Clinical trial NCT03654417
Conditions: Any Condition Requiring Vulvar Biopsy
Keywords: vulvar biopsy
Sponsor: Duke University
Start date: 2018-09-17; Completion date: 2019-03-12
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare pain control during vulvar biopsy following either (1) application of EMLA (a eutectic mixture of local anesthetics lidocaine 2.5% and prilocaine 2.5%) cream or (2) injection of 1% lidocaine. We hypothesize that lidocaine will provide better biopsy analgesia, but the benefit will be offset by the pain of lidocaine injection compared to EMLA application, thus there will not be a significant difference in highest pain scores between the two groups.

Detailed description:
Performing minor procedures in-office is essential to gynecologic practices. In-office procedures allow for evaluation and diagnosis of a variety of conditions while avoiding the expense, anesthesia, and time associated with the operating room. Pain and discomfort are frequently associated with these procedures, and ensuring that the patient has the least amount of discomfort is a priority. Very painful or uncomfortable procedures could potentially discourage a patient from returning to clinic or receiving the follow up that they may need. Psychological, physiologic, and social factors influence a patient's experience of pain. Previous studies, though mostly related to first trimester abortion procedures in the office, indicate that the procedure type, anxiety, depression, and general anticipation of pain predict increased pain during in office gynecologic procedures (1-4). A review by Ireland et al., found that a multimodal approach that includes patient counseling with other techniques is most effective in achieving optimum pain control for procedures (5,6).

Vulvar biopsies are associated with significant discomfort, and some form of anesthesia is required. The current standard in our group is to inject local anesthesia prior to vulvar biopsy. However, the injection itself is associated with its own level of pain that is not insignificant, and for many, the anticipation of receiving an injection is anxiety provoking. The use of topical anesthesia in lieu of injection or as pre-injection analgesia is variable.

Several previous studies have examined the use of topical anesthetics in the place of or in addition to injected anesthesia. Drouault et al. compared EMLA cream alone to injected lidocaine alone for pain relief in vulvar biopsy and found that pain associated with administration of anesthesia was significantly less for EMLA cream, but better biopsy analgesia was obtained with injected anesthesia. The study considered combined pain scores for both groups for the overall procedure (anesthesia + biopsy), it comments that the combined scores were lower for the EMLA group but failed to reach statistical significance. The study ultimately concluded that EMLA is the less painful procedure to obtain anesthesia and that it can be used as an alternative to injection for biopsies of the genital mucosa (7). This prior study did not compare the highest pain score between groups. Consideration of the highest pain score allows us to assess whether the injection of lidocaine could result in causing more pain than the biopsy itself using EMLA cream alone for anesthesia. Further, the study did not assess the subjects' or the providers' perception of the tolerability and acceptability of performing the procedure using either method. This is an important factor in any in office procedure

EMLA cream is the most extensively studied topical anesthetic. It is FDA approved for use as a topical anesthetic on the genital mucous membranes for superficial, minor surgery. EMLA cream requires between 7-10 minutes of absorption time on the genital mucosa for analgesic effect, with variable duration of analgesia following, usually around 15-20 minutes (9). There is a highly variable absorption rate for EMLA cream depending on the characteristics of the epithelium upon which it is applied as well as the duration and surface area of cream applied. On hair-bearing non-mucosal surfaces it can require 60 minutes of application time to obtain analgesic affect (10). The vulvar area is unique in that it contains both mucosal and non-mucosal and hair-bearing surfaces; this could greatly affect the absorption of EMLA and therefore affect analgesia. For this reason, we will exclude from the study patients requiring vulvar biopsy on hair bearing portion of the vulva.

Several previous studies have examined the use of topical anesthetics in the place of or in addition to injected anesthesia. Drouault et al. compared EMLA cream to injected lidocaine as described above. The study found that pain associated with administration of anesthesia was significantly less for EMLA cream, but better biopsy analgesia was obtained with injected anesthesia. However, there were some limitations to this study also noted above, that we plan to expand and improve upon with the current study.

Zilbert and Lewandoswki studied pre-treatment with EMLA cream prior to anesthesia injection and found that pain was decreased by 50% in patients pretreated compared to placebo prior to lidocaine injection.

Van den Berg studied application of EMLA alone versus lidocaine injection alone in punch biopsies and electrocoagulation of genital warts in men. The study found that in the punch biopsy cohort that the total pain scores (application of EMLA + biopsy versus injection of lidocaine + biopsy) were less for the EMLA group than the injected lidocaine group and the difference was statistically significant (11).

With its FDA approval for use as a topical anesthetic on the genital mucous membranes for superficial, minor surgery, it can be considered a standard of care to use EMLA for anesthesia prior to biopsy as an alternative to injection of lidocaine (10)

As there are no studies that consider the subjects' or the providers' perception of the acceptability or the tolerability of the procedure, this will be novel data for vulvar biopsy. However, acceptability and tolerability have been assessed in other procedural settings, such as in office endoscopic procedures, in which BS-11, a validated 11 point scale, is used to assess pain, anxiety, acceptability, tolerability, and levels of other procedure related symptoms (12-13).

Arms: arm 1: None arm 2: None
Interventions: intervention 1: EMLA intervention 2: Lidocaine
Intervention descriptions: intervention 1: Patients undergoing a vulvar biopsy will be randomized to receive EMLA cream or a lidocaine injection as their numbing agent prior to the procedure. intervention 2: Patients undergoing a vulvar biopsy will be randomized to receive EMLA cream or a lidocaine injection as their numbing agent prior to the procedure.

Protocol documents:
ICF_000.pdf: 
Informed Consent Form 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
NCT03654417 
ICF approved November 11, 2018 


 
Consent to Participate in a Research Study 
 
PI: Laura Havrilesky, MD 
 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
 
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INTRODUCTION 
You are being asked to take part in this research study because you are planning to have a vulvar biopsy 
at the Duke Gynecology Oncology Clinic or the Duke Womens Cancer Care Raleigh clinic.  Research 
studies are voluntary and include only people who choose to take part.  Please read this consent form 
carefully and take your time making your decision. As your study doctor or study staff discusses this 
consent form with you, please ask him/her to explain any words or information that you do not clearly 
understand.  We encourage you to talk with your family and friends before you decide to take part in this 
research study.  The nature of the study, risks, inconveniences, discomforts, and other important 
information about the study are listed below.  
 
Please tell the study doctor or study staff if you are taking part in another research study. 
 
Dr. Laura Havrilesky and her colleagues are conducting this study and it is being funded by the Duke 
University Department of Obstetrics and Gynecology. 
 
WHO WILL BE MY DOCTOR ON THIS STUDY? 
If you decide to participate, your regular healthcare provider will continue to be your doctor for the 
study. 
 
WHY IS THIS STUDY BEING DONE? 
We are performing this study to evaluate pain control during vulvar biopsy using two different numbing 
medicines and to analyze patient’s perspectives about the acceptability and tolerability of the procedure.   
 
Specifically, we are comparing patient perceived pain after the application of topical EMLA numbing 
cream versus patient perceived pain after an injection of lidocaine.  We will do this by collecting pain 
CONCISE SUMMARY
There are two approved numbing medicines for vulvar biopsies. The purpose of this study is to see if one of 
them is better tolerated by and/or more acceptable to patients. To do this we will compare pain control 
during vulvar biopsy following either application of EMLA (a Eutectic Mixture of Local Anesthetics; a 
numbing cream used on the skin) or injection of lidocaine. Participating in the study requires additional time 
in clinic to answer research related questions. You will be asked to answer some questions about yourself, to 
rate your pain at three different times during the procedure, and to tell us if you felt the procedure was 
acceptable to you. The numbing medicine you receive will be randomly assigned to you, so you have a 
50/50 chance of receiving either medication. 
You may not benefit from participating in this study.  If you are in the EMLA cream group, you will not 
receive a needle injection for anesthesia.  There is a risk of skin reaction at the site of application of the 
anesthesia.  This might result in being unable to perform the vulvar biopsy today and would necessitate 
a return clinic visit after the irritated area has resolved.  
If you are interested in learning more about this study, please continue to read below.
DUHS IRB
IRB NUMBER: Pro00094298
IRB APPROVAL DATE: 11/11/2018
IRB EXPIRATION DATE: 8/16/2019


 
Consent to Participate in a Research Study 
 
PI: Laura Havrilesky, MD 
 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
 
Page 2 of 7
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scores from participants at three different time points during their vulvar biopsy procedure.  We will also 
ask participants and the person performing the biopsy questions about the tolerability and acceptability 
of the procedure.   
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Approximately 120 people will be consented to take part in this study at Duke.   
 
WHAT IS INVOLVED IN THE STUDY? 
If you agree to be in this study, you will be asked to sign and date this consent form. A signed copy will 
be sent to the email address you provide or printed and provided to you for your records. 
 
You will be randomly assigned (like the flip of a coin) to receive either EMLA cream or injected 
lidocaine prior to your vulvar biopsy, both of which are FDA-approved.  You have a 50% chance of 
receiving either the EMLA cream or the lidocaine injection. All participants will receive some kind of 
numbing medicine prior to their procedure. 
 
In this study, you will receive all of the normal physical examinations and teaching about the biopsy 
procedure that are standard of care for this procedure. The biopsy site(s) will be identified and the 
anesthetic will be applied.   
 
If you are selected to receive EMLA cream, you will wait 10 minutes with the cream in place before the 
biopsy is done.   
 
If you were selected to injected lidocaine, you will receive injected lidocaine at the site(s) of biopsy and 
at least 1 minute will pass before the biopsy is performed. 
 
You will also be asked questions at three time points: 
 
1. Before your biopsy- You will be asked some basic questions about yourself. You will also be 
asked to rate your baseline anxiety and pain. 
 
2. After the administration of numbing medicine- You will be asked to rate your pain level. 
3. After your biopsy- You will be asked to rate your post-procedure pain level and to answer 
questions about your experience and whether you felt the procedure was acceptable and 
tolerable. 
 
You may decide at any time during your clinic visit to withdraw from the study.  Withdrawing from the 
study will not result in any changes in your care or your relationship with your provider or the care that 
you receive. 
 
DUHS IRB
IRB NUMBER: Pro00094298
IRB APPROVAL DATE: 11/11/2018
IRB EXPIRATION DATE: 8/16/2019


 
Consent to Participate in a Research Study 
 
PI: Laura Havrilesky, MD 
 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
 
Page 3 of 7
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If you decide not to sign the consent form, you will continue to receive the indicated care, but it will not 
be as part of this study.   
 
HOW LONG WILL I BE IN THIS STUDY? 
Your participation in this study will be for the duration of your clinic visit today. Once you have 
completed the post-procedure survey, your participation will be complete. 
 
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first. 
 
WHAT ARE THE RISKS OF THE STUDY? 
Being involved in this study, there is the potential risk of loss of confidentiality.  Every effort will be 
made to keep your information confidential; however, this cannot be guaranteed.  Some of the questions 
we will ask you as part of this study may make you feel uncomfortable.  You may refuse to answer any 
of the questions and you may take a break at any time during the study.  You may stop your 
participation in this study at any time. 
 
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with the study doctor and your regular health care provider if you choose.  
 
EMLA Cream may cause some, all or none of the side effects listed below. 
More likely  
 Temporary paleness (occurs in 37% of instances), redness (occurs in 30% of instances), and/or 
swelling of the skin at the site of application. This would not affect your doctor’s ability to 
complete the procedure. 
 Temporary topical irritation or skin reaction. There is a <1% chance of rash that could affect the 
biopsy being performed.   
 Accidental trauma to the skin with scratching or rubbing while the skin is still numb at the site of 
medication application. 
 
Less Likely  
 Blue mouth or nail beds indicating methemoglobinemia, a condition that causes too little oxygen 
to be delivered to cells, and can be lead to a medical emergency in rare cases. 
 If you are taking certain medications for irregular heartbeat, there is a risk of the medicines 
acting in combination resulting in abnormal heart rhythms or low blood pressure. 
 
There is a risk of topical reaction at the site of application of the topical anesthesia.  This would result in 
being unable to perform the vulvar biopsy during clinic and would necessitate a return clinic visit after 
the irritated area has resolved. 
 
DUHS IRB
IRB NUMBER: Pro00094298
IRB APPROVAL DATE: 11/11/2018
IRB EXPIRATION DATE: 8/16/2019


 
Consent to Participate in a Research Study 
 
PI: Laura Havrilesky, MD 
 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
 
Page 4 of 7
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Lidocaine injection may cause some, all, or none of the side effects listed below.  
 
More likely  
 Numbness, tingling at the site of injection 
 Redness, paleness at the site of injection 
 Accidental trauma to the skin with scratching or rubbing while the skin is still numb at the site of 
medication application 
 
Less Likely  
 Lightheadedness, ear ringing, dizziness 
 Decreased heart rate or low blood pressure 
 allergic reactions that may include itching, hives, swelling of the face, hands, mouth, or throat 
 Blue mouth or nail beds indicating methemoglobinemia: a condition that causes too little oxygen 
to be delivered to cells, and can be lead to a medical emergency in rare cases   
 If you are taking certain medications for irregular heartbeat, there is a risk of the medicines 
acting in combination resulting in abnormal heart rhythms or low blood pressure 
 
For those of reproductive potential: Being a part of this study while pregnant presents minimal risk of 
harming the pregnancy.  Pregnancy testing is not routinely performed prior to vulvar biopsy in clinic. 
You are not required to have a pregnancy test or any specific birth control method before or after the 
study is performed.   
 
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 
taking before you start the study and before starting to take any of these products while you are on the 
study. 
 
There may be risks, discomforts, drug interactions or side effects that are not yet known. 
 
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY? 
You do not have to participate in this research study if you do not want to. You may choose to use either 
of these medications prior to your procedure. Please talk to your doctor about these and perhaps other 
options. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, there may be direct benefit to you but this cannot be guaranteed.”. 
If you are in the EMLA cream group, you may consider it a benefit that you will not receive an injection 
for anesthesia. We hope that in the future the information learned from this study will benefit other 
people receiving vulvar biopsies in clinic. 
 
DUHS IRB
IRB NUMBER: Pro00094298
IRB APPROVAL DATE: 11/11/2018
IRB EXPIRATION DATE: 8/16/2019


 
Consent to Participate in a Research Study 
 
PI: Laura Havrilesky, MD 
 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
 
Page 5 of 7
DUKE UNIVERSITY HEALTH SYSTEM
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WILL MY INFORMATION BE KEPT CONFIDENTIAL? 
 
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law.  
 
Your records may be reviewed in order to meet federal or state regulations. Reviewers may include 
representatives from the Food and Drug Administration, the Duke University Health System 
Institutional Review Board, and others as appropriate. If any of these groups review your research 
record, they may also need to review your entire medical record. 
 
As part of this study, you will be asked to have certain procedures performed. Some of these procedures 
would have been done as part of your regular care. The study doctor will use these test results both to 
treat you and to complete this research.  These test results of the indicated procedure will be recorded in 
your medical record and will be reported to the research data office at Duke.  Results of tests and studies 
done solely for this research study and not as part of your regular care will also be included in your 
medical record. 
 
 
The study results will be retained in your research record for at least six years after the study is 
completed. At that time either the research information not already in your medical record may be 
destroyed or information identifying you will be removed from such study results at DUHS.  Any 
research information in your medical record will be kept indefinitely. 
 
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by federal privacy regulations. 
 
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed. 
 
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared.  Other laws may or may not protect sharing of private health information. 
 
WHAT ARE THE COSTS TO YOU? 
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
DUHS IRB
IRB NUMBER: Pro00094298
IRB APPROVAL DATE: 11/11/2018
IRB EXPIRATION DATE: 8/16/2019


 
Consent to Participate in a Research Study 
 
PI: Laura Havrilesky, MD 
 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
 
Page 6 of 7
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would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance.  Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it.  The 
amount of your out-of-pocket expense will depend on your insurance plan.  For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study.  You 
may have more or higher co-pays than with a Medicare Advantage plan.  Please discuss the costs of the 
study with Dr. Laura Havrilesky.  At your request, a Financial Counselor in the clinic may provide you 
with an estimate of costs for routine services. 
 
There will be no additional costs to you as a result of being in this study.   
 
WHAT ABOUT COMPENSATION? 
Subjects will be offered a $20 check for time spent participating in the study. 
  
WHAT ABOUT RESEARCH RELATED INJURIES? 
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., or your Duke physicians to provide monetary 
compensation or free medical care to you in the event of a study-related injury. 
 
For questions about the study or research-related injury, contact Dr. Laura Havrilesky at (919) 684-3765 
during regular business hours and at (919) 970-1613 after hours and on weekends and holidays. 
 
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY? 
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study.  If such an adverse 
event occurs, we may need to review your entire medical record.   
 
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke.  If you do 
decide to withdraw, we ask that you verbally notify the study staff during your clinic visit.   
 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study. 
 
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue.   
DUHS IRB
IRB NUMBER: Pro00094298
IRB APPROVAL DATE: 11/11/2018
IRB EXPIRATION DATE: 8/16/2019


 
Consent to Participate in a Research Study 
 
PI: Laura Havrilesky, MD 
 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
 
Page 7 of 7
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Your data may be stored and shared for future research without additional informed consent if 
identifiable private information, such as your name and medical record number, are removed. If your 
identifying information is removed from your samples or data, we will no longer be able to identify and 
destroy them. 
 
A description of this clinical trial will be available on https://clinicaltrials.gov/  as required by U.S. Law.  
This Web site will not include information that can identify you.  At most, the Web site will include a 
summary of the results.  You can search this Web site at any time. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Laura Havrilesky at (919) 684-3765 during regular 
business hours and at (919) 970-1613 after hours and on weekends and holidays. 
 
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111. 
 
STATEMENT OF CONSENT 
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time.  I have been told that I 
will be given a signed and dated copy of this consent form." 
 
 
__________________________________________ 
 
___________     ____________ 
Signature of Subject  
 
 
 
 
 
Date 
 
   Time 
 
__________________________________________ 
Printed name of Subject 
 
 
 
 
 
 
 
 
 
Subject’s Date of Birth 
 
__________________________________________ 
 
___________     ____________ 
Signature of Person Obtaining Consent 
 
 
 
Date 
 
   Time 
 
__________________________________________ 
Printed name of Person Obtaining Consent
DUHS IRB
IRB NUMBER: Pro00094298
IRB APPROVAL DATE: 11/11/2018
IRB EXPIRATION DATE: 8/16/2019

SAP_002.pdf: 
1 
 
Statistical Analysis Plan 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
NCT03654417 
SAP approved April 4, 2019 
 
 


2 
 
A comparison of pain perception using topical EMLA cream vs. lidocaine injection for vulvar biopsy: a 
randomized controlled trial 
Investigator:  
 
Logan Williams 
Faculty Mentor: 
Laura Havrilesky 
Statisticians: 
 
Jeremy Weber (author), Carl Pieper (faculty) 
Date:  
 
March 15, 2019 
Deadline: 
 
March 25, 2019 
Target Journal:  
 
Target Conference: 
Duke University School of Medicine Clinical Research Day (May 17, 2019) 
Project Summary 
The current standard at the Duke Cancer Center Gynecology Oncology Clinic is to use a lidocaine injection 
as local anesthesia prior to vulvar biopsy. The injection itself is not without pain and awaiting the injection 
frequently induces anxiety in patients. Other studies have examined the use of a topical anesthetic in 
addition to or in place of injected anesthesia. A previous study has found that EMLA cream is associated 
with less pain at the time of anesthesia administration, but injection anesthesia resulted in better biopsy 
pain control. Pain was measured on a 100 mm visual analog scale at the time of anesthesia administration 
and immediately following biopsy. The purpose of this study is to compare EMLA cream to lidocaine 
injection for analgesia for vulvar biopsy using the highest recorded pain score during the procedure. 
Contents 
Statistical Analysis Plan ................................................................................................................................. 3 
Primary Objective ..................................................................................................................................... 3 
Exposure.................................................................................................................................................... 3 
Primary Outcome ...................................................................................................................................... 3 
Secondary Objective ................................................................................................................................. 3 
Secondary Outcome .................................................................................................................................. 3 
Exploratory Objective ............................................................................................................................... 3 
Exploratory Outcomes .............................................................................................................................. 3 
Data ........................................................................................................................................................... 4 
Inclusion Criteria ....................................................................................................................................... 4 
Exclusion Criteria....................................................................................................................................... 4 
Analysis Objectives........................................................................................................................................ 4 
References .................................................................................................................................................. 10 
 


3 
 
Statistical Analysis Plan 
Primary Objective 
• 
To compare highest subjective pain score between patients receiving EMLA cream vs. lidocaine 
for analgesia for vulvar biopsy 
Exposure 
• 
Patients were randomly assigned with equal probability to receive either EMLA cream or a 
lidocaine injection for analgesia for vulvar biopsy  
Primary Outcome 
• 
Pain was recorded during the application of EMLA cream or injection of lidocaine, and 
immediately after the biopsy on a 100 mm visual analog scale. If multiple sites were biopsied 
and the pain level differed between sites, then the highest pain score was recorded. If the 
anesthesia was inadequate in either treatment arm prior to biopsy, then an additional lidocaine 
injection was given and pain was recorded prior to the additional injection. The highest of all 
these pain measurements will be used as the primary outcome.  
o Continuous variable ranging from 0 to 100 
Secondary Objective 
• 
To compare pain scores at vulvar biopsy between treatment arms 
Secondary Outcome 
• 
Pain score at vulvar biopsy measured on a 100 mm visual analog scale 
o Continuous variable ranging from 0 to 100 
Exploratory Objective 
• 
To compare subjects’ and providers’ perceptions of acceptability and tolerability of the 
procedure between EMLA cream and lidocaine 
Exploratory Outcomes 
• 
Patient’s response to “overall, how acceptable was the procedure performed today” measured 
on a 100 mm visual analog scale 
o Continuous variable ranging from 0 to 100 
• 
Patient’s response to “overall, how would you rate the experience of your biopsy procedure 
today” measured on a 100 mm visual analog scale 
o Continuous variable ranging from 0 to 100 
• 
Provider’s response to “overall, how well did the subject tolerate the procedure today” 
measured on a 100 mm visual analog scale 
o Continuous variable ranging from 0 to 100 
• 
Provider’s response to “overall, how satisfied are you with the procedure performed today” 
measured on a 100 mm visual analog scale 
o Continuous variable ranging from 0 to 100 


4 
 
Data 
• 
Subjects were recruited from patients visiting the Duke Cancer Center Gynecology Oncology 
Clinic for a vulvar biopsy. Patients were approached by the provider and asked about interest in 
participating in the study. If interested, research personnel then discussed the study with the 
patient. Informed consent was done via an electronic consent form. Enrollment log, study 
questionnaires, and pain assessment forms were all stored in REDCap. All exported copies are 
saved on secure Duke password protected servers. Randomization to a treatment arm was done 
using the randomization tool in REDCap. Data were exported from REDCap on March 13, 2019 
by Jeremy Weber and stored on the BERD Method Core’s shared drive.  
Inclusion Criteria 
• 
Females above 18 years old presenting to Duke Gynecology Oncology Clinic for vulvar biopsy 
• 
Able to provide informed consent in English and agree to the risks of the study 
Exclusion Criteria 
• 
Not able to provide informed consent 
• 
Vulvar biopsy on hair bearing surface 
Analysis Objectives 
1. Objective: Describe patient characteristics in the analysis cohort by treatment arm and overall 
Analysis: Create a baseline table of patient characteristics by treatment arm and overall. Continuous 
variables will be summarized with mean (SD), median (25th percentile, 75th percentile), and range. 
Categorical variables will be reported as frequency and percent. This table can be used to check that 
randomization approximately distributed confounders equally between the two treatment arms. P 
values will not be provided. 
Conclusions: All pre-procedure data are presented in Table 1.1. There was a total of 37 enrolled 
patients, with 19 and 18 in the EMLA cream and lidocaine injection group, respectively.  
Table 1.1. Patient demographics and characteristics 
 
 
EMLA cream 
(N=19) 
Lidocaine injection only  
(N=18) 
Total         
(N=37) 
Generalized Anxiety Disorder 7-Item Scale: Over the last 2 weeks, how often have you been bothered 
by the following problems? 
1.  Feeling nervous, anxious, or on edge 
  
  
  
    Not at all sure 
8 (42.1%) 
10 (55.6%) 
18 (48.6%) 
    Several days 
7 (36.8%) 
5 (27.8%) 
12 (32.4%) 
    Over half the days 
2 (10.5%) 
1 (5.6%) 
3 (8.1%) 
    Nearly every day 
2 (10.5%) 
2 (11.1%) 
4 (10.8%) 
  
  
  
  
2.  Not being able to stop or control worrying 
  
  
  
    Not at all sure 
13 (68.4%) 
13 (72.2%) 
26 (70.3%) 
    Several days 
5 (26.3%) 
3 (16.7%) 
8 (21.6%) 
    Nearly every day 
1 (5.3%) 
2 (11.1%) 
3 (8.1%) 
  
  
  
  


5 
 
Table 1.1. Patient demographics and characteristics 
 
 
EMLA cream 
(N=19) 
Lidocaine injection only  
(N=18) 
Total         
(N=37) 
3.  Worrying too much about different things 
  
  
  
    Not at all sure 
13 (68.4%) 
7 (38.9%) 
20 (54.1%) 
    Several days 
3 (15.8%) 
7 (38.9%) 
10 (27.0%) 
    Over half the days 
1 (5.3%) 
2 (11.1%) 
3 (8.1%) 
    Nearly every day 
2 (10.5%) 
2 (11.1%) 
4 (10.8%) 
  
  
  
  
4.  Trouble relaxing 
  
  
  
    Not at all sure 
13 (68.4%) 
6 (33.3%) 
19 (51.4%) 
    Several days 
4 (21.1%) 
8 (44.4%) 
12 (32.4%) 
    Over half the days 
1 (5.3%) 
1 (5.6%) 
2 (5.4%) 
    Nearly every day 
1 (5.3%) 
3 (16.7%) 
4 (10.8%) 
  
  
  
  
5.  Being so restless that it's hard to sit still 
  
  
  
    Not at all sure 
16 (84.2%) 
12 (66.7%) 
28 (75.7%) 
    Several days 
1 (5.3%) 
4 (22.2%) 
5 (13.5%) 
    Over half the days 
1 (5.3%) 
1 (5.6%) 
2 (5.4%) 
    Nearly every day 
1 (5.3%) 
1 (5.6%) 
2 (5.4%) 
  
  
  
  
6.  Becoming easily annoyed or irritable 
  
  
  
    Not at all sure 
14 (73.7%) 
9 (50.0%) 
23 (62.2%) 
    Several days 
5 (26.3%) 
8 (44.4%) 
13 (35.1%) 
    Nearly every day 
0 (0.0%) 
1 (5.6%) 
1 (2.7%) 
  
  
  
  
7.  Feeling afraid as if something awful might 
  
  
  
happen 
  
  
  
    Missing 
1 (.%) 
0 (.%) 
1 
    Not at all sure 
14 (77.8%) 
 14 (77.8%) 
28 (77.8%) 
    Several days 
3 (16.7%) 
4 (22.2%) 
7 (19.4%) 
    Nearly every day 
1 (5.6%) 
0 (0.0%) 
1 (2.8%) 
  
  
  
  
Total scores 
Total - Not at all sure 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
0.0 (0.0) 
0.0 (0.0) 
0.0 (0.0) 
    Median 
0.0 
0.0 
0.0 
    Q1, Q3 
0.0, 0.0 
0.0, 0.0 
0.0, 0.0 
    Range 
(0.0-0.0) 
(0.0-0.0) 
(0.0-0.0) 
  
  
  
  
Total - Several days 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
1.5 (1.5) 
2.2 (1.5) 
1.8 (1.5) 
    Median 
1.0 
2.0 
2.0 
    Q1, Q3 
0.0, 3.0 
1.0, 3.0 
1.0, 3.0 
    Range 
(0.0-5.0) 
(0.0-5.0) 
(0.0-5.0) 


6 
 
Table 1.1. Patient demographics and characteristics 
 
 
EMLA cream 
(N=19) 
Lidocaine injection only  
(N=18) 
Total         
(N=37) 
  
  
  
  
Total - Over half the days 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
0.5 (1.5) 
0.6 (1.3) 
0.5 (1.4) 
    Median 
0.0 
0.0 
0.0 
    Q1, Q3 
0.0, 0.0 
0.0, 0.0 
0.0, 0.0 
    Range 
(0.0-6.0) 
(0.0-4.0) 
(0.0-6.0) 
  
  
  
  
Total - Nearly every day 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
1.3 (3.5) 
1.8 (3.6) 
1.5 (3.5) 
    Median 
0.0 
0.0 
0.0 
    Q1, Q3 
0.0, 0.0 
0.0, 3.0 
0.0, 0.0 
    Range 
(0.0-15.0) 
(0.0-12.0) 
(0.0-15.0) 
  
  
  
  
Total Score 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
3.3 (4.0) 
4.6 (4.2) 
3.9 (4.1) 
    Median 
1.0 
3.5 
2.0 
    Q1, Q3 
0.0, 5.0 
2.0, 8.0 
1.0, 7.0 
    Range 
(0.0-15.0) 
(0.0-15.0) 
(0.0-15.0) 
  
  
  
  
If you checked off any problems, how difficult 
  
  
  
have these made it for you to do your work, take 
  
  
  
care of things at home, or get along with other 
  
  
  
people? 
  
  
  
    Missing 
1 (.%) 
0 (.%) 
1 
    Not difficult at all 
14 (77.8%) 
14 (77.8%) 
28 (77.8%) 
    Somewhat difficult 
4 (22.2%) 
3 (16.7%) 
7 (19.4%) 
    Extremely difficult 
0 (0.0%) 
1 (5.6%) 
1 (2.8%) 
  
  
  
  
Age 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
57.9 (16.3) 
58.7 (10.8) 
58.3 (13.7) 
    Median 
60.0 
58.5 
60.0 
    Q1, Q3 
46.0, 74.0 
51.0, 65.0 
51.0, 66.0 
    Range 
(27.0-81.0) 
(40.0-78.0) 
(27.0-81.0) 
  
  
  
  
Race 
  
  
  
    Black or African American 
7 (36.8%) 
9 (50.0%) 
16 (43.2%) 
    White or Caucasian 
12 (63.2%) 
9 (50.0%) 
21 (56.8%) 
  
  
  
  
Ethnicity 
  
  
  
    Not Hispanic 
18 (94.7%) 
18 (100.0%) 
36 (97.3%) 


7 
 
Table 1.1. Patient demographics and characteristics 
 
 
EMLA cream 
(N=19) 
Lidocaine injection only  
(N=18) 
Total         
(N=37) 
    Hispanic 
1 (5.3%) 
0 (0.0%) 
1 (2.7%) 
  
  
  
  
Highest level of education 
  
  
  
    Less than a high school diploma 
0 (0.0%) 
2 (11.1%) 
2 (5.4%) 
    High school degree or equivalent (GED) 
5 (26.3%) 
4 (22.2%) 
9 (24.3%) 
    Some college 
9 (47.4%) 
7 (38.9%) 
16 (43.2%) 
    Graduated college 
3 (15.8%) 
5 (27.8%) 
8 (21.6%) 
    Post graduate degree 
2 (10.5%) 
0 (0.0%) 
2 (5.4%) 
  
  
  
  
Prior vulvar biopsy 
16 (84.2%) 
17 (94.4%) 
33 (89.2%) 
  
  
  
  
Number of prior vulvar biopsies 
  
  
  
    N 
16 
17 
33 
    Mean (SD) 
3.2 (4.6) 
1.8 (1.0) 
2.5 (3.3) 
    Median 
2.0 
1.0 
2.0 
    Q1, Q3 
1.0, 3.0 
1.0, 3.0 
1.0, 3.0 
    Range 
(1.0-20.0) 
(1.0-4.0) 
(1.0-20.0) 
  
  
  
  
Takes any prescription medication for pain 
5 (26.3%) 
3 (16.7%) 
8 (21.6%) 
  
  
  
  
Takes any prescription medication for nerves or 
anxiety 
2 (10.5%) 
5 (29.4%) 
7 (19.4%) 
    Missing 
0 
1 
1 
  
  
  
  
Baseline vulva pain (mm) 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
7.7 (21.4) 
2.4 (4.5) 
5.1 (15.7) 
    Median 
0.0 
0.0 
0.0 
    Q1, Q3 
0.0, 5.0 
0.0, 3.0 
0.0, 3.0 
    Range 
(0.0-92.0) 
(0.0-17.0) 
(0.0-92.0) 
  
  
  
  
Baseline anxiety level (mm) 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
21.8 (21.5) 
38.1 (29.3) 
29.7 (26.5) 
    Median 
19.0 
31.5 
21.0 
    Q1, Q3 
0.0, 31.0 
12.0, 61.0 
8.0, 48.0 
    Range 
(0.0-65.0) 
(0.0-91.0) 
(0.0-91.0) 
 
 
 


8 
 
2. Objective: Compare highest subjective pain score between patients receiving EMLA cream vs. 
lidocaine 
Analysis: Linear regression will be used to test if the highest pain score differs between treatment 
arms, controlling for baseline pain.1 The regression coefficient, 95% confidence interval, and p value 
will be reported for the treatment effect. A significant p value would indicate that the highest pain 
score, on average, differed between the two treatment arms. If there is not a significant difference 
between treatment arms with regards to the highest pain score, then the mean and variance 
estimates from these patients will be used to recalculate the sample size needed (objective 3).  
 
Conclusions: The highest pain score was created as the maximum between pain during application 
of anesthesia and pain immediately following biopsy. The median highest pain score in the EMLA 
cream group was 20.0 mm vs. 56.5 mm in the lidocaine injection group.  
 
Table 2.1. Highest pain score by treatment arm 
 
 
EMLA cream    
(N=19) 
Lidocaine injection only   
(N=18) 
Total      
(N=37) 
Highest pain score (mm) 
  
  
  
    N 
19 
18 
37 
    Mean (SD) 
26.7 (29.0) 
52.5 (32.0) 
39.2 (32.8) 
    Median 
20.0 
56.5 
27.0 
    Q1, Q3 
5.0, 50.0 
26.0, 80.0 
12.0, 61.0 
    Range 
(0.0-100.0) 
(5.0-100.0) 
(0.0-100.0) 
 
All patients in the lidocaine injection group reported having the same as or more pain during the 
injection than the biopsy. Four out of nineteen patients in the EMLA cream group reported more 
pain from the application of the cream than the biopsy, and three reported the same amount of 
pain.  
 
Frequency 
Row Percent 
More pain from 
biopsy 
Same amount 
of pain 
More pain from 
application of 
anesthesia 
Total 
Lidocaine injection only 
0 
0.00 
1 
5.56 
17 
94.44 
18 
 
EMLA cream 
12 
63.16 
3 
15.79 
4 
21.05 
19 
 
Total 
12 
4 
21 
37 
 
From the linear regression model, patients that received EMLA cream were expected to report their 
highest pain score 25.7 mm lower than the lidocaine injection group (95% CI = [-45.1, -6.3], p < 
0.01). In other words, the highest pain score in the EMLA cream group was significantly lower than 
in the lidocaine injection group.  
 


9 
 
3.  Objective: Calculate the new sample size needed using effect estimates from the interim 
analysis 
Analysis: Using the difference in means between groups and the estimate of the standard deviation, 
the sample size needed to detect the observed difference in pain scores between the two treatment 
arms at 90% power with an alpha level of 0.05 using a two-sample t-test will be calculated. This will 
be the number of patients that will need to be NEWLY accrued. The current patients do not count 
towards this sample size.  
 
Conclusions: Since the highest pain score was significantly lower in the EMLA cream group 
compared to the lidocaine group, the trial does not need to continue. 
 
4. Objective: Compare secondary and exploratory outcomes between treatment arms 
Analysis: The secondary objective, pain at vulvar biopsy, will be compared between treatment arms 
using linear regression, controlling for baseline pain, similar to the primary objective. The 
exploratory objectives, excluding provider’s response to “overall, how satisfied were you with the 
procedure,” will be compared between treatment arms using Wilcoxon rank sum test. A significant p 
value would mean that one of the treatment arms tended to have higher scores on the VAS than the 
other. Since the same providers are rating their satisfaction with the procedure multiple times, the 
responses will be correlated. To take this into account, provider procedure satisfaction scores will be 
compared between treatment arms with a marginal model using generalized estimating equations 
(GEE) assuming a normal distribution. The working correlation matrix will be chosen using QIC and 
the robust variance estimator will be used.  
Conclusions:  There was not a significant difference between treatment arms with regards to pain at 
biopsy (EMLA cream 𝛽𝛽 = 6.9; 95% confidence interval [-12.0, 25.9]; p = 0.47). Patients that were 
randomized to EMLA cream had a significantly better experience with the procedure than those that 
received lidocaine (p = 0.02). There was not a significant difference between treatment arms for 
patient acceptability or provider’s perception of subject tolerance (p = 0.06 for both). A compound 
symmetric working correlation structure was used for the marginal model comparing provider 
satisfaction scores between treatment groups. There was not a significant difference between 
treatment arms for provider satisfaction scores (p = 0.35). As a note, do not place too much 
emphasis on the insignificant results as this is still a small sample size and the trial was not powered 
for these objectives. A lack of statistical significance does not prove that there is no difference. 
Summary statistics for the secondary and exploratory objectives are shown in table 4.1. A lower 
score indicates better results for all outcomes. 
 


10 
 
Table 4.1. Secondary and exploratory outcomes 
 
 
EMLA cream 
(N=19) 
Lidocaine injection only  
(N=18) 
Total       
(N=37) 
P value 
Pain at vulvar biopsy (mm) 
  
  
  
0.47 
    N 
19 
18 
37 
 
    Mean (SD) 
24.1 (30.3) 
17.4 (29.1) 
20.8 (29.5) 
 
    Median 
6.0 
3.0 
5.0 
 
    Q1, Q3 
1.0, 50.0 
0.0, 15.0 
0.0, 26.0 
 
    Range 
(0.0-100.0) 
(0.0-100.0) 
(0.0-100.0) 
 
  
  
  
  
 
Patient's experience with the procedure (lower is 
  
  
  
0.02 
better) 
  
  
  
 
    N 
19 
18 
37 
 
    Mean (SD) 
11.2 (23.1) 
27.1 (29.7) 
18.9 (27.3) 
 
    Median 
2.0 
17.0 
6.0 
 
    Q1, Q3 
0.0, 17.0 
5.0, 38.0 
0.0, 25.0 
 
    Range 
(0.0-99.0) 
(0.0-100.0) 
(0.0-100.0) 
 
  
  
  
  
 
Patient's acceptability of the procedure (lower 
  
  
  
0.06 
is better) 
  
  
  
 
    N 
19 
18 
37 
 
    Mean (SD) 
10.8 (21.1) 
17.9 (19.8) 
14.2 (20.5) 
 
    Median 
0.0 
10.5 
5.0 
 
    Q1, Q3 
0.0, 18.0 
1.0, 33.0 
0.0, 21.0 
 
    Range 
(0.0-86.0) 
(0.0-67.0) 
(0.0-86.0) 
 
  
  
  
  
 
Provider's perception of patient tolerance (lower 
  
  
  
0.06 
is better) 
  
  
  
 
    N 
19 
18 
37 
 
    Mean (SD) 
16.6 (28.7) 
20.4 (18.0) 
18.5 (23.8) 
 
    Median 
3.0 
15.0 
13.0 
 
    Q1, Q3 
0.0, 19.0 
9.0, 27.0 
0.0, 20.0 
 
    Range 
(0.0-99.0) 
(0.0-62.0) 
(0.0-99.0) 
 
  
  
  
  
 
Provider's satisfaction with the procedure (lower 
  
  
  
0.35 
is better) 
  
  
  
 
    N 
19 
18 
37 
 
    Mean (SD) 
21.2 (35.8) 
13.1 (13.5) 
17.2 (27.3) 
 
    Median 
3.0 
9.5 
7.0 
 
    Q1, Q3 
0.0, 18.0 
3.0, 18.0 
0.0, 18.0 
 
    Range 
(0.0-99.0) 
(0.0-51.0) 
(0.0-99.0) 
 
 
References 
1. Committee for Proprietary Medicinal Products (CPMP). Points to Consider on Adjustment for 
Baseline Covariates. Stat Med 2004;23(5):701-9. 

Prot_001.pdf: 
Study Protocol 
A comparison of pain perception using topical EMLA cream versus lidocaine injection for vulvar 
biopsy: a randomized controlled trial 
NCT03654417 
Study Protocol approved September 23, 2019 
 
 


Research Abstract 
 
The purpose of this study is to compare pain control during vulvar biopsy following either (1) application 
of EMLA (a eutectic mixture of local anesthetics lidocaine 2.5% and prilocaine 2.5%) cream or (2) 
injection of 1% lidocaine.  
 
Subjects recruited from the Duke Gynecology Oncology clinic and the Duke Womens Cancer Care 
Raleigh clinic who will be receiving a vulvar biopsy will be randomized to receive either EMLA cream or 
injectable lidocaine in preparation for the biopsy. Subjects will complete a baseline survey, and 
sociodemographic information will be collected. Pain will be assessed using a 100 mm visual analog 
scale: at baseline, after application of EMLA or lidocaine injection, and immediately after vulvar biopsy. 
Subjects will then complete an exit survey on their perception of the tolerability and acceptability of the 
procedures. The primary outcome is highest subjective pain score. We hypothesize that lidocaine will 
provide better biopsy analgesia, but the benefit will be offset by the pain of lidocaine injection 
compared to EMLA application, thus there will not be a significant difference in highest pain scores 
between the two groups. Subjects will be compensated $20 for their participation. 
 
We chose a 16-mm difference on a standard 100-mm visual analog pain scale as value of clinical 
significance. In order to detect at least a 16-mm difference with 90% power and alpha of .05, we 
estimated a total sample size of 53. Highest mean pain scores between anesthetic methods will be 
compared as the primary outcome using T-test vs Wilcoxon Rank sum test. Patient perception of 
tolerability and acceptability of the procedure as well as the provider’s satisfaction with the procedure 
will also be analyzed. There are no additional risks/benefits to the study participant for being part of the 
study as both methods of anesthesia are considered standards of care. 
 
Primary Objectives 
 
To compare highest subjective pain score with application of EMLA cream versus injection of lidocaine 
for analgesia for vulvar biopsy. 
 
Secondary Objectives 
 
To compare pain scores at vulvar biopsy 
To investigate possible pathologic changes associated with EMLA cream administration 
 


Purpose 
We hypothesize that lidocaine will provide better biopsy analgesia, but the benefit will be offset by the 
pain of lidocaine injection compared to EMLA application, thus there will not be a significant difference 
in highest pain scores between the two groups. 
 
Background and Significance 
 
Performing minor procedures in-office is essential to gynecologic practices.In-office procedures allow for 
evaluation and diagnosis of a variety of conditions while avoiding the expense, anesthesia, and time 
associated with the operating room.Pain and discomfort are frequently associated with these 
procedures, and ensuring that the patient has the least amount of discomfort is a priority.Very painful or 
uncomfortable procedures could potentially discourage a patient from returning to clinic or receiving 
the follow up that they may need.Psychological, physiologic, and social factors influence a patient’s 
experience of pain.Previous studies, though mostly related to first trimester abortion procedures in the 
office, indicate that the procedure type, anxiety, depression, and general anticipation of pain predict 
increased pain during in office gynecologic procedures (1-4).A review by Ireland et al., found that a 
multimodal approach that includes patient counseling with other techniques is most effective in 
achieving optimum pain control for procedures (5,6). 
  
Vulvar biopsies are associated with significant discomfort, and some form of anesthesia is required.The 
current standard in our group is to inject local anesthesia prior to vulvar biopsy.However, the injection 
itself is associated with its own level of pain that is not insignificant, and for many, the anticipation of 
receiving an injection is anxiety provoking.The use of topical anesthesia in lieu of injection or as pre-
injection analgesia is variable. 
  
Several previous studies have examined the use of topical anesthetics in the place of or in addition to 
injected anesthesia.Drouault et al. compared EMLA cream alone to injected lidocaine alone for pain 
relief in vulvar biopsy and found that pain associated with administration of anesthesia was significantly 
less for EMLA cream, but better biopsy analgesia was obtained with injected anesthesia.The study 
considered combined pain scores for both groups for the overall procedure (anesthesia + biopsy), it 
comments that the combined scores were lower for the EMLA group but failed to reach statistical 
significance. The study ultimately concluded that EMLA is the less painful procedure to obtain 
anesthesia and that it can be used as an alternative to injection for biopsies of the genital mucosa (7). 
This prior study did not compare the highest pain score between groups.Consideration of the highest 
pain score allows us to assess whether the injection of lidocaine could result in causing more pain than 
the biopsy itself using EMLA cream alone for anesthesia.Further, the study did not assess the subjects’ 
or the providers’ perception of the tolerability and acceptability of performing the procedure using 
either method.This is an important factor in any in office procedure 
  


EMLA cream is the most extensively studied topical anesthetic.It is FDA approved for use as a topical 
anesthetic on the genital mucous membranes for superficial, minor surgery.EMLA cream requires 
between 7-10 minutes of absorption time on the genital mucosa for analgesic effect, with variable 
duration of analgesia following, usually around 15-20 minutes (9).There is a highly variable absorption 
rate for EMLA cream depending on the characteristics of the epithelium upon which it is applied as well 
as the duration and surface area of cream applied.On hair-bearing non-mucosal surfaces it can require 
60 minutes of application time to obtain analgesic affect (10).The vulvar area is unique in that it contains 
both mucosal and non-mucosal and hair-bearing surfaces; this could greatly affect the absorption of 
EMLA and therefore affect analgesia.For this reason, we will exclude from the study patients requiring 
vulvar biopsy on hair bearing portion of the vulva. 
  
There have been case reports of EMLA induced pathologic changes in children with a variety of 
inflammatory skin conditions where disruptive changes on H&E were noted.  Similarly in a small series of 
patients with vulvar dermatoses, EMLA was associated with similar disruptive changes on H&E. The 
extent of these changes and their ability to impact pathologic diagnoses have not been studied. 
 
Design and Procedures 
 
Following informed consent enrollment, subjects will be randomized to an arm of the study using the 
randomization tool in REDCap. eConsent will be programmed in REDcapand. Study subjects, study staff, 
and performing providers will not be blinded to the intervention as the interventions are different; 
therefore, our study design is an unblinded randomized controlled trial.Selection criteria are listed in the 
table below. 
  
Selection Criteria 
Participant Inclusion Criteria 
Participant Exclusion Criteria 
• 
Females above age 18 presenting to 
Duke Gynecology Oncology clinic for 
vulvar biopsy 
• 
Able to provide informed consent in 
English and agree to the risks of the 
study 
a. Not able to provide informed 
consent 
b. Vulvar biopsy on a hair bearing 
surface 
It is not standard to perform pregnancy testing prior to vulvar biopsy in Duke Gynecology Oncology clinic 
and Duke Womens Cancer Care Raleigh clinic as the administration of anesthesia and procedure itself 
present minimal risk of harming a fetus.   Both EMLA cream and injected lidocaine are labeled pregnancy 
category B indicating that reproduction studies performed in rats have revealed no evidence of harm to 


the fetus, but there are no adequate and well-controlled studies in pregnant women (10, 14).  For these 
reasons, we will not perform pregnancy tests on possible study participants. 
  
Because participation in the study only lasts the duration of the clinic visit during that day, and EMLA 
and lidocaine are pregnancy category B, there are no specific contraceptive methods required preceding 
or following participation in the study.  
  
Measurement of anxiety, acceptability, and pain 
Before the procedure is performed, subjects will complete the GAD-7, a validated 7 item anxiety 
disorder scale(15). 
  
Subjects will report pain using a visual analog scale, a scale comprised of a 100 mm horizontal line 
anchored with 2 verbal descriptors, one for each symptom extreme.For pain, the scale is most often 
anchored by “no pain” (score of 0) and “worst imaginable pain” (score of 100 mm). The patient marks 
their pain with a vertical line perpendicular to the scale, and the distance from 0 is measured with a 
ruler (16-18). 
  
Subjects will also be asked to rate the overall acceptability and tolerability of the procedure performed 
with a visual analog scale.The provider performing the biopsy will rate their overall satisfaction and 
perception of patient tolerability of the procedure using the same scale.The subjects will also be asked if 
the procedure was better or worse than they expected. 
  
Study Procedures: 
Intake information: Patients will present to their scheduled Duke Gynecology Oncology Clinic or Duke 
Womens Cancer Care Raleigh clinic appointment.  If it is determined that a vulvar biopsy is indicated, the 
provider will briefly inquire about interest in the study.  If interested, a study coordinator will introduce 
the study to the patient and perform informed consent should they decide to participate.  After 
providing informed consent, the patient will complete a survey including sociodemographic information 
and a baseline anxiety survey (GAD7) (see appendices).  The following information will be collected: age, 
race, ethnicity, level of education, baseline vulvar pain using a 100 mm visual analog scale, history of 
previous vulvar biopsy, daily narcotic or anxiolytic use.  Information including BMI, chronic pain 
diagnoses, history of vulvar cancer will be collected by study coordinators from the medical record.  
  
Participants will complete questionnaires electronically with the exception of the pain assessment by 
visual analog scale.The data will be collected directly into REDCap.Pain scores will be entered into 
REDCap by measuring from 0 millimeters the hash mark made by the patient.There will be paper forms 
of the questionnaires available, as a secondary option should it become necessary. 


  
Randomization: After completing the entry intake information, the subject will be randomized to EMLA 
cream application or lidocaine injection using the randomization tool within REDCap 
  
Procedure: The subject will then be placed in dorsal lithotomy position on the Gynecology Oncology 
pelvic exam tables in preparation for the procedure.   If the patient is randomized to the EMLA cream 
group, the EMLA cream will be applied at the intended site of biopsy and left in place for a minimum of 
10 minutes prior to biopsy.  Approximately 5 g of EMLA should be applied in a thick layer to the area to 
be biopsied (a 1g strip is approximately 1.5 x 0.2 inches and squeezed from the tube in a narrow strip) 
(10).  The subject will report a pain score at time of EMLA application.  After 10 minutes vulvar biopsy 
will be performed.  
  
For subjects receiving lidocaine injection, approximately 2 mL of 1% lidocaine will be injected 
superficially at the planned biopsy site using a 25- or 27-gauge needle at the discretion of the 
physican.The subject will report pain at time of injection on a 100 mm visual analog scale before 
proceeding to vulvar biopsy. The provider will then wait at least one minute after lidocaine injection 
before performing the biopsy. 
  
In both arms, should the provider deem anesthesia to be inadequate prior to performance of the biopsy, 
an additional lidocaine injection will be allowed prior to biopsy and this will be recorded. 
  
Vulvar biopsies will be performed using standard biopsy forceps or a punch biopsy (3-4 mm) device 
depending on provider preference.The subject will report pain using a 100 mm visual analog scale 
immediately following biopsy. 
  
If there are multiple biopsy sites that are treated, and the pain differs between these locations, the 
highest pain score will be recorded. 
  
If the procedure is interrupted secondary to pain, a pain score will be recorded prior to injecting 
additional lidocaine, as described above. 
  
Exit Survey: After completion of the procedure, subjects will complete an exit survey, as described 
above(see appendices), answering questions about overall satisfaction/tolerability of the procedure. 
  


The provider performing the biopsy will also complete a brief survey answering questions about their 
satisfaction with the procedure and their perception of the acceptability of the procedure performed. 
  
As described above, participants will complete questionnaires electronically with the exception of the 
pain assessment by visual analog scale, which will be completed on paper and measured distances will 
be entered into REDCap. 
  
Participants will receive a $20 check for participation in the study.All completed surveys will be collected 
by the study coordinator who will store the documents in a password protected file on the Duke secured 
server. 
  
Post Study Pathologic Analysis: To address the concern that EMLA might induce pathologic changes that 
could result in altered diagnosis, pathologist independent from initial diagnostic read will re-evaluate 
tissue slides and look for the previously described EMLA induced pathologic changes (pallor, necrosis, 
spongiosis, basophilic granules, acantholysis, clefting, papillary dermal edema).  Pathologist will be 
blinded to whether or not patient received EMLA cream for biopsy.  They will provide a score for all 
specimens that will be used to analyse any pathologic differences between patients exposed to EMLA 
and those not exposed to EMLA.   
 
Selection of Subjects 
 
An electronic consent form will be used during the informed consent process, the signed copy of the 
study consent form will be emailed to the subject or printed and provided to her in clinic based on her 
preference. Subjects will then be assigned a unique subject number by the research coordinator. 
Research coordinators will maintain an enrollment log to serve as the master list for the enrolled 
subjects.  After their information is placed into the enrollment log, the subject will only be identified by 
their unique number.  The enrollment log as well as the study questionnaires and pain assessment forms 
will be collected into a REDCap data base with any exported copies saved in a password protected file on 
the Duke secured server. 
 
Subject’s Capacity to Give Legally Effective Consent 
 
Subjects who do not have capacity to give legally effective consent will not be included in the study. 
 
Risk/Benefit Assessment 


There is a potential benefit for the subjects in this study in that they may receive analgesia for the 
procedure without the pain of an injection.However, it will be emphasized to the subject that there may 
be increased pain during biopsy in the EMLA arm or increased pain with injection for the lidocaine arm. 
  
There are risks associated with vulvar biopsy including bleeding and infection.These risks are small, but 
they are not risks incurred as a result of participating in the study as these patients will be getting vulvar 
biopsies regardless of study participation. 
  
There is a small risk of topical reaction to the EMLA cream.If irritation does occur, the area of irritation 
will be cleansed with water and the procedure will be postponed until the irritation is resolved.The 
subjects will return to clinic to assess for resolution of the area and their indicated vulvar biopsy. 
 
Costs to the Subject 
 
No additional costs will be incurred by the participant as a result of participating in this study 
 
Data Analysis and Statistical Considerations 
 
A 16-mm difference on a standard 100-mm visual analog pain scale was deemed clinically significant. In 
order to detect a 16-mm difference with 90% power at an alpha level of 0.05 assuming a standard 
deviation of 25-mm, we estimated a needed sample size of 53 participants in each treatment arm. 
However, due to time limitations, data collection will end on March 12, 2019. Only patients consented 
on or prior to March 12, 2019 will be included in the study. Data will be recorded using Research 
Electronic Data Capture (REDCap), and the database will be locked on March 13, 2019. Pain will be 
measured during the application of EMLA cream or lidocaine injection, and immediately after biopsy. 
The primary outcome will be the highest pain score recorded during the procedure. The primary 
outcome will be compared between treatment arms using linear regression adjusting for baseline pain. 
Secondary outcomes include pain score at vulvar biopsy, patient tolerability and acceptability, and 
provider’s satisfaction with the procedure. All testing will be performed at a two-tailed significance level 
of 0.05.  
 
 If significance for the primary objective is not achieved, then patient accrual will continue based on a 
new sample size determined by the primary results of this analysis. This will be the number of new 
patients that need to be enrolled. Outcomes will be assessed again at the point when the final sample 
size is achieved.