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ARTICAINE
3
Years Later
O / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /
Stanley F Malamed
DDS
Introduction
ocal anesthesia forms the backbone of
pain
control techniques in dentistry. Local anesthet
ics represent the safest (when used properly)
and most effective drugs for the prevention and
management of perioperative and post-opera
tive pain.
The first known injection of a local anes-
thetic (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 ad
opted local anesthesia s 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
epineph
rine 1:50,000), led to a rapid increase in the use oflocal anes
thesia 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
synony
mous, to most people, s the 'shot' you receive
when
you visit
the
dentist.
The
amino-ester local anesthetics (LAs), primarily
pro
caine, 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 commo nly 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
4 oral
health FEBRUARY 2016
Figure
1
Chemical formula of
procaine
ester), l idoca i
ne
amide)
and art icaine.
profession.
The
ester local anesthetics are rarely employed
today for pain control in the denta l 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 grad
ually 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.
Art
icaine represents
the
first,
and
still only, local anesthetic developed specifi
cally for use in dentistry. Though articaine
is
classified as
an amide LA, articaine possesses chemical characteristics of
both the amide and ester groups Fi g . 1) . It has become an
extremely
popular
local anesthetic wherever
it
has been mad
available. In 2014, articaine was
the
second most used local
anesthetic in
the
United States with a 34.86
market
share
-
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(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]propionami
do)-2-thiophenecarboxylic acid, methyl ester hydrochloride
with a molecular weight of
320
.84.
I t
is the only
amide
local
anesthetic
that
contains a
thiophene
ring. In addition, artic
aine is the only widely used amide local anesthetic
that
also
contains an ester linkage (Fig.
1)
. Ester LAs undergo metab
olism (biotransformation, detoxification) as soon as the drug
diffuses into capillaries
and
veins (hydrolysis by plasma ester
ase) . Amide
LAs
enter the blood as still active drugs, circulat
ing 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 in plasma.
The elimination
(beta) half-life of a drug is the time
re
quired 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
remem
ber
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 pen
etrates tissue and is highly diffusible. Its plasma protein bind
ing
of approximately 95 percent is
higher than that
observed
with
many local anesthetics. Additionally, the thiophene ring
of articaine increases its liposolubility.
DENTAL PH RM COLOGY
1
Elimination Beta) Half-Life
Local Anesthet ic Half-life 1,rnn J
6·
h•l f-life
m in
hrs)
Procaine 6
36
Articaine
27 162
(2:42)
Cocaine
42 252 4:
52)
Lidoc
a
ine
-90
-540 (9:00)
Pr iloca ine
-90 -540 (9:00)
I
j
i
Mepivacaine
-120 -720 (12:00)
1260 (2 100)
upivac
a
ine
Ester _ Red
mide>=Blue
------------------
J
Elimination half-l ives of local anesthetics
///// / / // / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / /h
Articaine and
Allergy
The
incidence of true, documented
and
reproducible allergy to
amide LAs
is exceptionally low, though alleged 'allergy' is re
ported 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,
www
oral
healthgroup.com
43
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-DENTAL PH RM COLOGY
2
·
PHARMACOKINETIC
PROP RTI S
OF
COMMON
DENTAL
LOCAL ANESTHETICS
LOCAL
pKa*
ONSET
LIPID
USUAL
PROTEIN DURATION
ANESTHETIC
(pH) SOLUBILITYt
PERCENTAGE
BINDING( )
OF
DRUG
USED IN
ANESTHETIC
Articaine
7 8 Fast 1 5 4
9 5 M o d e r a t e
Bupivacaine
8 1 M o d e r a t e
3 0
.0 0 5
to0 75
9 5
L o n g
Etidocaine 7 9
Fast
1 4 0 0
1 5
9 4
L o n g
Lidocaine 7 8 Fast
4 0
2
6 5 M o d e r a te
Mepivacaine
7 7 Fast
1 0 2
t o
3 7 5
M o d e r a te
Prilocaine 7 9
Fast 1 5 4
5 5
M o d e r a t e
Procaine 9 1
S l o w
1 0
2
to
4 5
S h o r t
• pKa is a dissociation
constant
t Lipid solubility is a ratio using procaine
as
I .
Physicochemical
characteristics
of common
LAs
3
Drug Onset (textbook) Pulpal
Soft
Tissue
Lidocaine
Epi
3 - 5
min
60
min
3 - 5
hours
2°/o
1:50k 1:100k
Epi
Articaine 4°/o
1 :
100k
2 - 3 min
60 min
3 - 5
hours
1 :200k
Mepivacaine
Epi 1 :100k
3 - 5 min
60
min
3 - 5
hours
2°/o
Prilocaine
Epi
3 - 5 min
60 min
3 - 8
hours
4°/o
1 :200k
Intermediate duration LAs
north
america
44
oralhealth FEBRUARY
2016
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DENTAL PH RM COLOGY
bupivacaine and etidocaine administered as central nerve
block anestheti c for urological procedures (n = 103) indicated
no elevation of methemoglobin with articaine.14
t ica ine - C
li
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 anes
thesia 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
- TM
i a
1
se
s1Nus
un
SYSTEM
Articain
e, lidoca ine pulpal anesthesia success rat es - Rober tson ,
Nusste
in etal , reference 16
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assertion
is
not supported by clinical research.
10 16 In
stud
ies 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, epineph
rine 1:100,000 and 4% articaine epinephrine 1:100,000.
However, the administration of articaine by mandibular infil
tration 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%
'
-DENTAL
PHARMACOLOGY
Tooth Articaine onset Udocaine value
min)
+/- onset (min)
Standard +/-Standard
Deviation Deviation
2nd
molar
4.6 /-4.0 11.1 /-9.5
.0001
4.2 /-3.1 7.7 +/- 4.3
.0002
4.3 /-2.3
6.9
+[ -6.6
.0014
l
premolar
4.7 /-2.4 6.3 +/ - 3 .1
.0 137
Ar t
ica
ine ,
lid ocai
ne
onset
of pulpal anesthes ia - Robert son,
Nusste
in
etal , refe ren
ce
16
//./././/././././/./././/././././
articaine with epinephrine 1:100,000 and 2% lidocaine with
epinephrine 1:100,000 on
mandibular
incisors,
both
for
success
and
duration of pulpa l 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 buc
cal and lingual, is quite thin and might provide little resis
tance 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 infil tration
of
4% articaine
with
epi
nephrine 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
clas
sifies 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, an d epinephrine, are classified as
'B'
[Caution
advised - no evidence of 2 or 3
1
trimester risk; fetal harm
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8/17/2019 Articaine 30 Years Later
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possible
but
unlikely]
or
'C'
[Weigh risk/benefit
- weigh possible fetal risk vs. maternal benefit;
see package insert for drug-specific recommen
dations]. 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-li
fe
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.
Nur
s
in
g: FDA categories for nursing infants
are S (Safe for nursing infant); S? (Safety in
nursing infants unknown); S* (Potential for sig
nificant 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-
'
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I Orascoptic.com
I
I :
8
11 10
:
1
:
DENTAL
PHARMACOLOGY
Mandibular Incisors
+ Uol
eb
u. i .
*'
Attll
*
At t
b•I
Im :
O _O S 10 4 1 5
:zo
ZS JO
.
40 __ 45
TIM• MlllVTES)
..
....._
Duration of
pulpal
anesthesia following mandibular infi ltration . Meechan,
Ledvinka , reference #17
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DENTAL PHARMACOLOGY
I st
Molar
•
Troatment 1
Troatment 2
10 15 20 25 30 35 40 45
Timo after lnjoction (min)
a
h
u
g t ~
1:1a
c c
~ i i
h
i
e:::
8
_ii
§:ii
~
g
I/.
100
l st Premolar
90
80
70
00
50
40
30
20
10
0
4 e e 10 15 20 25 30
35 40 4
Tlmo a er lnjoction (min)
Figure 2
&
3 : Successful pulpal anesthesia. Blue= IANB - Lidocaine 2% +
epi
1:80 ,
000
+ " dummy" infi ltration.
P
ur
p le=
IANB
-
Lidocaine 2%
+ epi
1:80 ,000
+ "articaine" infi ltration. 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 imme
diately states that they do not want the drug. This becomes
problematic when
the
dental procedure is po tentially painful.
The
concept
of pump
and discard ' successfully handles this
situation. Following exposure to a drug the nursing
mother
should pump and discard the mi lk 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
mother
s may
choose to pump and discard breast milk for approximately
four hours (based on plasma
ha
lflife) 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
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DENTAL PH RM COLOGY
Drug
rticaine
H I
upivacaine
H I
Lidocaine
H I
Mepivacaine
H I
Prilocaine
H I
MRD: US - Food &
Drug
dministration , 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
7
Both
for
mulations provide a rapid onset of pulpal anesthesia (approxi
mately
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 anesthet
ics containing epinephrine. Because of articaine's greater lipid
solubility, the drug demonstrates increased clinical success
when administered by mandibular infiltration in molars, pre
molars 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 (
-
8/17/2019 Articaine 30 Years Later
10/19
iller
3S
3
2S
s
10
DENTAL
PH RM COLOGY
l ,800,000
1,600,000
l ,
4
00,000
l
,200 000
1,000,000
Adverst reacbcos
800,000 _ Use
600,000
4
00,000
I l _I
200,000
0
r '' r§
.
\'
'\'
h
-
8/17/2019 Articaine 30 Years Later
11/19
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
den-
tistry in the United States.6.36,37
5. Paresthesia: Paresthesia
has
exis
ted ever
since
injec-
tions
were
first administered. References to paresthesia
associated with the administrat ion 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 ocal anesthetic of 1 case
in
785,000 (1:785,000). Two and three percent
LAs
(mepiva
caine, 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 mar
ket.
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
(Laegemidde l Styrelsen). The paper recommended that
Until
factual information
is
available, a preference of
other
formu la
tions to Articaine 4% may be justified, especially for
mandib-
ular 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 artica lne
annually. Their findings, published
20 October 2006
stated
regarding articaine, the conclusion
is that
the safety pro-
file 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 ar ticaine and prilocaine.
DENTAL PH RM COLOGY
Figure 5:
Fascicles within
a
nerve
q //////////////////////.////////////////.///////
However, considering
the
number
of
patients treated, sensory
impairments rarely occur. For example, the incidence of senso
ry
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 Agenc y 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 reac
tions 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 2°c most
administered local anesthetic (34.86% market share) in
dentistry in the
USA.6
A 2010 paper by Garis to
et
al review
ing 248 reports of paresthesia to the United States FDAs
Adverse Eve nt
Reporting
System
(AERS)
occurring follow
ing dental procedures over
an
11-year period (1997 - 2008)
www
oral
healthgroup com
57
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8/17/2019 Articaine 30 Years Later
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DENTAL PH RM COLOGY
concluded that Reports involving 4 prilocaine and 4
articaine were
7.3
and
3.6
times, respectively, greater than ex
pected on the basis oflocal anesthetic use by U.S. dentists. 44
The
relative risks
of
paresthesia from this p aper are shown
in
T
able
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 pares
thesia 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 report
ed
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
How-
ever, a (December)
2011
paper
in
the same journal, cited
5
case reports of paresthesia following local anesthetic adminis
tration, concluded that Careful consideration needs to be giv
en before using higher concentration local anaesthetic agents
for mandib ular 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 shoc k' 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, present
ing
as prolonged numbness in the areas of distribution, often
with pain. This may be due to the higher concentration
of
the
8
oralhe
alth
FEBRU RY
2016
8.
Table
8.
USA
Ontario - 1993
Mepivacaine 1:623,112,900
1:1,125,000
Lidocaine
1 181,076,673
1:1,125,000
upivacaine 1 124.286,050
References 23.
OV ERALL 1: 13,800,970
1: 785 ,000
Artlcalne 1: 4,159,848
(2.27:1.000.000)
1: 440,529
Prilocaine 1:
2.070.678
(1 7 1.000,000
1:
588.235
Comparati
ve
incidence of paresthesia reported in US and
Ontario
solution
rather than
to the anaesthetic itself. Consequently,
is recommended that articaine should not be used for region
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 th
the
number
of reported adverse reactions for a
drug
rises
un
about the middle to end of the
2
dyear
of
marketing, peaks,
and then steadily declines despite steadily increasing prescri
ing 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 epidemio
logical phenomenon known as
the
Weber effect by replicati
Weber's original observation by using drugs (author's note -
NSAIDs) that were marketed in the United States and usin
reports from a U.S. database.
They
concluded The Weber
effect was replicable. 47
Publicity affects drug prescribing and usage habits . Fol
lowing 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 ,
r
line). In
2006
following the
European
Unions report stating
there was no scientific evidence
of
an increased risk
of
pares
thesia 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 fol
lowing dental treatment.
48
49
Informed
consent, specifical
~ ~
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8/17/2019 Articaine 30 Years Later
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-DENTAL PH RM COLOGY
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.
n 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. T
ab
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: f
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-
TM
i a1se SINUS LIFT
SYSTEM
lary teeth?
(
-
8/17/2019 Articaine 30 Years Later
14/19
Thamby
estimated the risk of permanent nerve damage fol
lowing 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
mech
anisms 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 neu
rotoxic 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
- DENTAL
PHARMACOLOGY
-
opens their mouth for an
IANB
probably prevents the lingual
nerve from 'getting out of the way'
of
the needle.
The
result
ing
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 lin
gual 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 cas
es
was actually unifascicular in the area where the
IANB
was
given.53
(
Fig.
5)
f
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. lin
gual nerve) is damaged, the resulting area
of
sensory involve
ment will be considerably larger.
It is
this author's opinion
that
if paresthesia involves the
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8/17/2019 Articaine 30 Years Later
15/19
DENT L
PH RM COLOGY
9
%Cases o aresthesia
<
1 0 =
Bette
r than
Expected
·1 0 =Exoectecl
= etter han
·1
•
> 1 0 Hig
h
er than Expec
t
ed
0
o
Market
share
2007
2012
Lidocaine
_ ~ } _ · ~ ~ : . /
( . s
Articaine
1.19 0.97
Mepivacaine
~ - - ~
t
Prilocaine
References 35,36
Market
share
and
ob ser
ved
inc i
dence
of
parae
s
th e
sia
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 con
tact
of
the metal needle
with
the nerve.
f
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.
Loc al nesthetics are Neurotoxins
All local anesthetics are neurotoxic. f 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.
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 tim
the ratio was 0.64, bet ter
than
expected. Table 9) Prilocain
on the other hand, with a 6 market share was involved with
29.8% (N=17)
of
the cases
of
paresthesia (4.96 ratio). Articain
with a market share
of25
had a 29.8% (N=17) involve-
ment for a ratio of 1.19. Pogrel concluded Therefore, using
62
oralheal
t
FEBRUARY 2016
-
8/17/2019 Articaine 30 Years Later
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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
n 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.
Is
rticaine a More Effective Local nesthetic and
Does it Have a
Greater
Risk of Paresthesia?
Meta-analyses comparing articaine to lidocaine have con-
eluded that articaine s compared with lignocaine provide
a higher rate of anaesthetic success,
with
comparable safety
to lignocaine
when
used s
infi
ltration or blocks for routine
dental treatments.
.. This
meta-analysis thus supports a re
ommendation for 4% articaine (1:100,000 epinephrine) in
tine d ental 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 t
the nervous
structure
and (that)
further
studies are necessa
to explain the possible relation between articaine injection
paresthesia. 56
n a 2013 clinical study, human neuroblastoma cells we
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
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8/17/2019 Articaine 30 Years Later
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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 be
havior
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-
'
DENTAL
PHARMACOLOGY
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 demon
strating
an increased risk
of
paresthesia following
the
admin
istration of articaine compared with
other
local anesthetics.
Choices for
IANB
include
1) continuing
the use of artic
aine 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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65
-
8/17/2019 Articaine 30 Years Later
18/19
Dr.
Stanley Ma
l
amed
is a
dent
i
st
anesthesio
l
ogist
and emeritus
professor of dentistry at
the
Herman
Ostrow Sc
h
oo
l of
Dent
i
stry
of
U.S.C,
in
Los A ngeles, Ca lifornia.
Oral
Health welcomes this original article.
Editors Note:
Ora l Health welcomes this original article from the well-respected
Dr. Stan ley
Ma
lamed on articaine. In his review, Dr. Malamed dis
cusses
artica in e
and
paraesthesias. It is worth not ing that the
use
of
articaine and
other
4 loc a l anaesthetic so lutions for mandib
ular blocks has been an
active
ly
debated topic
for
years.
With
re
gard
to paraesthesias
currently,
the bulk of the
li terature suggests
a
higher-than-expected incidence when higher concentrat
i
on
(4 ) local anaesthetic preparations
are
used. In the interest o f
presenting topics in a balanced way, and
acknow
l
edging
Dr. Mal
c;imed 's ,enthusiastic
support for
t he cont i
nued
use
of articaine for
inferior
alveo lar nerve b l
ocks in
this
artic
le,
our
readers
may
wish
to also
review
articles by Dr. Dan
Haas
and Dr.
S0ren
Hil lerup . Drs .
Haas
and Hille r
up
are
two of the more notab
le addi t io nal au th o rs
on
the
incidence
of
paraesthesias and
some assoc
iat ed factors.
Their
viewpoint
represents
a more guarded approach in t he use
of
4 solutions
for
mandibu lar b locks.
Also
at
issue
in
this article
is
the
use
of
articaine
in
pregnant
women. Dr. Ma lamed suggests that articaine, an FDA C-rated
agent should be used instead of B- rated lidocaine. The reason
given is
the shorter
fetal exposure
t ime to articaine
because
of
its
faster metabol i
sm.
What is not clear is why exposing a fetus
to a potent ia ll y
more
harmfu l drug,
even
for a
shorter
t ime is
advantageous.
As always, h
ow you choose to treat your patients
is ultimate ly
your decision . A t Oral Health we
would
l
ike
these decisions to
be based on the best information avai lable. We
hope
that
you
enjoyed Dr. Malamed's article.
Dr. Peter Nkansah
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