articaine 30 years later

8/17/2019 Articaine 30 Years Later

1/19

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


2/19

(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


3/19

-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


4/19

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-

J t

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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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7/19

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-

'

0 0 0 0 0®

800.369.3698

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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8/19

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


9/19

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 (


10/19

iller

3S

3

2S

s

10

DENTAL

PH RM COLOGY

l ,800,000

1,600,000

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4

00,000

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800,000 _ Use

600,000

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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


12/19

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

~ ~


13/19

-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?

(


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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www.oralhealthgroup.com 61


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


16/19

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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17/19

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

~

0

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65


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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