Conditions: Symptomatic Irreversible Pulpitis
Keywords: lidocaine articaine mepivacaine buffered local anesthetic irreversible pulpitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine whether a combination of anesthetics (numbing medicine) will adequately anesthetize teeth over a different combination. A second purpose is to see if the time needed to numb the nerve in a tooth is different between the two anesthetics.

Detailed description:
60 human subjects with Symptomatic Irreversible Pulpitis (SIP) in mandibular molars will be randomly allocated into 2 groups. One group will receive a combination of: 1 cartridge of buffered 2% lidocaine w/ 1:100k epi via inferior alveolar nerve block (IANB) followed by 1 cartridge of 3% mepivacaine via IANB. This will be followed by 0.5 cartridges (0.9mL) of buffered 4% articaine with 1:100k epi via buccal infiltration and 0.5 cartridges of buffered 4% articaine with 1:100k epi via lingual infiltration. All IANB injections will include a lingual block. The second group will be provided an unbuffered version of the same combination. An electronic pulp tester (EPT) will be used to determine the vitality of the treated tooth. Endodontic treatment will be initiated after two consecutive EPT readings of 80, displaying pulpal anesthesia. Profound pulpal anesthesia is described by the patient's report on the visual analog scale after the pulpotomy.

Arms:
arm 1: Buffered 2% lidocaine with 1:100,000 epinephrine Buffered 4% articaine with 1:100,000 epinephrine Buffered 3% mepivacaine Buffered local anesthetic (addition of sodium bicarbonate to make a 10% buffered solution) arm 2: Unbuffered 2% lidocaine with 1:100,000 epinephrine Unbuffered 4% articaine with 1:100,000 epinephrine Unbuffered 3% mepivacaine Standard local anesthetics

Interventions: intervention 1: Sodium bicarbonate intervention 2: Lidocaine w/ epi intervention 3: Articaine w/ epi intervention 4: Mepivacaine plain
Intervention descriptions: intervention 1: Onpharma's Onset sodium bicarbonate buffer to be added to a standard cartridge of dental local anesthetic intervention 2: Septodont's standard formulation of 2% lidocaine with epinephrine intervention 3: Septodont's standard formulation of 4% articaine with epinephrine intervention 4: Septodont's standard formulation of 3% mepivacaine

Protocol document:
Prot_SAP_000.pdf: 
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Buffered vs. Unbuffered Local Anesthesia using Lidocaine, 
Carbocaine, and Articaine in Mandibular 
Molars Diagnosed with Symptomatic Irreversible Pulpitis: A 
Controlled, Randomized, Double-blind Study  
 
Principle Investigator: Kenneth Spolnik 
1121 W. Michigan St. 
Room 280B 
Indianapolis, IN 
46202 
IUSD Department of Endodontics 
Sub-Investigators: 
Steven D. Magura, DDS, Resident 
Department of Endodontics 
Indiana University School of Dentistry 
 
Ygal Ehrlich, DDS, Associate Professor 
Department of Endodontics 
Indiana University School of Dentistry 
 
 
 
 
Support Provided by: 
Indiana University School of Dentistry 
 
 
  
 


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Table of Contents: 
 
Study Schema 
1.0 
Background & Rationale 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
3.0 
Outcome Measures 
3.1 
Primary Outcome Measures 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
5.0 
Study Design 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Reportable Events 
9.0 
Data Safety Monitoring 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Data Management 
13.0 
Privacy/Confidentiality Issues 
14.0 
Follow-up and Record Retention 
15.0 
References 
 
 
 
 
 
 
 
1.0 
Background & Rationale 
 
  
The success rate for pulpal anesthesia in mandibular molars diagnosed with symptomatic 
irreversible pulpitis has been shown to be between 45-70% (1). While the specific mechanism 
for inadequacy is unknown, it has been proposed that expression of variable sodium channels 
during inflammation, changes in tissue pH and, peripheral blood flow may contribute (2).  
OnPharmaTM offers a solution to increase the efficacy of local anesthetics by allowing the 
clinician to add a buffering agent to the solution prior to injection.  
The OnPharmaTM system adds sodium bicarbonate to the anesthetic solution to raise its 
pH to a level closer to the anesthetics pKa. In doing so, more of the free base form is present to 


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diffuse through cell membranes. The free base is the active ingredient in local anesthetic 
solutions that are responsible for analgesia. In addition, CO2 and water are produced through the 
addition of sodium bicarbonate to the anesthetic solution. CO2 converts the local anesthetic back 
into its active acid form once inside the cell membrane, trapping the local anesthetic inside (2,3).  
Recent studies have suggested that buffered anesthetics do not improve Inferior alveolar 
nerve block (IANB) success rate in symptomatic teeth (4,5,6).  This contrasts with another study 
showing increased success with sodium bicarbonate use with IANB blocks (7). While the field is 
not currently in agreement, Indiana University School of Dentistry (IUSD) has had a positive 
experience when using the OnPharmaTM system to anesthetize symptomatic teeth.  
Dr. Peter Alena, a previous resident of Indiana University Endodontics, investigated the 
efficacy of buffered and plain 2% lidocaine with 1:100k epinephrine. His data suggest that there 
is not a significant difference between the two when treating mandibular molars diagnosed with 
symptomatic irreversible pulpitis. This current iteration aims to investigate the synergistic ability 
of a combination of buffered anesthetics to improve patient analgesia. Previous studies have 
reported that a local infiltration of articaine with a IANB of lidocaine improve local anesthetic 
success rates in patients diagnosed with symptomatic irreversible pulpits (8,9). Carbocaine 
performs as well as lidocaine when used solely for an IANB but current data suggests it does not 
improve anesthesia when combined with other anesthetics (10,11).  
This study will include the administration of 1.8mL of 2% Lidocaine with 1:100k 
epinephrine and 1.8mL of 3% Carbocaine through an IANB. 1.8 mL of 4% Articaine with 
1:100k epinephrine will also be used to locally infiltrate. The anesthetic combination will either 
be unbuffered or buffered using the OnpharmaTM protocol and will administered in a double 
blinded fashion.  
 


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Investigational Products:  
 
2% Lidocaine with 1:100k epinephrine (Septodont Inc, New Castle, DE). A standard carpule of 
Lidocaine contains 1.8mL of solution. 1 carpule  will be administered via a IANB  of 2% 
Lidocaine w/ 1:100k epi as the standard anesthetic dosage.  
 
3% Carbocaine without epinephrine (Septodont INC, New Castle, DE). Each carpule contains 
1.8mL of solution. This will be administered via an IANB.  
 
4% Articaine with 1:100k epinephrine (Septo Inc, New Castle, DE). A standard carpule contains 
1.8 mL of solution. This will be used as a local infiltration.  
 
The Onset 8.4% Sodium Bicarbonate buffering system is marketed by OnPharma (Carson City, 
NV). Aside from the sodium bicarbonate buffer itself, OnPharma offers the Onset Mixing Pen 
along with an Onset Cartridge Connector which formulates the buffered local anesthetic solution. 
The OnPharma mixing protocol will be used to mix each anesthetic prior to administration.  
 
Vitality Scanner 2006 (Vitality Scanner 2006; SybronEndo, Orange, CA) is marketed and sold 
by Kerr Dental, and will be used to confirm pulpal anesthesia via Electric Pulp Testing (EPT). 
 
Endo-Ice (1,1,1,2 tetrafluoroethane; Hygenic Corp, Akron, OH) will be used to diagnose each 
tooth prior to treatment and once again to confirm pulpal anesthesia.  
 
 
2.0 
Objective(s)  
2.1 
Primary Objective 
2.1.1 
The primary objective of this study is to determine whether pulpal 
anesthesia will be obtained faster and more profoundly compared to using 
unbuffered local anesthetic in teeth diagnosed with symptomatic 
irreversible pulpitis. 
2.2 
Secondary Objective 
2.2.1 To measure a potential difference in the buffered anesthetic’s effect on 
time and profoundness in achieving pulpal anesthesia between mandibular 
first, second, or third molars diagnosed with symptomatic irreversible 
pulpitis 
 
 
3.0 
Outcome Measures/Endpoints   
3.1 
Primary Outcome Measures 
3.1.1 The primary outcome is to gauge the time it takes for the buffered 
anesthetic to provide profound anesthesia, displayed by an EPT reading of 
80. The time will be censored at 15 minutes if profound anesthesia is not 
achieved within 15 minutes. 
3.2 
Secondary Outcome Measures 
3.2.1 Failure to achieve profound anesthesia. 
3.2.2 Pain scores measured using a Visual Analog Scale (VAS).  
 
 


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4.0 
Eligibility Criteria   
4.1 
Inclusion Criteria 
• Between the ages of 18 and 80 years old 
• Ability and willingness to independently consent to treatment and study 
participation 
• Uncomplicated medical history (ASA I and II) 
• No allergies to local anesthetics/sulfites (confirmed or self-reported) 
• Not taking any medications that may affect the proper assessment of the 
anesthetic (OTC analgesics within 6 hours of treatment) 
• Not requiring nitrous oxide during treatment 
• No active pathology in the injection area or any other pre-existing conditions 
that may compromise an accurate collection of data per PI’s review of current 
and previous 30 days of medical history 
• Must be experiencing signs of irreversible pulpitis (mild, moderate, or severe) 
in a vital mandibular posterior tooth at the time of conducting the study 
 
4.2 
Exclusion Criteria 
• Patients lacking a response to cold in the affected tooth 
• A radiographic periradicular pathosis more advanced than a widened 
periodontal ligament (radiograph taken as standard of care) 
• 
No vital coronal pulp tissue noted upon access  
• 
Patient reported pain (other than pressure) upon endodontic access/pulpotomy 
 
 
5.0 
Study Design 
 
1. This study will be a single-center, controlled, randomized, double-blind (provider and 
subject), 2 treatment, 1 period, parallel study to determine the efficacy of buffered 2% 
Lidocaine w/ 1:100k epi, 3% Carbocaine and 4% Articaine with 1:100k epi,  on the 
time of efficacy and ultimate profoundness of pulpal anesthesia in mandibular molars 
diagnosed with symptomatic irreversible pulpitis compared to traditional unbuffered 
2% Lidocaine w/ 1:100k epi, 3 % Carbocaine and 4% Articaine with 1:100k epi. An 
electronic pulp tester (EPT) assesses the tooth’s ability to feel sensation, with a 
reading of 80 showing the tooth is adequately anesthetized.  
 
 
 


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6.0 
Enrollment/Randomization 
 
Potential research subjects will be pooled from patients scheduled to receive an endodontic 
evaluation and/or clinical treatment in the Graduate Endodontic clinic at Indiana University 
School of Dentistry. There are currently 7 endodontic residents enrolled in the graduate program 
who will be eligible to screen patients presenting to the graduate clinic for elective, urgent, or 
emergency endodontic treatment. If an endodontic resident other than the student researcher (Dr. 
Steven Magura) diagnoses their respective patient’s mandibular molar with symptomatic 
irreversible pulpitis, and all other inclusion/exclusion criteria are respected, then the student 
researcher will be eligible to further evaluate the patient and potentially include them in the 
study.  
 
The study biostatistician will provide a two-product randomization scheme which will randomize 
each subject on the order of their entry into the study. Subjects will be randomized equally to the 
two treatments using a block randomization, participants receiving multiple root canal 
procedures will be treated as a single subject. 30 subjects per treatment will be enrolled. The 
randomization scheme will be provided to clinic assistants Bridgette Smith and James Driver. 
They will prepare each anesthetic solution behind closed doors and provide each carpule to the 
60 mandibular molars diagnosed with 
symptomatic irreversible pulpitis 
EPT reading prior to 
anesthesia
30 teeth anesthetized with unbuffered 
anesthetic combination and 30  teeth 
anesthetized with buffered anesthetic 
combination
Wait 3 mins after 
administering 
anesthetic 
If EPT= 80 begin 
treatment 
If EPT does not = 80 
wait 10 minutes 
If EPT= 80 begin 
treatment
If EPT does not = 80 
wait 15 minutes, 
testing with an EPT 
every 2 minutes
If EPT = 80, begin 
treatment
If EPT does not =80 then 
anesthetic is considerd a 
failure. The patient will 
recieve an IO injection 
with    2% Lidocaine with 
1:100k epinephrine


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researcher at every appointment. The stopper of every carpule, regardless of experimental group, 
will be punctured to remove bias. The study subject will be blinded to treatment assignment. 
 
7.0 
Study Procedures 
 
Single Visit: Screening and Study procedure 
1. Review medical history (about 3-5 minutes) 
a. If previously on file, the patient will need to verbally confirm all forms are 
accurate 
b. If the patient is new to IUSD, then the proper medical history intake form will 
be completed and confirmed by the patient, as per standard of care 
c. Participants will be explained what an analgesic is, and will confirm they have 
not taken any within 6 hours prior to study participation 
2. Customary sensibility testing, specifically cold and Electric Pulp Testing (EPT), will 
be completed to ensure a diagnosis of symptomatic irreversible pulpitis in a 
mandibular molar specifically on the same day that the warranted endodontic 
treatment is to be rendered (about 5-10 minutes) as per standard of care.  
a. Prospective study participants will be given brief instructions on cold and EPT 
usage/expectations 
b. A vital, asymptomatic, contralateral posterior tooth (ideally molar) will 
undergo cold and EPT testing prior to administering anesthesia to serve as an 
internal control  
c. The pulpal diagnosis will be primarily confirmed using Endo-Ice 
3. Review inclusion/exclusion criteria to ensure that the subject qualifies to continue 
with the study (about 3 minutes) 
4. Perform consenting procedures for both the Non-surgical Root Canal Therapy 
(NSRCT) and the research study (about 5-10 minutes) 
a. Study participants will receive a concise explanation regarding the nature of 
the 2 possible anesthetic formations and the EPT testing intervals that are 
expected to follow. Participants will be explicitly notified that the anesthetic 
formulation will not affect the overall prognosis of the endodontic treatment 
needing to be rendered. Once profound anesthesia is confirmed, the NSRCT 
will proceed as usual and customary.  
5. Randomize the subject to the type of anesthetic formulation (about 5 minutes) 
6. Apply topical benzocaine jelly after thoroughly drying the tissues surrounding the 
Inferior Alveolar Nerve Block (IANB) injection site and the buccal vestibule of the 
tooth to be treated (about 1 minute), as per standard of care  
7. Administer 1 carpule (1.8mL) of the previously determined formulation of 2% 
Lidocaine w/ 1:100k epi and 1 carpule of 3% Carbocaine plane via IANB, followed 
by 0.5 carpules (0.9mL) of 4% Septocaine with 1:100k epi via buccal infiltration and 
0.5 carpules of 4% Septocaine with 1:100k epi via lingual infiltration (about 3 
minutes) 
8. Using a stopwatch, the student researcher will wait 3 minutes after administering 
anesthesia and then obtain the 2nd EPT reading on the tooth being treated, as well as 
assessing soft tissue anesthesia of the respective side of the mandible 


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a. EPT=80 (maximum stimulation) without pulpal or soft tissue sensations 
indicates profound pulpal anesthesia and the endodontic access may be 
initiated 
b. EPT80 with pulpal and/or soft tissue sensations indicates a need to wait 
additional time  
9. Retest the tooth being treated using EPT at 2-minute intervals until EPT=80 or when 
15 minutes have passed 
a. Participants who did not demonstrate total soft tissue and/or pulpal anesthesia 
within 15 minutes will be categorized as a failure (lack of anesthetic 
profoundness), with time to anesthesia censored at 15 minutes. No additional 
study outcomes will be collected from the patients, who will be withdrawn 
from the study, and further managed according to the best clinical practice 
(additional block/supplementary injections) so that the endodontic treatment 
may continue appropriately 
10. Patients who indicate any pain (excluding pressure) elicited from the tooth 
undergoing treatment upon endodontic access or a complete pulpotomy (after initially 
confirming pulpal anesthesia with the EPT) will also be categorized as a failure (lack 
of anesthetic profoundness), withdrawn from the study, and appropriately managed as 
previously described.  
a. Visual Analog Scales (VAS)  shown below will be used to report the patient’s 
perceived discomfort at the end of treatment.  
 
 
11. The student researcher will chart the data for each uniquely identified study 
participant regarding the initial EPT readings (treated tooth and control), the amount 
of time taken to reach both soft tissue and pulpal anesthesia, and the conditions that 
lead to a “failed” profoundness of anesthesia  
a. A trained research assistant will separately record each patient’s unique 
identifying code with the anesthetic formulation (buffered vs. unbuffered) that 
was prepared and administered  
  
 
8.0 
Reportable Events   
  
There are no additionally anticipated risks or adverse reactions by using 2% Lidocaine w/ 1:100k 
epi, 3% carbocaine without epi and 4% septocaine with 1:100k epi plane or with a sodium 
bicarbonate buffer as compared to a traditional, non-buffered formulation of the same local 
anesthetic. However, potential adverse events involving the traditional method of administering 
local anesthetic for mandibular teeth may involve hematomas, a temporary increase in heart rate, 
needle tract infections, temporary nerve damage (including Bell’s Palsy), and an inadequate 


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anesthetic delivery/lack of efficacy. Serious adverse events relating to local anesthetics may 
include overdose (drowsiness/loss of consciousness), permanent nerve damage, allergic 
reactions/anaphylaxis, or exacerbation of an underlying cardiovascular condition due to the 
presence of exogenous epinephrine.  
 
 
9.0 
Data Safety Monitoring  
 
The PI and student PI will be responsible for the data and safety monitoring.  They will monitor data 
quality, subject recruitment, accrual, retention, outcome and adverse event data, assessment of scientific 
reports or therapeutic development, results of related studies that may impact subject safety, and 
procedures designed to protect the privacy of subjects.  Safety data will be monitored on a regular basis 
and immediately upon discover of any SAE or major study event or protocol deviation.    
 
 
10.0 
Study Withdrawal/Discontinuation  
 
A subject may withdraw from the study for any reason and at any time during the study without penalty.  
There dental treatment will not be affected by their decision to stop study related procedures.  The 
Principal Investigator may also withdraw the subject if he feels study participation is not safe for the 
study to continue, or if the subject is not cooperating with study procedures. 
 
11.0 
Statistical Considerations   
 
 
The two groups will be compared for differences in the percentage of subjects who fail to achieve 
profound pulpal anesthesia using chi-square tests. The time needed to achieve profound pulpal anesthesia 
for the two groups will be compared using Kaplan-Meier survival curves and log-rank tests, with patients 
who fail to achieve profound pulpal anesthesia censored at 15 minutes. A logistic regression model for 
presence of profound pulpal anesthesia will be used to determine whether molar type (first, second, third 
molar) affects the group comparisons; the model will include both factors and their interaction. A similar 
Cox proportional hazards survival model will be used for the analysis of time needed to achieve profound 
pulpal anesthesia. VAS scores will be compared between treatments using a Wilcoxon Rank Sum test. A 
two-sided 5% significance level will be used for all tests. 
With a sample size of 28 subjects per group, the study will have 80% power to detect a hazard 
ratio of 2.25 between the two groups for time to profound pulpal anesthesia, using calculations with a 
two-sided 5% significance level and based on a log-rank test with median time to anesthesia 10 minutes 
in the control group. Sample size calculations were performed using PASS 2019 (NCSS, LLC. Kaysville, 
UT). To account for up to 2 subjects per group with unusable data, the study will enroll 30 subjects per 
group. 
 
12.0 
Statistical Data Management   
 
• 
Primary data will be collected via direct data capture from measurement instrument (Electronic 
Pulp Tester/EPT), time to profound anesthesia, molar type and VAS score  and stored 
electronically in SPSS files on Department Server.  The storage location will be backed up 
automatically every day.   


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• 
All other data will be stored in either a locked cabinet in the department of Endodontics that only 
the study team will have access to or on an encrypted, password protected computer that only the 
study team can access.   
• 
Data summary sheets will be stored for use by the statistician using an IRB approved sharable 
method such as Microsoft One Drive.     
 
 
13.0 
Privacy/Confidentiality Issues   
 
• 
Privacy will be maintained by consenting the subjects and performing the study procedures  in a 
private area like an endodontic operatory away from public places like the waiting room. 
• 
All other data will be stored in either a locked cabinet in the department of Endodontics that only 
the study team will have access to or on an encrypted, password protected computer that only the 
study team can access.   
• 
Data summary sheets will be stored for using an IRB approved method such as Microsoft One 
Drive.    
 
 
14.0 
Follow-up and Record Retention   
 
The study will be either a one or two visit study, depending on whether the subject and research staff 
prefer to separate the screening visit from the study/procedure visit.   
 
Study records will be stored for at least seven years, as per Indiana law. 
 
 
15.0 
References   
 
1-   Mikesell, P., Nusstein, J., Reader, A., Beck, M., & Weaver, J. (2005). A comparison 
of articaine and lidocaine for inferior alveolar nerve blocks. Journal of 
endodontics, 31(4), 265–270. 
2- Hargreaves, K.M. and Keiser, K. (2002), Local anesthetic failure in endodontics:. 
Endodontic Topics, 1: 26-39. 
3- CONDOURIS, G. A., & SHAKALIS, A. (1964). POTENTIATION OF THE NERVE-
DEPRESSANT EFFECT OF LOCAL ANAESTHETICS BY CARBON DIOXIDE. 
Nature, 204, 57–58. 
4- Saatchi, M., Khademi, A., Baghaei, B., & Noormohammadi, H. (2015). Effect of 
sodium bicarbonate-buffered lidocaine on the success of inferior alveolar nerve 
block for teeth with symptomatic irreversible pulpitis: a prospective, randomized 
double-blind study. Journal of endodontics, 41(1), 33–35. 
5- Schellenberg, J., Drum, M., Reader, A., Nusstein, J., Fowler, S., & Beck, M. (2015). 
Effect of Buffered 4% Lidocaine on the Success of the Inferior Alveolar Nerve 
Block in Patients with Symptomatic Irreversible Pulpitis: A Prospective, 
Randomized, Double-blind Study. Journal of endodontics, 41(6), 791–796. 


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6- Parirokh M. (2016). Buffered Lidocaine With Sodium Bicarbonate did not Increase 
Inferior Alveolar Nerve Block Success Rate in Patients Having Symptomatic 
Irreversible Pulpitis. The journal of evidence-based dental practice, 16(1), 59–61. 
7- Saatchi M, Farhad AR, Shenasa N, Haghighi SK. Effect of Sodium Bicarbonate Buccal 
Infiltration on the Success of Inferior Alveolar Nerve Block in Mandibular First Molars 
with Symptomatic Irreversible Pulpitis: A Prospective, Randomized Double-blind Study. 
J. Endod. 2016;42(10):1458-1461. 
8- Su, N., Li, C., Wang, H., Shen, J., Liu, W., & Kou, L. (2016). Efficacy and safety of 
articaine versus lidocaine for irreversible pulpitis treatment: A systematic review 
and meta-analysis of randomised controlled trials. Australian endodontic journal : 
the journal of the Australian Society of Endodontology Inc, 42(1), 4–15 
9- Kung, J., McDonagh, M., & Sedgley, C. M. (2015). Does Articaine Provide an 
Advantage over Lidocaine in Patients with Symptomatic Irreversible Pulpitis? A 
Systematic Review and Meta-analysis. Journal of endodontics, 41(11), 1784–1794 
10- Lammers, E., Nusstein, J., Reader, A., Drum, M., Beck, M., & Fowler, S. (2014). Does 
the combination of 3% mepivacaine plain plus 2% lidocaine with epinephrine 
improve anesthesia and reduce the pain of anesthetic injection for the inferior 
alveolar nerve block? A prospective, randomized, double-blind study. Journal of 
endodontics, 40(9), 1287–1292. 
11- Vieira, W. A., Paranhos, L. R., Cericato, G. O., Franco, A., & Ribeiro, M. (2018). Is 
mepivacaine as effective as lidocaine during inferior alveolar nerve blocks in 
patients with symptomatic irreversible pulpitis? A systematic review and meta-
analysis. International endodontic journal, 51(10), 1104–1117