Vol. 113 No.

4 April 2012

Comparison of 4% articaine with epinephrine (1:100,000) and

without epinephrine in inferior alveolar block for tooth extraction:
double-blind randomized clinical trial of anesthetic efficacy
Peer W. Kämmerer, MD, DMD,1,a Victor Palarie, DDS,1,b Monika Daubländer, MD, DDS, PhD,c
Constantin Bicer, DDS,d Niloufar Shabazfar,a Dan Brüllmann, DDS,c and Bilal Al-Nawas, MD, DMD, PhD,a
Mainz, Germany; and Chisinau, Moldova
UNIVERSITY MEDICAL CENTER MAINZ, STATE UNIVERSITY OF MEDICINE AND PHARMACY

Objective. The purpose of this clinical prospective, randomized, double-blind study was to compare the anesthetic efficacy of
4% articaine with epinephrine (1:100,000) and without epinephrine in inferior alveolar nerve block anesthesia for extractions
of mandibular teeth.
Study Design. Eighty-eight patients received intraoral inferior alveolar nerve blocks using 4% articaine with 1:100,000
epinephrine (n ⫽ 41; group 1) or without epinephrine (n ⫽ 47; group 2) for extractions of mandibular teeth. The primary
objectives were differences in onset as well as in length of soft tissue anesthesia. The amount of anesthetic solution, need of a
second injection, pain while injecting, pain during treatment, postoperative pain, and possible complications were surveyed.
Results. In both groups, anesthesia was sufficient for dental extractions. In group 1, a significantly faster onset of the
anesthetic effect (7.2 min vs. 9.2 min; P ⫽ .001) and a significantly longer duration of soft tissue anesthesia (3.8 h vs. 2.5 h;
P ⬍ .0001) were seen. There was no significant difference in the amount of anesthetic solution needed, in the need for a
second injection, in the injection pain, in pain during treatment, or in postoperative analgesia. In both groups, no
complications were seen.
Conclusions. To minimize the epinephrine-induced side effects, 4% articaine without epinephrine is a suitable anesthetic
agent for dental extractions in the mandible after inferior alveolar nerve block anesthesia. There could be less postoperative
discomfort due to the shorter duration of anesthesia without increased postoperative pain. (Oral Surg Oral Med Oral Pathol
Oral Radiol 2012;113:495-499)

Articaine is a common local anesthetic agent (LA).1 Its
thiophene ring confers greater lipid solubility than li-
docaine, which allows enhanced diffusion through
nerve sheaths. It also has an increased potency com-
pared with lidocaine. Evidence suggests that it is the
LA that best diffuses within soft and hard tissues.2 The
ester side chain of articaine is hydrolyzed by plasma
esterases rendering the molecule inactive. This results
in a short half-life of 20 minutes compared with ⬃90
minutes for other amides (e.g., lidocaine) that require
hepatic clearance.3 Accordingly, it was suggested that
articaine does not possess any relevant side effects or
gross toxicity.4
a ischemic changes,11-13 a further release of endogenous
Department of Oral and Maxillofacial Surgery, University Medical
Center Mainz.
b
Clinic of Oral and Maxillofacial Surgery, Implantology, and Ortho-
pedic Stomatology, State University of Medicine and Pharmacy,
Chisinau.
c
Department of Oral Surgery, University Medical Center Mainz.
d
Unit of Oral Surgery, Polyclinic of Stomatology, State University of
Medicine and Pharmacy, Chisinau.
Received for publication Feb. 10, 2011; returned for revision Mar. 26,
2011; accepted for publication Apr. 29, 2011.
© 2012 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
doi:10.1016/j.tripleo.2011.04.037
1
The first 2 authors contributed equally to this work.
Dental LA are often combined with vasoconstrictors,
such as epinephrine, to increase depth and duration of
analgesia.5 They also provide hemostasis and concen-
trate the agent at the injection site, which results in
decrease of systemic toxicity (i.e., dose-dependent de-
pression of the central nervous system) of the corre-
sponding LA. It has been shown that when using artic-
aine, adverse reactions occur mainly due to the amount
of vasoconstrictor in the LA solution.6 Even small
doses of epinephrine in LA have an influence on car-
diovascular function.3 Physiologic responses of solu-
tions containing a vasoconstrictor include changes in
heart rate and blood pressure.7-9 Other known side
effects are cardiac dysrrhythmia10 as well as cardiac
catecholamines,14 and hypokalemia.15 Flu-like symp-
toms16 and potentiation of adverse drug reactions17 also
have been reported.
Although most current literature accepts epinephrine
to have a safety range,18 its threshold of concentration
remains unclear.19,20 It can be concluded that, if the
vasoconstrictor-induced physiologic events exceed
the normal range, an increase in morbidity or even
mortality can be observed.13 Because LA adminis-
tration can be as stressful as the operative procedure,
an LA with none or at least modest cardiovascular

495
ORAL AND MAXILLOFACIAL SURGERY
496 Kämmerer et al.
effects (as less vasoconstrictor as possible) would be
preferable.6,13,21-24
Owing to its low systemic toxicity, routine use of
articaine without vasoconstrictor can be considered. Of
course, this has to be limited to cases in which the duration
of treatment is short and the epinephrine-induced hemo-
stasis may not be necessary, such as conservative treat-
ment or less complicated dental extractions.
The primary objectives of the present study were to
compare the differences in time of onset and length of
soft tissue anesthesia of 4% articaine with (1:100,000)
epinephrine and 4% articaine without epinephrine when
used in inferior alveolar nerve block for dental extrac-
tions. The secondary objectives were to compare de-
scriptively the amount of anesthetic solution, the need
of a second injection, pain while injecting, pain during
treatment, postoperative pain, and other possible com-
plications.
MATERIALS AND METHODS
Eighty-eight patients (male 43, female 45) in need of
single tooth extraction owing to caries and/or periodon-
titis in the mandible were included in this prospective,
randomized, double-blinded, confirmatory analysis
study.25 The study took place at the State University of
Medicine and Pharmacy of Moldova between January
2009 and December 2009 after approval by the local
Ethics Committee. Equal randomization was achieved
with the use of a computer-generated random number
list. Inclusion criteria for the study were all patients
who required single tooth extractions in the mandibular
arch. Signed inform consent was obtained from every
patient included in the study. The exclusion criteria
were as follows: cardiovascular instability, including
unstable angina pectoris, recent myocardial infarction
(⬍6 months), refractory dysrrythmias, untreated or un-
controlled hypertension, uncontrolled diabetes mellitus,
sulfite sensitivity or allergy to any part of the solution,
steroid-dependent asthma, pheochromacytoma, tricy-
clic antidepressant treatment, and history of psychiatric
illness. Patients requiring open surgical extractions and
with infected teeth were excluded from the study.
The mean age of patients was 36.7 years (range
18-80, SD 12.6). Twenty-six patients (29.5%) had tooth
pain before treatment, of which 18 patients (20%) took
pain medication (ibuprofen 17, aspirin 1). Concomitant
diseases were hypertension (n ⫽ 3), carcinoma in re-
mission (n ⫽ 2), hepatitis (n ⫽ 2), epilepsy (n ⫽ 1),
hypothyroidism (n ⫽ 1), and migraine (n ⫽ 1). In each
patient, 1 tooth in the mandible was extracted. The
affected teeth were #38 (n ⫽ 18), #46 (n ⫽ 15), #48
(n ⫽ 13), #47 (n ⫽ 12), #36 (n ⫽ 9), #7 (n ⫽ 8), #45
(n ⫽ 6), #35 (n ⫽ 3), #34 (n ⫽ 2), and #44 (n ⫽ 2). All
patients were examined clinically and radiographically
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April 2012
(panoramic x-ray). No presence of acute or chronic oral
infections was seen. In all cases, articaine 4% was
given as local anesthetic. In 41 cases (40.2%, group 1)
an epinephrine adjuvant of 1:100,000 (Ultracaine D-S
Forte; Sanofi-Aventis, Frankfurt, Germany) was used.
Forty-seven patients (46%, group 2) received articaine
solution without epinephrine (Ultracaine D; Sanofi-
Aventis). A dental nurse gave the different solutions in
identical syringes (2 mL) marked with the patient’s
randomization number only. The blinding was rendered
when evaluating the data. The same LA was used in
second and repeated injections.
Treatment protocol
In all cases, an inferior alveolar nerve block with direct
access of the cannula to the injection site was admin-
istered as previously described.26 An additional buccal
nerve block to obtain vestibular soft tissue anesthesia
was administered. The required amount of local anes-
thetic was estimated clinically via patients’ character-
istics (body weight and constitution). Two milliliters
was available in each syringe. The duration of injection
was standardized to ⬍1 minute per syringe. Dental
extraction was performed after full anesthesia, tested
with a probe on the vestibular mucosa and oral gingiva
and on the tooth itself each minute after injection, and
after subjective symptoms of numbness by the patient. If
a patient declared full numbness (i.e., soft tissue anesthe-
sia), the onset was subsequently tested. Time taken to
reach complete anesthesia was evaluated with a stop
watch. The injection as well as the treatment was per-
formed by 2 experienced dentists. Repeated injections
were given if the patient reported pain during treatment.
Need of a second injection and injected amount of LA
were noted for each patient. After extraction, the gingiva
was adapted over the alveolae with sutures. After treat-
ment, the subjective efficiency of anesthesia by means of
pain while injecting and pain during treatment were col-
lected via questionnaire. Pain was rated by visual analog
scale (VAS) from 0 (no pain) to 10 (worst pain). Patients
were recommended to take 1 tablet of paracetamol (1,000
mg) 6 hours after operation.27 Patients were instructed to
monitor the time of fading of soft tissue anesthesia as well
as unexpected bleeding events (⬎30 minutes of bleeding,
excessive bleeding). The patients were contacted via tele-
phone on the first postoperative day. Fading of soft tissue
anesthesia with exact time, the postoperative pain (VAS),
and possible bleeding complications were documented.
Statistics
A prior calculation showed a sample size of 27 in each
group to be sufficient to achieve a study power of 90%.
The primary objectives were differences in soft tissue
anesthesia, measured from onset to full anesthesia
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Volume 113, Number 4
Fig. 1. Boxplots comparing the time until full anesthetic
effect between group 1 (with epinephrine 1:100,000) and
group 2 (without epinephrine). Without epinephrine, the time
was significant longer (P ⫽ .001).
(min) as well as length of anesthesia (min). Here, a
Fisher test was used to examine the statistical signifi-
cance of the differences. Because of multiple testing, a
Bonferroni correction was used. Therefore, a difference
was seen to be statistically significant if P ⬍ .025. The
further analyses were regarded as explorative, and the P
values of the corresponding tests are presented for
descriptive reasons only. To compare amount of anes-
thetic solution (mL), pain while injecting (VAS), pain
during treatment (VAS), and postoperative pain (VAS),
2-tailed ␹2-tests were used. Differences in need of a
second injection were calculated with Fisher exact test.
All analyses were performed with SPSS version 16.0
(SPSS, Chicago, IL).
RESULTS
The mean time of extraction from beginning of total
anesthesia to end of the operation with sutures was 14.4
minutes (SD 13.92 min). In all cases the operation was
finished successfully.
Primary objectives
In group 1, the mean time between injection and full
anesthetic effect was 7.2 minutes (SD 2.97 min). In group
2, it took 9.2 minutes (SD 2.7 min). In group 1, the effect
could be seen significantly earlier (P ⫽ .001; Fig. 1) and
the mean duration of anesthesia was 3.8 hours (SD
0.57 h), whereas in group 2, the duration was significantly
shorter (2.5 h; SD 0.97 h; P ⬍ .0001; Fig. 2).
Secondary objectives
In group 1, 1.86 mL (SD 0.17 mL) of LA was primarily
injected, whereas in group 2, 1.94 mL (SD 0.23 mL)
was used. There was no significant difference between
ORIGINAL ARTICLE
Kämmerer et al. 497
Fig. 2. Boxplots comparing the duration of anesthetic effect
between group 1 (with epinephrine 1:100,000) and group 2
(without epinephrine). Without epinephrine, the duration was
significant shorter (P ⬍ .0001).
the 2 groups (P ⫽ .202). In 70 cases (79.5%; group 1:
n ⫽ 34 (82.9%); group 2: n ⫽ 36 (76.6%)) a single
injection was seen to be sufficient. No significant dif-
ference between the groups was detected (P ⫽ .461).
For injection pain, in group 1, the mean VAS score
was 2.56 (SD 1.41), and in group 2 it was 2.72 (SD
1.84). The difference was not significant (P ⫽ .647).
For pain during treatment, a mean VAS score of 0.8
(SD 1.54) was evaluated in group 1. In group 2, a mean
VAS score of 0.79 (SD 1.08) was seen. There was no
significant difference between the 2 groups (P ⫽ .95).
For postoperative pain, a mean VAS score of 0.4 (SD
0.5) was evaluated in group 1. In group 2, a mean VAS
score of 0.3 (SD 0.4) was observed. This difference was
not significant (P ⫽ .96).
DISCUSSION
To our knowledge, this is the first study comparing 4%
articaine with (1:100,000) and without vasoconstrictor
after inferior alveolar nerve block in a clinical situation,
such as tooth extraction. A reduction of the vasocon-
strictor epinephrine for block anesthesia may be favor-
able to minimize potential side effects.22 Owing to the
low toxicity of articaine, even without the use of epi-
nephrine, it seems to be reasonable for treatments with
short duration in oral surgery.
Significant differences were detected in time of onset
and duration of action. The onset described in litera-
ture24 as well as the anesthetic duration of 4% articaine
with 1:100,000 epinephrine in inferior alveolar nerve
block anesthesia28,29 are in accordance with our results.
It has been shown that vasoconstrictor concentration
may influence anesthetic diffusion owing to a slower
absorption rate.30 This explains the longer time of onset
ORAL AND MAXILLOFACIAL SURGERY
498 Kämmerer et al.
as well as the shorter duration of 4% articaine without
vasoconstrictor, though this fact does not seem to exist
for infiltration anesthesia.31
In our study, the mean duration of anesthesia was
enough for a tooth extraction in both groups. It could be
shown that there are no differences in amount of LA, in
the need for a second injection and in anesthetic success
rate [pain while injecting (with different pH values),
pain during treatment, and postoperative pain] between
the 2 groups. In an experimental setting, Petrikas et
al.32 described that articaine without vasoconstrictor
has no prospects in application in endodontology due to
its lacking pulp anesthesia. In an experimental trial,
Moore et al.31 observed an unsatisfactory success rate
of articaine without epinephrine. It has to be kept in
mind that neither pulpal anesthesia nor the duration of
pulpal anesthesia were tested separately in the present
study. All pain measurements were done subjectively
considering soft tissue anesthesia. Accordingly, higher
ratings of success may be possible. Clinically satisfac-
tory results for anesthesia for tooth extraction were
obtained with both solutions, and no significant differ-
ences between them were seen in the present study. No
adverse reactions were observed by the surgeon or
reported by the patients the day after surgery. This
finding is in accordance with the known low allergenic
and toxic potential of articaine.6 However, it has to be
kept in mind that a follow-up period of 1 day may be
too short to observe later complications.
Because the amount of LA used in inferior alveolar
nerve block in both groups is normal24,29 and the sub-
jective pain experiences were not different, a further
use of 4% articaine without epinephrine may be rec-
ommended for this clinical situation.
CONCLUSIONS
Differences between the 2 solutions were seen in terms
of time of onset as well as in duration of anesthesia.
Four percent articaine solution without epinephrine
does not seem to influence the clinical efficacy in terms
of several anesthetic properties (need of second injec-
tion, injection pain, intra- and postoperative pain). Be-
cause the duration of the LA without epinephrine is
shorter and postoperative pain is the same, this could
add to increased patient comfort after treatment. There-
fore, it is possible to successfully use the 4% articaine
without epinephrine formulation for dental extractions
in the mandible after inferior alveolar nerve block.
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Reprint requests:
Peer W. Kämmerer, MD, DMD
Department of Oral and Maxillofacial Surgery
University Medical Center Mainz
Augustusplatz 2
55131 Mainz
Germany
peer.kaemmerer@unimedizin-mainz.de