Eur J Oral Sci 2018; 1–8 Ó 2018 Eur J Oral Sci

DOI: 10.1111/eos.12406 European Journal of

Printed in Singapore. All rights reserved
Oral Sciences

Mohammad H. Al-Shayyab ,
Factors predictive of the onset and Zaid H. Baqain
Department of Oral and Maxillofacial Surgery,
duration of action of local anesthesia Oral Medicine and Periodontology, School of
Dentistry, The University of Jordan, Amman,
Jordan
in mandibular third-molar surgery: a
prospective study
Al-Shayyab MH, Baqain ZH. Factors predictive of the onset and duration of action
of local anesthesia in mandibular third-molar surgery: a prospective study.
Eur J Oral Sci 2018; 00: 1–8. © 2018 Eur J Oral Sci
The aim of this study was to assess the influence of patients’ and surgical variables
on the onset and duration of action of local anesthesia (LA) in mandibular third-
molar (M3) surgery. Patients scheduled for mandibular M3 surgery were considered
for inclusion in this prospective cohort study. Patients’ and surgical variables were
recorded. Two per cent (2%) lidocaine with 1:100,000 epinephrine was used to
block the nerves for extraction of mandibular M3. Then, the onset of action and
duration of LA were monitored. Univariate analysis and multivariate regression
analysis were used to analyze the data. The final cohort included 88 subjects (32
Mohammad H. Al-Shayyab, Department of
men and 56 women; mean age  SD = 29.3  12.3 yr). With univariate analysis,
Oral and Maxillofacial Surgery, School of
age, gender, body mass index (BMI), smoking quantity and duration, operation Dentistry, The University of Jordan, Amman,
time, and ‘volume of local anesthetic needed’ significantly influenced the onset of 11942 Jordan
action and duration of LA. Multivariate regression revealed that age and smoking
E-mail: mhshayyab@ju.edu.jo
quantity were the only statistically significant predictors of the onset of action of
LA, whereas age, smoking quantity, and ‘volume of local anesthetic needed’ were
the only statistically significant predictors of duration of LA. Further studies are Key words: local anesthesia; surgery; wisdom
recommended to uncover other predictors of the onset of action and duration of teeth
LA. Accepted for publication December 2017

Effective pain control during dental procedures is essential
for dental patients, particularly for oral surgical proce-
dures. Third-molar (M3) surgery is one of the most com-
mon surgical procedures, and effective pain control during
such surgery is expected, enhancing clinician–patient rela-
tions and improving patients’ attitudes toward dental sur-
gery (1).
Local anesthesia (LA) is the mainstay for pain con-
trol during dental procedures; it is safe and effective (2,
3). Different local anesthetic agents are available with
different physical properties and hence with variable
clinical actions. They vary in the onset of action, anes-
thetic volume required, and duration and depth of
anesthesia (4). Several factors govern the physical prop-
erties and clinical actions of a given local anesthetic:
some, such as the concentration of the drug and the
pH of the solution, are under the operator’s control;
others, including the diffusion constant (pKa) of the
anesthetic drug, the pH and vascularity of the injected
tissue, and variation in the anatomic diffusion barriers
of the nerve, are not (2, 3). The onset of action is pri-
marily influenced by the pKa value, the pH of the
injected tissue, and the anesthetic technique employed
(5). The duration of action is governed by the protein-
binding properties of the drug, the volume used, the
presence or absence of a vasoactive agent, and the vas-
cularity of the tissue (2, 3, 5). It has been suggested
that a patient’s behavioral and anthropometric factors,
such as smoking (6–8), gender (9), body mass index
(BMI) (10), and age (11–13) may influence these gov-
erning factors and hence contribute to the effectiveness
of the local anesthetic. In addition, a possible direct
influence of a patient’s anthropometric and surgical fac-
tors on the physical properties of local anesthetics has
been reported (9, 10, 14–16).
In Jordan, smoking and obesity are becoming seri-
ous health concerns: smoking is endemic, with more
than 48% of adult males being smokers (17); and,
among Jordanian women 15–49 yr of age, the overall
prevalence of overweight is 30% and 38.8% are obese
(18). Therefore, the aim of this study was to assess
the influence of patients’ behavioral and anthropomet-
ric factors (gender, age, BMI, and smoking) and sur-
gical factors (difficulty of extraction, operation time,
and volume of local anesthetic needed) as independent
variables on the onset of action and duration of LA
in mandibular M3 surgery among healthy adult
patients.
2 Al-Shayyab & Baqain
Material and methods
This prospective study was conducted over 9 months,
from 1 April 2016 to 31 December 2016, in Amman, Jor-
dan. It was approved by the Research Ethics Committee
of the University of Jordan (reference number 10/2015/
24418) and was carried out in accordance with the Decla-
ration of Helsinki. Patients scheduled for surgical extrac-
tion of an impacted mandibular M3 under LA in the Oral
and Maxillofacial Surgery (OMFS) unit at the University
of Jordan Hospital (UJH) were invited to participate in
the study. Clinical and radiographic examinations utilizing
orthopantomographic images were used to determine M3
teeth that met the following inclusion criteria: patients
with American Society of Anesthesiologists (ASA) Scores
I and II (19); not on any preoperative medication; ≥18 yr
of age; no sign of active inflammation or infection at the
site of extraction; and willingness to abide by postopera-
tive recommendations. Regarding the M3 to be removed,
it had to be position A or B and Class I or II on Pell and
Gregory’s classification (20) and Grade II (bone removal
or tooth division), III (bone removal and tooth division),
or IV (the same as III but very difficult) of CAMPBELL
et al.’s (21) method of determining the difficulty of surgical
extraction procedure, and had to be in vertical or mesioan-
gular positions on Winter’s classification (22). Patients
were excluded if they were taking analgesics before sur-
gery; if they were pregnant or lactating women; if they
reported even mild systemic diseases; and if they smoked
anything other than cigarettes (e.g. cigar, narjila, and
pipe). Written informed consent was obtained from all
subjects.
Participants’ age, gender, BMI, and the quantity and
duration of cigarette smoking were recorded by an OMFS
resident not involved in the surgical procedure. Based on
the criteria set by the World Health Organization (WHO)
global database on BMI in adults (23), BMI was defined
as ‘the weight in kilograms divided by the square of the
height in meters (kg m 2)’ and was used to classify the
nutritional status of the patients: underweight for
BMI < 18.5; normal for BMI ≥ 18.5–24.9; overweight for
BMI ≥ 25–29.9; and obese for BMI ≥ 30. The BMI was
calculated for each patient and then, using WHO criteria
and similarly to a previous study (10), patients were classi-
fied into two groups: low-normal weight (LNW), for those
whose BMI was <25, and overweight-obese (OWO), for
those whose BMI was ≥25. Regarding cigarette smoking
status, this was defined according to the standard set by
the Centers for Disease Control and Prevention (CDC)
definition (24):
Smokers were identified as those who reported cigarette
smoking on a daily or occasional basis during the last
30 d (current smokers), or those who reported cigarette
smoking before, but reported cessation at the time of
survey (ex-smokers). Non-smokers were defined as those
who had never undertaken any type of smoking in their
lifetime.
The quantity and duration of cigarette smoking in the
current study were defined and recorded similarly to previ-
ous studies (25, 26). The quantity was defined as the aver-
age number of cigarettes consumed per day in the
smoking period(s) of the patient’s lifetime. Subjects were
accordingly classified as light smokers (≤10 cigarettes d 1)
and moderate to heavy smokers (>10 cigarettes d 1), and
compared with non-smokers. Smoking duration was
calculated after summing the number of smoking periods
and, accordingly, smokers were divided into two groups –
short (≤10 yr) and long (>10 yr) – and compared with
non-smokers.
The surgical procedures were performed by one of the
authors (M.A.). The operator was blinded to the indepen-
dent variables before administration of local anesthetic.
The anesthetic solution used was 2% lidocaine with
1:100,000 epinephrine, respecting the average volume rec-
ommended and employed for such experiments (10, 27,
28); 1.8 ml was administered over a 1-min period for
blocking the inferior alveolar and lingual nerves and
0.5 ml was administered over a 1-min period for blocking
the long buccal nerve. The anesthetic technique, as
described by MALAMED (2) and REED et al. (29), was
started by assuming the recommended position for both
the surgeon and patient, and identifying three landmarks,
namely the coronoid notch, the pterygomandibular raphe,
and the occlusal plane of mandibular posterior teeth. The
insertion point was approached from the contralateral pre-
molar area with a long needle positioned approximately
1.5 cm above the mandibular occlusal plane and placed
three-quarters of the anterior–posterior distance from the
coronoid notch back to the pterygomandibular raphe. The
mucosa was then pierced at the insertion point and the
needle was advanced until bony contact was felt, usually
at about 25 mm depth of penetration. Furthermore, bony
contact with mandibular lingula was assured to account
for variability in the anatomy and to ensure that the block
technique was performed in a standard manner. The nee-
dle was then withdrawn 1–2 mm and careful aspiration
was performed before depositing the recommended vol-
ume (1.8 ml) for inferior alveolar nerve and then lingual
nerve block anesthesia. Lastly, a further 0.5 ml of the
anesthetic was used to anesthetize the long buccal nerve
through infiltration lateral to retromolar triangle, which
would also aid hemostasis. All patients were asked to
report the initial perception of anesthetic effect (the first
report of lip and tongue numbness), which was recorded
as a subjective symptom. This was followed immediately
(30) by regular probing of the gingival tissues, bone and
periodontium of M3, and the patient’s first report of pain-
free probing was recorded as an objective sign. If the
patient did not report numbness of the lip within 5 min,
the block injection was judged to be unsuccessful and the
patient was excluded from the study. However, if the
patient experienced some pain during surgery, additional
amounts of infiltration or block anaesthesia were adminis-
tered at 0.5-ml increments and then the total volume used
was calculated.
The surgical procedure was performed in the same the-
atre using the same surgical instruments. A triangular
mucoperiosteal flap was elevated to provide access to the
M3 from the buccal approach. Bone removal was per-
formed using a round bur in a straight handpiece under
copious sterile irrigation. When tooth sectioning was
needed, a fresh tungsten carbide fissure bur was used
before elevation with a straight elevator. After complete
removal of the tooth, the socket was inspected to deter-
mine the need for curettage and removal of dental follicu-
lar or granulation tissues, and was then irrigated with
copious amounts of normal saline before repositioning
and suturing the flap with a 3-0 silk. Lastly, the patient
was asked to bite on a wet gauze pack designed to trans-
mit the pressure on the surgical site. Postoperatively, all
patients were given postsurgical instructions and drug

prescription consisting of a 5-d-course of a non-steroidal
analgesic and a mouthwash of 0.2% chlorhexidine diglu-
conate with use starting from the second day. Patients
were then discharged and instructed to record (on a given
paper) the moment when the effect of anesthesia started to
wear off. One week later, all patients were reviewed and
reported the recorded moment in which the effect of anes-
thesia began to fade, and the suture material was
removed.
The following variables were investigated in the present
study and recorded using the same method described in a
recent report (5): (i) Onset of action of LA, recorded
using an automatic timer by calculating the time from
removal of needle to the patient’s first report of lip and
tongue numbness as a subjective symptom and starting
pain-free extraction as an objective symptom (5). (ii)
Duration of LA, recorded by calculating the time from
the patient’s first report of lip and tongue numbness to
the moment when the effect of anesthesia started to wear
off (5). (iii) ‘Volume of local anesthetic needed’ (ml),
which was calculated by adding any additional amount of
local anesthetic to the respected volume administered for
each patient (5). (iv) Operation time (min), recorded by
calculating the time from commencing the incision to
placement of the last suture (5). (v) Difficulty of surgery,
measured by the same surgeon considering the pre-opera-
tive clinical and radiological assessment, the actual surgi-
cal experience recorded on completion of surgery, and
operation time (21, 31).
Power analysis
For this study, the power analysis was calculated using
statistical software package G*Power version 3.1.5 (Franz
Faul, Universit€at Kiel, Kiel, Germany). Post-hoc power
analysis was computed given a, sample size, and effect size.
A linear multiple regression model was set as a statistical
test to perform power analysis using a = 0.05, sample size
of 88 subjects valid for analysis, medium effect size = 0.15,
and an estimate of seven independent predictors. Analysis
computation yielded 72% power of this study.
Statistical analysis
Statistical analysis was performed using the Statistical
Package for Social Sciences for Windows version 19
(SPSS, Chicago, IL, USA). Descriptive statistics of both
patients’ and surgical variables, and the subjective and
objective onsets of action and duration of LA, were gener-
ated. Student’s t-test and one-way ANOVA were used to
analyze differences in the subjective and objective onsets
of action and duration of LA across potential predictor
variables: gender; age; BMI; difficulty of extraction; smok-
ing quantity and duration; operation time; and ‘volume of
local anesthetic needed’. When one-way ANOVA was used,
the statistical significance for each pair of means was
determined using post-hoc multiple comparisons. To
reduce the number of variables available for the multiple
linear regressions, variables with a univariate P < 0.1 were
included. Multiple linear regression analysis was then used
to determine the best predictors of the time to subjective
and objective onset of action and the duration of LA
among individual behavioral, anthropometric, and surgical
factors. For each significant predictor, calculation of
regression coefficients and 95% confidence intervals were
obtained. Statistical significance was set at P < 0.05.
Predictors of action of local anesthetics 3
Results
Of the 100 patients initially enrolled in the study, 12
(12%) were excluded because they failed to report lip
numbness within 5 min after administration of inferior
alveolar nerve block. Therefore, the final group com-
prised 88 participants: 32 (36.4%) men and 56 (63.6%)
women, with a mean age  SD of 29.3  12.3 yr (range:
18–72 yr). There were 37 patients with Grade II difficulty
of extraction, 41 with Grade III, and 10 with Grade IV.
Table 1 shows the descriptive statistics of both patients’
and surgical variables, and characteristics of the LA
used, overall and in the two main age groups (18–30 and
>30 yr of age). The average operation time was
33.3  13.9 min and an average volume of local anes-
thetic of 2.6  0.35 ml was needed. The average time to
onset of local anesthetic action was 119.8 (20.2) s for sub-
jective symptoms and 152.7 (30.3) s for objective symp-
toms. The average duration of LA was 234.9  21.8 min
(range: 200–280 min).
In the univariate analysis of independent variables
(Table 2), all patients’ variables and most surgical vari-
ables significantly (P < 0.001) influenced the time to
onset of action and the duration of LA; older age
(> 30 yr), male gender, being overweight, being a smo-
ker, longer operation time, and larger volumes of LA
needed were associated with an increase in mean values
of the time to subjective and objective onsets of action
and duration of LA. Differences among groups in
smoking quantity and duration were also statistically
significant (P < 0.001); post-hoc comparisons revealed
that this significance was found only for moderate to
heavy smokers and those who had smoked for a long
duration. Post-hoc comparisons also revealed signifi-
cant differences (P < 0.001) between every pair of ‘vol-
ume of local anesthetic needed’. However, differences
among groups of ‘difficulty of extraction’ variable were
not statistically significant.
When three separate multiple linear regression analyses
(Table 3) were conducted to identify the impact of inde-
pendent variables on the time to subjective and objective
onsets of action, and duration of LA, no multicollinearity
was detected [gender: Tolerance = 0.69, variance inflation
factor (VIF) = 1.44; age: Tolerance = 0.23, VIF = 4.35;
BMI: Tolerance = 0.39, VIF = 2.59; smoking quantity:
Tolerance = 0.43, VIF = 2.35; smoking duration: Toler-
ance = 0.27, VIF = 3.71; operation time: Toler-
ance = 0.61, VIF = 1.65; and ‘volume of local anesthetic
needed’: Tolerance = 0.36, VIF = 2.80]. When the effects
of other factors on the subjective and objective onsets of
action were controlled, age and smoking quantity main-
tained their significance (P < 0.001) and were found to be
the most important predictors of the time to subjective
and objective onsets of action. However, when the effects
of other factors on the duration of LA were controlled,
age, smoking quantity, and ‘volume of local anesthetic
needed’ maintained their significance (P < 0.001) and
were found to be the most important predictors of the
duration of LA. For each 1-yr increase in age, the time to
subjective onset of action would increase from 0.86 to
1.44 s (average 1.15 s), the time to objective onset of action
4 Al-Shayyab & Baqain

Table 1
Description of the study group and the distribution of present smoking habits, body mass index (BMI), operation time (OT), volume
of local anesthetic needed (VLA), the subjective onset of action (SOA), the objective onset of action (OOA), and duration of anes-
thesia (DA) (n = 88)

Age (yr) Smoker BMI OT (min) VLA (ml) SOA (s) OOA (s) DA (min)
Age group, (yr) Mean  SD n n (%) Mean  SD Mean  SD Mean  SD Mean  SD Mean  SD Mean  SD

18–30 22.4  3.1 61 23 (37.7) 23.1  2.4 29.5  13.2 2.5  0.30 110.2  10.1 138.2  20.7 223.5  12.4
>30 44.7  11.2 27 18 (66.7) 29.6  5.5 41.8  11.8 2.9  0.34 141.4  20.7 185.4  21.8 260.7  15.5
≥18 29.3  12.3 88 41 (46.6) 25.1  4.7 33.3  13.9 2.6  0.35 119.8  20.2 152.7  30.3 234.9  21.8

Table 2
Subjective onset of action (SOA), objective onset of action (OOA), and duration of anesthesia (DA) in relation to gender, age, body
mass index (BMI), difficulty of extraction, smoking quantity and duration, operation time, and ‘volume of local anesthetic needed’
(n = 88)

SOA (s) OOA (s) DA (min)

Variables n Mean SD P* Mean  SD P* Mean SD P*

Gender
Female 56 113.6  12.5 <0.001 143.4  23.1 <0.001 228.8  16.7 <0.001
Male 32 130.6  26.1 168.9  34.6 245.7  25.6
Age
18–30 (yr) 61 110.2  10.2 <0.001 138.2  20.7 <0.001 223.5  12.5 <0.001
>30 (yr) 27 141.4  20.7 185.4  21.9 260.7  15.5
BMI
LNO 54 111.5  12.4 <0.001 141.7  26.0 <0.001 227.6  16.9 <0.001
OWO 34 132.9  23.4 170.1  28.7 246.5  23.9
Difficulty
Grade II 37 115.4  17.1 0.169 145.2  27.6 0.117 230.5  22.1 0.270
Grade III 41 124.0  23.1 156.9  31.9 238.4  21.3
Grade IV 10 118.6  15.9 163.3  29.7 237.1  21.8
Smoking
No 47 111.1  11.0 <0.001 139.9  19.9 <0.001 225.6  15.9 <0.001
Yes 41 129.8  23.7 167.3  33.6 245.6  23.0
Smoking quantity
No 47 111.1  11.0 <0.001 139.9  19.9 <0.001 225.6  15.9 <0.001
1–10 cigarettes d 1 17 115.2  20.1 142.5  26.9 230.5  20.6
>10 cigarettes d 1 24 140.1  20.6 184.9  26.0 256.3  18.3
Smoking duration
No 47 111.1  11.0 <0.001 139.9  19.9 <0.001 225.6  15.9 <0.001
≤10 (yr) 27 119.4  17.5 152.6  29.1 233.0  15.6
>10 (yr) 14 149.8  21.1 195.8  21.2 269.9  12.8
Operation time
≤30 (min) 52 109.0  8.7 <0.001 135.3  17.4 <0.001 222.8  12.6 <0.001
>30 (min) 36 135.4  22.0 177.8  27.1 252.5  20.3
Volume of local anesthetic needed
2.3 ml 48 108.9  8.4 <0.001 134.6  15.5 <0.001 221.9  12.2 <0.001
2.8 ml 32 128.3  20.4 168.9  27.4 246.8  18.7
3.3 ml 8 150.6  22.9 196.4  28.3 265.6  12.5

LNO, low-normal weight; OWO, overweight-obese.

*P-value of Student’s t-test or ANOVA.

would increase from 1.15 to 2.13 s (average 1.64 s), and
the duration of LA would increase from 0.78 to 1.56 min
(average 1.17 min) (Fig. 1). Moderate to heavy smokers
reported delayed subjective and objective onsets of action
of 8–20 s (average 14.08 s) and 16–36 s (average 25.85 s),
respectively, and the duration of LA was prolonged by 5–
21 min (average 13.1 min), compared with non- and
light-smoker groups. Additionally, for every 1 ml
increase in the ‘volume of local anesthetic needed’, the
duration of LA increased by 2.94–26.15 min (average
14.55 min).
Discussion
Ample literature (4, 5, 27, 32, 33) has compared differ-
ent types, volumes, and concentrations of local anes-
thetics with the aim of improving the physical
 Predictors of action of local anesthetics 5

Table 3
Models of multiple regression analysis in predicting the influence of patients’ and surgical variables (n = 88) on the subjective and
objective onset of action, and duration of anesthesia

Measure Predictors B SE B 95% CI (B) P

Subjective onset of action (s) Constant 65.98 10.59 44.90 to 87.05 <0.001
Gender (female* vs. male) –1.13 2.14 –5.40 to 3.13 0.598
Age (yr) 1.15 0.15 0.86 to 1.44 <0.001
BMI –0.02 0.29 –0.61 to 0.57 0.943
Smoking quantity (others* vs. moderate-to-heavy) 14.08 2.96 8.20 to 19.96 <0.001
Smoking duration (yr) 0.02 0.18 –0.34 to 0.39 0.907
Operation time (min) –0.04 0.08 –0.21 to 0.12 0.588
Volume of local anesthetic needed (ml) 7.20 4.38 –1.52 to 15.92 0.104
R2 = 0.85
Objective onset of action (s) Constant 70.83 17.97 35.07 to 106.58 <0.001
Gender (female* vs. male) –0.79 3.64 –8.02 to 6.45 0.829
Age (yr) 1.64 0.25 1.15 to 2.13 <0.001
BMI –0.48 0.50 –1.47 to 0.52 0.345
Smoking quantity (others* vs. moderate-to-heavy) 25.85 5.01 15.87 to 35.82 <0.001
Smoking duration (yr) –0.33 0.31 –0.95 to 0.29 0.289
Operation time (min) 0.27 0.14 –0.01 to 0.55 0.054
Volume of local anesthetic needed (ml) 12.31 7.43 –2.48 to 27.10 0.102
R2 = 0.81
Duration of anesthesia (min) Constant 168.99 14.10 140.93 to 197.05 <0.001
Gender (female* vs. male) –1.42 2.85 –7.10 to 4.26 0.620
Age (yr) 1.17 0.20 0.78 to 1.56 <0.001
BMI –0.37 0.39 –1.15 to 0.41 0.344
Smoking quantity (others* vs. moderate-to-heavy) 13.10 3.93 5.27 to 20.93 0.001
Smoking duration (yr) –0.04 0.24 –0.52 to 0.45 0.879
Operation time (min) 0.02 0.11 –0.19 to 0.24 0.825
Volume of local anesthetic needed (ml) 14.55 5.83 2.94 to 26.15 0.015
R2 = 0.78

B, nonstandardized regression coefficient; BMI, body mass index; SE, standard error.
*Reference category.

properties and providing the best clinical actions. This
study evaluated the clinical actions of dental LA, in
relation to behavioral, anthropometric and surgical fac-
tors among healthy adult patients. The sample size
included subjects 18–72 yr of age, which was a wider
age range than in the majority of studies investigating
LA and M3 surgery (28, 33). Two per cent (2%) lido-
caine was used in this study as it is still the most widely
used local anesthetic and considered a reference for any
new local anesthetic product (2). In this study, the min-
imum recommended dose of local anesthetic solution
was used (5); NUSSTEIN et al. (27) proved no significant
difference in the success of inferior alveolar nerve block
with either 1.8 ml or 3.6 ml volumes of lidocaine with
epinephrine. Earlier studies assessed time to onset and
the duration of action of LA using two methods: elec-
tric pulp testing (32); and patients’ evaluation based on
the perception of the anesthetic effect (5, 33). Despite
the limitations of both techniques, the authors chose
the latter as it is more applicable to M3 surgery and
has been used to assess the above parameters in inferior
alveolar nerve block anesthesia (33, 34). In this study,
the patient’s first report of lower lip and tongue numb-
ness was recorded as a subjective onset of local anes-
thetic action because it is a good indicator of inferior
alveolar nerve and lingual nerve anesthesia but not a
reliable indicator of the depth of LA and pain-free
extraction. By contrast, pain-free probing was recorded
as an objective onset of local anesthetic action because
it is a reliable indicator of the depth of LA and pain-
free extraction (2). Although the number of subjects
included in this study was greater than in previous
studies that used similar methods (5, 30, 33), analysis
computation yielded 72% power, which could be con-
sidered reasonable for such a clinical study implement-
ing appropriate selection criteria of patients scheduled
for mandibular M3 surgery across a 9-month period.
In this study, some precautions were taken by the
researchers to assure more control over the extraneous
variables that may affect reliability and validity of the
results (35); thus, to eliminate operator’s experience as
a confounding variable, only a single surgeon (M.A.)
delivered the local anesthetic solution to all patients
and performed all surgeries for the purpose of this
study. The average values of the time to subjective and
objective onsets of action, and duration of LA,
recorded in this study were in accordance with the find-
ings in other studies (5, 30).
For accurate evaluation of the time to subjective and
objective onsets of action, and duration of LA, the sig-
nificant independent predictors had to be controlled
using multivariate regression analysis. In this study, age
and smoking quantity were the only independent predic-
tors of the time to subjective and objective onsets of
action. By contrast, age, smoking quantity, and ‘volume
of local anesthetic needed’ were the only independent
6 Al-Shayyab & Baqain
Fig. 1. Scatter diagrams with regression lines showing the
existing exact effects of age increase on (A) the subjective
onset of action, (B) the objective onset of action, and (C) the
duration of anesthesia.
predictors of the duration of LA. However, future stud-
ies should seriously consider these factors. In the multi-
variate regression model, age and smoking quantity
were able to explain only 85% (R2) of the variation in
the subjective onset of action and 81% (R2) of the differ-
ences in the objective onset of action. Age, smoking
quantity, and ‘volume of local anesthetic needed’ were
able to explain only 78% (R2) of the variation in the
duration of LA. These prediction rates are considered to
be high but require further study to identify other pre-
dictors explaining the variations in the subjective and
objective onsets of action, and duration of LA, as
demonstrated in this study. Cigarette smoke contains
many active substances, some of which may potentiate
or have antagonistic pharmacological effects on a certain
drug, thereby altering its clinical pharmacodynamics
and efficacy (6). Smoking leads to local tissue hypoxia
which affects the vascularity of the tissue (7) as well as
the intracellular and extracellular pH of specific tissues
(8). The gingival blood vessels in smokers, for example,
have shown decreased blood flow and respond to the
use of local anesthetic solution containing epinephrine
differently from those of non-smokers (36). Further-
more, it has been shown that nicotine affects the pro-
tein-binding property of lidocaine (6) and has a
stimulatory effect on a number of sensory receptors in
the peripheral nervous system (37). Indeed, prolonged
subjective and objective onsets of action and duration of
LA are associated with an increase in the pH of the
injection site and the protein-binding properties of the
local anesthetic agent, and a decrease in vascularity of
the injected tissue (2, 3, 5). To the authors’ knowledge,
the quantity and duration of smoking have not previ-
ously been considered in relation to the physical proper-
ties and clinical actions of a given local anesthetic.
Nevertheless, the abovementioned potentiating and
antagonistic pharmacological effects of smoking could
explain the differences in the time to onset of action and
the duration of LA found in this study between moder-
ate and heavy smoker, and non- and light-smoker
groups. However, although smoking quantity main-
tained significance in the multivariate analysis, differ-
ences between the groups of smoking duration lost their
statistical significance; it is possible that smoking has
dose-related, rather than accumulative, vascular and tis-
sue effects (24). Similarly, it is known that older age is
associated with an increase in the time to onset of action
and the duration of LA (14). Older age is associated
with a variety of physiological and pathological changes
in the oral hard and soft tissues (38). The bone mineral
density (BMD) of the mandibular body and ramus was
demonstrated to be significantly age-related and greater
at all sites of the mandible than of the maxilla (39), par-
ticularly in patients over 30 yr of age (31). Age-related
changes in enamel, dentine, and cementum tend to
reduce the perception of pain (40), and to make teeth
brittle and susceptible to fracture during extraction (38).
Some oral tissues, such as the pulp of teeth, may
undergo age-related physiological and reactive changes;
they become less vascular, less cellular, more fibrotic,
and have a reduced nerve supply (11). There are also
age-related changes in the peripheral nerve function,
resulting in loss of receptors and a reduction in conduc-
tion velocity (11). Furthermore, changes in the intracel-
lular and extracellular pH of specific tissues (12),
changes in protein binding of the drugs, and changes in
the mechanical and structural properties of the vascular
wall (13), have all been reported as age-related and hav-
ing possible significant clinical implications. Indeed,

these age-related changes would result in reduced diffu-
sion and induction of the local anesthetic, preservation
of the local anesthetic solution in the injected site for
longer periods, an increase in the difficulty of extraction,
a reduced response to injury, and decreased healing
potential (2, 11, 31, 38). This may explain the significant
positive relationship between increased time to onset of
action (subjective and objective) and duration of LA,
and age, as demonstrated in this study. Lastly, it is
known that a greater volume of local anesthetic adminis-
tered results in a longer duration of LA; it provides a
larger number of lipophilic molecules for diffusion and
dissociation to the active cation form through the nerve
membrane, once intraneural local anesthetic molecules
begin to diffuse out of the nerve (2, 27, 41, 42). In this
study, the univariate significant influence of the ‘volume
of local anesthetic needed’ on the duration of LA was
real and therefore was maintained as one of the most
important predictors in the multivariate analysis.
Regarding gender, it is known that lidocaine could
have a larger distribution volume and plasma protein-
binding properties in women than in men. In addition,
the adverse drug effects with local anesthetics seem to
be more frequent in women than in men (9, 43). How-
ever, there is very little information on the influence of
gender on the efficacy of LA (9, 15, 16) and gender dif-
ferences have not been demonstrated to date (44). The
relationship between BMI and the pharmacokinetics of
local anesthetics, such as plasma protein-binding prop-
erties, does not appear to be significant (45). In this
study, when multivariate analysis was applied, gender
and BMI lost their significant influence on the subjec-
tive and objective time to onset of action, and the dura-
tion of LA parameters. This is consistent with a few
studies that reported no influence of patient’s gender
and BMI on the clinical effectiveness of inferior alveo-
lar nerve block anesthesia (9, 10). One possible expla-
nation is that the influence of the latter factors was not
independent and affected by other predictors, highlight-
ing the need for multivariate analysis. Some investiga-
tors reported a correlated influence of gender, race and
age, and BMI (46). Therefore, when the effects of all
anthropometric factors were considered, the significant
gender and BMI differences disappeared in multivariate
analysis. Finally, although operation time and ‘volume
of local anesthetic needed’ have been linked to
increased difficulty of extraction and duration of LA
(5, 31), the present study showed no significant influ-
ence of the difficulty of extraction and operation time
on duration of LA; this could be attributed to the
method of measuring difficulty (31) adopted in this
study and indicates that the influence of these surgical
factors was not independent, once again highlighting
the need for multivariate analysis.
Acknowledgements – The authors would like to thank Dr. Mah-
mood Nassif, OMFS resident, for his help in recording patients’
details.
Conflicts of interest – The authors have no conflict of interests
and the work was not supported or funded by any drug company.
Predictors of action of local anesthetics 7
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