Trial Information

A Randomized Trial of Buffered vs Nonbuffered Lidocaine With Epinephrine for Cervical Loop Excision

Specific aims:

1. To determine whether buffering the agent used for intracervical anesthetic at the time
of cervical loop excision reduces injection-related pain. (Hypothesis: buffering
significantly reduces injection-related pain.)

2. To determine whether other components of pain from LEEP (procedural pain, and cramping)
can be reduced by buffering of intracervical anesthetic among women undergoing cervical
loop excision. (Hypothesis: only injection pain will be reduced by buffering, as
procedural pain will be reduced by lidocaine equally in both arms and cramping will not
be reduced in either arm.)

Background:

Although cervical cancer rates have been dramatically reduced by Pap test screening and the
eradication of precursors, more than 100,000 U.S. women develop premalignant cervical
lesions each year that require treatment (1). The cervical loop electrosurgical excision
procedure (LEEP) is the most common therapy for CIN among U.S. gynecologists. LEEP is
performed using one or more 1-2 cm electrosurgical diathermy loops to excise involved and
at-risk cervical epithelium including underlying stroma containing glands. Destroying this
tissue eliminates cells infected with human papillomavirus, the proximate cause of cervical
cancer, and radically reduces the risk of later developing cervical cancer (2, 3).

LEEP is usually performed as an outpatient procedure using intracervical anesthesia, most
commonly combining lidocaine as an anesthetic agent with epinephrine as a hemostatic agent;
final hemostasis is achieved using electrosurgical fulguration and topical hemostatic agents
(4). Prior literature has suggested that pain from LEEP has 3 components: pain from
injection of the anesthetic combination, pain from the excision, and cramping from reflex
uterine contractions (5). While cramping can be controlled with oral nonsteroidal
anti-inflammatory agents, injection and procedural pain are not. Most women categorize the
pain of LEEP as 3-7 on a 0-10 Likert scale (5, 6).

Studies of dermal and ocular anesthesia and bone marrow biopsy have found that buffering of
acidic local anesthetic agents reduces injection pain (7-14), with up to 66% reduction in
pain and significant results in randomized trials involving 30-50 participants. However,
the use of buffered lidocaine has not yet been tested for LEEPs. The principal
investigator has used both forms of anesthesia and considers both acceptable forms of
therapy; he is unaware of any evidence to support the superiority of either arm.

Inclusion criteria 1. Subjects ≥ 18 years who meet any of the following indications for
LEEP:

a. Antecedent biopsy read as i. cervical intraepithelial neoplasia (CIN) grade 2 or 3 or
microinvasive cancer ii. adenocarcinoma in situ iii. persistent CIN1 b. Antecedent Pap read
as i. high grade squamous intraepithelial lesion ii. atypical glandular cells iii.
persistent low grade squamous intraepithelial lesion Exclusion criteria

1. Anatomy unsuitable for safe office loop excision based on operator judgment

2. Inability to tolerate procedure under local anesthesia

3. Pregnancy

4. Age less than 18 years

5. Inability to understand spoken or written English

6. Refusal of consent

7. Prisoner

8. Mental incapacity

9. Anticoagulant or antiplatelet therapy, or known bleeding diathesis

10. Use of analgesics other than over the counter medications (OTC meds include NSAIDS or
Tylenol) within 7 days of scheduled LEEP

Methods Eligible, consenting women who have either a negative pregnancy test or are
postmenopausal women who present for LEEP in the Gynecologic Treatment Center in the Center
for Advanced Medicine will be randomized to either buffered or nonbuffered lidocaine. The
LEEP clinic is run by the PI, Dr. Leslie Massad, and as such this is the PI's patient
population and clinic. Women will be asked about analgesics and antiplatelet or
anticoagulant therapy, and records will be reviewed for a history of bleeding diathesis.
Subjects will not be excluded for use of over the counter medications such as Ibuprofen or
Tylenol. Subjects who have taken stronger prescription analgesics (ie codeine, or other
narcotics) within 7 days of her scheduled LEEP procedure will be excluded.

Randomization will be by computerized random number generation by the Division of Clinical
Research in the Department of Obstetrics & Gynecology at Washington University in St. Louis.
Treatment assignments will be sequenced accordingly, and prepared, opaque envelopes will be
opened in order by either the medical assistant (MA) or registered nurse (RN) responsible;
neither the MA or the RN will perform the procedure or obtain pain scores. Only the RNs
will prepare the study drug solution.

The randomization envelopes will be prepared by Dr. Peipert's team and, then will be
submitted sealed to the LEEP clinic where they will be stored by the MAs. Only the MAs and
the RNs will have access to these envelopes. Once randomization of the participant is noted
by one of two gynecologic oncology RNs (Gina Vansickle, RN or Vanessa Thomas-Homes, RN), she
will then fill syringes with either 10 ml 1% lidocaine with epinephrine 1:100,000 (control)
vs 9 ml 1% lidocaine with epinephrine 1:100,000 and 1 ml of a 1mEq/ml (8.4%) solution of
NaHCO3 (study) in a separate room adjacent to the LEEP procedure room. The RNs will prepare
the anesthesia solution as if in standard clinical practice. Anesthetic will be carried
immediately to the treatment area, so storage will not occur. Neither the treating
clinicians performing LEEP nor the patient will be informed of allocation. Either the MA or
RN will inform the study coordinator (Lynne Lippmann) of the treatment allocation once the
participant has completed the post-procedure questionnaire and she is finished with her
participation in the study. The principal investigator along with all members of the study
team involved in data analysis will remained blinded to the study groups until the analyses
are fully completed.

After informed consent for procedure and study, and after cervical visualization as per
standard clinical care to determine suitable cervical anatomy for excision, the anesthetic
solution will be injected intracervically. The injection technique will not differ from
routine practice and will be done within 30 minutes of mixing the solution. The patient
will be advised that pain experienced at this point is "injection pain." LEEP will be
tailored to individual needs according to lesion size, lesion grade, and depth into the
endocervical canal. Once the procedure begins, the patient will be informed that the
subsequent cramping pain is distinct from the pain felt at the time of injection and is
considered "procedural" pain.

Within 30 min of completion of the procedure and after instruction by the primary
investigator, women will represent the intensity of their pain by marking single lines
across 100mm Likert visual analog scales employed in prior nongynecologic studies of
buffered lidocaine (5, 7-10) (See appendix). Scales will not include hashmarks or internal
descriptors, as these have been shown to bias responses and diminish reliability (12).
Separate scales will be marked to represent the previously identified domains of intensity
of pain from injection, pain from LEEP, and cramping (3). Buffering will be assumed to have
influenced pain for any of the three domains with a significant reduction in pain score.
Self-designated ethnicity will be solicited to facilitate description of the study
population to allow for generalization of results. This information will be obtained as
part of the pain assessment questionnaire given to the participant post-procedure (See
appendix).

Patient participation in the study will end on completion of the pain scoresheet. Clinical
follow-up will continue as per usual standard care. The principal investigator will review
charts for additional demographic information and procedural data, again to allow for
generalization of results.

Risks No serious risks are likely. Less likely risks may include greater pain from a
diluted lidocaine solution, though this has not been seen with buffered lidocaine used for
other procedures, and increased bleeding from dilution of the epinephrine in the anesthetic
solution. Alkalinization of epinephrine-containing local anesthetic solutions takes several
hours; since buffered lidocaine with epinephrine will be injected within 30 min of mixing,
this should not be relevant to the current study (13).

Statistical analysis Patient marks on 100mm Likert scale lines will be measured by the PI
and a score defined by the length marked off in mm. We will first perform basic descriptive
statistics on the baseline data of the two groups. We will then assess whether the
randomization achieved balance of baseline characteristics using standard chi-square and
Fisher Exact tests (for categorical variables), and t-tests or nonparametric tests for
continuous data. We expect the pain scores will not approximate a Gaussian distribution, so
we will use a Mann-Whitney non-parametric test to compare pain scores of the two groups.
Assuming an alpha (type I error rate) of 0.05, a power of 80% (type II error rate of 0.20),
a pain score of at least 5 for 80% of women in the standard treatment arm, and a 50%
reduction in pain with buffering to 40% scoring pain above 5, with no loss to follow-up, 27
women will need to be accrued per group, or 54 women in the trial. This should be
achievable within 2 years.

Registration:

When a patient is found to be eligible for study, verbal and signed informed consent will be
required by the managing physician. Nora Kizer, MD, physician and study team member, will
contact the potential study participant by telephone to discuss the research project,
evaluate eligibility criteria, and answer any questions. Information included in the
consent form will be discussed. However, the potential participant will not view the actual
consent document until the day of her scheduled LEEP. There will be an approximate 1-2 week
wait period between the phone conversation and the date of the LEEP where the patient may
discuss with study with family and friends, if desired. Individuals who agree to
participate by phone, will be asked to sign a consent document in clinic at the time of
their regularly scheduled LEEP. A paper copy of the consent form will be mailed to those
individuals who agree to participate or remain undecided after the telephone conversation.
The potential participant may to decline to participate at that time, even if she initially
agreed to participate over the phone. An eligibility checklist will be submitted to the
Contact Person/Data Manager at Washington University, Lynne Lippmann (FAX # 314-362-2893).
Questions concerning eligibility may be addressed to the Study Chair(s), Contact Person, or
Data Manager. A protocol number will be assigned and the designated study team member (Dr.
Nora Kizer) will be informed of this number. All patient entries will also be reported to
the Siteman Cancer Center by the Gynecologic Oncology Data Manager for entry into their
database. The following forms will be completed in a timely fashion as per the schedule
below and will be placed in the subject's study chart: Eligibility checklist, datasheet,
patient scoresheet, consent.

Data Safety and Monitoring The principal investigator will supervise or perform all LEEPs.
A separate research member (Dr. Nora Kizer) will complete all data entry sheets (including
measurement of Likert scores and description of adverse events), and will enter
de-identified data to a spreadsheet.

The frequency and severity of all toxicities will be tabulated on an ongoing basis and
summarized for review under the Data Safety and Monitoring Plan for this study (DSMP) as per
the guidelines for the Siteman Cancer Center at Washington University. Data for this study
will be reviewed by L. Stewart Massad, M.D. (Gynecologic Oncology), Nora Kizer, M.D.
(Gynecologic Oncology), and Lynne Lippmann, CCRP (Research Administrator) (Gynecologic
Oncology). Statistical support will be provided by Jeffery Peipert, MD, MPH, MHA and Feng
Gao, MD, PhD. Data will be reviewed every six months for toxicities and response, prior to
the bi-annual report to the Quality Assurance and Safety Monitoring committee of the Siteman
Cancer Center. All serious and/or unexpected events will be communicated to the Study Chair
and reviewed within 2 working days for consideration of notification, amendment, or
immediate study suspension.

The principal investigator will review all patient data at least every six months, and
provide a semi-annual report to the Siteman Cancer Center Quality Assurance and Safety
Monitoring (QASM) Committee. This report will include

1. The protocol title, IRB protocol number, and the activation date of the study.

2. The number of patients enrolled to date

3. The date of first and most recent patient enrollment

4. A summary of all adverse events regardless of grade and attribution

5. A response evaluation for evaluable patients

6. A summary of any recent literature that may affect the ethics of the study Privacy will
be protected by storing all records and the master list in a locked office (Dr. Kizer);
all computerized records will be stored on a password-protected computer with backup on
a flash drive stored in a locked cabinet in the same locked office.

Study Calendar Study Phase Recruitment Consent Research Participation Follow-up Time Frame
2 weeks prior to scheduled LEEP Day of LEEP Day of LEEP N/A Activity 1 Patient is called to
discuss their potential participation in the study and review consent form. On day of
procedure, the consent form is reviewed with the patient and signed. The participant
undergoes LEEP in routine fashion. She receives either buffered or plain lidocaine for
anesthesia. There is no follow-up specific to the study. Each patient will follow-up per
routine clinical practice.

Activity 2 Paper copy of consent form is mailed. All questions and concerns are addressed.
Post-procedure questionnaire is completed by the participant.

 

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