Clinical trial NCT02708433
Conditions: Anesthesia
Keywords: lidocaine, jaw
Sponsor: University of North Carolina, Chapel Hill
Start date: 2016-03-01; Completion date: 2017-09-01
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Anecdotal data suggest that the buffered form of the local anesthetic is more potent at equal dosages, and a lower dosage of the drug might be used with an effect equal to higher dosage not buffered. Clinical data are needed to confirm these anecdotal data. No data exist comparing buffered local anesthetics at lower drug concentrations to current dosages commonly used in dental and oral surgical procedures

Detailed description:
Specific Aims:

Compare clinical depths of pulpal anesthesia (cold, Electronic Pulp Test) for mandibular molar, and canine teeth at 30 minute intervals post injection for mandibular block anesthesia with buffered 1% lidocaine with 1/100,000 epinephrine as compared to non-buffered 2% lidocaine with 1/100,000 epinephrine.

Hypotheses:

No differences exist in anesthetic depth for pulpal anesthesia after intraoral injection for mandibular block anesthesia between buffered 1% lidocaine with 1/100,000 epinephrine as compared to non-buffered 2% lidocaine with 1/100,000 epinephrine.

Study Time Frame: 6 months Month One: Recruit 24 volunteers as subjects. Prepare case-books. Months Two-Three: Clinical Study, Months Four-Five: Analyze data Month Six: Prepare Abstracts, Papers Methods: Blinded, Randomized Clinical Design Recruit subjects with Institutional Review Board approved consent at UNC Subjects will serve as their own controls in a cross-over AB/BA study design which is uniform within sequences, uniform within periods, and balanced Randomized subjects to be injected orally for mandibular block (inferior alveolar, lingual, buccal nerves) alternatively with 4cc of buffered 1% lidocaine with 1/100,000 epinephrine and 4cc non-buffered of 2% lidocaine with 1/100,000 epinephrine.

Assessment: pre, and post-anesthetic administration for pulpal anesthesia with cold, Electronic Pulp Test: Mandibular molar, canine at 30 minute intervals Inclusion Criteria: Age 18-30 years, American Society Anesthesiologists (ASA) I Exclusion Criteria Allergy to lidocaine class of anesthetic drugs, Local anesthetic drug past week Current symptoms teeth or oral mucosa. SAS will be used for database management and statistical analysis.

Arms: arm 1: In week one each subject would receive either anesthetic (Buffered 1% lidocaine with 1/100,000 Epinephrine) or (Non-Buffered 2% lidocaine with 1/100,000 Epinephrine) to block the inferior alveolar, lingual, buccal nerves.

In week two the alternate anesthetic would be administered.

Mandibular molar and canine tested for pulpal anesthesia arm 2: In week two each subject would receive the alternate anesthetic (Buffered 1% lidocaine with 1/100,000 Epinephrine) or (Non-Buffered 2% lidocaine with 1/100,000 Epinephrine) to block the inferior alveolar, lingual, buccal nerves.

Mandibular molar and canine tested for pulpal anesthesia
Interventions: intervention 1: Lidocaine
Intervention descriptions: intervention 1: Lidocaine

Protocol documents:
Prot_SAP_000.pdf: 
 
Comparison of Buffered 1% vs. Non-Buffered 2% Lidocaine 
Used in Mandibular Nerve Block 
 
 
 
 
 
 
 
NCT number: NCT02708433 
  
Document Date: 01/01/2016 
 
 
 


 
 
1 
 
1/1/2016 Version  
Research Protocol 
Pilot Study: Comparison of Buffered 1% vs. Non-Buffered 2% Lidocaine used in 
Mandibular Nerve Block: Clinical Outcomes 
 
PI Dr R. White.  
Co-PI Dr G. Reside, Dr C. Phillips Dr E. Rivera 
 
Goal: 
Assess the clinical impact of buffered 1% lidocaine with epinephrine as compared to the 
non-buffered 2% lidocaine with epinephrine used in dental and oral surgical procedures. 
 
Background: 
Based on discovery of the anesthetic effects followed by the invention of the hypodermic 
syringe at the end of the 19th century, cocaine was rapidly adopted as a means of blocking 
painful sensory impulses during surgical procedures.(1) The discovery of procaine early 
in the 20th century led to this newer drug replacing cocaine avoiding the potential 
addictive properties of the latter. Lidocaine and its derivatives, products of the late 20th 
century, mepivicaine, bupivacaine, and articaine, are widely used today with invasive 
procedures.(2) Innovation continues allowing clinicians wider use of local anesthetics in 
the head and neck region. Recently local anesthetics have been administered in vehicles 
such as liposomes to produce longer term sensory nerve blockade, reducing the need for 
analgesic drugs, chiefly opioids, to reduce pain.(3) New options for improving local 
anesthetic effectiveness continue to emerge with a better understanding of the 
pharmacology.(4) Buffering local anesthetics just prior to use produces positive outcomes 
including less “sting” on injection, faster onset of the drug, and possibly added drug 
potency, ie the same positive clinical effect at lower dosage. 
 
The addition of a vasopressor, usually epinephrine, to lidocaine and other injected local 
anesthetics serves to prolong the anesthetic effect by reducing blood flow to the anatomic 
area and the diffusion of the drug away from the anatomic site of injection. To prolong 
the shelf life of the vasopressor, the drug combination must be formulated with a low pH, 
approximately pH 3.5 for lidocaine with 1/100k epinephrine. When injected, the low pH 
causes the “sting” felt by patients on injection. Buffering to a neutral pH eliminates the 
discomfort. (5-9) 
 
Perhaps more important, the local anesthetic drug is more effective if the pH is closer to 
the local anesthetic drugs pKa,, approximately 8.0 for the most commonly used, since 
more of the unionized form of the drug is available to affect the nerve membrane. The 
drug injected at a neutral pH reduces the need for buffering by tissue fluid while retaining 
the desired qualities of the vasopressor. The clinical outcome is a rapid onset of the local 
anesthetic.(8,9) 
 
Anecdotal data suggest that the buffered form of the local anesthetic is more potent at 
equal dosages, and a lower dosage of the drug might be used with an effect equal to 
higher dosage not buffered. Clinical data are needed to confirm these anecdotal data. No 


 
 
2 
 
data exist comparing buffered local anesthetics at lower drug concentrations to current 
dosages commonly used in dental and oral surgical procedures 
 
Until recently, buffering the drug combination with bicarbonate just prior to injection was 
impractical for the small quantities used in intraoral procedures. However, today we do 
have a kit capable of efficiently accomplishing this end.(Anutra Medical, NC) This 
option greatly facilitates clinical studies of dosages common for intraoral injections.  
 
 
Rationale: 
Anecdotal reports suggest buffering lidocaine with epinephrine just before intraoral 
injection reduces time of onset, results in a deeper anesthetic effect, without the “sting” 
with injection from a low pH. Additional data are needed to establish clinical important 
outcomes such as depth of local anesthesia with lower drug dosages of buffered lidocaine 
with epinephrine as compared to the non-buffered drug combinations currently in wide 
use. 
 
Clinical pilot studies are proposed as the start of a series of investigations to support or 
modify the use of the buffered anesthetic for intraoral procedures. 
. 
 
Specific Aims: 
Compare clinical depths of pulpal anesthesia for mandibular molar, and canine teeth at 
30min intervals post injection for mandibular block anesthesia with buffered 1% 
lidocaine with 1/100k epinephrine as compared to non-buffered 2% lidocaine with 
1/100k epinephrine. 
 
Hypotheses: 
No differences exist in anesthetic depth for pulpal anesthesia after intraoral injection for 
mandibular block anesthesia between buffered 1% lidocaine with 1/100k epinephrine as 
compared to non-buffered 2% lidocaine with 1/100k epinephrine. 
 
 
Study Time Frame: 6 months 
Month One 
IRB approvals. Recruit 24 volunteers as subjects.  Prepare case-books. 
Months Two-Three 
Clinical Study 
Months Four-Five 
Analyze data 
Month Six 
Prepare Abstracts, Papers 


 
 
3 
 
 
Methods: Blinded, Randomized Clinical Design  
Recruit subjects with IRB approved consent at UNC  
Obtain NIH clinical trial registration 
Target enrollment 24 subjects 
Subjects will serve as their own controls in a cross-over AB/BA study design which is  
               uniform within sequences, uniform within periods, and balanced  
Sample size justification:  Primary interest is estimation of effect size from pilot study.  
24 subjects should be sufficient to provide data to assess whether a larger study is    
               warranted and provide estimates for sample size calculation for larger studies.  
Vital signs recorded: 10 min before, just after drug administration, and 30min later after 
Randomized subjects to be injected orally for mandibular block (inferior alveolar, 
lingual, buccal nerves) alternatively with 4cc of buffered 1% lidocaine with   
          1/100k epinephrine and 4cc non-buffered of 2% lidocaine with 1/100k epinephrine. 
SAS will be used to create randomization schedules:  
     The randomization will be performed first to type of drug given with a balanced        
      randomization (half subjects buffered; half to non-buffered)  
An OMS resident or clinical OMS faculty will administer the drugs in the OMS clinic. 
  
In week One each subject would receive anesthetic to block the inferior alveolar  
          and lingual N; Halstead or Gow-Gates techniques. Buccal N. block.to complete   
              injection. 
At least a week later, longer than the elimination half-life of the drug lidocaine= 1.5-2hr, 
injections would involve the alternate local anesthetic combination. 
 
Ipsilateral Mandibular teeth to be tested 
     Pulpal anesthesia first molar  
      Pulpal anesthesia canine  
      
Timed Assessment: pre, and post-anesthetic administration for Clinical Signs 
     Onset of Anesthesia Signs: subject reported numb lower lip on injected side. 
 
Assessment: pre, and post-anesthetic administration for pulpal anesthesia  
       Pulp Tester/electrical stimulation: Record level of first response 
              Testing interval: Pre-local anesthetic,  
                      Post-local anesthestic at 30min. 90min, 120min.  
        Response to Cold/ice cone Yes or No  
                Testing interval: Pre-local anesthetic, 
                       Post-local anesthestic at 30min. 90min, 120min. 
 


 
 
4 
 
Study Subjects: 24 
Inclusion Criteria 
Age 18-30 years 
ASA I  
Willingness to participate in two sessions 
Exclusion Criteria 
Allergy to lidocaine class of anesthetic drugs 
Local anesthetic drug use in past week 
Current symptoms teeth or oral mucosa 
 
Data Collection: UNC OMS clinic 
Timed assessment pre, and post-anesthetic clinical effects  
         Signs: molar area anesthesia, canine area anesthesia  
Pulpal anesthesia first molar: quantitative (pulp tester), qualitative (cold) 
Pulpal anesthesia canine: quantitative (pulp tester), qualitative (cold) 
 
Data Collection/Analysis: 
Data will be managed by Dr Phillip’s staff. Data collection forms and questionnaires for 
clinical data will be developed to use Teleform for direct scanning input into an ACCESS 
database.  Similar forms have been used in previous studies. All databases are stored on a 
password protected School of Dentistry server with specific group assignment.  SAS will 
be used for database management and statistical analysis.  Descriptive statistics are used 
to verify correct entry through range and logical checks.  
 
Statistical analysis:  
Effect sizes are currently unknown for the difference time to molar/canine response.  
Primary interest is the difference between type of injection. In order to check the 
assumption of negligible carryover effects, an unpaired t-test or a Wilcoxon Rank Sum 
test, depending on the distribution of the outcome, will be used to compare the within 
subject sums of the results from sequence AB to the within subject sums from sequence 
BA.  Under the assumption that the carryover effects are equal ( λA = λA = λ ), the 
differences for every patient will be calculated and multiplied by ½.  The two sequences will 
be compared using a two-sample t test or a Wilcoxon rank sumtest depending on the 
distribution of the outcome.  
H0 : μAB - μBA = 0 
The expression: 
μAB - μBA = 2( μA - μB ) 
so testing H0 : μAB - μBA = 0, is equivalent to testing: 
H0 : μA - μB = 0 
 
Sample Size:  With a sample size in each sequence group of 12 (a total sample size of 24) 
a 2x2 crossover design will have 90% power to detect a difference in means of -10.00 


 
 
5 
 
assuming that the Sq(MSE) is 10 using a two group t-test with a 0.05 two sided 
significance level 
 
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J Dent Res77:535, 1998. 
2-Wildsmith T: History and development of local anesthesia. In 4TH edition of Principles 
and Practice of Regional Anaesthesia .Ed McLeod G, McCartney C, Wildsmith T 
Oxford, UK Oxford University Press 2012. 
3-Liposomal bupivacaine: A long-acting local anesthetic for postsurgical analgesia. 
Formulary 47:212, 2012. 
4-Strichartz GR, Sanchez V, Arthur R, Chafetz R, Martin D: Fundamental properties of 
local anesthetics II. Measured octanol: Buffer partition coefficients and Pka values of 
clinically used drugs. Anesth Analg 71: 158, 1990 
5-Christoph RA, Buchanan L, Begalia K, Schwaryz S: Pain reduction in local anesthetic 
administration through pH buffering. Ann Emerg Med 17:117, 1988. 
6-Masters JE: Randomised control trial of pH buffered lignocaine with adrenalin in 
outpatient operations. Br J Plastic Surg 51:385, 1998. 
7-Meechan JG, Day PF: A comparison of intraoral injection discomfort produced by 
plain and epinephrine-containing lidocaine local anesthetic solutions: a randomized, 
double-blind, split-mouth, volunteer investigation. Anesth Prog 49: 44, 2002. 
8-Kashyap VM, Desai R, Reddy PB, Menon S: Effect of alkinisation of lignocaine for 
intraoral nerve block on pain during injection, and speed of onset of anaesthesia. Br J 
Oral Maxillofac Surg 49: e72, 2011. 
9-Lee HJL, Cho YJ, Gong HS, Rhee SH, Park HS, Baek GH: The effect of buffered 
lidocaine in local anesthesia: a prospective, randomized, double-blind study. J Hand Surg 
38A: 971, 2013.