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ANESTHESIOLOGY www.stomaeduj.com
UNCLARITIES ABOUT ARTICAINE: CONTRAINDICATIONS
Review Articles
Nicolas de Ridder1a , Constantinus Politis1b*
1
Department of Oral and Maxillo-Facial Surgery, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium
MD, Student in Master of Medicine; e-mail: nicolas.deridder@student.kuleuven.be; ORCIDiD: https://orcid.org/0000-0003-1826-8470
a
MD, DDS, MM, MHM, PhD, Professor and Head; e-mail: constantinus.politis@uzleuven.be; ORCIDiD: https://orcid.org/0000-0003-4772-9897
b
ABSTRACT https://doi.org/10.25241/stomaeduj.2020.7(2).art.4
Background Articaine is one of the most widely used local anesthetics in dentistry. It is formulated with
epinephrine in a 1:100,000 or 1:200,000 concentration as a vasoconstrictor. The addition of epinephrine gives
the drug an extensive list of formal contraindications.
Objective To review the literature on the chemistry and safety of articaine with epinephrine, and to review
the validity of each of the contraindications.
Data sources The base knowledge was the result of reading a handbook on local anesthesia. Afterward, a
literature search was made for publications between 1990 and 2019 concerning contraindications to articaine
and dental epinephrine. Some articles about the pharmacological properties of articaine were also used.
Finally, what was used was the list of contraindications in the package leaflet of articaine in Belgium as stated
on 11/11/2019.
Study selection Articles of good quality and with clear information discussing and explaining these
contraindications were included.
Data extraction Information about which contraindications, which drug interactions, and what physiological
reasoning is behind them was extracted.
Data synthesis This information was synthesized in an extensive overview. First, the profile, safety and
pharmacological properties of articaine with epinephrine were reviewed. Afterwards, an overview of the
contraindications and drug interactions was given as stated in the package leaflet and each of them was
explained.
KEYWORDS
Articaine; Epinephrine; Pharmacology; Contraindications; Pregnancy.
1. INTRODUCTION tor, epinephrine.While most contraindications theo-
retically make sense, the majority of them do not
Articaine is a dental local anesthetic of the amide elicit a clinically significant hazard.
group. It is the only anesthetic specifically developed This paper is aimed to review the clinical character-
for use in dentistry. It was first synthesized in 1969 istics of articaine and to analyze the validity of the
when it was still referred to as carticaine. Its name contraindications to this drug as mentioned in the
changed to articaine in 1976 when it reached the package insert.
markets in Germany [1]. In the following years, arti-
caine got approval for clinical use around the world 2. MATERIALS AND METHODS
and has steadily become increasingly popular.
It is the second most used dental local anesthetic For the preparation of this review and introduction to
in the United States with a market share of 39,3% this subject in general, Malamed’s Handbook of Lo-
in 2018 (the most popular still being lidocaine, the cal Anesthesia (seventh edition) was read. After that
golden standard in local anesthetics) [1]. In Germany, PubMed, Trip database and Limo were searched for
it is even more popular, accounting for 97% of local the different aspects of articaine discussed in this pa-
anesthetic use by dentists in 2018 [2]. per. For articaine, a search was conducted on differ-
The package insert of articaine in Belgium (Septanest ent keywords for safety, clinical characteristics, inter-
by Septodont) contains a lot of contraindications to actions, and contraindications. The same was done
articaine itself as well as to the added vasoconstric- for epinephrine in dental use and pregnancy, cardio-
OPEN ACCESS This is an Open Access article under the CC BY-NC 4.0 license.
Peer-Reviewed Article
Citation: de Ridder N, Politis C. Unclarities about articaine: contraindications. Stoma Edu J. 2020;7(2):109-116.
Received: January 22, 2020; Revised: February 13, 2019; Accepted: February 20, 2020; Published: February 22, 2020
*Corresponding author: Professor Constantinus Politis, MD, DDS, MM, MHM, PhD, Head, Department of Oral and Maxillo-Facial Surgery
Faculty of Medicine, Catholic University of Leuven, Kapucijnenvoer 33, BE-3000 Leuven, Belgium
Tel: / Fax: 0032 (0)16332462; e-mail: constantinus.politis@uzleuven.be
Copyright: © 2020 the Editorial Council for the Stomatology Edu Journal.
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3.1.3. Duration of action and elimination half-life
Review Articles
Articaine is an intermediate-acting local anesthetic
providing pulpal anesthesia for approximately 60
minutes and soft tissue anesthesia for 3 to 5 hours [2].
Because of the rapid plasma hydrolysis, articaine has a
significantly shorter elimination half-life (27 minutes)
than the other amide anesthetics like lidocaine (90
minutes) [1]. This half-life is not related to the duration
of clinical action but is a measure for how long it takes
Figure 1. The chemical structure of articaine. for the drug to be eliminated from the circulation.
Malamed SF. Handbook of Local Anesthesia. 7th ed. St Louis: Mosby; 2019, This fast elimination means it is clinically advanta-
Fig. p72 geous when treating pregnant, lactating or pediatric
patients because there is less exposure time to the
vascular effects, safety in cardiovascular compro- drug [2].
mised patients, contraindications and interactions. 3.1.4. Maximum dosage
The most relevant articles were selected to create a Articaine has a maximum recommended dose (MRD)
narrative review, portraying an overall picture of the of 7.0 mg/kg to prevent the occurrence of an over-
current ambiguities about articaine. dose reaction [1]. Although local anesthetics are safe
drugs, an overdose is possible as with any drug, so
3. CLINICAL CHARACTERISTICS there are a few things to keep in mind. Hepatic and
renal dysfunction will lead to increased anesthetic
In Belgium, Articaine cartridges are currently avail- blood levels [1]. Liver dysfunction is not an absolute
able in two formulations: Articaine hydrochloride 4% contraindication to local anesthetics, but they should
with epinephrine 1:200.000 (Septanest Normal®) and be used thoughtfully as their half-life will increase
1:100.000 (Septanest Special®). and blood levels will be higher. In this case, articaine
could be the anesthetic of choice because of its partial
3.1. Articaine Hydrochloride 4% metabolization in blood plasma. Moreover, some
3.1.1. Structure patients have atypical serum pseudocholinesterase,
Articaine (or 4-methyl-3-[2-(propylamino) propion- which occurs in approximately 1 in 2820 individuals
amido-2-thiophenecarboxylic acid methyl ester) is [1]. To prevent overdose reactions, there are injection
classified as an amide local anesthetic, although it is a techniques that should be respected. Before injecting
unique entity within the amide local anesthetics (see the drug, the practitioner should always carefully
Fig. 1). It is the only one containing an aromatic ring aspirate the syringe to avoid intravascular injec-
rather than a benzene ring [2]. This thiophene ring tions. Furthermore, the injection rate appears to be
ensures greater lipid solubility which makes it great one of the most important factors for overdose: a
for penetrating tissue and would ensure better bone rapid intravenous injection (<15 seconds) of a car-
penetration, thereby increasing potency [1]. Further- tridge lidocaine 2% gives highly elevated blood
more, the structure contains an ester-linkage which levels, which can cause an overdose reaction [1].
makes it susceptible to hydrolyzation by plasma es- Therefore, it is recommended to administer the
terases. Articaine also has a higher degree of protein cartridge slowly (>60 seconds) so the blood levels
binding (95%) than the other amide anesthetics [2]. will not be as high and the risk of overdose reactions
It exerts its pharmacodynamic action by reversibly will be significantly reduced [1].
binding and inhibiting the alfa-unit of the voltage- Finally, the maximum dosage of 7.0 mg/kg is of
gated sodium channels, which prevents the propa- utmost importance. A 1.8 ml cartridge of 4% articaine
gation of action potentials in neurons [3]. contains 72 mg of articaine, meaning a healthy adult
3.1.2. Pharmacokinetics weighing 72 kg can receive a maximum of 7 cart-
The ester-linkage embedded in the amide struc- ridges (504 mg). However, it is unlikely these maxi-
ture makes articaine a hybrid molecule. This gives it mum numbers would be achieved during routine
a unique pattern of metabolization. As soon as the dental care since there is rarely a need for more than
drug reaches the plasma, the carboxylic acid ester three to four cartridges in one appointment [1].
groups are hydrolyzed by plasma esterases producing Obtaining anesthesia of the complete adult mouth is
a primary inactive metabolite: articainic acid [2]. About possible with only six cartridges using regional block
90% of the drug undergoes this rapid process and anesthesia, and only two cartridges in the primary
this would contribute to the lower systemic toxicity dentition.
of the drug. Further metabolization of the amide link- Nonetheless, the use of excessive volumes is the
age happens by microsomal enzymes in the liver just most frequent cause of overdose reactions [1]. As a
like the other amide anesthetics. This turns articainic dentist or oral surgeon, you should always calculate
acid into articainic acid glucuronide, which is in turn the maximum recommended dose for your patient,
excreted through the kidneys. Approximately 5-10% especially in risk populations (pregnant women, chil-
is excreted unchanged [3]. dren, cardiac patients).
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3.2. Epinephrine A recent systematic review confirmed the safe use of
Review Articles
Epinephrine, a vasoconstrictor, is added to the local ≤ 4 cartridges of the higher concentrated lidocaine
anesthetic solution for several reasons. Its vasocon- with 1:100,000 epinephrine in cardiac patients [6].
strictor effect delays the absorption of the local an- Although this is a useful guideline, it should not cre-
esthetic, reducing systemic toxicity. It increases the ate a false sense of security. The practitioner should
depth and duration of anesthesia, the dose of anes- always proceed with caution and be aware of pos-
thetic can be reduced, and it provides good hemo- sible side effects. In any case, for cardiac patients the
stasis [1]. lowest concentrated articaine formulation (1:200
3.2.1. Implications 000) seems to be the anesthetic of choice given the
Epinephrine has a direct effect on the myocardium lower epinephrine load.
and on the vascular tone that can result in hyperten-
sion or even ventricular fibrillation. Especially in car- 4. CONTRAINDICATIONS AND PRECAUTIONARY
diac patients, who do not have as much reserve as CIRCUMSTANCES
healthy patients, this could potentially be a problem.
That is why the addition of epinephrine to a local an- As with all medications, there is a package insert with
esthetic cartridge comes with a lot of clinical implica- contraindications (either absolute or relative), condi-
tions. A lot of the contraindications listed in the pack- tions that require extra caution, possible drug inter-
age leaflet of articaine formulations (like Septanest) actions (see Fig. 2) [7]. As mentioned above, a lot of
are actually contraindications to the administration these contraindications are included because of the
of epinephrine, which will be discussed later. presence of epinephrine. Several of these contrain-
3.2.2. Cardiovascular effect dications or precautions are historic in nature and
There are a few considerations to be made on the more of a formality. There are numerous comments
dental epinephrine use in cardiovascular patients. to be made on the package leaflet that are contrary
Pain and fear induce endogenous catecholamine re- to everyday clinical practice. This makes it a debat-
lease which emphasizes the importance of adequate able subject in the context of possible litigation. A
pain control, especially in cardiac patients [1]. Effec- general rule can be applied in most of the following
tive pain control is less likely to be achieved when a instances, as explained by Malamed: if the patient is
vasoconstrictor is excluded from the local anesthetic deemed healthy enough to undergo elective dental
solution. Even when using precautions (careful as- treatment, the use of proper anesthesia is indicated
piration, slow injection), using the vasoconstrictor [1]. When using a vasoconstrictor in your local anes-
can cause an elevation of epinephrine blood levels thesia, the maximum recommended dose should be
and can result in a moderate increase in the cardiac calculated and in some cases, it could be necessary to
output and stroke volume. Blood pressure and heart restrict the dose. Always use as minimal vasoconstric-
rate are minimally affected at these low dosages [1]. tor as possible.
It should be noted that the dosages in the cartridges
are minimal (a 1.8 mL cartridge of epinephrine 1:200 4.1. Contraindications
000 contains only 0.009 mg of epinephrine). By com- 4.1.1. Allergy
parison, when other clinicians use epinephrine, it is Historically, with the use of ester anesthetics,
usually intramuscular/intravascular in an emergency although still rare, an allergic reaction occasionally
setting (anaphylaxis, cardiac arrest) and the dose is happened. With the rise of the amide anesthetics
considerably higher (0.3 to 1 mg). In the small quan- however, this changed for the better. Articaine has
tities used in dentistry, the cardiovascular effects of low immunogenicity and it does not have the aller-
the systemically absorbed epinephrine are modest gen p-aminobenzoic acid as a metabolite (contrary
[1]. There are of course several situations where va- to ester local anesthetics) [2]. The sulfur contained in
soconstrictors in local anesthetics should be avoided the thiophene ring will also not provoke allergic reac-
because the risk is too great. However, most of these tions as it is embedded in the ring and cannot be seen
circumstances (like uncontrollable hypertension, by our immune system [2]. Although the incidence
uncontrollable arrhythmias, …) are actually contra of ‘alleged’ allergy is rather high, true documented
indications to elective dental care altogether [1]. allergy to an amide local anesthetic is extremely low
3.2.3. Maximum Dosage but it has been reported [8]. However, the cartridge
In this context the New York Heart Association solution contains 0,15 to 2.0 mg/ml sodium metabi-
recommended a maximal dose of 0.2 mg for cardiac sulfite, an antioxidant added to prevent the oxidation
patients back in 1955 [1]. Later, Bennett recommended of epinephrine thus increasing preservability, but
a maximum dose of epinephrine in cardiac risk also a known allergen [2,9]. Adverse reactions to the
patients (ASA 2 or 3) of 0.04 mg or roughly 4 cartridges ingestion of alimentary sulfites can cause a severe
of a 1:200 000 epinephrine solution [4]. Malamed also and prolonged asthmatic crisis or even anaphylactic
states that a smaller dose of 0.04 mg appears to be shock [9]. However, the dose in a typical meal after
tolerated in cardiac patients [1]. This 40 µg can be which such reactions occur appears to be a lot higher
administered safely to cardiovascular compromised (25 to 200 mg of sulfites) than those used in dentistry
patients [5]. [9]. If a true allergy to the amide local anesthetics or
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4.1.5. Children younger than 4 years of age
Review Articles The greatest concern in this population is the risk of
overdose: a rapid (<15 seconds) intravenous injec-
tion of a full cartridge would likely induce a rapid on-
set of severe seizure activity [1,2]. Proper techniques
like aspiration and slow injection are of utmost im-
portance in the pediatric population [1,2].
As most of the local anesthetic overdoses develop
as a result of an overadministration, articaine (with
its short elimination half-life) is the least likely to in-
duce an overdose [1]. However, two concerns should
always be considered. First, because of the smaller
weight, children are more susceptible to an overdose
reaction [1]. Second, prolonged anesthesia can pos-
sibly lead to self-inflicted injury by biting the lip or
tongue after the procedure [1].
The MRD should always be calculated according to
their weight. It should be noted that the entire prima-
ry dentition can be anesthetized using approximately
only two cartridges. This means that for dental treat-
ment, usually less than one cartridge is needed [1].
The package insert states that articaine should not
be used on children under four years of age given the
lack of data about the safety in this population [7].
However, a survey of 373 American dentists showed
that 21% had used articaine in the age group of 2-3
Figure 2. Contraindications and precautionary circumstances in the
package insert of Septanest normal in Belgium (articaine 4% with year-olds [13]. A retrospective study that dates back
1:200,000 articaine), consulted on 10/10/2019 (translated in English). to 1989 found data on 211 children under the age of
four years of age receiving 240 doses of articaine [14].
sulfites exists, it is an absolute contraindication for its There were no adverse reactions known to the clini-
use. The actual incidence of an allergy to either arti- cians or noted in the medical file [13].
caine or to metabisulfite is unknown, but a clinically Limited data suggest the use of articaine in children
relevant reaction remains extremely rare. under four years of age appears to be safe as long as
4.1.2. Severe arrhythmias without a device the clinician keeps to the maximum dose restrictions,
Severe arrhythmias like ventricular tachycardia or but more research is needed to fully establish the
ventricular fibrillation are life-threatening types of safety in this population. A study about safety in chil-
arrhythmias with the risk of sudden death [10]. Logi- dren under four years of age is now in progress [15].
cally, patients with severe arrhythmias that are not 4.1.6. Disease by overproduction of thyroid hormones
under control by medication or do not have a device The thyroid hormone has a direct effect on the
(like an implantable cardioverter-defibrillator (ICD) myocardium, which is why we see a lot of hyper-
or a pacemaker) should not receive a local anesthetic tension, atrial tachydysrhythmias and cardiac insu-
with a vasoconstrictor [10]. On the other hand, such a fficiency in patients with hyperthyroidism [9].
condition is considered a contraindication to elective A life-threatening complication concerning the thy-
dental care whatsoever [1]. roid is thyrotoxic crisis [9]. Because of the resem-
4.1.3. Refractory epilepsy blance of the cardiac effects of thyroid hormone to
Overdose reactions caused by the toxicity of local an- those of catecholamines, it has been suggested that
esthetics include possible seizures, which is why local a synergistic effect might occur between the two [9].
anesthetics should not be used if a patient’s epilepsy The possible potentiation of the vascular effect of
is not under control with medication [1]. thyroid hormone by a vasoconstrictor would plead
4.1.4. Porphyria for a formal contraindication for the use of vasocon-
There were historical reports of local anesthetics caus- strictors in such patients [9]. However, studies test-
ing methemoglobinemia, a cyanosis-like state with ing this possible hypersensitivity to catecholamines
decreased oxygen-carrying capacity of the blood [1]. show inconsistent results [9].
These reports concerned prilocaine (not articaine) In the case of thyrotoxicosis, elective dental care
and being only a relative contraindication for prilo- altogether is absolutely contraindicated [9].
caine, methemoglobinemia should not develop in If a patient’s hyperthyroidism is under control, proper
a healthy ambulatory dental patient [1]. In the data- local anesthetic use with vasoconstrictor is indicated
base of drugs for use in porphyria from Sweden and [1]. In patients with clinically overt hyperthyroidism
the UK, articaine is listed as "safe" and "probably not (also bearing in mind the often-associated subclini-
porphyrinogenic" [11,12]. cal cardiac disease), there would be a higher risk to
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hyperrespond on these epinephrine doses (tachycar- a minority of sulfite-sensitive patients would react
Review Articles
dia, elevated blood pressure) [9]. to a challenge test smaller than 10 mg/ml (a multi-
In these cases, vital signs should be monitored when tude of the dose normally used in local anesthetics)
using vasoconstrictors [1]. [9].
4.1.7. Diabetes mellitus It should be noted that most of these papers date from
This contraindication has been based on a warning before 1990 and are not up to date. For the last 20
concerning the use of large quantities of epineph- years, there are only limited data like case reports or
rine (like for the treatment of allergic reactions or reviews on reactions to local anesthetics in asthmatic
regional anesthesia) [9]. Epinephrine opposes the ac- patients.
tion of insulin, making it a hyperglycemic hormone Given the high prevalence of asthmatic disease and
[9]. Chances of complications vary within the popu- the absence of reported cases in the literature, this
lation: For example, insulin-dependent diabetics or contraindication could be disputed.
uncontrolled diabetics are at greater risk for com- 4.2.3. Severe hepatic disorder
plications such as acid ketosis and hyperglycemic Severe hepatic disease would logically suggest a rel-
coma, although this is very unlikely to happen at the ative contraindication as amide anesthetics are me-
low dosages used in dentistry [9]. Another possible tabolized in the liver [1].
problem with (insulin-dependent) diabetics is that Hepatic disease would decrease the elimination of the
they usually defer eating for a few hours after a den- drug, increasing possible toxicity [1]. However, given
tist appointment because of the residual anesthetic the ability of articaine to be rapidly hydrolyzed for
effect [1]. This can alter their normal diet with a risk of 90% by plasma esterases into an inactive compound,
hypoglycemia, which is why a diabetic should modify articaine is the preferred option in patients with he-
their insulin doses in advance if needed [1]. patic dysfunction [1].
Vasoconstrictors can be used safely for the majority 4.2.4. Do not use it in infected or inflamed areas because
of diabetic patients as long as their condition and the efficacy will decrease
diet are under control [9]. As with all risk popula- The increased acidity in an inflamed or infected area
tions, to minimize the risk the lowest possible dose results in less effective and profound anesthesia as
should be used [9]. However, we must detect patients this disturbs the mechanism of action [1]. However,
with uncontrolled diabetes as they could pose an in- stating that in this case this drug should not be used
creased risk for complications [9]. is a bit curious as you will obviously need the best
anesthesia possible when providing dental care in an
4.2. When should you be extra careful with this drug? already inflamed or infected area.
4.2.1. Cardiovascular disorders (arrhythmias, hypo- 4.2.5. Pseudocholinesterase deficiency
tension, coronary insufficiency, arterial hypertension) Another ambiguous point is the clinical significance
Some other cardiovascular disorders also present a of a pseudocholinesterase deficiency. As it turns out
contraindication to elective dental care: unstable an- 1 in 2820 individuals have an atypical serum pseudo-
gina, 6 months after coronary artery bypass surgery cholinesterase, a genetic trait resulting in a relative
or myocardial infarction or hypertension in excess of pseudocholinesterase deficiency [1].
200 mmHg systolic or 115 mmHg diastolic [1]. This results in a decreased metabolization of ester an-
Each of these cases is a medical emergency and esthetics and it presents a relative contraindication
requires treatment to stabilize the situation. Obvi- to their use. Haas states that little clinical effect would
ously, these should be taken care of before going to be expected unless the dose would be very high [16].
the dentist. If the patient is deemed healthy enough Malamed states that amide local anesthetics do not
to receive dental care, correct local anesthesia is in- present an increased risk of high blood levels in these
dicated [1]. patients given their hepatic metabolization [1].
The safe use of vasoconstrictors in cardiac patients For articaine, however, as a hybrid molecule classified
is the subject of a huge debate. The dose restriction, as an amide local anesthetic, the clinical significance
recommended by Malamed and Bennett, of 0.04 mg is unclear as it is still metabolized by the liver.
of epinephrine appears to be safe and beneficial in Given this dual metabolism, the clinical impact of this
cardiac patients who have stable disease [1,4]. trait in a patient would be small. However, the prac-
4.2.2. Asthma titioner should still be cautious for possible overdose
A few papers in the 1980s warned dentists to avoid reactions as articaine blood levels could be some-
local anesthetics with vasoconstrictors in asthmatic what increased.
patients because allegedly a substantial proportion
of asthmatics are potentially sensitive to sulfite [9]. 4.3. Drug-drug interactions
Pérusse addressed this matter already in 1989 and 4.3.1. Guanethidine and analogues
explained that this recommendation should at least Guanethidine is an adrenergic neuronal block-
be restricted to steroid-dependent asthma patients er inhibiting the release of norepinephrine from
[9]. Given this concern, there was a study reporting an sympathetic nerve terminals [17]. Long-term use
alleged sulfite sensitivity threshold of 0.6 to 0.9 mg [9]. could result in postsynaptic receptor upregula-
However, a later investigation documented that only tion increasing the responsiveness to adrenergic
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vasoconstric tors [17]. Another possible mecha- Yagiela states that "the continued listing of this inter-
Review Articles
nism of potentiation is the competi- action in the package insert for local anesthetics with
tive inhibition of the adrenergic reuptake vasoconstrictors is simply a testament to the bureau-
transporter [17]. This interaction received a 4 rating cracy of the U.S. FDA" [17].
(just like thyroid hormone) as a reaction is "possible"
[17]. The same recommendation as for TCA’s apply 4.4. Pregnancy and lactation
[17]. All local anesthetics can cross the placenta and enter
4.3.2. Halogenated inhalation anesthesia the system of a developing fetus [1]. In general, den-
The use of halogenated inhalation anesthetics like hal- tal treatment should optimally be avoided in the first
othane could potentiate the arrhythmogenic effect 10 weeks because this is when the teratogenic risk is
of epinephrine and result in a cardiac dysrhythmia the greatest [21]. Elective dental treatment is usually
[17]. The treating anesthesiologist should be aware planned in the second trimester [21]. Although artic-
of this possible interaction. aine is classified as a class C drug, Malamed prefers
4.3.3. TCA and SNRI the use of articaine because of the shorter exposure
Tricyclic antidepressants (TCA’s) are mainly used time as the elimination half-life is only 27 minutes
in the treatment of depression. TCA’s act the same compared to the 90 minutes of lidocaine [2]. A for-
as SNRIs by inhibiting serotonin (SERT) and mulation with a vasoconstrictor is indicated as they
norepinephrine (NERT) transporters thus blocking the reduce systemic toxicity and will not affect uterine
reuptake of neurotransmitters in the synaptic cleft blood flow in the low dosages used in dentistry [22]
[18]. This way, they could enhance the cardiovascular A prospective study following 210 women that un-
actions of exogenously administered vasopressors. derwent local anesthetic exposure during pregnancy
This enhancement appears to be fivefold to tenfold found no significant difference in gestational age or
for levonordefrin and norepinephrine, two rarely median birth weight [23]. Within the study limitations
used vasoconstrictors [18]. For epinephrine, this po- (small sample size, heterogeneous nature of birth
tentiation is approximately twofold [18]. anomalies) that permit detection of a 2.65-fold in-
Whether or not this potentiation results in a clinically crease, no associated increased risk was found for ma-
significant adverse reaction with the dosages used in jor anomalies [23]. Amide local anesthetics are con-
dentistry is debatable [18]. Reports of this interaction sidered safe to use during pregnancy if administered
resulting in a series of hypertensive crises in patients, with the proper aspiration technique. Lidocaine is the
of which one patient died, contributed to the fear of drug with the most experience and data in pregnant
using vasoconstrictors in patients taking TCAs [19]. women and is categorized as a class B drug. Because
These cases are referred to a lot in the literature. How- of the lack of data, articaine is categorized as a class C
ever, this needs some rectification as Boakes et al drug. For breastfeeding, lidocaine is the only “S” local
were misquoted: the patient who died was not taking anesthetic. Articaine is considered “S?” (safety in nurs-
a TCA [20]. The other patients with adverse reac- ing infants unknown) [2]. The current recommenda-
tions appeared to experience these reactions because tion is to use the "pump & discard" method: following
of the use of norepinephrine as a vasoconstrictor exposure of the drug to a nursing woman, she should
(instead of epinephrine) [20]. Patients taking TCAs pump and discard for a 4-hour period (covering six
may also have different electrocardiographic changes. elimination half-lives) to minimize infant gestation
While antiarrhythmogenic in low doses they are ar- [2].
rhythmogenic in overdose, making it a hazard for
serious arrhythmias in combination with a local anes- 5. DISCUSSION
thetic [18]. Yagiela et al recommend limiting the dose
of epinephrine to one-third of the normal maximum There are some comments to be made about the
dose for patients taking TCAs [17]. This should pre- package insert of articaine. There should be no un-
serve the patient for any problem arising because of founded statements about the possible contrain-
interactions [17]. dications or interactions concerning articaine with
4.3.4. MAO-I epinephrine. A restricted dose of 40 µg epinephrine
Mono-amine-oxidase inhibitors (MAO-I) could theo- (4 cartridges of 1:200,000) is tolerated in cardiac
retically potentiate the actions of vasopressors by in- patients whose disease is under control. Some other
hibiting their biodegradation by monoamine oxidase contraindications are too generalized (diabetics, asth-
in the presynaptic neuron [1]. matic patients, …). Interaction of epinephrine with
This could result in a hypertensive crisis, which can TCA’s and general anesthetics is well-documented
be seen with phenylephrine, a vasoconstrictor cur- and should be prevented by using a dose restriction
rently no longer used [1]. However, research on this [17]. The interaction with thyroid hormones and gua-
subject is unified on the fact that there is no clinically nethidines is much less compelling, meaning a vaso-
significant interaction taking place with epinephrine constrictor can be used safely within the normal dos-
[17,18]. This is partially due to the fact that this ex- ages [17]. For MAO-I’s there is absolutely no scientific
ogenously administered epinephrine is preferably evidence of a significant interaction [17]. Something
metabolized by catechol O-methyltransferase [17]. to keep in mind concerning the drug-drug interac-
114 Stoma Edu J. 2020;7(2): 109-116 pISSN 2360-2406; eISSN 2502-0285
Contraindications of Articaine
www.stomaeduj.com
tions is the tendency for receptor down-regulation lute or relative) that are open to debate.
Review Articles
after repeated exposure to a certain compound Theoretically, a lot of interactions with either diseases
[17,18]. This phenomenon, which would apply to or other drugs are possible. In the current literature,
a patient taking TCA’s for a longer time or a patient however, there are not many cases that demonstrate
with hyperthyroidism, would reduce the possible risk these interactions. In clinical practice the relevance of
of a damaging effect as a result of an interaction [20]. most of the possible interactions is modest. Most of
There exist a lot of other interactions and contrain- the adverse reactions are caused by the overadminis-
dications, but with a dose restriction in some cases if tration of the drug. Adverse reactions can be prevent-
necessary, articaine can be administered safely with- ed by being aware of the maximum recommended
out or with minimally increased risk. The relevance of dose and by using proper injection techniques (as-
these contraindications could be argued in case of piration and slow injection). The contraindications in
litigation. To summarize the debate on the contrain- the package leaflet are mainly too broad and should
dications, Malamed states that if a patient is deemed be better defined for use in everyday clinical practice.
healthy enough to undergo elective dental treat-
ment, local anesthetics are indicated [1]. CONFLICT OF INTEREST
We declare no conflict of interest of any kind.
6. CONCLUSION
FUNDING
Because of its unique properties (plasma hydrolyzation)
This article did not require funding.
and its lower epinephrine concentration compared
to the lidocaine formulation, articaine is the better ACKNOWLEDGMENTS
choice in certain clinical situations (like hepatic dys-
function, patients with cardiovascular morbidity or This study required no funding, and there was no conflict of in-
terest of any kind. This study was conducted as a master thesis to
cases where the clinician wants to be prudent for acquire the degree of master in medicine at the Catholic University
possible interactions). In the package insert of arti- of Leuven.
caine, there are a lot of contraindication (either abso-
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Stoma Edu J. 2020;7(2): 109-116 pISSN 2360-2406; eISSN 2502-0285 115
de Ridder N, et al.
www.stomaeduj.com
Review Articles
Nicolas de RIDDER
MD, Student in Master of Medicine
Department of Oral and Maxillo-Facial Surgery
Faculty of Medicine
Catholic University of Leuven
Leuven, Belgium
CV
Nicolas De Ridder (DOB: 28th of May, 1996) obtained his bachelor’s degree in Medicine at the Catholic University of Leuven,
Belgium (magna cum laude). He is currently in his final year of master in Medicine, expected to graduate in July 2020. He has
acquired experience in internships in the department of Stomatology, Oral and Maxillofacial surgery under the supervision of
Professor Constantinus Politis at UZ Leuven.
Questions
1. What is the current maximum recommended dose of epinephrine in dental cartridges
for patients with cardiovascular disease per dental appointment?
qa. 9 µg;
qb. 40 µg;
qc. 200 µg;
qd. There is no dose restriction.
2. In which case is articaine absolutely contraindicated?
qa. Allergy to amide anesthetics;
qb. Patients taking MAO-I;
qc. Patients with (controlled) hyperthyroidism;
qd. Patient with diabetes.
3. What would ensure a greater bone penetration capacity of articaine compared to
other local anesthetics?
qa. Thiophene ring;
qb. Ester-linkage;
qc. High protein binding;
qd. Primary metabolite (articainic acid).
4. Which positive effect is not attributed to the addition of epinephrine to articaine?
qa. Less blood loss and better vision;
qb. Longer and more profound anesthesia;
qc. Less systemic absorption;
qd. Faster time of onset.
116 Stoma Edu J. 2020;7(2): 109-116 pISSN 2360-2406; eISSN 2502-0285