Addition of Buprenorphine to Paracervical Block Prior to Osmotic Dilator Insertion for Dilation and Evacuation: A Randomized Controlled Trial
Phase: PHASE4
Conditions: Procedural Pain, Buprenorphine, Adjuvants, Anesthesia, Dilation and Evacuation, Analgesics
Sponsor: University of California, San Diego

 
 
 
 
 
 
 
 
 
 
Study Protocol and Statistical Analysis Plan for Clinical Trials 
 
Official Title: Addition of Buprenorphine to Paracervical Block for Pain Control During Osmotic Dilator Insertion 
 
NCT# NCT04254081 
 
Original Approval Date: April 02, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN INSTRUCTIONS 
These are instructions are for completing the Research Plan that is available in MS Word format from the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response in for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 12/10/19 
1. 
PROJECT TITLE 
Addition of Buprenorphine to Paracervical Block Prior to Osmotic Dilator Insertion for Dilation and Evacuation: 
A Randomized Controlled Trial 
2. 
PRINCIPAL INVESTIGATOR  
Sheila Mody, MD MPH 
Associate Professor 
Department of Obstetrics, Gynecology and Reproductive Sciences 
University of California, San Diego  
3. 
FACILITIES 
University of California, San Diego – Villa La Jolla Women’s Health Clinic, Medical Offices South Women’s 
Health Clinic  
Planned Parenthood of the Pacific Southwest 
4. 
ESTIMATED DURATION OF THE STUDY 
18 months 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Cervical dilators are commonly used for preparation prior to second trimester abortion. Women have 
described the pain of osmotic dilator insertion as moderate to severe yet there have been few studies aimed 
at addressing pain during and after osmotic dilator insertion. One strategy to decrease pain with other 
gynecologic procedures is a paracervical block, or injection of anesthetic medication into the tissue 
surrounding the cervix. A randomized trial found that use of a paracervical block with 1% buffered lidocaine 
decreased pain with osmotic dilator insertion compared to a sham block. In addition, there are adjunct 
treatments to optimize analgesia with local anesthetics at a variety of other anatomic locations. 
Buprenorphine, a partial mu-opioid receptor agonist, has been found to increase the quality of the anesthetic 
at the time of administration and increase the duration of nerve block analgesia at several anatomic sites, 
though has never been studied as an adjunct in a paracervical block. This has been used extensively in 
orthopedic surgery with significant prolongation of the local anesthetic effect by almost threefold in some 
studies. 
 
6. 
SPECIFIC AIMS 
Primary aim: 
To compare the mean pain score at the time of osmotic dilator insertion among women randomized to a 1% 
lidocaine and buprenorphine paracervical block compared to a 1% lidocaine paracervical block alone. 
 
We hypothesize that in patients undergoing osmotic dilator insertion in preparation for dilation and 
evacuation, the addition of buprenorphine 0.15mg to a 1% lidocaine paracervical block will be associated with 
lower mean pain scores at time of osmotic dilator insertion compared to women who receive a 1% lidocaine 
paracervical block alone.  
 

 
 
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Secondary aims: 
1. To compare the mean pain score 2 hours after osmotic dilator insertion among women randomized to 
a lidocaine and buprenorphine paracervical block compared to a lidocaine paracervical block alone.  
2. To assess overall narcotic and ibuprofen use after osmotic dilator placement and before dilation and 
evacuation procedure. 
3. To assess opioid related side effects. 
4. To determine patient satisfaction with pain control during and after osmotic dilator insertion. 
 
7. 
BACKGROUND AND SIGNIFICANCE 
 
Dilation and evacuation (D&E) is the most common method of second trimester abortion in the United 
States1. Cervical preparation prior to the procedure is essential in order to allow passage of operative 
instruments and pregnancy tissue safely through the cervix and to decrease the risk of complications.1–4 In the 
second trimester, cervical preparation is typically achieved with placement of osmotic dilators prior to the 
procedure. Women have described the pain of osmotic dilator insertion as moderate to severe yet there have 
been few studies aimed at addressing pain during and after osmotic dilator insertion.5–8 A lidocaine 
paracervical block is commonly used for pain control during other gynecologic procedures including 
procedures involving cervical dilation like dilation and curettage.6,7 One randomized controlled trial found that 
use of a paracervical block with 1% lidocaine decreased pain with osmotic dilator insertion compared to a 
sham block.9 Because the dilators slowly expand after insertion, there is continued discomfort for several 
hours after placement. Research has shown that pain after osmotic dilator insertion peaks at 2 hours post-
insertion with use of a lidocaine paracervical block and a local anesthetic is not sufficient to provide lasting 
pain relief.10 Systemic medications, such as gabapentin and narcotic analgesics have been studied to treat 
post-insertional dilator pain, however these treatments have not been shown to be effective.10,11  
 
There are many adjunct treatments to optimize the duration of local analgesia from a peripheral nerve 
block. Opioid receptors are expressed in the central as well as peripheral nervous system on peripheral 
sensory neurons.12–17 Opioids can produce potent analgesic effects on peripheral receptors outside the central 
nervous system.15 Various studies have provided evidence that opioid receptors, specifically mu-receptors, 
are found in the peripheral nervous system.18–20 Essentially, opioid receptors are not restricted to the central 
nervous system, but are present in the peripheral nervous system, where their activation has been shown to 
exert analgesic effects without centrally mediated side effects.15,21 The administration of local opioid agonists 
can result in a significant analgesic effect through the activation of peripheral opioid receptors while 
bypassing the central nervous system, and thus the centrally mediated side effects such as respiratory 
depression, alterations in mental status, and activation of reward pathways in the brain can be bypassed.15 
With the identification of opioid receptors in the peripheral nervous system, there has been interest in opioid 
adjuvants to peripheral nerve block to enhance analgesic effects and prolong duration of local anesthetic 
effect. 
 
Buprenorphine, a partial mu-opioid receptor agonist, is a high potency, lipophilic opioid and has a high 
binding capacity for the mu-opioid receptor.22,23 Because of the high binding capacity, buprenorphine has the 
longest duration of action of all opioids. When administered perineurally in combination with a local 
anesthetic, buprenorphine has been found to drastically increase the duration of analgesia at several 
anatomic sites, including axillary and subclavian brachial plexus blocks and infragluteal sciatic nerve blocks.22–
30 With the addition of buprenorphine at doses of 0.15 – 0.3mg, there is significant prolongation of the 
anesthetic sensory blockade up to three times the duration of the local anesthetic alone.28 The use of 
perineural buprenorphine is well established for postoperative analgesia.22,23  
 
Buprenorphine itself also has local anesthetic properties. Buprenorphine blocks voltage gated sodium 
channels and inhibits C-fiber action potentials, thereby contributing to an analgesic effect.30,31 One study using 

 
 
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buprenorphine in conjunction with bupivacaine for a subclavian perivascular brachial plexus block found that 
the addition of buprenorphine improved the quality of the local anesthetic in terms of a denser sensory 
blockade at the time of administration.27 Therefore, buprenorphine not only prolongs the duration of local 
anesthetic effect but also improve the analgesic properties when administered in a perineural block.  
The addition of buprenorphine to a perineural local anesthetic has not been studied in with a paracervical 
block. This study will be the first trial to assess the efficacy of buprenorphine to provide analgesia for a 
gynecologic procedure. This medication has the additional benefit of providing long lasting pain relief for 
procedures that cause continued discomfort after the end of the procedure. We hypothesize that the addition 
of 0.15mg of buprenorphine to a lidocaine paracervical block will improve pain during osmotic dilator 
insertion and provide continued pain relief several hours after osmotic dilator insertion. If this intervention 
proves to provide better pain control than a lidocaine paracervical block alone, it would be an intervention for 
women during a painful clinic procedure.  
 
Much of the information about buprenorphine as an adjunct for local pain control is found in the 
anesthesia literature. With the addition of buprenorphine at doses of 0.15 – 0.3mg, there is significant 
prolongation of the anesthetic sensory blockade up to three times the duration of the local anesthetic 
alone.22,23 The use of perineural buprenorphine is well established for postoperative analgesia at several 
different anatomic sites though the use of buprenorphine as an adjunct to a paracervical block has never been 
studied.22–32 Most peripheral nerve blocks are performed using ultrasound guidance to avoid large vessels, 
especially with brachial plexus and sciatic nerve blocks. Although visualization is used to avoid large vessels, 
there is still likely a small amount that is absorbed systemically. Because a paracervical block is performed 
blindly (though clinicians draw back before injection to ensure no entrance into a vessel) and there is a higher 
concentration of vessels around the cervix, we will be studying the lower 0.15mg dose of buprenorphine. This 
dose has still been shown to significantly prolong post-procedure analgesia, thus we anticipate that it will be 
effective in prolonging analgesia in our study.22,33,34 In the orthopedic literature, there were no cases of 
respiratory depression from systemic absorption with either dose of adjunct buprenorphine.35  
 
This study will be the first RCT to assess the efficacy of adding buprenorphine to a paracervical block 
for pain during osmotic dilator insertion.  
 
 
In terms of potential risks to the fetus, a study by Mark et al. (2019) reported that less than 1% of 
women who present for second-trimester abortions and received osmotic dilators for cervical preparation had 
their dilators removed with the intent to continue the pregnancy.36 Only case reports have been published 
with this clinical situation.37 Women are counseled that the placement of osmotic dilators is the start of her 
two-day procedure. If a participant chooses to continue her pregnancy after osmotic dilators are placed and 
after study medication is administered (which as indicated, is extremely rare), a single dose of non-
systemically administered buprenorphine in the second trimester is unlikely to affect the developing fetus. 
Studies in rats and rabbits have not found buprenorphine exposure to increase congenital malformations.38 
Studies in vitro studies have demonstrated that about 10 % of buprenorphine crosses the placenta and about 
5% is metabolized to the active metabolite.39 In this study, we are administering a single local dose of 
buprenorphine in a nerve block formulation. Very little of this medication (if any) would be systemically 
absorbed, and as such, almost none would cross the placenta and enter the fetal circulation. 
 
There are no well controlled studies investigating the effects of buprenorphine in pregnant women. 
Overall, there is limited data about the rate of major congenital malformations with the use of 
buprenorphine, but the available data do not show an increased risk when compared to other opioids like 
methadone.40–42 Additionally, women who use buprenorphine during pregnancy use it for a prolonged period 
of time as a daily medication and the amount of exposure is much higher than a single dose as used in this 
research study. There are no studies investigating a single dose of buprenorphine and the impact on a fetus. 

 
 
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From the available literature, there is no clear evidence of risk of major congenital malformations with use of 
buprenorphine in pregnancy.35,36,37 If a woman changes her mind after insertion of osmotic dilators and 
desires to continue the pregnancy, she will be referred to perinatology (high risk pregnancy specialists) for 
follow up and monitoring of her pregnancy. The risks are described further in section 15.  
 
8. 
PROGRESS REPORT 
Not applicable 
 
9. 
RESEARCH DESIGN AND METHODS 
This is a randomized, 2-arm (1:1), double blinded clinical trial comparing pain scores at the time of osmotic 
dilator insertion and at specific points after insertion with a buprenorphine plus 1% lidocaine paracervical 
block compared to a paracervical block alone in women who have osmotic cervical dilators placed.  
 
Primary Hypothesis: 
In patients undergoing osmotic dilator insertion in preparation for dilation and evacuation, the 
addition of buprenorphine 0.15mg to a 1% lidocaine paracervical block will be associated with lower 
mean pain scores at time of osmotic dilator insertion compared to women who receive a 1% lidocaine 
paracervical block alone.  
Secondary hypotheses: 
In patients undergoing osmotic dilator insertion in preparation for dilation and evacuation, the 
addition of buprenorphine 0.15mg to a 1% lidocaine paracervical block will be associated with lower 
mean pain scores 2 hours after osmotic dilator insertion compared to women who receive a 1% 
lidocaine paracervical block alone.  
 
In order to investigate this hypothesis, the following study design is proposed:  
 
We plan to recruit at two study sites – the University of California, San Diego (UCSD) and Planned 
Parenthood of the Pacific Southwest (PPPSW). The UCSD study team will be responsible for all study 
procedures conducted at Planned Parenthood. Members of the UCSD study team will be determining 
eligibility, consenting patients, administering patient questionnaires, collecting data, and performing data 
analysis. Planned Parenthood clinicians will be administering the study medication during the procedure and 
will not be involved in any other research procedures.   
 
Included in the study are women who present to the UCSD or PPPSW clinics seeking dilation and 
evacuation for any indication and who will require cervical preparation with osmotic dilators as determined by 
the evaluating clinician. Patients between 14 weeks 0 days gestation to 23 weeks 6 days gestation at the time 
of osmotic dilator insertion will be candidates for study inclusion. Participants will be excluded based on a 
brief questionnaire if they have a known allergy to the study medication or ibuprofen, any chronic pain 
conditions, have taken any narcotic medications in the last 24 hours, have chronic opiate use or any other 
drug abuse, request sedation during laminaria insertion, or have a history of chronic liver disease. Stratified 
randomization with be performed among participants based on vaginal parity (nulliparous and multiparous).  
Participants will be randomized to one of two study groups allocated one to one: (1) paracervical block with 
20mL of 1% buffered lidocaine or (2) paracervical block with 20mL of 1% buffered lidocaine plus 0.15mg of 
buprenorphine.   
 
During the procedure, the study team member will present the numeric rating scale (NRS) to the 
participant and ask her to mark her level of pain at each time point during the procedure (paracervical block 
placement, osmotic dilator insertion, 5 minutes post procedure) and will remain blinded to the study arm. 
These NRS scores will be recorded into REDCap utilizing an electronic tablet. The participant will be asked 

 
 
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about side effects such as dizziness and nausea during the procedure. The clinician will perform the osmotic 
dilator insertion in the usual fashion, and the study team member will record the time from speculum 
insertion to speculum removal.  
 
After the procedure, the clinician will answer a brief questionnaire detailing if there were any adverse 
events or difficulty related to either the paracervical block or the osmotic dilator insertion. The clinician will 
also note whether or not cervical dilation was performed prior to osmotic dilator insertion and to what size 
dilator. They will also indicate their level of training. At 5 minutes after osmotic dilator insertion, the 
participant will indicate her level of pain and answer questions regarding side effects and satisfaction with 
pain control during the procedure.  
 
The primary outcome of the study is pain as measured on the NRS at the time of osmotic dilator 
insertion. Studies have varied in the time point at which pain is measured during the procedure, as some 
assessed pain with dilator insertion and others have recorded it 5 minutes after dilator insertion8-11. Research 
studies addressing pain during osmotic dilator insertion have used the VAS, while studies looking at pain after 
dilator insertion have used the numeric rating scale (NRS)8-11. We plan to capture pain using the NRS (an 11-
point scale from 0-10) as we are evaluating pain at multiple different timepoints, both during and after dilator 
insertion.   
 
Our secondary outcome is pain at 2 hours post dilator insertion. Given that buprenorphine can extend 
the length of analgesic effect by 2-3 times, we anticipate that the prolonged anesthetic effect should last 
anywhere from 2-6 hours using 1% lidocaine and provide pain relief as the dilators are expanding. Patients will 
be receiving text messages with links to questionnaires at three different time points (1 hour, 2 hours, and 6 
hours post-insertion) in order to assess their level of pain, analgesic use, as well as any other symptoms. These 
text messages will be time stamped depending on time of dilator insertion and will be sent out at the intervals 
we specify in the text messaging software.  
 
Schedule of Assessments 
The table below indicates the time point at which the various assessments will be performed. Assessments 
will be performed over one to two days: on the day of osmotic dilator insertion and on the day of D&E. If 
same day dilators are used, the final assessment will be performed immediately prior to D&E. Overall, the 
process of clinician evaluation, procedural consent, study recruitment, study consent, performance of 
procedure, and immediate post-procedure questionnaire should take about 30 minutes. The follow up 
questionnaires and questionnaire prior to D&E will take about 10 minutes.  Participants will receive a 
questionnaire sent via text message link at 1 hour, 2 hours, and 6 hours post-procedure. This questionnaire 
 
Before 
procedure 
Paracervical 
block 
Osmotic 
dilator 
placement 
(0 minutes) 
5 minutes 
post dilator 
placement  
1 hour 
post 
dilator 
placement 
2 hours 
post 
dilator 
placement 
6 hours 
post 
dilator 
placement  
Prior to 
D&E 
Baseline survey 
x 
 
 
 
 
 
 
 
Pain scale 
x 
x 
x 
x 
x 
x 
x 
x 
Side effect 
assessment 
 
 
x 
x 
x 
x 
x 
x 
Clinician survey 
 
 
 
x 
 
 
x 
 
Assessment of 
oral analgesic 
medications 
needed 
 
 
 
 
x 
x 
x 
x 
Participant 
satisfaction with 
pain control 
 
 
 
x 
x 
x 
x 
x 

 
 
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assesses the need for oral analgesics for pain as well as participant satisfaction with their pain control at that 
study point. Participants will take a questionnaire on the morning of D&E asking them to rate their current 
pain and to recall their maximum pain score over the preceding day and their overall satisfaction with their 
pain control. The need for follow up will be determined per usual clinician practice and preference.  
 
 
Randomization:  
Block randomization will be performed in alternating blocks of 4 and 6 stratified by vaginal parity (vaginally 
nulliparous versus vaginally multiparous). The study team member will open the designated sealed 
sequentially numbered opaque randomization envelope containing computer generated randomization code 
of the type of paracervical block and hand it to the clinician performing the procedure. A clinician who will not 
be administering the paracervical block will then open the envelope and prepare the designated paracervical 
block into two 10 mL syringes.  A different clinician blinded to the treatment group will perform the 
standardized procedure for osmotic dilator insertion using a speculum, 25-gauge spinal needle to inject the 
paracervical block, Dennison dilators to dilate the cervix if that is the clinician’s practice, and insertion of 
laminaria and/or Dilapan-S. The amount of time it takes to inject the paracervical block will be recorded.  
 
Intervention: A paracervical block with 20mL of 1% buffered lidocaine plus 0.15mg of buprenorphine will be 
injected prior to osmotic dilator insertion. A paracervical block with 20mL of 1% buffered lidocaine will be 
used in the control group. The patient will not be charged for the study drug. All drug costs will be covered by 
the study (this is also stated in the consent form). 
 
Outcomes: 
1) Sociodemographic and clinical data: age, race, ethnicity, level of education, marital status, height, 
weight, obstetric history, history of cervical procedures (e.g. LEEP procedure or Conization), chronic 
baseline pain 
2) Primary outcome: Level of pain as rated on an 11-point (0-10) numeric rating scale during osmotic 
dilator insertion.   
3) Secondary outcomes: 
a. Pain (Numeric Rating Scale): 
i. Baseline (before procedure) 
ii. Paracervical block placement 
iii. 5 minutes post procedure 
iv. 1 hour post procedure 
v. 2 hours post procedure 
vi. 6 hours post-procedure 
b. Satisfaction  
i. Likert scale questions  
1. How satisfied are you with the amount of pain control that you had during the 
procedure? 
2. If you had to have these dilators placed for a procedure in the future, would you 
choose to have the same pain medication that you received today? 
c. Adverse events – side effects at time of paracervical block placement and after procedure 
d. Survey of provider (resident, fellow, attending, advance practice clinician) performing 
procedure 
i. Number of dilators placed 

 
 
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ii. Ease of osmotic dilator placement 
iii. If patient will return for second set of dilators 
iv. Major complications 
v. Type of clinician (resident, attending, advance practice clinician) 
 
No specimens will be collected for research purposes. All research data will be collected on electronic tablets 
and de-identified via REDCap.  
 
Power Calculation:  
             It is suggested that a 2-point reduction in pain on the numeric rating scale (NRS) is clinically 
meaningful.24-27 No existing study parallels the outcomes of our proposed research (pain at time of osmotic 
dilator insertion using the numeric rating scale). One previous study used the Visual Analog Scale (a 0-100mm 
linear scale) to compare pain at the time of osmotic dilator insertion between a 1% lidocaine paracervical 
block and vaginal lidocaine gel.8 The visual analog scale and the numeric rating scale have modest 
correlation.42 The median pain score during osmotic dilator insertion in the 1% lidocaine paracervical block 
group was 61 (which correlates to 6 on the numeric rating scale) with a range from 0-100.  
 
In order to detect a 2-point difference on the NRS at the time of osmotic dilator insertion with 80% 
power and a two-sided alpha of 0.05, we will need a total of 52 patients in each study arm (26 per arm). We 
plan to stratify the groups by vaginal parity (nulliparous versus multiparous) as vaginal parity may affect pain 
at the time of osmotic dilator insertion. In order to stratify by vaginal parity, we will need a total of 104 
women (52 in each strata) to see a difference between strata per group. We plan to enroll an additional 10% 
to account for protocol deviation and participant dropout for a total of 114 participants. With a one to one 
randomization allocation, approximately half will be randomized to receive a paracervical block with 
buprenorphine and 1% lidocaine and half will receive a paracervical block with 1% lidocaine alone. 
Additionally, randomization will be stratified by vaginal parity (vaginally nulliparous versus vaginally 
multiparous).   
 
Data Analysis 
 
The baseline participant survey, NRS scores, side effects, and post-procedure participant and provider 
surveys will be performed by the study coordinator using REDCap loaded on to an electronic tablet. This data 
will be transferred to a spreadsheet in SPSS. Bivariate comparisons will be analyzed using chi squared test or 
Fisher’s Exact test for categorical variables and t-test or Mann-Whitney for continuous variables depending on 
the distribution of the data as appropriate.  The primary outcomes will be evaluated per intent-to-treat 
analysis.  
 
10. HUMAN SUBJECTS 
Inclusion criteria:  
1) Women over the age of 18 presenting to UC San Diego or Planned Parenthood of the Pacific 
Southwest for Dilation and Evacuation for any indication 
2) Require cervical preparation with osmotic dilators based on clinician judgement 
3) Speak English or Spanish 
Exclusion criteria:  
1) Women who desire sedation for osmotic dilator insertion 
2) Dilation and evacuation planned on same day as osmotic dilator insertion 
3) Pre-viable preterm rupture of membranes (PPROM) as indication for procedure 

 
 
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4) Known allergy/sensitivity to or refusal of any study medication (buprenorphine, ibuprofen, 
lidocaine) 
5) If they have taken any narcotic medication (including prescription opiates, buprenorphine, 
methadone) or recreational drug in the preceding 24 hours 
6) Current liver disease  
7) Severe uncontrolled asthma, COPD, or other respiratory disorders 
8) Severe respiratory depression as assessed by vital signs 
9) Current or history of gastrointestinal obstruction 
10) Incarceration 
 
11. RECRUITMENT 
 
The study will take place at UCSD and Planned Parenthood of the Pacific Southwest. Patients either 
self-refer to these clinics or are referred by another clinician. At UCSD, appointments are coordinated by a 
Family Planning Manager. During the time of the study, when a participant presents to clinical care for a D&E 
for any indication, she will be counseled on options including induction termination and D&E.  If the patient 
desires a D&E and is at PPPSW, she will be assessed for ability to perform this procedure in the outpatient 
surgical center. If the patient has medical co-morbidities that increase the risk of the procedure, she may be 
referred to UCSD or another tertiary care center.  
 
If the patient is a good candidate for D&E and the procedure is scheduled to occur the next day, the 
clinician will assess the need for osmotic dilator placement for cervical preparation; this is usually known 
based on gestational age, however patients between 14 weeks to 16 weeks may receive either dilators or 
misoprostol alone. This will be determined per clinician judgement. If the patient is eligible for osmotic dilator 
placement, informed consent will be obtained for the procedure, per standard clinic practice, and the clinician 
will notify the study team member. The study team member will then assess if the patient is interested in 
participating in the study, ensure that the patient is willing to be randomized to the study medication, and 
assess whether or not she has already taken ibuprofen that day in preparation for osmotic dilator placement. 
Eligibility criteria will be verified by the study team member using the script below. The study team member 
will obtain written informed consent to participate and perform the baseline survey.  The participant will 
receive 800mg of oral ibuprofen if she has not already taken this medication prior to the appointment.  
 
We will use the below recruitment script: 
 
“We are conducting a study on pain control during osmotic dilator insertion. You are eligible to participate 
because your clinician has determined that is necessary to place dilators before your procedure. We are 
studying the addition of a medication called buprenorphine to cervical anesthesia. We would like to know if 
this medication helps to decrease pain during and after the procedure. We are looking for volunteers to 
participate in this study. This study will require that you participate in a pre-screening interview in which you 
will be asked questions about your basic health history.” 
We are requesting a Waiver of Documented Consent before beginning the recruitment process. We are 
requesting approval to obtain a verbal consent before administering the pre-participation questionnaire. This 
questionnaire is a pre-screening tool asking only inclusion/exclusion questions. It is necessary to carry out the 
research as we need to determine if they qualify for the study. It is justified because the only record linking 
the subject and the research would be the consent document and the principal risk would be potential harm 
resulting from a breach of confidentiality. Each subject will be asked whether the subject wants 
documentation linking the subject with the research, and the subject's wishes will govern. It is minimal risk 

 
 
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and the waiver will not adversely affect the rights and welfare of the subjects. Subjects will be provided with 
all additional pertinent information after they are enrolled as participants in the study. 
 
12. INFORMED CONSENT 
The patient will be consented by the research coordinator, a research assistant, or any of the co-investigators. 
The consent process will occur prior to randomization or completion of any study questionnaire. The consent 
process will occur in the patient room. We will only enroll patients who speak English or Spanish. Consent and 
all other study instruments will be translated into Spanish. Only study staff who are authorized interpreters at 
the respective study sites will deliver the pre-screening eligibility form and the consent to participate for 
Spanish-speaking participants. Medical Center Interpretation Services will be used as needed. The availability 
of medical interpreter services differs across sites and our study instruments are only available in English and 
Spanish. Therefore, to maintain consistency across sites and to ensure a consistent interpretation of the study 
instruments, we have limited enrollment to English and Spanish speakers. The consent form and HIPAA 
authorization will be signed and scanned into the participant’s electronic medical record. Copies will be 
provided to the participant. 
 
13. ALTERNATIVES TO STUDY PARTICIPATION 
If the patient chooses not to participate in the study, they would receive the standard of care which is a 1% 
lidocaine paracervical block.  
 
14. POTENTIAL RISKS 
1) Loss of confidentiality 
2) Pain with paracervical block injection or insertion of osmotic dilators 
3) Side effects of the study medication include feeling sleepy, vertigo, dizziness, headache, fatigue, 
itching, sweating, nausea, constipation, vomiting, temporary elevation of liver enzymes 
4) Rare side effects of the study medication include swelling, bruising or redness at the injection site; low 
blood pressure; constricted pupils; fainting; or slow breathing. 
5) Unknown risks 
6) Risk of randomization: one assigned study group might prove to be less effective or have more side 
effects than the other study group 
 
 
We will be purchasing intramuscular naloxone in the rare event of respiratory depression from 
systemic absorption of the buprenorphine. This is an extremely rare anticipated side effect as the partial mu-
agonist properties of this drug typically causes a ceiling effect and prevents respiratory depression. However, 
we will have this medication on hand in clinic in case of this extremely rare event.  
 
Each clinic site is equipped with basic emergency equipment in the rare event that a medical 
emergency should happen during the study procedures. In the rare event of serious side effects (such as 
slowed breathing), naloxone would rapidly reverse all side effects. Given the low dose of buprenorphine being 
administered, only one dose of naloxone would be necessary to reverse the effects of the medication. 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
1) Ensuring confidentiality by assigning a patient study number and avoiding the use of patient 
identifiers. 

 
 
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2) The clinic is equipped with medical supplies if a participant has dizziness or vasovagal symptoms. 
These symptoms are usually transient. 
3) If a woman decides to continue her pregnancy after administration of the study medication, there is 
unlikely to be any additional increased risk to the developing fetus from buprenorphine itself. There 
are far greater risks to pregnancy continuation due to osmotic dilator placement and resulting cervical 
dilation, and the buprenorphine does not mitigate or increase this risk. If a woman does decide to 
continue her pregnancy after she receives the study medication, she will be referred to perinatology 
for evaluation and for prenatal care.  
4) Data will not be shared between UCSD and Planned Parenthood. All study instruments and data 
collection forms will be on a UCSD tablet and administered by UCSD study personnel. There will be no 
exchange of data between the two study sites. 
5) All adverse events will be reported to the UCSD IRB in a timely fashion. The management of 
information that is relevant to the protection of participants including adverse events, UPRs, protocol 
violations/deviations, interim results and protocol modifications will be the responsibility of the PI (Dr. 
Mody).  
 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
Consent will be obtained in the patient’s private exam room, in the private clinical space where 
participant can ask questions without feelings of embarrassment or discomfort. The physical exam will be 
conducted in the private examination room. Data will be reviewed by the principal investigator and research 
coordinators to ensure accuracy and completeness. Data will be monitored quarterly to ensure that data 
collection, coding, and management procedures are being conducted according to protocol and ethical 
guidelines.  
There is a need for medical record access to assess patient demographics, history, and clinical 
outcomes. The baseline patient survey, NRS scores, side effects, and post-procedure participant and clinician 
surveys will be performed by the study team member using REDCap loaded on to an electronic tablet. REDCap 
is a secure, web-based application designed to support data capture for research studies, providing: 1) an 
intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common statistical packages; 
and 4) procedures for importing data from external sources.  Study data will be stored in the HIPPA-secure de-
identified online REDCap data base housed at UCSD. Any printed study data will be secured in a locked 
cabinet/filebox, and only those directly involved in the study will have access to this including the 
investigators who will process it. Only de-identified data will be stored. Data entry and analysis will be 
performed on password-protected, institutionally secured computers. The research database will be banked 
indefinitely for the purpose of future research questions and will contain only de-identified information as 
above.   
Participants will be contacted via text message to complete questionnaires at three different time 
points. The questionnaires will be sent over text via a hyperlink that connects to a secure platform that will 
input the data directly into a REDCap database. The application’s template function will be used to ensure all 
outgoing text messages are uniform. Any incoming text messages are returned to the secure application 
platform. A key linking the participant’s contact information to her participant ID will be stored in a locked 
cabinet in the study office separate from any data or patient information. 
 
There will also be a need to collect participant email addresses to send compensation via Amazon e-
gift cards.  The research coordinator at UCSD, Marisa Hildebrand, is the only member of the study team who 
will have access to the email addresses from both sites; she will need email addresses in order to send e-gift 
cards.  

 
 
Biomedical IRB Application Instructions 
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17. POTENTIAL BENEFITS 
Participants may not experience direct benefit from participation in this study. However, we hope that this 
study will help us determine if the addition of buprenorphine to a lidocaine paracervical block is effective in 
reducing pain with and after osmotic dilator placement. We hope that this study may change the practice of 
pain relief with osmotic dilator placement for women in the future. 
 
18. RISK/BENEFIT RATIO 
The benefit of possibly decreased pain during and after osmotic dilator placement outweighs the small chance 
of any unknown risk in the buprenorphine group.  
19. EXPENSE TO PARTICIPANT 
None 
20. COMPENSATION FOR PARTICIPATION 
Study participants will be compensated with up to $40 in Amazon e-gift cards for their time. 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Co-investigators:  
Sheila Mody MD, MPH, Sarah Averbach MD, MAS, Nicole Economou MD, Marisa Hildebrand MPH, and Gennifer 
Kully MSc will organize and process the study data. They will also be involved in recruitment and consenting for 
participants in the study. Marisa Hildebrand MPH is the research coordinator/manager at UCSD, and Gennifer 
Kully MSc is the research assistant at UCSD.  
 
Salary support is provided to Gennifer Kully, a research assistant on the study. No other salary support is 
provided to any of the co-investigators. All of the research team members have completed CITI training. 
 
22. BIBLIOGRAPHY 
1.  
Newmann S, Dalve-Endres A DE. Cervical preparation for surgical abortion from 20 to 24 weeks’ 
gestation. Contraception. 2008. doi:10.1016/j.contraception.2008.01.004 
2.  
Schulz KF, Grimes DA, Cates W. Measures to prevent cervical injury during suction curettage abortion. 
Lancet. 1983;321(8335):1182-1185. doi:10.1016/S0140-6736(83)92464-9 
3.  
Grimes DA, Schulz KF, Cates WJ. Prevention of Uterine Perforation During Curettage Abortion. JAMA J 
Am Med Assoc. 1984;251(16):2108-2111. doi:10.1001/jama.1984.03340400036021 
4.  
Darney PD, Atkinson E, Hirabayashi K. Uterine perforation during second-trimester abortion by cervical 
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Mercier RJ, Liberty A. Intrauterine lidocaine for pain control during laminaria insertion: A randomized 
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6.  
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doi:10.1016/j.contraception.2008.11.005 
7.  
Renner RM, Nichols MD, Jensen JT, Li H, Edelman AB. Paracervical block for pain control in first-
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8.  
Schivone GB, Lerma K, Montgomery C, et al. Self-administered lidocaine gel for local anesthesia prior to 
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doi:10.1016/j.contraception.2018.11.013 

 
 
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9.  
Soon R, Tschann M, Salcedo J, Stevens K, Ahn HJ, Kaneshiro B. Paracervical {Block} for {Laminaria} 
{Insertion} {Prior} to {Second}-{Trimester} {Abortion}: {A} {Randomized} {Controlled} {Trial}. Obs 
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10.  
Nagendra D, Schreiber CA SS. A Randomized Trial of Opioids versus Nonopioids for Pain Control after 
Osmotic Dilator Placement in Abortion Care. In: Abstract Presented at Fellowship in Family Planning 
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11.  
Creinin MD, Schimmoeller NR, Matulich MC, Hou MY, Melo J, Chen MJ. Gabapentin for pain 
management after osmotic dilator insertion and prior to dilation and evacuation: A randomized 
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Stein C, Schäfer M, Cabot PJ, et al. Peripheral opioid analgesia. Pain Rev. 1997;4(3):173-187. 
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Stein C, Lang LJ. Peripheral mechanisms of opioid analgesia. Curr Opin Pharmacol. 2009;9(1):3-8. 
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Stein C. Opioid Receptors on Peripheral Sensory Neurons. 2013. 
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Sehgal N, Smith H, Manchikanti L. Narrative Review Peripherally Acting Opioids and Clinical Implications 
for Pain Control. Pain Physician. 2011;14:249-258. 
www.painphysicianjournal.comwww.painphysicianjournal.com. Accessed March 18, 2020. 
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Published 2004. Accessed March 18, 2020. 
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Stein C. The Control of Pain in Peripheral Tissue by Opioids. Epstein FH, ed. N Engl J Med. 
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Coggeshall RE, Zhou S, Carlton SM. Opioid receptors on peripheral sensory axons. Brain Res. 
1997;764(1-2):126-132. doi:10.1016/S0006-8993(97)00446-0 
19.  
Stötzner P, Spahn V, Celik MÖ, Labuz D, Machelska H. Mu-Opioid Receptor Agonist Induces Kir3 
Currents in Mouse Peripheral Sensory Neurons – Effects of Nerve Injury. Front Pharmacol. 2018;9. 
doi:10.3389/fphar.2018.01478 
20.  
Mambretti EM, Kistner K, Mayer S, et al. Functional and structural characterization of axonal opioid 
receptors as targets for analgesia. Mol Pain. 2016;12. doi:10.1177/1744806916628734 
21.  
Schmidt Y, Machelska H. Immunohistochemical analysis of opioid receptors in peripheral tissues. 
Methods Mol Biol. 2015;1230:155-165. doi:10.1007/978-1-4939-1708-2_12 
22.  
Kosel J, Bobik P, Tomczyk M. Buprenorphine - The unique opioid adjuvant in regional anesthesia. Expert 
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23.  
Bailard NS, Ortiz J, Flores RA. Additives to local anesthetics for peripheral nerve blocks: Evidence, 
limitations, and recommendations. Am J Heal Pharm. 2014;71(5):373-385. doi:10.2146/ajhp130336 
24.  
Swain A, Nag DS, Sahu S, Samaddar DP. Adjuvants to local anesthetics: Current understanding and 
future trends. World J Clin Cases. 2017;5(8):307. doi:10.12998/wjcc.v5.i8.307 
25.  
Candido KD, Hennes J, Gonzalez S, et al. Buprenorphine enhances and prolongs the postoperative 
analgesic effect of bupivacaine in patients receiving infragluteal sciatic nerve block. Anesthesiology. 
2010;113(6):1419-1426. doi:10.1097/ALN.0b013e3181f90ce8 
26.  
Candido KD, Franco CD, Khan MA, Winnie AP, Raja DS. Buprenorphine added to the local anesthetic for 
brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth Pain Med. 
2001;26(4):352-356. doi:10.1053/rapm.2001.23931 
27.  
Thakur DP, Malde A. Buprenorphine for postoperative analgesia: Axillary brachial plexus block versus 
intramuscular administration in a placebo-controlled trial. J Anaesthesiol Clin Pharmacol. 
2015;31(3):360-364. doi:10.4103/0970-9185.161673 

 
 
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28.  
Jadon A, Panigrahi MR, Parida SS, Chakraborty S, Agrawal PS, Panda A. Buprenorphine improves the 
efficacy of bupivacaine in nerve plexus block: A double blind randomized evaluation in subclavian 
perivascular brachial block. J Anaesthesiol Clin Pharmacol. 2009;25(2):207-210. doi:10.5580/280d 
29.  
F A, B W, A B, A C, BM C. Buprenorphine versus tramadol as perineural adjuvants for postoperative 
analgesia in patients undergoing arthroscopic rotator cuff repair under middle interscalene block: a 
retrospective study. Minerva Anestesiol. 2014;80(11):1198-1204. 
30.  
Modi M, Rastogi S, Kumar A. Buprenorphine With Bupivacaine for Intraoral Nerve Blocks to Provide 
Postoperative Analgesia in Outpatients After Minor Oral Surgery. J Oral Maxillofac Surg. 
2009;67(12):2571-2576. doi:10.1016/j.joms.2009.07.014 
31.  
Leffler A, Frank G, Kistner K, et al. Local anesthetic-like inhibition of voltage-gated Na + channels by the 
partial μ-opioid receptor agonist buprenorphine. Anesthesiology. 2012;116(6):1335-1346. 
doi:10.1097/ALN.0b013e3182557917 
32.  
Kirksey MA, Haskins SC, Cheng J, Liu SS. Local anesthetic peripheral nerve block adjuvants for 
prolongation of analgesia: A systematic qualitative review. PLoS One. 2015;10(9). 
doi:10.1371/journal.pone.0137312 
33.  
Kirksey MA, Haskins SC, Cheng J, Liu SS. Local Anesthetic Peripheral Nerve Block Adjuvants for 
Prolongation of Analgesia: A Systematic Qualitative Review. PLoS One. 2015;10(9). 
doi:10.1371/journal.pone.0137312 
34.  
Behr A, Freo U, Ori C, Westermann B, Alemanno F. Buprenorphine added to levobupivacaine enhances 
postoperative analgesia of middle interscalene brachial plexus block. J Anesth. 2012;26(5):746-751. 
doi:10.1007/s00540-012-1416-4 
35.  
Rowbotham MC. What is a “clinically meaningful” reduction in pain? Pain. 2001;94(2):131-132. 
doi:10.1016/S0304-3959(01)00371-2 
36.  
Mark A, Grossman D, Foster AM, Prager SW, Winikoff B. When Patients Change Their Minds After 
Starting an Abortion: Guidance from the National Abortion Federation’s Clinical Policies Committee. 
Contraception. 2020;0(0). doi:10.1016/j.contraception.2020.01.016 
37.  
Mark K, Merchant RM, Hu K. Pregnancy outcomes after removal of osmotic dilators in patients who 
presented for second-trimester abortion. Contraception. 2019;99(5):285-287. 
doi:10.1016/j.contraception.2018.09.007 
38.  
Jones HE, Finnegan LP, Kaltenbach K. Methadone and buprenorphine for the management of opioid 
dependence in pregnancy. Drugs. 2012;72(6):747-757. doi:10.2165/11632820-000000000-00000 
39.  
Willeford A, Atayee RS, Winters KD, et al. Buprenorphine Hydrochloride (buprenorphine hydrochloride) 
dose, indications, adverse effects, interactions. Clin J Pain. 2009;14(4):343-349. 
doi:10.1097/AOG.0000000000002149 
40.  
Tran TH, Griffin BL, Stone RH, Vest KM, Todd TJ. Methadone, Buprenorphine, and Naltrexone for the 
Treatment of Opioid Use Disorder in Pregnant Women. Pharmacotherapy. 2017;37(7):824-839. 
doi:10.1002/phar.1958 
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Lacroix I, Berrebi A, Garipuy D, et al. Buprenorphine versus methadone in pregnant opioid-dependent 
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Jensen, Mark; Miller, Leslie; Fisher L. Assessment of Pain During Medical Procedures: A Comparison of 
Three Scales. Clin J Pain. 1998;14(4):343-349. 
 
23. FUNDING SUPPORT FOR THIS STUDY 
Society of Family Planning 

 
 
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24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable. 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Not applicable. The IND Exemption Supplement is included with the submission. 
26. IMPACT ON STAFF 
May increase time spent per patient. There will be a strong effort for the research assistant to consent 
patients in a timely fashion in order minimize the effect on clinic flow the day of osmotic dilator insertion and 
prior to the D&E procedure. The clinic manager will be notified of possible changes to clinic work flow.  
27. CONFLICT OF INTEREST 
None 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not applicable. 
29. OTHER APPROVALS/REGULATED MATERIALS 
Not applicable. 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
Not applicable. 
 
 
Version date: May 11, 2011