Comparison of Three Anxiety

Management Protocols for Extraction

of Third Molars With the Use of
Midazolam, Diazepam, and Nitrous
Oxide: A Randomized Clinical Trial
Michelle Bianchi de Moares, DDS, MS, PhD,* Winnie Souza Barbier, DDS,y
Fernando Vagner Raldi, DDS, MS, PhD,z Rodrigo Dias Nascimento, DDS, MS, PhD,x
ucio Murilo dos Santos, MD, MS, PhD,k and F

L
abio Ricardo Loureiro Sato, MD, MS, PhD{
Purpose: The objective of the present study was to compare 3 sedation protocols using diazepam, mid-
azolam, and nitrous oxide.
Patients and Methods: A total of 120 patients with an indication for extraction of third molars were
selected. All 120 patients had had moderate to severe levels of anxiety according to the Corah Dental Anx-
iety Scale. The patients were randomly divided into 3 groups. The patients’ vital signs were measured, and
the results analyzed by descriptive statistical analysis and statistical tests of comparison.
Results: No statistically significant differences were found in the patients’ heart rate. However, the dif-
ferences in the systolic and diastolic blood pressure were statistically significant after 15 minutes of nitrous
oxide sedation. The oximetry data showed no differences among the 3 sedation protocols. We also found
no statistically significant differences in the retrograde amnesia test. The differences in anxiety from pre-
operatively to postoperatively were statistically significant for all techniques, demonstrating their effective-
ness in anxiety control.
Conclusions: All 3 preoperative sedation techniques for anxious patients undergoing extraction of third
molars used in the present study were effective in controlling the anxiety, with little effect on the patients’
vital signs and retrograde amnesia.
Ó 2019 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 77:2258.e1-2258.e8, 2019

The fear of dental procedures is real and can be consid- estimated that 6 to 14% of the population will avoid
ered one of the main reasons many patients avoid seeking dental treatment because of fear. These
dental treatment. In the United States, it has been patients have been classified as being highly anxious,

Received from College of Dentistry, State University of S~ao Paulo, S~ao
Jos
e dos Campos, Brazil.
*Assistant Professor, Oral and Maxillofacial Surgery Area,
Department of Diagnosis and Surgery.
yDDS Student, Oral and Maxillofacial Surgery Area, Department
of Diagnosis and Surgery.
zAssistant Professor, Oral and Maxillofacial Surgery Area,
Department of Diagnosis and Surgery.
xAssistant Professor, Oral and Maxillofacial Surgery Area,
Department of Diagnosis and Surgery.
kAssistant Professor, Department of Biosciences and Oral
Diagnosis.
{Assistant Professor, Oral and Maxillofacial Surgery Area,
Department of Diagnosis and Surgery.
Conflict of Interest Disclosures: None of the authors have any
relevant financial relationship(s) with a commercial interest.
Address correspondence and reprint requests to Dr Sato: Oral and
Maxillofacial Surgery Area, Department of Diagnosis and Surgery,
College of Dentistry, State University of S~ao Paulo, Av Eng Francisco
Jos
e Longo, 777, S~ao Jos
e dos Campos, SP 12245-000, Brazil; e-mail:
fabio.sato@ict.unesp.br
Received February 11 2019
Accepted June 7 2019
Ó 2019 American Association of Oral and Maxillofacial Surgeons
0278-2391/19/30629-9
https://doi.org/10.1016/j.joms.2019.06.001

2258.e1
DE MOARES ET AL
and they represent a double challenge for the profes-
sional treating their dental complaints owing to the
need to also manage these patients’ psychologi-
cal anxiety.1
At present, we have a wide variety of local anes-
thetic drugs available, enabling us to control our
patients’ pain more efficiently in daily clinical practice.
However, even in the absence of painful stimuli, many
patients will still experience high anxiety.2 In addition
to the local anesthetic drugs, sedation techniques are
available that can be used to alter the patient’s con-
sciousness state and lead to a decrease in anxiety.
This technique is termed sedation, which according
to the American Dental Association in 2016, is defined
as the ‘‘minimally depressed level of consciousness al-
lowing the patient to keep his or her airway func-
tioning independently and to respond to physical
stimulation and verbal commands accordingly, which
is achieved by means of pharmacological and non-
pharmacological methods or a combination of both.’’3
In the reported data, several techniques have been
described for performing sedation using oral and inha-
lation techniques. Of the oral sedatives, benzodiaze-
pines have been the most used, in particular,
diazepam and midazolam, with nitrous oxide the
most commonly used agent of the inhalation
techniques.
Benzodiazepines have been the most commonly
used antianxiety agents. They act as a central nervous
system depressant, producing sedation and hypnosis.
After oral administration, most benzodiazepines will
be rapidly absorbed and become highly bound to
plasma protein. The peak blood concentration will
generally occur within 1 to 3 hours. However, the ef-
fect of the different drugs from this pharmacological
class differ in their lipid-soluble capacity. Diazepam,
for example, will accumulate in body fat, and this char-
acteristic partially accounts for the prolonged half-life,
which can range from 1 to as many 8 days. In contrast,
midazolam has a very short half-life elimination period,
which varies from 2 to 5 hours.4
The mechanism of action of the nitrous oxide is still
unknown; however, almost all forms of sensation will
become depressed (eg, sight, hearing, touch, pain).
Memory will be affected to a minimal degree, similar
to the ability to concentrate or perform acts requiring
logical reasoning. When administered with a physio-
logical level of oxygen (>20%), nitrous oxide will pro-
duce mild depression of the central nervous system,
primarily in the cerebral cortex. The main advantages
of the inhalation techniques compared with the oral
sedation such as benzodiazepines, include the rapid ef-
fects, with the peak concentration occurring within
3 to 5 minutes, variable duration of action, and that
it can be titrated, allowing a rapid return to normal
2258.e2
activity. The major disadvantage is the cost, mainly
for the equipment.5
Regardless of the sedation technique used, it is
essential that it should be well accepted by the patient
and safe, not compromising the airways or promoting
hyperventilation or bradycardia. The ideal anxiolytic
drug should change the vital signs only minimally, pro-
mote rapid recovery, and be associated with a low inci-
dence of adverse reactions.6
A doubt frequently raised by practitioners is which
technique or medication should be indicated for seda-
tion of a patient because few comparative studies have
been performed. Therefore, the aim of the present
study was to perform a comparative analysis of seda-
tion techniques using midazolam, diazepam, and
nitrous oxide for tooth extraction of third molars in
anxious patients.
Patients and Methods
STUDY DESIGN
The method of the present study followed the CON-
SORT (consolidated standards of reporting trials)
guidelines for publication.7,8 The local research
ethics committee approved the present clinical
randomized trial (approval no. CAAE:
49562015.0.0000.0077), which was registered at
ClinicalTrials.gov (identifier NCT03165500). In the
present clinical trial, 120 subjects aged 18 to
30 years with an indication for extraction of upper
third molars were selected. All the patients had an
American Society of Anesthesiologists (ASA)
classification of I and had moderate to severe anxiety
using the Corah Dental Anxiety Scale (DAS).9
PATIENTS
The included patients were those who had volun-
tarily presented to the Department of Oral and Maxil-
lofacial Surgery for extraction of a totally impacted
upper third molar in a vertical position.
The inclusion criteria were as follows:
1. ASA classification I requiring extraction of an up-
per third molar
2. Age 18 to 30 years
3. Provision of written informed consent
4. Moderate to severe anxiety using the Corah DAS
The exclusion criteria were as follows:
1. The presence of any local or systemic issue that
contraindicated the procedure
2258.e3 COMPARISON OF THREE ANXIETY MANAGEMENT PROTOCOLS FOR THIRD MOLAR SURGERY
2. The use of anti-inflammatory medication or
adrenergic antagonists within the previous
15 days
3. Refusal of written informed consent
4. The presence of mild anxiety only
Initially, the sample had included 380 patients who
had required upper third molar tooth extraction. After
the anamnesis and initial clinical examination, 260 pa-
tients were excluded from the sample for the
following reasons: the presence of mild anxiety
(n = 124), the presence of a systemic issue (n = 89),
the use of proscribed medication (n = 27), and refusal
to participate in the research, for 120 patients in the
final sample (Fig 1).
SAMPLE SIZE
We assumed a standard deviation of 10 on a 100-
point scale. With this assumption, a sample size of at
least 88 patients would be required for an 80% chance
of detecting, at a significance level of 5%, a decrease in
the primary outcome measure from 98 in the control
group to 92 in the experimental group.
GROUP ALLOCATION
The patients were randomly divided into 3 groups of
40 patients each and received a different anxiety man-
agement protocol:
 Group I: sedation with 5 mg of diazepam orally
30 minutes before the beginning of the surgery
 Group II: sedation with 7.5 mg of midazolam
orally 30 minutes before the beginning of the sur-
gery
 Group III: sedation with 40% nitrous oxide and
60% oxygen via inhalation using a Porter MXR
3000 flowmeter (Parker Hannifin, Hatfield, PA)
5 minutes before the beginning of the surgery
For groups I and II, sedation was administered 30 mi-
nutes before the surgery to achieve the peak plasma
levels of the orally administered sedatives at the time
of procedure. For group III, sedation was administered
5 minutes before the procedure to reach the percent-
age of 40% nitrous oxide and 60% oxygen at the time of
the procedure.
Midazolam is available in tablet form at a 7.5- or
15-mg dose. Studies such as that by Luyk and Whitley10
have demonstrated that a 7.5-mg dosage will result in
significant anxiolysis and amnesia, with patient prefer-
ence for this type of sedation. In addition, the 7.5-mg
dose is far from the maximum dosage, which should
never exceed 20 mg.5
Diazepam in tablet form is available at a 5- or 10-mg
dose. Aeschliman et al11 demonstrated that a 5-mg
FIGURE 1. Flowchart of the sample selection.
de Moares et al. Comparison of three anxiety management proto-
cols for third molar surgery. J Oral Maxillofac Surg 2019.
diazepam dosage provided good control of stress and
anxiety with no significant respiratory depression
and below the maximum dosage of 10 mg.5
The patient’s vital signs (ie, blood pressure, heart
rate, oxygen saturation) were measured and recorded
before and after sedation (30 minutes after oral seda-
tion and 5 minutes after inhalation sedation), as well
as during surgical procedure and 15 minutes after
tooth extraction.
SURGICAL PROCEDURE
All upper third molar tooth extraction procedures
were performed by the same surgeon (F.V.R.) at the
oral and maxillofacial surgery clinic. The patients un-
derwent antisepsis using 0.2% chlorhexidine digluco-
nate, followed by placement of surgical drapes for
delimitation of the contamination area. Next, anes-
thesia was performed by blockage of the posterior
alveolar nerve, with palatal complementation at the
side of the upper tooth to be extracted using 1 tube
with 1.8 mL of 2% mepivacaine hydrochloride and
epinephrine at a 1/100,000 ratio per tooth. Only an
additional 0.9 mL (one half tube) was allowed for
complementation of anesthesia. If more than that
was required, the patient was excluded from the pre-
sent sample. A straight incision was made on the tuber
region using a no. 15C surgical blade, followed by
another intrasulcular incision in the interdental papilla
between the molars. Next, a full-thickness flap was
created using a Molt dissector until adequately
exposing the surgical field for tooth extraction. Osteot-
omy and odontosection were performed after eleva-
tion of the mucoperiosteal flap, and, whenever
needed, a no. 4 spherical burr at high speed was
used with abundant irrigation using 0.9% saline
DE MOARES ET AL 2258.e4

Table 1. DEMOGRAPHIC PATIENT DATA

Variable Midazolam Diazepam Nitrous Oxide Total Sample

Patients (n) 40 40 40 120

Age (yr) 22.9  5.3 23.2  7.3 21.8  5.6 22.6  6.2
Gender (n)
Male 13 10 18 41
Female 27 30 22 79

de Moares et al. Comparison of three anxiety management protocols for third molar surgery. J Oral Maxillofac Surg 2019.

solution. The third molar was extracted using Seldin
(straight and angled) and Potts elevators. Next, the
transoperative vital signs were assessed, followed by
inspection of the cavity, and abundant irrigation with
0.9% saline solution. The flap was repositioned and su-
tured using 4-0 silk thread (Ethicon, Johnson & John-
son, S~ao Paulo, SP, Brazil).
After the surgical procedure, the patients remained
in the recovery room of the dental clinic where the
tooth extraction had been performed. They were
monitored throughout the recovery period and were
released only after their vital signs had returned to
normal, including responsiveness to verbal commands
and lucidity. The duration was for at least 15 minutes
after the end of the procedure, when the vital signs
were measured. Those patients sedated with nitrous
oxide also underwent the Trieger test, in accordance
with recommendations, to determine the patient’s re-
covery after sedation.12
ANXIETY ASSESSMENT
The patients were initially asked to complete the
Corah DAS to determine their level of anxiety before
the surgical procedure.9 At 15 minutes after the end
of the surgery, the patients were invited to complete
the DAS to determine whether the sedation technique
used had been effective in controlling the patient’s
anxiety.
VITAL SIGN ASSESSMENT
The vital signs assessed were the blood pressure,
heart rate, and oxygen saturation, which were
measured before sedation, 30 minutes after oral seda-
tion and 5 minutes after inhalation sedation, during
the surgical procedure; and 15 minutes after the surgi-
cal procedure. The values of these vital signs were re-
corded on the dental surgery record chart.
RETROGRADE AMNESIA ASSESSMENT
Retrograde amnesia was assessed using 6 images
shown to the patients at intervals of 5 seconds. Three
of the images (image 1, an apple; image 2, a car; and
image 3, swimming) were shown to the patients
before sedation and the other 3 (image 4, an airplane;
image 5, a watermelon; and image 6, a football game)
after sedation (30 minutes after oral sedation and 5 mi-
nutes after inhalation sedation). The same images were
shown to the patients after the surgical procedure but,
this time, mixed with another 6 images (ie, an orange,
a helicopter, a motorcycle, grapes, a volleyball game,
and tennis). The patients were asked whether the im-
ages were the same as those previously shown to

Table 2. DATA FROM ANALYSIS OF HEART RATE

Heart Rate (bpm)

Measurement Point Midazolam Diazepam Nitrous Oxide P Value

Before sedation 82.56  13.82 84.52  13.95 81.92  11.28 .790

15 Minutes after sedation 80.86  12.47 82.50  15.26 77.59  11.34 .307
End of surgery 80.85  13.08 80.72  14.92 76.56  13.08 .208
15 Minutes after surgery 79.56  13.94 80.67  11.36 77.20  11.15 .316
P value .733 .719 .107 NA

Note: Data presented as mean  standard deviation.

Abbreviation: NA, not applicable.
de Moares et al. Comparison of three anxiety management protocols for third molar surgery. J Oral Maxillofac Surg 2019.
2258.e5 COMPARISON OF THREE ANXIETY MANAGEMENT PROTOCOLS FOR THIRD MOLAR SURGERY

them. The total score for matches was compared be-

DBP (mm Hg)

tween the groups to verify the retrograde amnesia of
the sedation method.13

<.05
.176
.274
.94

NA
SUBJECTIVE EVALUATION
P Value

At 7 days after the tooth extraction, the patients

SBP (mm Hg)

were given a questionnaire to assess their transopera-

tive comfort, sedation-related amnesia, and possible
<.05
.714

.504
.58

NA adverse effects.

STATISTICAL ANALYSIS
The Shapiro-Wilk normality test was used to verify
DBP (mm Hg)

7.25  1.22
6.20  1.03
6.61  1.33
7.58  0.99

whether the resulting data had followed a normal dis-

<.05

tribution pattern for further statistical analysis with

SPSS software, version 11 (IBM Corp, Armonk, NY).
Nitrous Oxide

Analysis of variance (ANOVA) and Tukey’s test were

used for parametric data (ie, oxygen saturation, retro-
grade amnesia) and the Kruskal-Wallis test for nonpara-
SBP (mm Hg)

11.64  1.54
10.43  0.99
11.28  1.23
11.97  1.30

metric data (ie, heart rate, blood pressure).

<.05

de Moares et al. Comparison of three anxiety management protocols for third molar surgery. J Oral Maxillofac Surg 2019.

Results
PATIENT RECRUITMENT
The patients were initially asked to complete the
DBP (mm Hg)

7.37  0.89
7.15  0.76
6.95  1.43
6.60  2.23

Corah DAS during the clinical interview for selection

Abbreviations: DBP, diastolic blood pressure; NA, not applicable; SBP, systolic blood pressure.
.647

of those with moderate to severe anxiety.9 This scale

ranges from 4 to 20 points, with a score of less than
Diazepam

11 points indicating low anxiety, 11 to 15 points indi-

Table 3. DATA FROM ANALYSIS OF SYSTOLIC AND DIASTOLIC BLOOD PRESSURE

cating moderate anxiety, and greater than 15 points

indicating severe anxiety. Therefore, those patients
SBP (mm Hg)

11.82  1.10
11.47  1.17
11.60  1.23
11.87  1.30

with a score of less than 11 points were excluded

.228

from present study. The score was also used as a base-

line for the assessment of the sedation techniques. The
included patients were also asked to complete the vi-
sual analog scale for anxiety, with the score ranging
DBP (mm Hg)

from 0 (not at all anxious) to 10 (highly anxious).

7.29  1.07
6.95  0.89
6.87  1.72
7.07  1.61

The patients recruited for the present study were fol-

.413

lowed for 7 days. Their demographic data are listed

in detail in Table 1.
Midazolam

Note: Data presented as mean  standard deviation.

VITAL SIGNS
SBP (mm Hg)

11.70  1.55
11.29  1.38
11.39  1.39
11.73  1.74

Heart Rate
.389

After analyzing the data on heart rate using the

Kruskal-Wallis test, no differences were found among
the 3 groups nor among the experimental periods
(before, during and after surgery; Table 2).
15 Minutes after sedation

15 Minutes after surgery

Blood Pressure
For blood pressure, the data were divided into 2 sub-
Measurement Point

groups: systolic blood pressure (SBP) and diastolic

Before sedation

End of surgery

blood pressure (DBP), which were compared indepen-

dently. Because these data were nonparametric, both
P value

subgroups were evaluated using the Kruskal-Wallis

test, which showed a statistically significant difference
only for SBP after 15 minutes of sedation. With
DE MOARES ET AL 2258.e6

Table 4. DATA FROM THE OXIMETRIC ANALYSIS

Oxygen Saturation (%)

Measurement Point Midazolam Diazepam Nitrous Oxide P Value

Before sedation 97.00  2.26 98.00  1.43 97.25  1.90 .057

15 Minutes after sedation 97.22  3.87 98.05  1.05 98.31  1.13 .142
End of Surgery 97.90  1.80 98.12  1.22 98.02  1.83 .830
15 Minutes after surgery 98.22  1.69 98.01  1.01 97.85  1.52 .516
P value .124 .96 < .05 NA

Note: Data presented as mean  standard deviation.

Abbreviation: NA, not applicable.
de Moares et al. Comparison of three anxiety management protocols for third molar surgery. J Oral Maxillofac Surg 2019.

administration of nitrous oxide, the SBP was also lower
compared with that in the other groups (Table 3). The
Kruskal-Wallis test also showed that the only statisti-
cally significant difference for DBP occurred after
15 minutes of sedation, with the DBP lower in the
nitrous oxide group compared with that in the midazo-
lam and diazepam groups (Table 3).
Oximetry
The results of the ANOVA and Tukey’s test showed
no differences among the 3 methods of sedation in
oxygen saturation. However, a difference was found
when comparing the oxygen saturation among the
experimental periods for nitrous oxide (Table 4).
RETROGRADE AMNESIA
The data for retrograde amnesia were analyzed using
ANOVA. However, no statistically significant differ-
ences were found among the 3 groups of sedation
for retrograde amnesia (P = .621; Table 5).
ANXIETY ASSESSMENT
The data from the Corah DAS were analyzed using
ANOVA and Tukey’s test. The results demonstrated a
statistically significant difference between the mean
value obtained at the first visit (DAS score,
14.5  2.2) and that obtained at the end of the surgical
procedure for all 3 sedation techniques (midazolam,
11.5  1.8; diazepam, 11.4  1.8; nitrous oxide,
11.7  2.1). However, no difference was found among
the techniques (Fig 2).
Discussion
In an interview of a group of dentists, 57% reported
that the most stressful factor in their professional prac-
tice was the so-called difficult patient, especially those
with a high level of anxiety.14 The attempt to perform
any type of treatment for these patients without ad-
dressing their fears and anxieties will result in frustra-
tion and much stress for the professional, which, in
turn, significantly increases the patients’ level of fear.1
The anxiety of patients undergoing dental surgical
procedures, such as extraction of third molars, has
become habitual and has been shown to be directly
related to the pain patients’ will experience. Knowing
the procedure and sharing experiences can lead to an
increase in the anxiety level of patients, which quan-
tifies the experience of pain.15 Patients who become
very anxious about surgical procedures will

Table 5. DATA FROM ANALYSIS OF RETROGRADE

AMNESIA*

Protocol Matches (n)

Midazolam 5.36  0.91

Diazepam 5.52  0.84
Nitrous oxide 5.53  0.88

Note: Data presented as mean  standard deviation.

* P = .621. FIGURE 2. Data from the Corah Dental Anxiety Scale.
de Moares et al. Comparison of three anxiety management proto- de Moares et al. Comparison of three anxiety management proto-
cols for third molar surgery. J Oral Maxillofac Surg 2019. cols for third molar surgery. J Oral Maxillofac Surg 2019.
2258.e7 COMPARISON OF THREE ANXIETY MANAGEMENT PROTOCOLS FOR THIRD MOLAR SURGERY
experience more pain during the postoperative period
than will those who were less anxious in the preoper-
ative period.15,16 Therefore, the use of sedation by
professionals has been increasing to allow greater
ease with, and better performance of, surgical
procedures.17
A systematic review assessed the effectiveness of
midazolam in the management of anxiety for extrac-
tion of third molars. The review included studies of
both oral and intravenous sedation and concluded
that this medication can be efficient in relieving
patients’ anxiety and can be administered safely, either
alone or in association with other drugs.18
A comparative study on the effects of the oral admin-
istration of diazepam and midazolam on the vital signs
of patients undergoing surgery for impacted lower
third molars found statistically significant differences
related to an increase in heart rate in most of the mid-
azolam groups and in the DBP in 2 diazepam groups.19
By analyzing the blood pressure after sedation, we
found that the DBP and SBP were significantly
different statistically only after 15 minutes of sedation.
However, another study using the same benzodiaze-
pines that we had used, but with a different applica-
tion method (intravenous administration), found no
statistically significant differences in the vital signs
after analysis.12
Another study of the use of oral midazolam (15 mg)
for third molar extraction demonstrated that a lower
DBP was noted during suturing and not during the
initial period or during extraction. The participants
might have felt relieved when the tooth removal had
been completed and, thus, were able to relax more
effectively. However, the heart rate had increased dur-
ing extraction and remained higher than the initial
levels until suturing. Only 20% of the participants re-
ported- anterograde amnesia.20
A study comparing the oral administration of mida-
zolam and nitrous oxide showed that the former
reduced anxiety better when assessed by the salivary
cortisol levels.21 In contrast, the latter had a variable
ratio with oxygen, impairing the results.21 Although
the nitrous oxide and oxygen ratio was standardized
in the present study for oximetry, the comparison
between midazolam and diazepam showed statistically
significant differences regarding the DBP because the
value was less compared with that in the other
2 groups.
Although the percentages of nitrous oxide and
oxygen required to obtain the ideal level of sedation
will vary from patient to patient, a review study of
more than 6000 cases of sedation showed that in
70% of cases it was possible to obtain optimal sedation
with a concentration of nitrous oxide ranging from 30
and 40%.5 In another study, no changes in heart rate or
oxygen saturation were observed at 50% nitrous
oxide.22 However, no change was found in the heart
rate in the present study with a lower percentage of
nitrous oxide, despite the difference in oxygen
saturation.
In conclusion, we found that all 3 preoperative seda-
tion protocols for anxious patients undergoing extrac-
tion of third molars used in the present study were
effective in controlling the anxiety, with little effect
on the vital signs and retrograde amnesia.
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