
other reactions whose signs and symptoms overlap with
those of allergic reactions to the compounds in local anesthetic solutions, thus causing confusion and favoring the
false criterion that many reactions are due to allergic
responses to local anesthetic. Below we provide some
examples:
1) Psychogenic reactions
As seen at the beginning of this chapter, psychogenic
reactions caused by factors such as emotional tension,
anxiety (Aldrete and Jonhson 1970; Doyle and
Goepferd1989), and needle phobia can overlap with the
allergic response and account for 40% of confusing
cases (Table23.14). This group includes vasovagal reactions and even rare cases of urticaria caused by the anxiety associated with dental local anesthetic (Milan
et al. 1983; Tauberg et al. 1983) or, even more rarely,
anxiety-
induced angioedema (Barclay and Edwards
1971; Chue 1976). It is important to remember that
adverse reactions have also been reported after administration of placebo (Batinac etal.2013).
2) Toxicity reactions
In this case, we include both reactions caused by toxicity to local anesthetics and reactions to sympathomimetic vasoconstrictors caused by intravascular injection,
overdose, and rapid absorption. This situation can occur
in 25% of cases (Table23.14).
3) Allergic reactions to other compounds
Allergic reactions to compounds that are not local anesthetic solutions (Rood2000), as follows:
● Allergy to latex in rubber dams or gloves (Wildsmith
et al. 1998; Brown et al. 2002; Greenwood 2008;
Harboe etal.2010) is the most frequent allergy in the
dentist’s office (Greenwood2008).
● Allergy to drugs such as antibiotics (penicillin), disin-
fectants (chlorhexidine), and NSAIDs that were being
taken when local anesthetic is administered
(Wildsmith et al. 1998; Greenwood 2008; Harboe
etal.2010).
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Table23.14 Percentage ofcases ofpsychogenic reaction and
toxicity that were initially classified asallergy tolocal anesthetic.
Psychogenic
reaction
Sample
Reference
Incaudo etal. (1978) 71 4 5.6 29 42
Adriani etal. (1986) 450 91 20 175 39
Fisher and Bowey
(1997)
Wildsmith etal.
(1998)
Rood (2000) 44 26 59 7 16
Rood (2000) 97 75 77 22 23
Nettis etal. (2001) 17 9 53 2 12
● Allergy to other materials used during dental treatment,
size N % N %
205 92 45 —
25 8 32 3 12
Mean 42 23
Rounded mean 40 25
Toxicity
reaction
—
such as endodontic products (Wilson etal.2000).
It is easy to understand why confusion arises. The signs
and symptoms of the reaction are almost the same as
those of allergy, although the cause is totally different.
In addition, we tend to think that any allergic reaction
occurring during dental treatment is caused by the local
anesthetic.
Of note, although the diaphragm of the mouth of the
cartridge of dental local anesthetic and the plunger
are made of latex and a similar reaction could occur
during injection, there have been no reports of this type
of latex allergy to date (Shojaei and Haas2002).
4) Other factors leading to confusion
Other situations that have nothing to do with allergy
but that may be confused with an allergic reaction and,
in this case, are caused by or associated with local anesthetic solution include the following:
● Swelling and hematoma caused by needle injury
(Milgrom and Fiset 1986; Fisher and Bowey 1997;
Wildsmith etal.1998; Rood2000).
● Bacteremia and sialometaplasia (Wildsmith
etal.1998).
● Infection (Fisher and Bowey1997).
● Angioedema or hereditary angioneurotic edema
(Fisher and Bowey1997).
● Unknown or idiopathic factors (Adriani et al.1986;
Levy and Baker1986; Jackson etal.1994; Wildsmith
etal.1998; Rood2000).
Clinical Manifestations
Allergic reactions can occur minutes after administration
of local anesthetic, although they may also take hours or
sometimes a few days. The manifestations are classed as
minor and major according to their severity for the patient’s
life, although it is interesting to note that the clinical mani-
festations that most commonly lead us to suspect an allergic
reaction are cutaneous reactions and difficulty breathing
(Kelly and Patterson1974).
Below, we describe the various manifestations in separate sections. Although several may occur simultaneously
and overlap with others in clinical practice, their course is
very variable (Kelly and Patterson1974).
Minor Manifestations
These are the most frequent and, fortunately, the least
severe. They are usually cutaneous reactions.
1) Cutaneous reactions, mainly affecting the face, neck,
and chest. Less frequently affecting the abdomen and
arms. This is the main type of response.
● Maculopapular rash. This appears suddenly on the
skin (rash) and is characterized by reddish patches
(erythematous macules) and solid circumscribed elevations that are swollen by local edema (papules).
● Itching (pruritus), which may occur alone or accom-
pany skin lesions.
● Urticaria, which is a mix of the conditions described
above. Urticaria comprises wheals or hives accompanied by itching. The welts are solid edematous elevations (papules) that are swollen and reddish
(erythematous) and in which the raised center may
be pale and the surrounding skin reddish. They form
large plaques that are always itchy (pruritus).
2) Gastrointestinal reactions. These are caused by involve-
ment of the digestive mucosa and are much less frequent.
● Nausea and vomiting.
● Abdominal pain caused by spasms of the diges-
tive tract.
● In severe cases, diarrhea and urinary incontinence.
Major Manifestations
These responses may be serious and life- threatening, as
they affect the respiratory and/or cardiovascular system.
1) Angioedema or angioneurotic edema or Quincke edema.
This type is noninflammatory edema of the subcutaneous and/or submucosal tissue characterized by the following (Barclay and Edwards1971; Megerian etal.1992):
● Edema or swelling is the basic sign, affecting the face in
70% of cases, with compromise of the lips, tongue, periorbital area, and/or neck in 40% of cases and generally
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asymmetric involvement of the throat and pharynx.
Involvement of the tongue and pharynx can cause
obstruction of the upper airway with the following:
○ Symptoms:
■ Difficulty breathing (dyspnea), with a sensation
of breathlessness and asphyxia.
■ Difficulty swallowing (dysphagia).
■ Anxiety and nervousness.
○ Signs:
■ Occasionally, breath sounds owing to difficulty
breathing (stridor).
■ Hoarseness (dysphonia).
Note: Swelling is not accompanied by fever, pain, or itching and usually resolves spontaneously in 1–2
days once
the contact with the antigen disappears (in this case,
local anesthetic solution).
● Occasionally, reddening of the skin on the neck and
face (erythema).
● Swelling of the feet, hands, and genitals in 10% of
cases. In some cases, swelling of the abdominal viscera, which may cause abdominal pain.
2) Bronchospasm or asthmatic reaction. Affects the lower
airway (bronchioles):
● Symptoms:
○ Difficulty breathing (dyspnea), with a sensation of
breathlessness or asphyxia.
○ Anxiety and nervousness.
● Signs:
○ Breath sounds, mainly on expiration, that are pro-
longed and have a musical tone (wheezing).
○ Cough and sneezing.
○ Rapid breathing (tachypnea) involving use of the
accessory breathing muscles (neck muscles).
○ Sweating (diaphoresis).
● Examination reveals increased heart rate (tachycar-
dia) and arterial pressure.
3) Cardiovascular. Typically, hypotension, which, if very
marked, leads to anaphylactic shock.
● Malaise, dizziness, and vertigo, which may lead to
loss of consciousness.
● Palpitations caused by increased heart rate (tachycar-
dia) to compensate the hypotension.
● Pale skin with cold sweat.
● Examination reveals increased heart rate (tachycar-
dia) and a considerable reduction in arterial blood
pressure that can progress in the final phases to
severely reduced heart rate and arterial blood pressure.
Diagnosis
The diagnosis of drug allergy is based on clinical opinion.
As we have seen, cutaneous reactions and difficulty
breathing are the manifestations that provide the most
information (Kelly and Patterson 1974). The reaction is
confirmed using specific tests, mainly skin tests, with the
suspect drug (pure anesthetics without vasoconstrictors,
sulfites, additives, and preservatives tested independently
against saline solution), which is not easy (Riedl and
Casillas2003). In any case, diagnostic suspicion must be
confirmed by a specialist.
Management by theDentist
As we saw at the beginning of this chapter, once the signs
and symptoms of allergy have started, basic measures must
be taken (e.g. suspend dental treatment, consider the
patient’s position, i.e. place the patient in a seated position
if he/she has difficulty breathing, place the patient supine
if he/she is dizzy and about to lose consciousness, etc.). If
the patient loses consciousness, start the PABC or PCAB
protocol. Specific measures for major and minor manifestations are set out below.
Treatment ofMinor Manifestations
First, administer antihistamines orally, subcutaneously, or
intramuscularly. Itching disappears 10–30
minutes after
intramuscular injection, although this approach has little
effect on skin lesions (Malamed1993). Continue with oral
administration for 24
up to 3
days (Ravindranathan1975; Malamed 1993). The
hours (Kelly and Patterson1974) or
most commonly used antihistamines are:
● Oral or intramuscular hydroxyzine at 25–50 mg (MacColl
and Young1989).
● Oral or intramuscular diphenhydramine at 25–50 mg
(MacColl and Young1989).
● Oral or intramuscular dexchlorpheniramine at 4–10 mg.
Treatment ofMajor Manifestations
This treatment involves the most potent drugs because
these act rapidly and in the most severe conditions.
1) Epinephrine (Malamed1993; Ball1999).
Injected from 1- ml ampoules at a concentration of
1:1000 (1000 μg/ml), with a dose of 0.3–0.5 ml for adults
and 0.15 mg (0.15 ml) for children.
Action is very rapid with intramuscular injection.
The drug acts before 30 seconds (Sklar and
Schwartz1965; Nichols and Cutright1971), although
the effect is short (approximately 10 minutes) (Sklar and
Schwartz1965; Greenwood2008), therefore it is sometimes necessary to repeat the injection at 10–20 minutes
until bronchospasm and hypotension have resolved
(Malamed1993).
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