Clinical trial NCT02620683
Conditions: Blood Levels of Buffered vs Non-buffered Lidocaine Anesthetics, Local
Keywords: lidocaine, jaw
Sponsor: University of North Carolina, Chapel Hill
Start date: 2015-12-01; Completion date: 2017-09-01
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
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 the peak blood level of lidocaine as compared to the non-buffered drug combination.

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.

Detailed description:
Specific Aims:

Compare blood levels at 30min post injection mandibular block with buffered and non- buffered 2% lidocaine with 1/100k epinephrine. Assess outcomes (pain levels during and post-injection, and onset of anesthesia symptoms) after buffered and non-buffered oral administration of 2% lidocaine with 1/100k epinephrine. Assess possible topical anesthetic properties of buffered and non-buffered oral administration of 2% lidocaine with 1/100k epinephrine

Hypotheses:

No difference in peak blood levels exist between buffered and non-buffered intraoral injection of 2% lidocaine with 1/100k epinephrine.

Injection of buffered local anesthetic will produce less discomfort for the subject as compared to the drug with a low pH.

Buffered local anesthetic will not produce a topical anesthetic effect

Study Time Frame: 6 months Month One IRB approvals. Recruit volunteers as subjects. Prepare case-books. Months Two-Three Clinical Study Months Four-Five Analyze Lab, QOL data Month Six Prepare Abstracts, Papers

Methods: Blinded, Randomized Clinical Design Recruit subjects with IRB approved consent at UNC 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, during at 30min intervals and after post-anesthetic clinical signs disappear: targeted lower lip no longer numb. Randomized subjects to be injected alternatively with 4cc of buffered and 4cc non-buffered oral administration 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, Dr Phero, 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. No Buccal N. block. At least a week later injections would involve the alternate local anesthetic combination.

Venous blood samples would be drawn from the antecubital fossa 30min post oral injection and assayed for blood lidocaine levels Timed Assessment: pre, during injection, and post-anesthetic for Clinical Onset of Anesthesia Signs: subject reported molar area numbness and numb lower lip on ipsilateral injected side. Assessment for pain level on injection; modified Likert-type scale

In addition at each clinic session an assessment of a topical anesthetic effect on contralateral lower lip with 5 drops of the injected drug placed on the clinically dry lower lip mucosa, Outcome yes/no.

Data Collection: UNC OMS clinic Venous blood samples (10cc) will be drawn from the antecubital fossa 30min post oral injection. Timed assessment pre, during injection, and post-anesthetic clinical Signs: molar area anesthesia, incisor area anesthesia, and numb lower lip for topical

Data Collection/Analysis:

Data will be managed by study 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.

Arms: arm 1: In week One each subject would receive anesthetic to block the inferior alveolar and lingual N; Halstead or Gow-Gates techniques. No Buccal N. block.

Venous blood samples would be drawn from the antecubital fossa 30min post oral injection and assayed for blood lidocaine levels arm 2: In week One each subject would receive anesthetic to block the inferior alveolar and lingual N; Halstead or Gow-Gates techniques. No Buccal N. block. At least a week later injections would involve the alternate local anesthetic combination.

Venous blood samples would be drawn from the antecubital fossa 30min post oral injection and assayed for blood lidocaine levels
Interventions: intervention 1: Lidocaine
Intervention descriptions: intervention 1: See above

Protocol documents:
Prot_SAP_000.pdf: 
 
Comparison of Buffered vs. Non-Buffered Lidocaine 
used in Dental and Oral Surgical Procedures:  
Clinical Outcomes 
 
 
 
NCT number NCT02620683 
Document Date 10/30/2015 
Most recent IRB approval Date  
(for this document version) 07/10/2017 
 


 
 
 
10/30/2015 
Page 1 of 4 
  
RESEARCH PROTOCOL 
Comparison of Buffered vs. Non-Buffered Lidocaine used in dental and oral 
surgical procedures: Clinical Outcomes 
 
PI Dr R. White.  
Co-PI Dr G. Reside, Dr C Phillips 
 
Goal: 
Assess the clinical impact of buffered lidocaine with epinephrine as compared to the non-
buffered drug combination used in dental and oral surgical procedures. 
 
Background: 
Based on discovery of the anesthetic effects and 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) 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)  
 
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.  
Perhaps more important, the local anesthetic drug is more effective both in onset and 
potency if the pH is closer to the drugs pKa, over 8.0. The drug injected at a neutral pH 
reduces the need for buffering by tissue fluid while retaining the desired qualities of the 
vasopressor.   
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) 
Mean maximum blood levels of non-buffered local anesthetic drugs occurs 
approximately 30min post oral injection.(4) No data exist on peak blood levels for 
buffered local anesthetics used in dental and oral surgical procedures 
 
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 the peak blood level of lidocaine as compared to the non-buffered drug 
combination. 


 
 
 
10/30/2015 
Page 2 of 4 
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 blood levels at 30min post injection mandibular block with buffered and non-  
      buffered 2% lidocaine with 1/100k epinephrine. 
Assess outcomes (pain levels during and post-injection, and onset of anesthesia   
         symptoms) after buffered and non-buffered oral administration  
          of 2% lidocaine with 1/100k epinephrine. 
Assess possible topical anesthetic properties of buffered and non-buffered oral     
           administration of 2% lidocaine with 1/100k epinephrine 
 
Hypotheses: 
No difference in peak blood levels exist between buffered and non-buffered intraoral    
          injection of 2% lidocaine with 1/100k epinephrine. 
Injection of buffered local anesthetic will produce less discomfort for the subject as  
        compared to the drug with a low pH. 
Buffered local anesthetic will not produce a topical anesthetic effect 
 
Study Time Frame: 6 months 
Month One 
IRB approvals. Recruit dental student volunteers. Prepare case-books. 
Months Two-Three 
Clinical Study 
Months Four-Five 
Analyze Lab, QOL data 
Month Six 
Prepare Abstracts, Papers 


 
 
 
10/30/2015 
Page 3 of 4 
 
Methods: Blinded, Randomized Clinical Design  
Recruit subjects with IRB approved consent at UNC  
Target enrollment 24 subjects 
Subjects will serve as their own controls in a cross-over study design.  
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, during at 30min intervals and after post-anesthetic    
              clinical signs disappear: targeted lower lip no longer numb. 
Randomized subjects to be injected alternatively with 4cc of buffered and   
           4cc non-buffered oral administration 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, Dr Phero, 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. No Buccal N. block. 
At least a week later injections would involve the alternate local anesthetic combination. 
Venous blood samples would be drawn from the antecubital fossa 30min  
           post oral injection and assayed for blood lidocaine levels 
Timed Assessment: pre, during injection, and post-anesthetic for Clinical   
     Onset of Anesthesia Signs: subject reported molar area numbness  
         and numb lower lip on ipsilateral injected side. 
Assessment for pain level on injection; modified Likert-type scale  
 
In addition at each clinic session an assessment of a topical anesthetic effect on   
      contralateral lower lip with 5 drops of the injected drug placed on the clinically dry        
      lower lip mucosa, Outcome yes/no. 
 
Study Subjects: 
Inclusion Criteria 
Age 20-35 years 
ASA I  
Willingness to complete QOL instrument 
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 
Venous blood samples (10cc) will be drawn from the antecubital fossa 30min  
           post oral injection. . Ms Marsh, RN OMS clinic 
Timed assessment pre, during injection, and post-anesthetic clinical   
         Signs: molar area anesthesia, incisor area anesthesia, and numb lower lip for topical 


 
 
 
10/30/2015 
Page 4 of 4 
 
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 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 Primary interest is the difference between type of injection – 95% 
confidence intervals for the difference between injection types will be calculated.  For all 
outcome variables, an assessment of treatment difference, calculated as 1% Buffered 
minus 2% Non-Buffered, will be performed using Wilcoxon rank sum tests with Proc 
NPAR1WAY  (SAS v 9.3). Statistical significance was set as P < 0.05 for all outcomes. 
Ref: http://www2.sas.com/proceedings/sugi24/Posters/p221-24.pdf   
 
For Lidocaine levels from venous blood, samples will be transported immediately after 
blood draw to the analytic lab (Macdonald, Jeffrey M-Biomedical Engineering, 
Medicine) 
 
References: 
1-Leonard M: Carl Koller: Mankind’s gretest benefactor? The story of local anesthesia. 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-Moore et al: Pharmacokinetics of lidocaine with epinephrine following local anesthesia 
reversal with phentolamine mesylate. Anesth Prog 55:40, 2007.