Accepted Manuscript

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 Moraes, Winnie Souza Barbier, Fernando Vagner Raldi, Rodrigo
Dias Nascimento, Lúcio Murilo dos Santos, Fábio Ricardo Loureiro Sato

PII: S0278-2391(19)30629-9
DOI: https://doi.org/10.1016/j.joms.2019.06.001
Reference: YJOMS 58804

To appear in: Journal of Oral and Maxillofacial Surgery

Received Date: 11 February 2019

Revised Date: 23 April 2019
Accepted Date: 7 June 2019

Please cite this article as: Bianchi de Moraes M, Barbier WS, Raldi FV, Nascimento RD, Murilo dos
Santos L, Loureiro Sato FR, Comparison of three Anxiety Management Protocols for Extraction of Third
Molars with the Use of Midazolam, Diazepam and Nitrous Oxide: A Randomized Clinical Trial, Journal of
Oral and Maxillofacial Surgery (2019), doi: https://doi.org/10.1016/j.joms.2019.06.001.

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 ACCEPTED MANUSCRIPT
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 Moraes1

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Winnie Souza Barbier2

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Fernando Vagner Raldi1

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Rodrigo Dias Nascimento1

Lúcio Murilo dos Santos3

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Fábio Ricardo Loureiro Sato1
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1 Assistant Professor, DDS, MS and PhD - Oral and Maxillofacial Surgery Area, Department of
Diagnosis and Surgery, State University of São Paulo – UNESP, College of Dentistry, São José
dos Campos
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2 DDS, Oral and Maxillofacial Surgery Area, Department of Diagnosis and Surgery, State
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University of São Paulo – UNESP, College of Dentistry, São José dos Campos

3 MD, MS and PhD, Assistant Professor, Department of Biosciences and Oral Diagnosis, State
University of São Paulo – UNESP, College of Dentistry, São José dos Campos
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Corresponding Author:
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Fábio Ricardo Loureiro Sato

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Department of Oral and Maxillofacial Surgery

State University of São Paulo – UNESP
College of Dentistry – São José dos Campos
Av. Eng. Francisco José Longo, 777 – 12245-000
São José dos Campos – SP - Brazil
Phone/Fax: +55 12 3947-9000
Email: fabio.sato@ict.unesp.br
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Comparison of three Anxiety Management Protocols for

extraction of third molars with the Use of Midazolam,
Diazepam and Nitrous Oxide: A Randomized Clinical Trial

ABSTRACT
Purpose: The objective of this study was to compare three sedation
protocols, using diazepam, midazolam and nitrous oxide. Methods: 120

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patients were selected with indication of extraction of third molars, all
with moderate to severe levels of anxiety according to Corah Dental
scale. Patients were randomly divided into three groups. His vital signs
were measured, and the results were submitted to descriptive statistical

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analysis and statistical tests of comparison. Results: There were no
statistically significant differences in heart rate. However, systolic and
diastolic blood pressure was statistically different just after 15 minutes in

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nitrous oxide sedation. Oximetry data showed no differences between
the three sedation protocols and there was also no statistically significant
difference in the retrograde amnesia test. The anxiety before the

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procedure showed statistical difference between the preoperative and
postoperative for all techniques, demonstrating their effectiveness in
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anxiety control. Conclusion: all three protocols of pre-operative sedation
techniques for anxious patients undergoing extraction of third molars
used in this study were effective to control the anxiety, with little impact in
the vital signs and retrograde amnesia.
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Key-words: Third molars; Sedation; Nitrous oxide; Benzodiazepines.

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INTRODUCTION
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The fear of dental procedures is real and can be considered one of

the main reasons why many patients avoid dental treatments. In the
United States, it is estimated that approximately 6-14% of the population
avoid seeking dental treatment because of fear. These patients are
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classified as being highly anxious and they represent a double challenge

for the professional, who needs to treat their dental complaints and also
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manage their psychological anxiety1.

Today we have a wide variety of local anaesthetic drugs available,
which enables us to control the patient’s pain more efficiently in the daily
clinical practice. However, even in the absence of painful stimuli, many
patients still show high anxiety2. In addition to the local anaesthetic
drugs, there are sedation techniques that can be used to alter the
patient’s consciousness state and lead to a decrease in anxiety. This
technique is termed sedation, which according to the American Dental
Association in 2016, was defined as the “minimally depressed level of
consciousness allowing the patient to keep his or her airway functioning
independently and to respond to physical stimulation and verbal
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commands accordingly, which is achieved by means of pharmacological

and non-pharmacological methods or a combination of both”3.
In the literature, there are several techniques described for
performing sedation, with oral and inhalation techniques. Among the oral
sedatives, benzodiazepines are the most used ones, particularly
diazepam and midazolam, whereas nitrous oxide is the most commonly
used for inhalation techniques.
The benzodiazepines are most commonly used antianxiety

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agents, acting as a central nervous system depressant, producing
sedation and hypnosis. Following oral administration, most of the
benzodiazepines are rapidly absorbed and highly bound to plasma

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protein. Peak blood concentration is generally obtained in 1 to 3 hours.
However, the effect of the different drugs from this pharmacological class
differ from their lipid-soluble capacity, diazepam, for example,

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accumulates in body fat, and this characteristic partially accounts for the
prolonged half-life which can range from 1 day to much as 8 days. On
the other hand, midazolam has a very short half-life elimination period,
that varies from 2 to 5 hours4.

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The mechanism of action of the nitrous oxide is still unknown, but
almost all forms of sensation are depressed (sight, hearing, touch and
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pain). Memory is affected to a minimal degree, just like the ability to
concentrate or perform acts requiring logical reasoning. When
administered with physiological level of oxygen (greater than 20%),
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nitrous oxide produces a mild depression of the central nervous system,

primarily in the cerebral cortex. The main advantages of the inhalation
techniques over the oral sedation like benzodiazepines, are the rapid
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effect, with peak around 3 to 5 minutes, variable duration of action and

may be titrated, allowing a rapid return to normal activities. The major
disadvantage is the cost, mainly the equipment5.
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Regardless of the sedation technique being used, it is essential

that it should be well accepted by the patient and safe, not compromising
the airways and not promoting hyperventilation or bradycardia. The ideal
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anxiolytic drug should change vital signs minimally, promote rapid

recovery and being associated with low incidence of adverse reactions6.
A doubt frequently raised by practitioners is which technique or
medication should be indicated for sedation of a patient as there are
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currently few comparative studies. Therefore, the aim of this study was to
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perform a comparative analysis of sedation techniques with midazolam,

diazepam and nitrous oxide for tooth extraction of third molars in anxious
patients.
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METHODS

Study Design
The methodology of the present study has followed the
CONSORT guidelines for publication7,8. This is a clinical randomised trial
approved by the local research ethics committee under number CAAE:
49562015.0.0000.0077
and registered on the site ClinicalTrials.gov
according to protocol number ID NCT03165500. In this clinical trial, 120

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subjects aged 18-30 years old and with indication for extraction of upper
third molars were selected, all classified as ASA-I and having moderate
to severe anxiety level according to the Corah’s Dental Anxiety Scale

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(DAS)9.
Subjects
The subjects were those who voluntarily sought the Department of

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Oral and Maxillofacial Surgery for upper third molar tooth extraction
totally impacted and in a vertical position.
Inclusion Criteria
1) ASA-I patients needing extraction of upper third molars;

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2) Patients aged between 18 and 30 years old;
3) Patients agreeing in participating in the study by signing an
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informed consent form;
4) Patients with moderate-severe anxiety according to Corah’s dental
anxiety scale.
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Exclusion Criteria
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1) Presence of any local or systemic issue that contra-indicates the

procedure;
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2) Use of anti-inflammatory medication or adrenergic antagonists in

the past 15 days;
3) Patients not signing the informed consent form;
4) Patients with mild anxiety.
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Initially, the sample was of 380 patients that required the upper third
molar tooth extraction. After the anamnesis and initial clinical
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examination, 260 patients were excluded from the sample, due to mild
anxiety (124 patients), presence of systemic issue (89 patients), use of
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medication (27 patients) or not agreeing to participate in the research,

remaining 120 patients for the final sample (Figure 1).

Sample Size
The authors assumed a standard deviation of 10 on a 100-point
scale. Under this assumption, a sample size of at least 88 patients are
required to have an 80% chance of detecting, as significant at the 5%
level, a decrease in the primary outcome measure from 98 in the control
group to 92 in the experimental group.

Group Allocation
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The patients were randomly divided into three groups of 40

patients each and then submitted to the following anxiety management
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 surgery;
• Group III – Sedation with 40% nitrous oxide and 60% oxygen via

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inhalation by means of a Porter MXR 3000 flowmeter (Parker Hannifin -
Hatfield, PA, Philadelphia, USA) 5 minutes before the beginning of the
surgery;

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For the groups I and II, the sedation was done 30 minutes before the
surgery to achieve the peak plasma levels of the orally administered

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sedatives at the time of procedure, and for group III, 5 minutes before, to
reach the percentage of 40% nitrous oxide and 60% oxygen.
The presentation of Midazolam in tablet is 7.5 or 15 mg, and studies like
from Luyk & Whitley10 demonstrate that a 7.5 mg dosage demonstrated a

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significant anxiolysis, amnesia and patient preference for this kind of
sedation, far from the maximum dosage that should never exceed 20
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mg5.
Diazepam in tables is available in 5 or 10 mg. Aeschliman et al.11
demonstrated that a 5 mg diazepam dosage provided a good control of
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stress and anxiety with no significant respiratory depression, as working

below maximum dosage, that is 10 mg5.
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The patient’s vital signs (blood pressure, heart rate and oxygen
saturation) were measured and recorded prior to and after sedation (30
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minutes after oral sedation and 5 minutes after inhalation sedation) as

well as during surgical procedure and 15 minutes after tooth extraction.

Surgical Procedure
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All upper third molar tooth extraction was performed by the same
surgeon (FVR) at the oral and maxillofacial surgery clinic. The patients
were submitted to antisepsis using 0.2% chlorhexidine digluconate
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followed by placement of surgical drapes for delimitation of the

contamination area. After that, anaesthesia was performed through
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blockage of the posterior alveolar nerve and palatal complementation at

the side of the upper tooth to be extracted by using 1 tube with 1.8 mL of
2% mepivacaine hydrochloride and epinephrine at 1/100,000 ratio per
tooth. Complementation of the anaesthesia was allowed just more 0.9
mL (half tube), if more than that was needed, the patient was excluded
from the sample. Straight incision was made on the tuber region by using
a #15C surgical blade followed by another intra-sulcular incision in the
interdental papilla between the molars. Next, a full thickness flap was
made by using a Molt dissector until adequately exposing the surgical
field for tooth extraction. Osteotomy and odontosection were performed
after elevation of the mucoperiosteal flap, and whenever needed, a #4
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spherical burr at high speed was used with abundant irrigation with 0.9%
saline solution. The third molar was extracted by using Seldin (straight
and angled) and Potts elevators. Trans-operative vital signs were
assessed at this moment, followed by inspection of the cavity left and
abundant irrigation with 0.9% saline solution. The flap was re-positioned
and sutured by using a 4.0 silk thread (Ethicon – Johnson & Johnson,
São Paulo, Brazil).
After the surgical procedure, the patients remained in the recovery

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room in the dental clinic where tooth extraction was performed,
monitored all the time and they were released only after their vital signs
were normal, including responsiveness to verbal commands and lucidity,

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with at least 15 minutes after the end of the procedure, when the vital
signs were measured. Those patients sedated with nitrous oxide were
also submitted to the Trieger test, according to recommendations12, to

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reach the recovery of the sedation procedure.

Anxiety Assessment
The patients were initially asked to complete the Corah’s Dental

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Anxiety Scale9 to reach the level of anxiety of the patients before the
surgical procedure. After 15 minutes of the end of the surgery, the
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patients were invited to fill again the DAS to determine if the sedation
technique used of effective to control the anxiety.
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Vital Sign Assessment

Vital signs being assessed were blood pressure, heart rate and
oxygen saturation, which were measured at the following moments:
•
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Before sedation;
• 30 minutes after oral sedation and 5 minutes after inhalation
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sedation;
• During surgical procedure;
• 15 minutes after the surgical procedure.
The values of these vital signs were recorded on the dental
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surgery record chart.

Retrograde Amnesia Assessment

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Retrograde amnesia was assessed by using six images shown to

the patients at intervals of 5 seconds each, with three of them (Image 1:
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an apple; Image 2: a car; and Image 3: swimming) before sedation and

other three (i.e. Image 4: an airplane; Image 5: a watermelon; and Image
6: football game) after sedation (30 minutes after oral sedation and 5
minutes after inhalation sedation). The same images were again shown
to the patients after surgical procedure, but this time mixed with other six
images (i.e. orange, helicopter, motorcycle, grapes, volleyball game, and
tennis), and the patients were asked whether the images were the same
as those previously shown to them. The total hit score was compared
between the groups to verify the retrograde amnesia of the sedation
method13.
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Subjective evaluation
Seven days after the tooth extraction, the patients were given a
questionnaire for assessment of trans-operative comfort, sedation-
related amnesia and possible adverse effects.

Statistical Methods
The resulting data were initially submitted to Shapiro-Wilk normality test
to verify whether they followed a normal distribution pattern for further

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statistical analysis with SPSS software 11 (IBM Corp, Armonk, USA).
Analysis of variance (ANOVA) and Tukey’s test were used for
parametric data (oxygen saturation and retrograde amnesia) and

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Kruskal-Wallis’ test for non-parametric data (heart rate and blood
pressure).

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RESULTS

Recruitment
The patients were initially asked to complete the Corah’s Dental

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Anxiety Scale9 during clinical interview for selection of those having
moderate-severe anxiety. This scale ranged between 4 to 20 points, with
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score below 11 points meaning low anxiety, between 11 and 15 points
meaning moderate anxiety, and above 15 points meaning severe
anxiety. Therefore, those patients scoring less than 11 points were
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excluded from study. This same score was used as baseline for
assessment of the sedation techniques. The included patients were
asked to complete the Visual Analogue Scale for Anxiety, with score
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ranging from 0 (not at all anxious) to 10 (highly anxious). The recruited

patients for study were followed up for seven days and their demographic
data are listed in detail in Table 1.
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Vital Signs

Heart Rate
After analysing the data on heart rate by using Kruskal-Wallis’ test,
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no differences were found between the three groups nor between the
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experimental periods (before, during and after surgery), as shown in

Table 2.

Blood Pressure
As for blood pressure, the resulting data were divided into two
sub-groups, namely, systolic blood pressure (SBP) and diastolic blood
pressure (DBP), which were compared independently. Because these
data were non-parametric, both sub-groups were submitted to Kruskal-
Wallis’ test, which showed statistically significant difference only for SBP
after 15 minutes of sedation. As for nitrous oxide, SBP was also lower
compared to other groups, as shown in Table 3.
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Kruskal-Wallis’ test showed also that the results for DBP there
only statistically significant difference were found after 15 minutes of
sedation, with blood pressure being lower in the group of nitrous oxide
compared to midazolam and diazepam, as shown in Table 3.

Oximetry
As for oximetric data, ANOVA and Tukey’s test showed no
differences between the three ways of sedation regarding oxygen

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saturation but difference between the experimental periods for the nitrous
oxide, as shown in Table 4.

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Retrograde amnesia
The resulting data were submitted to ANOVA, which showed no

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existence of statistically significant differences between the three groups
of sedation regarding retrograde amnesia (p=0.621), as shown in Table
5.

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Anxiety Assessment
The data about the Corah Dental Anxiety Scale was submitted to
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ANOVA and Tukey’s test, that demonstrate a statistically significant
difference between the mean obtained at the first visit (DAS=14.5 ± 2.2)
and at the end of the surgical procedure for all sedation techniques
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(midazolam=11.5 ± 1.8; diazepam=11.4 ± 1.8; nitrous oxide=11.7 ± 2.1),

but with no difference between the techniques, as shown in Figure 2.
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DISCUSSION
In an interview with a group of dentists, 57% reported that the
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most stressful factor in their professional practice was the so-called

“difficult patient”, especially those with high level of anxiety14. The
attempt to perform any type of treatment for these patients without
addressing their fears and anxieties ends up causing frustration and
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much stress for the professionals, which in turn increases significantly

the patients’ level of fear1.
Anxiety in patients undergoing dental surgical procedures, such as
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extraction of third molars, has become habitual and directly related to

pain. Knowing the procedure and sharing experiences lead to an
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increase in the anxiety level of the patients, which quantifies the

experience of pain15. Patients who become very anxious towards surgical
procedures experience more pain during the post-operative period
compared to those who are less anxious in the pre-operative period15,16.
Therefore, the use of sedation techniques by professionals is currently
increasing so that the surgical procedures can be better performed17.
A systematic review assessed the effectiveness of midazolam in
the anxiety management for extraction of third molar, with studies with
both with oral and intravenous sedation, concluded that this medication
can be efficient in cases of anxiety and administered safely, either alone
or in association with other drugs18.
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A comparative study on the effects of the oral administration of

diazepam and midazolam on vital signs of patients submitted to surgery
for impacted lower third molars found statistically significant differences
related to an increase in heart rate in the majority of midazolam groups
as well as in diastolic blood pressure in two diazepam groups19.
By analysing the blood pressure after sedation, it was observed
that DBP and SBP were statistically different only after 15 minutes of
sedation. However, another study using the same benzodiazepines as

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we did, but differing in the application method only (intra-venous
administration); found no statistical differences after analysis of vital
signs12.

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Another study with the use of oral midazolam (15mg) for third
molar extraction, demonstrated that lower diastolic blood pressure values
were noted during suturing than during the initial period and extraction.

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Participants may have felt relieved when the tooth removal was
completed and, thus, were able to relax more effectively. However, heart
rate increased during extraction and remained higher than initial levels
until suturing. Only 20% of the participants reported anterograde

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amnesia20.
A study comparing the oral administration of midazolam and nitrous
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oxide showed that the former better reduced the anxiety when assessed
by means of salivary cortisol levels, whereas the latter had a variable
ratio with oxygen, thus impairing the result21. Although the nitrous oxide
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and oxygen ratio was standardised in this study for oximetry, the
comparison between midazolam and diazepam showed statistical
differences regarding DBP as the value found was smaller in relation to
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the other two groups.

Despite the fact that the percentages of nitrous oxide and oxygen
for obtaining an ideal level of sedation vary from patient to patient, a
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review study of more than 6,000 cases of sedation showed that in 70% of
the cases it was possible to obtain optimal sedation with concentrations
of nitrous oxide ranging between 30 and 40%5. In another study, no
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changes in heart rate and oxygen saturation were observed for 50-
percent nitrous oxide22. However, there was no change in the heart rate
in this study using a lower percentage of nitrous oxide, despite the
difference in oxygen saturation.
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Therefore, we can conclude that all three protocols of pre-

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operative sedation techniques for anxious patients undergoing extraction

of third molars used in this study were effective to control the anxiety,
with little impact in the vital signs and retrograde amnesia.

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2. Van Wijk A, Lindeboom J. The effect of a separate consultation on

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preliminary study on oxygen saturation levels of patients during

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12. Khader R, Oreadi D, Finkelman M, Jarmoc M, Chaudhary
S, Schumann R, Rosenberg M. A Prospective Randomized Controlled
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Adults. J Oral Maxillofac Surg 73: 224, 2015.
13. Bulach R, Myles PS, Russnak M. Double-blind randomized controlled
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trial to determine extent of amnesia with midazolam given immediately

before general anaesthesia. Br J Anaesth 94: 300, 2005.
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15 Okawa K, Ichinohe T, Kaneko Y. Anxiety may enhance pain during

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dental treatment. Bull Tokyo Dent Coll 46: 51, 2005.

16. Averill JR. Personal control over aversive stimuli and its relationship
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17 Joshi S, Ansari AS, Mazumdar S, Ansari S. A comparative study to
assess the effect of oral alprazolam as premedication on vital parameters
of patients during surgical removal of impacted mandibular third molars.
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18 Chen Q, Wang L, Ge L, Gao Y, Wang H. The anxiolytic effect of
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0121410, 2015.
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19. de Morais HH, Barbalho JC, de Holanda Vasconcelos RJ, Landim

FS, da Costa Araújo FA, de Souza Dias TG. Comparative study of
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Oral Surg Oral Med Oral Pathol Oral Radiol Endod 98: 637, 2004.

FIGURE LEGEND
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Figure 1 – Flowchart of the sample selection
Figure 2 – Data of the Dental Anxiety Scale (DAS)
Table 1 – Demographic data of the patients
Table 2 – Data on the analysis of heart rate (bpm – beats per minute)
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Table 3 – Data on the analysis of systolic and diastolic blood pressure

(mmHg)
Table 4 – Data on the oximetric analysis (Sp02)
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Table 5 – Data on the analysis of retrograde amnesia

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Midazolam Diazepam Nitrous Oxide Total sample

Sample 40 40 40 120

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Age 22.9± 5.3 23.2 ± 7.3 21.8 ± 5.6 22.6± 6.2
Male =13 Male = 10 Male = 18 Male = 41
Gender

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Female = 27 Female = 30 Female = 22 Female = 79

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Table 1 – Demographic data of the patients

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Midazolam Diazepam Nitrous Oxide p-value

Pre-sedation 82.56 ± 13,82 84,52 ± 13.95 81.92 ± 11.28 0.790
15 min after Sedation 80.86 ± 12.47 82.50 ± 15.26 77.59 ± 11.34 0.307
End of the Surgery 80.85 ± 13.08 80.72 ± 14.92 76.56 ± 13.08 0.208
15 min after Surgery 79.56 ± 13.94 80.67 ± 11.36 77.20 ± 11.15 0.316
p-value 0.733 0.719 0.107

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Table 2 – Data on the analysis of heart rate (bpm – beats per minute)

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Midazolam Diazepam Nitrous Oxide p-value

SBP DBP SBP DBP SBP DBP SBP DBP
Pre-sedation 11.70 ± 1.55 7.29 ± 1.07 11.82 ± 1.10 7.37 ± 0.89 11.64 ± 1.54 7.25 ± 1.22 0.714 0.94

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15 min after sedation 11.29 ± 1.38 6.95 ± 0.89 11.47 ± 1.17 7.15 ± 0.76 10.43 ± 0.99 6.20 ± 1.03 <0.05 <0.05
End of the Surgery 11.39 ± 1.39 6.87 ± 1.72 11.60 ± 1.23 6.95 ± 1.43 11.28 ± 1.23 6.61 ± 1.33 0.58 0.176

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15 min after surgery 11.73 ± 1.74 7.07 ± 1.61 11.87 ± 1.30 6.60 ± 2.23 11.97 ± 1.30 7.58 ± 0.99 0.504 0.274
p-value 0.389 0.413 0.228 0.647 <0.05 <0.05

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Table 3 – Data on the analysis of systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg).

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Midazolam Diazepam Nitrous Oxide p-value

Pre-sedation 97.00 ± 2.26 98.00 ± 1.43 97.25 ± 1.90 0.057
15 min after sedation 97.22 ± 3.87 98.05 ± 1.05 98.31 ± 1.13 0.142
End of the Surgery 97.90 ± 1.80 98.12 ± 1.22 98.02 ± 1.83 0.830
15 min after surgery 98.22 ± 1.69 98.01 ± 1.01 97.85 ± 1.52 0.516
p-value 0.124 0.96 <0.05

PT
RI
Table 4 – Data on the oximetric analysis (Sp02)

U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Nitrous
Midazolam Diazepam p-value
Oxide
Hits 5.36 ± 0.91 5.52 ± 0.84 5.53 ± 0.88 0.621

Table 5 – Data on the analysis of retrograde amnesia

PT
RI
U SC
AN
M
D
TE
CEP
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC