ARTICAINE

30 Years Later
O"//////////////////////////////////////////////////////////////////////////////////////////////////////////////////////h

Stanley F. Malamed, DDS

Introduction

ocal anesthesia forms the backbone of pain

control techniques in dentistry. Local anesthetics represent the safest (when used properly)
and most effective drugs for the prevention and
management of perioperative and post-operative pain.
The first known injection of a local anesthetic (1885) was an inferior alveolar nerve block administered
by the famed medical surgeon Dr. William Stewart Halsted
(1852-1922).1 The drugs injected were the combination of
cocaine and epinephrine. The dental profession quickly adopted local anesthesia as its primary means of controlling pain
eschewing general anesthesia that had been, along with no
anesthesia, the techniques of choice prior to 1885.
The introduction, in 1905, of procaine (2% with epinephrine 1:50,000), led to a rapid increase in the use oflocal anesthesia by dentists and to the burgeoning of access to dentistry
for millions of people worldwide.2 Known everywhere by its
primary proprietary name 'Novocain,' procaine is synonymous, to most people, as the 'shot' you receive when you visit
the dentist.
The amino-ester local anesthetics (LAs), primarily procaine, propoxycaine and tetracaine, were the drugs used from
1906 until the mid-1940's when Astra Pharmaceuticals, in
Sweden, synthesized and introduced the first amino-amide
local anesthetic, lidocaine (Xylocaine) in 19483 (Fig . 1). The
demonstrably superior clinical characteristics oflidocaine
compared to the most commonly used esters in dentistry led
to its rapid adoption and to the development of other drugs in
this same category. The amide local anesthetics mepivacaine
(1960), prilocaine (1965), bupivacaine (1972), and etidocaine
(1976), were 'borrowed' from medicine for use in the dental

42

oralhealth FEBRUARY 2016

Figure 1. Ch e mical form ula of procaine (ester), lidocai ne (amide)

and a rt icaine.

profession. The ester local anesthetics are rarely employed

today for pain control in the dental profession, worldwide.
Carticaine, first prepared by Rusching and colleagues
in 1969, had its generic name changed to articaine when it
entered clinical practice in Germany in 1976.4 Its use gradually spread, entering North America in Canada in 1983.5
The United Kingdom launched the drug in 1998, the United
States in 2000, and Australia in 2005. Articaine represents
the first, and still only, local anesthetic developed specifically for use in dentistry. Though articaine is classified as
an amide LA, articaine possesses chemical characteristics of
both the amide and ester groups ( Fig . 1) . It has become an
extremely popular local anesthetic wherever it has been made
available . In 2014, articaine was the second most used local
anesthetic in the United States with a 34.86% market share

-DENTAL PHARMACOLOGY-

(lidocaine was first at 49.35%).6 In Australia 70% of dentists

use articaine.7 In 2012, in Germany, where the drug was
introduced in 1976, 97% oflocal anesthetic use by dentists
was articaine. 8 Articaine is being used increasingly by the
medical profession. 9

Articaine - Chemistry and Pharmacokinetics

Articaine is 4-methyl-3(2-[propylamino]propionamido) -2-thiophenecarboxylic acid, methyl ester hydrochloride
with a molecular weight of 320.84. It is the only amide local
anesthetic that contains a thiophene ring. In addition, articaine is the only widely used amide local anesthetic that also
contains an ester linkage ( Fig. 1). Ester LAs undergo metabolism (biotransformation, detoxification) as soon as the drug
diffuses into capillaries and veins (hydrolysis by plasma esterase) . Amide LAs enter the blood as still active drugs, circulating throughout the body until they enter the liver where they
undergo metabolism by hepatic microsomal enzymes. Unlike
the other amide local anesthetics that undergo metabolism in
the liver, the biotransformation of articaine occurs in both the
liver a~d in plasma.
The elimination (beta) half-life of a drug is the time required to decrease its blood (plasma) level or concentration by
50%. It is commonly stated that a drug is 'gone' (eliminated)
from the body in six half-lives (The blood level has actually
decreased by 98.25%at six-halflives).
The elimination half-lives of esters and amides are found in
Table 1. Elimination half-lives of esters is comparatively short
to those of the amides. Procaine has a half-life of 6 minutes,
lidocaine approximately 90 minutes. It is important to remember that the half-life of a drug has absolutely no relevance to
the clinical duration of action of that drug. A drug is clinically
effective as long as it remains in its target organ (e.g. inferior
alveolar nerve) in a high enough (therapeutic) concentration.
The clinical action (e.g. 'anesthesia') of the drug ceases when
it diffuses out of the target organ into capillaries and veins. It
is then that the elimination half-life starts.
Articaine, possessing both ester and amide characteristics,
has an elimination half-life of approximately 27 minutes.
It is eliminated from the blood in 162 minutes (2 hours 42
minutes). This becomes clinically significant when treating (1)
pregnant patients, (2) nursing mothers, and (3) lighter weight
patients (persons weighing less than 30 kg).
Articaine has many of the physicochemical properties of the
most commonly used local anesthetics (lidocaine, mepivacaine
and prilocaine) with the exception of the aromatic ring and its
degree of protein binding (Table 2) . Articaine effectively penetrates tissue and is highly diffusible . Its plasma protein binding of approximately 95 percent is higher than that observed
with many local anesthetics. Additionally, the thiophene ring
of articaine increases its liposolubility.

1.

Elimination
Local Anesthetic

(Beta)

Half-life

1,rnn J

Half-Life
6

hl f-life m in (hrs )

Procaine

Articaine

27

162

Cocaine

42

252 (4:52)

Lidocaine

-90

-540 (9:00)

Prilocaine

-90

-540 (9:00)

Mepivacaine

-120

Bupivacaine

36

-720 (12:00)
1260

Ester,_ Red
mide>=Blue

(2:42)

I
j

(2 1 00)

------------------ _______________ J

Elimination half-l ives of local a nesthetics

/////./././/././././././././././././././././././././././././././././././././././././h

Articaine and Allergy

The incidence of true, documented and reproducible allergy to
amide LAs is exceptionally low, though alleged 'allergy' is reported occasionally. True allergy to the ester LAs is - though
still quite rare - more common . The immunogenic potential
of articaine is very low. Historical experiences indicate that
allergic reactions resulting from sensitivity to articaine are
rare. However, all LA solutions with a vasoconstrictor (e.g.
epinephrine) contain the antioxidant, sodium bisulfite, which
can cause allergic reactions . Allergic reactions that have been
reported with articaine include edema, urticaria, erythema
and anaphylactic shock. In three studies (number of subjects
= 1332) comparing articaine 4% with epinephrine 1:100,000
to lidocaine 2% with epinephrine 1:100,000, reports of rash
or pruritis were no more frequent with articaine (n = 2) than
with lidocaine (n = 4), and no serious allergic reactions were
seen in either treatment group. Patients allergic to articaine
likely would be allergic to lidocaine and the other amide local
anesthetics.10-12 Furthermore, the allergen paraminobenzoic
acid (PABA), a frequent metabolite of ester metabolism, is not
a byproduct of the hydrolysis phase of articaine.13
As articaine possesses a sulfur-containing thiophene ring
(Figure 1) this author is frequently asked if a patient having a
sulfa, sulfite or sulfur allergy represents a contraindication to
its administration. The answer is 'no'. The 'S' in articaine is an
integral part of the thiophene ring and as such cannot be 'seen'
or recognized by the patient's immune system .
Methemoglobinemia has been shown to develop with
some types oflocal anesthetics . Clinical tests of articaine,
wwworalhealthgroup.com

43

-DENTAL PHARMACOLOGYI

PHARMACOKINETIC PROPERTIES OF COMMON DENTAL LOCAL ANESTHETICS.

LOCAL
ANESTHETIC

pKa*
(pH)

ONSET

LIPID
SOLUBILITYt

USUAL
PERCENTAGE
OF DRUG
USED IN
ANESTHETIC

PROTEIN
BINDING(%)

DURATION

Articaine

7.8

Fast

1.5

95

Moderate

Bupivacaine

8.1

Moderate

30 .0

0.5 to0.75

95

Long

Etidocaine

7.9

Fast

140.0

1.5

94

Long

Lidocaine

7.8

Fast

4.0

65

Moderate

Mepivacaine

7.7

Fast

1.0

2 to 3

75

Moderate

Prilocaine

7.9

Fast

1.5

55

Moderate

Procaine

9.1

Slow

1.0

2 to 4

Short

pKa is a dissociation constant.

t Lipid solubility is a ratio , using procaine as I .

Physicochemical characteristics of common LAs

3.

Drug

Onset

Soft Tissue

3 - 5 min

60 min

3 - 5 hours

2 - 3 min

60 min

3 - 5 hours

Lidocaine
2/o

Epi
1:50k, 1:100k

Articaine 4/o

Epi
1 :100k
1 :200k

Mepivacaine
2/o

Epi 1 :100k

3 - 5 min

60 min

3 - 5 hours

Prilocaine
4/o

Epi
1 :200k

3 - 5 min

60 min

3 - 8 hours

Intermediate duration LAs north america

44

Pulpal

(textbook)

oralhealth FEBRUARY 2016

-DENTAL PHARMACOLOGY-

bupivacaine and etidocaine administered as central nerve

block anesthetic for urological procedures (n = 103) indicated
no elevation of methemoglobin with articaine.14

II

Art ica ine - Cli nical Characteristics

The clinical preparations of articaine in North America - 4%
with 1:100,000 and 1:200,000 epinephrine - are classified
as intermediate duration local anesthetics ( Table 3) . Patients
responding normally to the drug (normo-responders on a
'bell-shaped curve') should experience pulpal anesthesia of
approximately 60 minutes duration and soft tissue anesthesia
of between three to five hours duration. Duration of pulpal
anesthesia is of slightly longer duration following nerve block
compared with infiltration.15 The depth and duration of anesthesia are the same with both epinephrine concentrations.
Many doctors report that 'in their opinion' the onset of
anesthesia following both infiltration and nerve block with
articaine is more rapid than with other local anesthetics. This

Articain e, lidoca ine pulpal anesthesia success rat es - Robert son,

Nusstein etal, reference #16

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oralhealth FEBRUARY 2016

-DENTAL PHARMACOLOGY-

assertion is not supported by clinical research.10,16 In studies including a combined 1554 patients there was no clinical
difference noted in the onset of pulpal anesthesia following
inferior alveolar nerve block between 2% lidocaine, epinephrine 1:100,000 and 4% articaine epinephrine 1:100,000.
However, the administration of articaine by mandibular infiltration in adults has been shown to be significantly more effective
in providing pulpal anesthesia than lidocaine infiltration when
used as a sole injection for mandibular anesthesia.17 Successful
pulpal anesthesia was assessed (using electric pulp tester [EPT])
following articaine or lidocaine infiltration ofl.8 mL in the
buccal fold adjacent to the mandibular 1" molar. Table 4 shows
the percentages of successful pulpal anesthesia (Table 4). Onset
time for pulpal anesthesia was also considerably more rapid with
articaine than lidocaine ( Table 5). The result was attributed to
articaine's thiophene ring, which is more lipid-soluble than the
benzene ring found in other local anesthetics.
Meechan and Ledvinka compared the infiltration of 4%

Tooth

Articaine onset
(min)

2nd molar

l" premolar

+/-

Standard
Deviation
4.6+/-4.0
4.2 +/-3.1
4.3 +/-2.3
4.7+/-2.4

Udocaine
onset (min)
+/-Standard
Deviation
11.1 +/-9.5
7.7 +/- 4.3
6.9 +[ -6.6
6.3 +/ - 3 .1

P value

.0001
.0002
.0014
.0137

Art ica ine, lidocai ne onset o f p ulpal anesthes ia - Robertso n,

Nusstein etal , reference #16

..........................................................................................................................
.//./././/././././/./././/././././
articaine with epinephrine 1:100,000 and 2% lidocaine with
epinephrine 1:100,000 on mandibular incisors, both for
success and duration of pulpal anesthesia.18 Infiltrating 0.5
mL in the buccal fold produced a 94% success rate for artic-

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-DENTAL PHARMACOLOGY-

aine compared with 70% for lidocaine. Infiltrating 0.5 mL

on both the buccal and lingual of the lateral incisor increased
the success rate to 97% for articaine and 88% for lidocaine.
The duration of pulpal anesthesia was also significantly longer
with both articaine infiltrations. ( Table 6). The increased
success rate for infiltration in the adult mandible was thought
to be due to the fact that the cortical plate of bone, both buccal and lingual, is quite thin and might provide little resistance to infiltration.18
Given articaine's ability to diffuse through the thick cortical
plate of bone following infiltration in the adult mandible,
Kanaa et al looked at the ability of articaine infiltration to
increase the success rate of pulpal anesthesia following an
inferior alveolar nerve block (IANB) with 2% lidocaine with
epinephrine 1:80,000.19Patients received IANBs at each of
two occasions (2.0 mL lidocaine with epinephrine). Then they
received either a buccal infiltration of 4% articaine with epinephrine 1:100,000 or a 'dummy' injection in the buccal fold

by the mandibular 1" molar. The 1" molar and 1" premolar
were pulp tested every three minutes for 45 minutes. Results
are shown in Figures 2 and 3. In both teeth the additional
articaine infiltration significantly increased the success rate
of pulpal anesthesia (55.6% to 91.7% for 1" molar; 66.7% to
88.9% for 1" premolar). Though the study concluded at 45
minu'tes there was no indication that pulpal anesthesia was
waning at that time.19

Articaine in Special Patient Populations:

Pregnancy, Nursing and Pediatrics.
In the United States the Food and Drug Administration classifies drugs by their safety during pregnancy and nursing.20
The author is unaware of similar listings by Health Canada
(www.hc-sc.gc.ca).
Pregnancy: All injectable local anesthetics, including
articaine, and epinephrine, are classified as 'B' [Caution
advised - no evidence of 2"" or 3"1 trimester risk; fetal harm

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oralhealth FEBRUARY 2016

-DENTAL PHARMACOLOGY-

possible but unlikely] or 'C' [Weigh risk/benefit

- weigh possible fetal risk vs. maternal benefit;
see package insert for drug-specific recommendations]. Lidocaine and prilocaine are 'B' rated,
all other local anesthetics (including articaine),
and epinephrine are 'C'. To minimize exposure
of the fetus to the effects of the local anesthetic
drug, a drug with a shorter elimination half-life
is preferred. The 27-minute half-life of articaine
is preferable to the 90-minute or greater half-life
of the other available local anesthetics .
Nursing : FDA categories for nursing infants
are 'S' (Safe for nursing infant); ' S?' (Safety in
nursing infants unknown); 'S*' (Potential for significant effects on nursing infants) and 'NS' (Not
safe for nursing infants). 20 Lidocaine is the only
'S' local anesthetic. All others are 'S?' including
epinephrine (in dental concentrations). As nurs-

Mandibular Incisors

I!:
~~

11

80

10

11 :

1! :

Uoleb

**'

Attll
Att bI

u.i. ....

Im :
~

O ....._O- S- 1 0-415-:zo-ZS-JO- .- 4 0___.45

. ......_.............

TIM (MlllVTES)

Duration of pulpal anesthesia following mandibular infiltration . Meechan,

Ledvinka , reference #17

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-DENTAL PHARMACOLOGY-

I st Molar

h
u

i~

l st Premolar

100
90

80

gt~ 70
1:1a
cc 00

~'ii 50

Ii
e:::_8 _ii
..

:ii 20
~E

- - - Troatment 1
Troatment 2

Og
I/.

10
15
20
25
30
Timo after lnjoction (min)

35

40

40
30

10
0

45

10
15
20
25
30
Tlmo alter lnjoction (min)

35

40

45

Figure 2 & 3 : Successful pulpal anesthesia. Blue= IANB - Lidocaine 2 % + epi 1:80,000 + " dummy" infiltration.
Purp le= IANB - Lidocaine 2 % + epi 1:80,000 + " articaine" infiltration. Reference #18

ing mothers are normally reluctant to expose their infant to

any drug that child does not need, it is not uncommon in the
dental environment to have a nursing mother in need of dental
care ask their dentist, 'Will the drug (e.g. lidocaine) be in the
milk?" The answer will always be 'Yes.' The mother immediately states that they do not want the drug. This becomes
problematic when the dental procedure is potentially painful.
The concept of"pump and discard ' successfully handles this
situation. Following exposure to a drug the nursing mother
should pump and discard the milk for a period covering six
elimination half-lives of the drug administered. For all local
anesthetics except articaine this is a period of nine hours.
The FDA states 'When using articaine, nursing mothers may
choose to pump and discard breast milk for approximately
four hours (based on plasma halflife) following an injection
of articaine (to minimize infant ingestion) and then resume
breastfeeding."
Ped iatrics: All local anesthetics can produce seizures (a
classic local anesthetic overdose manifests as a generalized
tonic-clonic convulsion) if their blood level becomes elevated
above the seizure threshold for that drug. One cartridge of any
local anesthetic administered rapidly (<10 seconds) intravenously will induce a rapid onset severe seizure. Aspiration for
blood prior to administration of a local anes thetic and slow
injection of the drug can prevent this from occurring.
Most local anesthetic overdoses, however, develop as a result
of the overadministration of the drug. Once injected into the
oral cavity the local anesthetic will be absorbed into capillaries and a blood level of the drug becomes detectable . Local
anesthetic overdose is most likely to occur in patients weighing under 30 kg (66 lb.), who are well-behaved and in need
of multiple quadrants of dental care.21 Of the amide local
anesthetics, articaine - because of its 27-minute elimination

52

oralhealth FEBRUARY 2016

6. ~

Year

Haas,
Lennon . Canada

1995

70.6

22

' Hillerup Denmark

2006

77

23

Author

Country

'

! Kingon, '
j

Sambrook ! Australia

G~~~~o, ,

Reference #

--+-----------+-

2011

USA
2010
L.__._J____ -----'~- ........
j

Lingual

80

25

92.7

24

L----.L.--_J

Lingual nerve involvement in reports of paresthesia

half-life - is least likely to induce an overdose resulting from

the administration of too many cartridges.
Maximum recommended doses (MRDs) oflocal anesthetics are provided by the US FDA (Table 7) . Though Health
Canada does not specify MRDs, there are authoritative Canadian publications listing recommended maximum doses that
are generally considered the 'standard of care' in Canada.22
Some subtle differences are noted in several of the available
formulations. In the USA, the articaine MRD is 7 mg/ kg,
with no absolute dose listed (due to its 27-minute elimination
half-life). In Canada the dose for adults is 7.0 mg/kg. with an
absolute maximum of 500 mg, and 5.0 mg/kg for 'children.'
To summarize the clinical characteristics of available articaine formulations, it is a 4% solution containing epinephrine

-DENTAL PHARMACOLOGY-

Drug
Articaine

HCI

Bupivacaine
Lidocaine

HCI

Mepivacaine
Prilocaine

HCI

HCI

HCI

MRD: USA - Food & Drug Administration , Canada - va ri ous sources

in either a 1:100,000 or 1:200,000 concentration. Cartridges

contain 72 mg. of articaine. (Recent labeling changes state the
cartridge contains a 'minimum volume of 1. 7 mL. A clinical
study determined the actual volume of both lidocaine and
articaine cartridges to be 1.76 mL +/- 0.02 mL .17 Both formulations provide a rapid onset of pulpal anesthesia (approximately 2 to 5 minutes), pulpal anesthesia of approximately 60
minutes in duration, and residual soft tissue anesthesia lasting
between 3 to 5 hours, 15 similar to other amide local anesthetics containing epinephrine. Because of articaine's greater lipid
solubility, the drug demonstrates increased clinical success
when administered by mandibular infiltration in molars, premolars and incisors. Reports of palatal soft tissue anesthesia
developing after articaine maxillary infiltration in the buccal
fold, though anecdotal, can be attributed to the drugs greater
lipid solubility.
As a result of it undergoing metabolism in the plasma (as well
as in the liver) articaine is a preferred local anesthetic during
pregnancy, nursing and in lighter-weight patients (<30 kg).

Articaine and Paresthesia

As described above, articaine possesses significant advantages
over the other currently available local anesthetic formulations. However, there have been reports that the administration of 4% local anes thetic formulations by inferior alveolar
nerve block is associated with a greater risk of paresthesia than

54

oralheolth FEBRUARY 2016

that of 2% and 3% formulations. 23 -26 As a result of these

reports, regulatory bodies in the province of Ontario, Can~da,
have cautioned against the dental use of 4% local anesthetics
by inferior alveolar nerve block.27,28
What is paresthesia? Stedman's Medical Dictionary29
defines a paresthesia as an abnormal sensation, such as of
burning, pricking, tickling, or tingling. Paresthesias are one of
the more general groupings of nerve disorders known as neuropathies. Paresthesias may manifest as total loss of sensation
(e.g., anesthesia), burning or tingling feelings (ie, dysesthesia), pain in response to a normally non-noxious stimulus (ie,
allodynia), or increased pain in response to all stimuli (e.g.,
hyperesthesia). 30
For simplicity's sake, the term paresthesia will be used to
encompass all forms of nerve dysfunction . We will define
paresthesia as a "persistent anesthesia or altered sensation well
beyond the expected duration of anesthesia." Symptoms can
vary significantly, including sensations of numbness, swelling,
tingling and itching, tongue biting, drooling, loss of taste, and
speech impediment.23 ,31-34
Prior to delving into this subject there are a number of'truisms' regarding anatomy, injections and local anesthetics that
need to be considered.
1. Anatomy: Everybody is different. We teach technique
based on 'normal' anatomy (e.g. insert needle here, advance 25 mms, aspirate, deposit the drug). We hope, or it

-DENTAL PHARMACOLOGY-

~)

l ,800,000

Hiller

~o

1,600,000

3S

l ,-400,000

l ,200 ,000

2S

1,000,000

800,000 _

600,000

10

-400,000

I l _I

s
0

r!''

r',,

'\'

'\'

. .<f'
.

r'~

'\'

'\'

Adverst reacbcos
Use

200,000

f:l'~

'\'

The number of suspected adverse reactions reported to the Danish

Medicines Agency for articaine. The chart shows which year a reported
adverse reaction began. It also shows the use of articaine in dental
o 201 or. stan1er F. m L.
practi.ces m
A ll Rlghts,,_,._,

'

:I

Figure 4 : Articaine sales (red line) and adverse event reports (blue bars) in Denmark, 2001-2010, refe rence #42

___,,,,,,,,,,,,,,,,,,///////////././
is assumed that, the nerve is in the area - if the patient's
anatomy is 'normal.'
2. Injections: Once a needle penetrates skin or mucou s
membrane, every injection is blind. In most intramuscular (IM) injections when therapeutic drugs are being
administered, the site selected for IM administration is
one that it is considered anatomically 'safe'. The vastus
lateralis muscle (located in the anterior lateral portion
of the thigh) is considered the safest place in the human
body to administer an IM injection with minimal risk
of damaging important structures (e.g. nerves, arteries,
veins). Local anesthetic administration in dentistry is
different. Consider that with a local anesthetic injection
we are 'aiming' to deposit a volume oflocal anesthetic

solution as close to the 'target nerve as possible (a few

millimeters) so the deposited local anesthetic can diffuse
into it and block nerve conduction. Yet, we cannot 'see'
where the needle tip actually is located.
3. Local anesthetics: Local anesthetics are chemicals that
t ransiently (hopefully) interrupt the nor mal functioning of a nerve (they interrupt the nerves ability to
conduct a nerve impulse either to [sensory nerve] or from
[motor nerve] the brain).
4. Local anesthetics: A U local anesth etics are neurotoxic they can damage nerves. Miller, in his seminal textbook
on anesthesia 35 has stated "All the clinically used local
anesthetics can produce direct toxicity to nerves if they
achieve sufficiently high intraneural concentrations." In
www.oralhealthg roup.com

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11

-DENTAL PHARMACOLOGY-

the United States the dental local anesthetic producing

the greatest number of reports of paresthesia is lidocaine.
Lidocaine is also the most used local anesthetic in dentistry in the United States.6.36,37
5. Paresthesia: Paresthesia has existed ever since injections were first administered. References to paresthesia
associated with the administration oflocal anesthetics,
both in medicine38 and dentistry,31-33,39-41 predate the
introduction of articaine in North America by decades.
The first publication to address the incidence of paresthesia
following the administration of 4% local anesthetics appeared
in 1995.23 Reviewing reports of paresthesia from dentists in
the province of Ontario, Canada to the Provincial Insurance
Commission, Haas and Lennon reported an overall risk of
paresthesia following injection of local anesthetic of 1 case in
785,000 (1:785,000). Two and three percent LAs (mepivacaine, lidocaine) had an incidence of 1:1,250,000. The two 4%
LAs, prilocaine and articaine had reported risks of 1:588,235
and 1:440,529 respectively.
This paper has become the most cited reference purporting
to demonstrate that 4% LAs are associated with a greater risk
of paresthesia. Virtually all papers reporting increased risk
of paresthesia from articaine ultimately cite this reference as
their initial source.
Articaine was introduced into Denmark in 2001 and by
2005 had garnered 35% of the dental local anesthetic market. 24 A 2006 paper by Hillerup and Jensen reported that
articaine was the drug most often associated with reports
of paresthesia by dentists to the Danish Medicines Agency
(Laegemiddel Styrelsen). The paper recommended that "Until
factual information is available, a preference of other formu lations to Articaine 4% may be justified, especially for mandibular block analgesia."24 As a consequence of this paper the
Danish Dental Association recommended that articaine not
be used by inferior alveolar nerve block.
The Pharmacovigilance Working Party of the European
Union (the EUs equivalent of the United States FDA and
Canada's TGA) investigated the question of paresthesia
and dental local anesthetics, specifically articaine. 42 They
reviewed the use of articaine in 57 countries, estimating that
approximately 100 million dental patients received articalne
annually. Their findings, published 20 October 2006 stated
"regarding articaine, the conclusion is that the safety profile of the drug has not significantly evolved since its initial
launch. Thus, no medical evidence exists to prohibit the use
of articaine according to the current guidelines listed (in) the
summary of product characteristics."
The report went on to state: "All local anaesthetics may
cause nerve injury (they are neurotoxic in nature). The
occurrence of sensory impairment is apparently slightly
more frequent following the use of articaine and prilocaine.

Figure 5: Fascicles within a nerve

q"//////////////////////.////////////////.///////

However, considering the number of patients treated, sensory

impairments rarely occur. For example, the incidence of sensory impairment following the use of articaine is estimated to be
1 case in 4.8 million treated patients."... "Nerve injubes may
result from several incidents: Mechanical injury due to needle
insertion; Direct toxicity from the drug; Neural ischaemia."
And finally: "There is no need for new experimental studies
or clinical trials."42
In October 2011 the Danish Medicines Agency followed up
with this report: "The Danish Medicines Agency's database
of side effects contain 160 reports on adverse reactions from
articaine that occurred from 2001-2005. The adverse reactions are mainly sensory impairment and nerve damage. Since
2005, we have seen a drop in the number of reports of new
adverse reactions, up until 1 October 2011, we have received
2 reports on suspected adverse reactions from articaine which
occurred in 2011. In both cases, the patients have experienced
sensory impairment after treatment with articaine."43
This is an example of two phenomena: (1) the Weber Effect
and (2) the effect of publicity, either negative or positive, on
drug prescription and usage (Fig. 4) .
Articaine was introduced into the United States in June
2000 and, as in most countries, quickly became a popular
dental local anesthetic. In 2014 articaine was the 2c1 most
administered local anesthetic (34.86% market share) in
dentistry in the USA.6 A 2010 paper by Garisto et al reviewing 248 reports of paresthesia to the United States FDAs
Adverse Event Reporting System (AERS) occurring following dental procedures over an 11-year period (1997 - 2008)
wwworalhealthgroup.com

57

-DENTAL PHARMACOLOGY-

concluded that "Reports involving 4% prilocaine and 4%

articaine were 7.3 and 3.6 times, respectively, greater than expected on the basis oflocal anesthetic use by U.S. dentists."44
The relative risks of paresthesia from this paper are shown in
Table 8 , compared with the same drugs in the 1995 Ontario
paper.
Regarding articaine, it appears from the numbers in these
two papers that the risk of paresthesia is 9.4 times greater in
Ontario than in the United States. The overall risk of paresthesia from a dental local anesthetic injection in Ontario is
17.58 times greater.23.44
Regarding the AERS data base, the following is posted on
its website:45 "AERS data do have limitations. First, there
is no certainty that the reported event was actually due to
the product. FDA does not require that a causal relationship
between the product and event be proven. Furthermore,
FDA does not receive all adverse event reports that occur
with a product." (authors note: it is estimated that only about
10% of all adverse events are reported). "Many factors can
influence whether or not an event will be reported, such as
the time a product has been marketed (Weber Effect) and
publicity about an event. Therefore, AERS cannot be used
to calculate the incidence of an adverse event in the US
population."45
Resolution of paresthesia was reported in 108 of the 248
cases, with complete resolution occurring between 1 day and
736 days. Confirmed resolution of the paresthesia was reported in 34 of the 108 cases. Of these, 25 resolved in less than 2
months with the remaining 9 resolving within 240 days .44
92. 7% of the reports involved the lingual nerve (89.0% lingual
nerve alone, 3.7% both lingual and IA nerves).44
Articaine was approved for use in 2005 in Australia. It was
reported in a (January) 2012 paper that 70% of Australian
dentists were using articaine in their clinical practices. 7 However, a (December) 2011 paper in the same journal, cited 5
case reports of paresthesia following local anesthetic administration, concluded that "Careful consideration needs to be given before using higher concentration local anaesthetic agents
for mandibular and lingual blocks as lower concentration local
anaesthetics are safer." The report also stated that, "It is safe
to use the higher concentration agents for infiltrations way
from major nerves."26 Four of the five reported cases involved
paresthesia of the lingual nerve only, and in two of these
cases an 'electric shock' was experienced by the patient during
injection.
Citing this paper, the 2012 edition of the Australian Dental
Associations Therapeutic Guidelines (Oral and Dental)
stated: "Articaine has been claimed to be more effective, but
there are reports of an increased risk of neurotoxicity, presenting as prolonged numbness in the areas of distribution, often
with pain. This may be due to the higher concentration of the

II

58

8.

USA

Table 8.

Ontario - 1993

Mepivacaine

1:623,112,900

1:1,125,000

Lidocaine

1 :181,076,673

1:1,125,000

Bupivacaine

1 :124.286,050

References 23. 44
OVERALL

1 : 13,800,970

Artlcalne

1:

4,159,848

Prilocaine

1:

2.070.678

1:

785,000

(2.27:1.000.000)

1:

440,529

(1 7 1.000,000)

1:

588.235

Comparative incidence of paresthesia reported in USA and

Ontario

solution rather than to the anaesthetic itself. Consequently, it

is recommended that articaine should not be used for regional
blocks (e.g. inferior alveolar).28

The Weber Effect and the Effect of Publicity on

Drug Usage
The Weber Effect, named after the epidemiologist, Dr. JCP
Weber46 is an epidemiological phenomenon which states that
the number of reported adverse reactions for a drug rises un"til
about the middle to end of the 2"d year of marketing, peaks,
and then steadily declines despite steadily increasing prescribing rates."
The validity of the Weber Effect has been challenged
and demonstrated to be verifiable. 4 7 Hartnell and Wilson
attempted to 'validate or refute a widely accepted epidemiological phenomenon known as the Weber effect by replicating
Weber's original observation by using drugs (author's note NSAIDs) that were marketed in the United States and using
reports from a U.S. database." They concluded "The Weber
effect was replicable."47
Publicity affects drug prescribing and usage habits . Following the Danish Dental Associations 'recommendation'
to avoid the use of articaine by inferior alveolar nerve block
(IANB), its use in Denmark declined significantly (Fig . 4 , red
line) . In 2006 following the European Unions report stating
there was no scientific evidence of an increased risk of paresthesia from articaine, use of the drug increased.
Paresthesia Following Non-Surgical Dental
Treatment
Surgery, especially 3'd molar extraction and placement of
mandibular implants, is the primary cause of paresthesia following dental treatment. 48 .4 9 Informed consent, specifically

oralhealth FEBRUARY 2016

----------------------------~----------------------~----~

-DENTAL PHARMACOLOGY-

discussing the risk of paresthesia is required prior to these

procedures.
Given that most dental treatment is non-surgical (e.g.
restorative, periodontal), the primary risk of paresthesia would
involve local anesthetic administration.
In a Medline search for reported cases of paresthesia in
dentistry dating to 1946, more than 95% of all cases occurred
in the mandible.SO The overwhelming percentage involve the
lingual nerve. Tab le 6 shows lingual nerve involvement in four
published articles.
Considering we have been told that 4% articaine appears to
be more neurotoxic than other local anesthetic formulations,
and that its administration by inferior alveolar nerve block
should be avoided, the following needs to be considered: If
4% articaine is more neurotoxic than other local anesthetics,
then how do we explain that paresthesia is rarely reported in
the maxilla when half of all dental treatment involves maxil-

~
R

a1se

lary teeth? (<5% of all cases in the dental literature dating to

the 1950s involve the maxilla). 50 Considering the mandible,
paresthesia has not been reported following alternative nerve
blocks, such as the Gow-Gates mandibular nerve block. 50
Articaine has been used increasingly in medicine, primarily
derm.atology, plastic and reconstructive surgery, ophthalmology and orthopedic surgery. There are no reported cases of
paresthesia following the non-dental use of articaine.9.51
Is it possible for a drug to be so specifically neurotoxic that
it only damages nerves with the oral cavity, specifically in the
mandible and more specifically the lingual nerve?

The Lingual Nerve

The lingual nerve appears to be involved in reports of dentally-related paresthesia a disproportionate percentage of cases.
( Tab le 6 ). Pogrel has studied paresthesia, with publications
dating to the early 1990s. 31-33 In a 2000 paper, Pogrel and

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oralhealth FEBRUARY 2016

- DENTAL PHARMACOLOGY-

Thamby estimated the risk of permanent nerve damage following IANB at 1in26,762 injections.52 They stated that "it
is reasonable to suggest that during a career, each dentist may
encounter at least one patient with an inferior alveolar nerve
block resulting in permanent nerve involvement. The mechanisms are unknown and there is no known prevention or
treatment."52 In the course of a twenty- to thirty-year dental
career, it is estimated that more than 30,000 IANBs will be
administered. 52
Why is it that the lingual nerve is primarily involved in
cases of paresthesia? Considering that when administering the
IANB the vast majority of local anesthetic volume is deposited
close to the IAN (e.g. 1.3 to 1.5 mL), not the lingual nerve
(e.g. 0.2 to 0.3 mL), if paresthesia was a local anesthetic neurotoxic phenomenon, we would expect the IAN to be affected
much more often than the lingual nerve.
The fact that the lingual nerve is stretched when the patient

opens their mouth for an IANB probably prevents the lingual

nerve from 'getting out of the way' of the needle. The resulting injury is more likely than not to be a result of mechanical
trauma to the lingual nerve from the metal needle. Stated in
another manner: "the lingual nerve is in the way."
A 2003 paper by Pogrel et al attempted to explain why lingual nerve damage was commonly seen as more profound.53
At the level at which the injection is administered, the inferior
alveolar nerve had 5 to 7 fascicles, whereas the lingual nerve
in that area usually had around three, but in a third of the cases was actually unifascicular in the area where the IANB was
given.53 ( Fig. 5) If a nerve with many fascicles (e.g. IANB)
is damaged, only a small portion of the sensory distribution
would be affected. When a nerve with 1 to 3 fascicles (e.g. lingual nerve) is damaged, the resulting area of sensory involvement will be considerably larger.
It is this author's opinion that if paresthesia involves the

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61

lI

- DENTAL PHARMACOLOGY-

9.

% Cases of aresthesia
0
o Market share

< 1.0 =Better

etter than
han Expected
1.
~ 1.0

> 1.0 = Higher than Expected

2007

Lidocaine

(_~} ~ (_~~:. /

1.19

Articaine

= Exoectecl

Mepivacaine

2012

('. s
0.97
,~--~

L.

t)
L

Prilocaine
References #35,36
Market sh ar e and obser ved incidence of paraesthesia

distribution of the lingual nerve - and especially when an

'electric shock' (e.g. 'zap') is experienced during injection, the
cause is likely to be mechanical trauma caused by direct contact of the metal needle with the nerve. If paresthesia involves
the distribution of the IAN (e.g. chin, lip, mucous membrane)
then possible etiologies include (1) neurotoxicity of the LA,
(2) mechanical contact of the needle to the IAN, (3) edema,
and (4) hemorrhage.
Local Anesthetics are Neurotoxins
All local anesthetics are neurotoxic. If all local anesthetics
were equally neurotoxic than the percentage of reported cases
of paresthesia for the drug should be equal to its market share.
The resulting fraction ideally should be 1.0.

62

In Pogrel's 2007 paper36 of 52 patients, lidocaine produced

the greatest number (20) and percentage (35%) of cases of
paresthesia. However, with a market share of 54% at the time
the ratio was 0.64, better than expected. (Table 9) . Prilocaine,
on the other hand, with a 6% market share was involved with
29.8% (N=17) of the cases of paresthesia (4.96 ratio). Articaine
with a market share of25% had a 29.8% (N=17) involvement for a ratio of 1.19. Pogrel concluded "Therefore, using

oralhealth FEBRUARY 2016

~---~----

-DENTAL PHARMACOLOGY-

our previous assumption that approximately half of all local

anesthetic used is for inferior alveolar nerve blocks, then on
the figures we have generated from our clinic we do not see a
disproportionate nerve involvement from articaine."36
In a 2012 update reporting on 38 patients seen in his clinic
between 2006 and 2011, Pogrel stated that "articaine is still
causing permanent inferior alveolar and lingual nerve damage
(36%) which is proportionate to its market share (37%)."37
"The number of cases caused by lidocaine, on the other hand,
appears to be only around 50% of its market share." Prilocaine
however by causing 26% of all cases seen since 2005 with a
market share of only 8% is somewhat disproportionate to its
market share."37 Table 9 shows the results of the two papers.

eluded "that articaine as compared with lignocaine provides

a higher rate of anaesthetic success, with comparable safety
to lignocaine when used as infiltration or blocks for routine
dental treatments." ... "This meta-analysis thus supports a recommendation for 4% articaine (1:100,000 epinephrine) in routine dental practice over and above 2% lidocaine (1:100,000
epinephrine). 54,55
A 2012 paper reporting on a histological analysis of the
neurotoxicity of lidocaine, articaine and epinephrine on the
mental nerve in rats, concluded that "articaine is not toxic to
the nervous structure and (that) further studies are necessary
to explain the possible relation between articaine injection and
paresthesia."56
In a 2013 clinical study, human neuroblastoma cells were
exposed to varying concentrations of articaine, lidocaine
and prilocaine to determine neurotoxicity at six different
drug concentrations. 57 The results of this in-vitro study

Is Articaine a More Effective Local Anesthetic and

Does it Have a Greater Risk of Paresthesia?
Meta-analyses comparing articaine to lidocaine have con-

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-DENTAL PHARMACOLOGY-

stated that lidocaine 2% had a lower neurotoxicity profile

compared to prilocaine 4% and that articaine 4% had a lower
neurotoxicity profile compared to lidocaine 2%. In-vitro
studies are accurate, sensitive and reproducible because
they are conducted in a controlled environment. However,
in-vitro studies do not take into account other factors such
as (1) local pharmacokinetics (concentration in tissues, local
diffusion, absorption); (2) potential influence of other drugs
on local pharmacokinetics (e.g. epinephrine); (3) systemic behavior of the drug after absorption (distribution, elimination,
metabolism), and (4) all other variables such as differences
between patients.

So, What Should You Do?

Doctors must always consider the benefit to be gained from
use of a procedure or drug versus the risk involved in the
procedure or drug. Only when, in the opinion of the treat-

ing doctor, the benefit to the patient to be gained clearly

outweighs the risk should the procedure be done or the drug
administered.
All reports claiming an increased risk of paresthesia with
articaine are anecdotal. There is no scientific evidence demonstrating an increased risk of paresthesia following the administration of articaine compared with other local anesthetics.
Choices for IANB include (1) continuing the use of articaine 4% with epinephrine 1:100,000 or 1:200,000, or (2) if
unconvinced or still concerned, use either lidocaine 2% with
epinephrine 1:100,000 or mepivacaine 2% with epinephrine
1:100,000 for IANB, following it immediately with a buccal
infiltration of 0.6 to 0.9 mL of articaine at the apex of the
tooth to be treated.
The administration of 4% prilocaine with epinephrine
appears to be associated with a considerably greater risk of
paresthesia to the lingual and/or inferior alveolar nerves. OH

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www.oralhealthgro up.com 65

I~
i~

-DENTAL PHARMACOLOGY~

4.

Dr. Stanley Ma lamed is a dentist anesthesio logist and emeritus

professor of dentistry a t the Herman Ostrow Sc h oo l of Dent istry
of U.S.C, in L os A n geles, Ca lifornia.

Muschaweck R, Rippel R. Ein neues Lokalanasthetikum (Carticain)

aus der Thiophenre ihe [A new local anaesthetic (carticaine) in the
thiophene ser ies]. Prakt Anaesth g(3):135-146, lg74

5 . Lemay H; Albert G; Helie P; Dufour L; Gagnon P; Payant L;

Laliberte R. Ultracaine en dentisterie operatoire conventionnelle.

Oral Health welcomes this original article.

[Ultracaine in conventional operative dentistry]. J Can Dent As

soc. 50(g):703-708, lg34

Editors Note:

6.

Dental local anesthetic market share , United States, Calendar

year-2014, 23 April 2015. Septodont Inc. Lancaster, PA

Ora l Health welcomes this original article from the well-respected

7.

Yapp KE; Hopcraft MS; Parashos P. Dentists' perceptions of a new

Dr. Stan ley Ma lamed on articaine. In his review, Dr. Malamed dis-

loca l anaesthetic drug-articaine. Aust Dent J. 57(1):18-22; quiz

cusses artica in e and paraesthesias. It is worth noting that the use

10g, 2012

of articaine and other 4% loca l anaesthetic so lutions for mandib-

8.

Deutcher Denta lmarkt Jahresbericht (DOM) 2010 (German

ular blocks has been an active ly debated topic for years. With re-

Dental Market Annua l Report 2010). GfK HealthCare, Nuremberg,

gard to paraesthesias currently, the bulk of the literature suggests

Germany

a higher-than-expected incidence when higher concentrat ion

(4%) local anaesthetic preparations are used. In the interest of
presenting topics in a balanced way, and acknow ledging Dr. Malc;imed 's ,enthusiastic support for t h e cont inued use of articaine for
inferior alveo lar nerve b locks in this artic le, our readers may wish
to also review articles by Dr. Dan Haas and Dr. S0ren H il lerup. Drs.
Haas and H ill e r up are two of the more notable addi t ion al au tho rs
on the incidence of paraesthesias and some assoc iat ed factors.

9.

Vree TB; Gielen MJ. Clinical pharmacology and the use of articaine for local and regional anaesthesia. Best Pract Res Clin
Anaesthesiol. lg(2):2g3-308, 2005

10. Malamed SF, Gagnon S, Leblanc D: Efficacy of articaine: a new

amide local anesthetic. J Amer Dent Assoc 131(5):635-642, 2000

11 . Malamed SF, Gagnon S, Leblanc D: Safety of articaine: a new am-

ide local anesthet ic. J Amer Dent Assoc, 132(2):177-185, 2001

12. Malamed SF, Gagnon S, Leblanc D: Articaine hydrochloride in

Their viewpoint represents a more guarded approach in t h e use

pediatric dentistry: safety and efficacy of a new am ide-type local

of 4% solutions for mandibu lar b locks.

anesthetic. Pediatr Dent 22(4):307-311, 2000

13. Hawkins, JM, Moore, PA. Local anesthesia: advances in agents

Also at issue in this article is the use of articaine in pregnant

women. Dr. Ma lamed suggests that articaine, an F DA C-rated

and techniques. Dent Clin N Amer 46:719-732,2002.

14. Rupieper N; Stocker L. Haemiglobinspiegel unter Lokalanaesth-

agent should be used instead of B - rated lidocaine. T he reason

esie mit Bupivacain, Carticain und Etidocain. [Met-Hb formation

given is the shorter fetal exposure time to articaine because of

and local anesthesia using bupivacaine, carticaine and etido-

its faster metabol ism. What is not clear is why exposing a fetus
to a potent ia ll y more harmfu l drug, even for a shorter time is
advantageous.

caine]. Anaesthesist. 30(5):23-25, 1981

15. Ultracaine DS Forte 1:100,000, Drug package insert. HANSAmed,

Mississauga, Ontario, Canada, September 2015

16. Malamed SF, Tavana S, Falke l M. Faster onset and more com-

As always, h ow you choose to treat your patients is ultimately

fortab le injection with alka linized 2% lidocaine with epinephrine

your decision . A t Oral Health , we would like these decisions to

1:100,000. Compendium 34(Spec issue #1):1-11, 2013

be based on the best information avai lable. We hope that you

enjoyed Dr. Malamed's article.

17. Robertson D, Nusstein J, Reader A , Beck M, McCartney M. The

anesthetic efficacy of articaine in buccal infiltration of mandibular

posterior teeth. J Am Dent Assoc 138:1104-lll2, 2007

Dr. Peter Nkansah

18 . Meechan JG, Ledvinka JI. Pulpal anaesthesia for mandibular central incisor teeth: a comparison of infiltration and intraligamentary

References
1.

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