A Double-Blind, Randomized Study to Compare Onabotulinumtoxin A Versus Kenalog for Intravaginal Trigger Point Injections in the Treatment of Chronic Pelvic Pain
Phase: NA
Conditions: Pelvic Pain
Sponsor: Jamie Bartley, DO

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A DOUBLE-BLIND, RANDOMIZED STUDY TO COMPARE ONOBOTULIUMTOXIN A 
VERSUS KENALOG FOR INTRAVAGINAL TRIGGER POINT INJECTIONS IN THE 
TREATMENT OF CHRONIC PELVIC PAIN
Principal Investigator: Jamie Bartley, DO
Version Date: August 23, 2017
Study Overview
Background
Chronic pelvic pain (CPP) is a common and often debilitating problem among women. 
A practical clinical definition of CPP is non-cyclical pelvic pain that is of at least 6 
months duration1.   CPP occurs below the umbilicus and is severe enough to cause 
functional impairment or require treatment.  CPP affects approximately 15% of women 
and the health care burden is substantial.  The direct cost of physician/clinician visits is 
estimated to be over $880 million and the indirect costs due to lost work is estimated at 
$555 million2.  
Patients with CPP often go undiagnosed for years and see many different healthcare 
providers before getting the correct diagnosis and subsequent improvement in their 
symptoms3, 4.  Depending on the treating specialists, patients may be diagnosed with 
bladder pain syndrome/interstitial cystitis (BPS/IC), endometriosis, vulvodynia, or 
irritable bowel syndrome.  A definitive diagnosis may be lacking in up to 60% of 
patients seeking treatment for CPP5.  Patients with CPP report that their quality of life is 
diminished and their relationships with loved ones are often damaged6, 7.  They may 
have lost their job as a result of missed work days or inability to function appropriately 
due to pelvic pain symptoms.  
The musculoskeletal system is an important factor in chronic pelvic pain, specifically 
the persistent and refractory type8.  Myofascial pain and hypertonic pelvic floor 
dysfunction are present in as many as 85% of patients with bladder pain 
syndrome/interstitial cystitis and/or chronic pelvic pain syndromes9. The pelvic floor 
muscles are arranged in deep and superficial layers and act as a sling to support the 
pelvic organs and the bones and ligaments of the pelvis provide support to the pelvic 
muscles. The deep levator ani muscles, often referred to as the pelvic diaphragm, are 
the most important of the pelvic floor muscles and consist of the pubococcygeus, 
iliococcygeus, and the coccygeus.  The main function of the muscles are to control 
continence and both bowel and urine elimination. 
 An important concept to understand when treating pelvic pain is that of cross-system 
interactions.  This is a loss of peripheral specificity when a stimulus arrives in the 
central nervous system making it difficult to sort out the exact source of the stimulus10.  
In the case of pelvic floor dysfunction, the levator muscles may be stretched and 
irritated but the patient may perceive it as bladder pain or vaginal pain.  Studies have 
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demonstrated that women with CPP had more frequent musculoskeletal findings and 
had less control over their pelvic floor compared to control subjects11.  On physical 
examination, myofascial trigger points have been described.  These hyperirritable 
bands of muscle can be palpated through the vaginal walls.  They are often knot- like or 
taut and are painful on compression, reproducing the patient’s pain symptoms12,13.   
Trigger points are thought to be discreet areas of abnormal muscle spasms whereas 
high-tone pelvic floor muscle dysfunction (HT-PFD) refers to a more global pelvic floor 
hypertonicity causing diffuse spasm of the levator complex14. Both have been 
implicated in chronic pelvic pain but in our experience, patients with chronic pelvic pain 
present with more global pelvic floor hypertonia than one area of tenderness as the 
term trigger point would suggest. 
Prior studies of treatments directed towards hypertonic pelvic floor dysfunction in 
women with CPP have been promising. In a recent NIH-funded multicenter study, 
investigators found that 59% of patients receiving myofascial physical therapy reported 
moderate or marked improvement in their symptoms compared to 29% of the control 
group of patients receiving global therapeutic massage15.  This and other studies have 
resulted in pelvic floor physical therapy to be first line treatment of women with chronic 
pelvic pain and hypertonic pelvic floor dysfunction16.
In patients that fail non-invasive techniques, intralevator trigger point injections (TPIs) 
are often the next step.  This is often combined with physical therapy and typically 
requires 3-5 injections to help the muscle relax and return to normal function.   Langford 
and coworkers injected palpable vaginal trigger points with 5cc of a mixture of 10 cc of 
0.25% bupivacaine, 10 cc of 2% lidocaine and 1cc of 40 mg triamcinolone17.  Success, 
defined as a decrease in pain of 50% or more, occurred in 73% (13/18) with 33% (6/18) 
being completely pain free.  
 
Intralevator trigger point injections with onabotulinumtoxinA has also been shown to 
improve pain in patients with chronic pelvic pain and is often the next step following 
steroid trigger point injections.  Typically we use this for patients that respond to steroid 
TPIs but the effects are not long lasting.  OnabotulinumtoxinA has been shown to 
provide relief for 6-9 months with minimal side effects including, infection, hematoma, 
and pain all of which are similar to traditional TPI16.   
In a study of 30 patients that received 80 units of  onabotulinumtoxinA and 30 patients 
that received placebo (saline) injection into the pelvic floor muscles for dysmenorrhea, 
dyspareunia, dyschezia, and nonmenstrual pelvic, there was a significant change in 
baseline in the onabotulinumtoxinA  group in nonmenstrual pelvic pain18.  Both groups 
had changes in dyspareunia and pelvic floor pressures (cm H20) but these patients 
were also allowed to undergo pelvic floor physical therapy during the course of 
treatment, which may have affected the results in both groups.  OnabotulinumtoxinA  
150U-400U has also been shown to be very effective in treatment of women with 
refractory vaginismus19.
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OnabotulinumtoxinA  injection has been compared to 80 mg methylprednisone  injection 
in patients with chronic myofascial pain in the piriformis (100u), iliopsoas (150u) or 
scalenus anterior (80u) muscles and was found to have similar results at 30 days but at 
60 days the  onabotulinumtoxinA group had statistically significant improvements in their 
pain scores, compared to the methylprednisone group and also compared to their 
scores at 30 days20. 
As discussed above, onabotulinumtoxinA is often used for patients that have failed 
conservative therapy with medications, pelvic floor physical therapy and/or steroid 
trigger point injections.  However, the optimal dosing and frequency of use has not been 
determined and needs further study.   In addition, the effect of onabotulinumtoxinA  
injections on the need for additional therapy is unclear but may be beneficial for several 
reasons.  First, if relief is able to be maintained over a longer time period initially, 
patients may be able to avoid having to undergo repeated TPI over 3 to 5 sessions 
which can be painful, costly, and time consuming and they may progress to needing  
onabotulinumtoxinA  anyway.  Second, by providing more immediate and prolonged 
relief, requirements for other therapies such as pelvic floor physical therapy and narcotic 
pain medications may be reduced.  Third, because many of our patients with pelvic pain 
present with high tone pelvic floor dysfunction, we expect global intralevator trigger point 
injections to be more effective than single site injections. Lastly, we know that chronic 
pelvic pain is associated with anxiety and depression and we hope that the more 
immediate and prolonged result of onabotulinumtoxinA will provide patients with 
improved mental health scores.
Objectives and/or Endpoints 
The primary objective of this study is to assess changes in overall pain score using 
the visual analog scale (VAS) (Appendix 1), the Brief Pain Inventory (BPI) 
(Appendix 2) and Global Response Assessment (GRA)(Appendix 3) questionnaire 
at one month following transvaginal trigger point injections with a steroid 
(triamcinolone) and a local anesthetic (ropivacaine) vs. onabotulinumtoxinA and a local 
anesthetic (ropivacaine) in patients with CPP and high-tone pelvic floor dysfunction. We 
hypothesize that patients in the Botox group will have lower pain scores following 
treatment and that the treatment will have a longer effect compared to patients in the 
Kenalog group. 
The secondary objective is to determine if there are persistent changes in pain scores 
using the VAS, BPI, and GRA at 3 and 6 month follow up. Lastly, patients will be asked 
to complete a questionnaire to determine what other treatments have been needed 
since the original TPI (Appendix 4).    
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Patients will be asked to refrain from any additional treatments including pelvic floor 
physical therapy, or new prescriptions for intravaginal muscle relaxants or narcotic 
medications during the first month following the initial TPI.  If patients are already taking 
muscle relaxants or narcotics, they will need to either remain stable or decrease the 
dosage and frequency of the medication.  If patients are already receiving pelvic floor 
physical therapy, they may continue treatment. If patients require increased use of 
these medications or additional therapies due to worsening or uncontrolled symptoms, 
these treatments will be provided at the discretion of the treating clinician.  These 
patients will then be evaluated as an intention to treat cohort. In addition, at the one 
month follow-up visit with the clinician, further treatments will be offered based on the 
patient’s need for further symptom control.   
We hope that the information obtained by this study will help guide clinicians to make an 
evidenced based decision on the clinical efficacy as well as cost effectiveness of two 
transvaginal trigger point injection protocols for patients with high-tone pelvic floor 
dysfunction. 
Methodology
A randomized, double blind two arm study.  Up to 40 women will be included to 
complete this study. We may enroll up to 60 patients to account for possible dropouts, 
with each arm having up to 20 subjects.  This is a pilot trial and a formal sample size 
has not been completed.  Subjects will be recruited by physician referral or word of 
mouth.  Study activities will take place at the Women’s Urology Center in the south 
tower of Beaumont Hospital, Royal Oak.
Screening
Subjects are eligible to participate in this study if they are a woman greater than 18 
years old and have pain localized to the pelvis for greater than 3 months. Overall pelvic 
pain score must be greater than 4 on the VAS. They will be screened with assessment 
of last menstrual period (LMP) and a urine pregnancy test.  If the woman has had a 
tubal ligation or a hysterectomy, the pregnancy test will be waived. 
A vaginal exam will be performed obtaining a pH and wet mount.  If the woman has 
vaginitis on her wet mount at screening, she may be given a prescription for the 
appropriate medication per standard of care and be re-screened. She must wait at least 
3 days after treatment and may be re-screened once. The vaginal exam will also include 
a levator exam and the patient must have the finding of high tone pelvic floor 
dysfunction.  This will be determined by the clinician and is defined as diffuse spasms 
and pain with palpation of the levator complex. Pain scores from 0-10 on the VAS will 
be recorded according to positions on a clock as rated by the patient (Figure 1).  
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Informed consent will be obtained from women meeting the screening and inclusion 
criteria (see below). 
Following screening, consent and enrollment, a complete medical history will be 
obtained and/or confirmed from a prior visit.  The intake form will be the same history 
form that all patient’s presenting to the Women’s Urology Center are asked to fill out.  
Information obtained includes demographics, current and past medical conditions, 
surgical history, social history (smoking, drugs, education, caffeine use, and 
employment), current medications, and allergies.  Past treatment history for pelvic pain 
including physical therapy, trigger point injections, hydrodistension, cystoscopy, and 
surgery will be recorded.   Subjects in both groups will then be asked to fill out baseline 
questionnaires including pain score on the VAS and the BPI.   
The woman will then be randomized to one of 2 treatment arms in a 1:1 pattern.
Proposed intervention, if applicable (e.g., study visits, surgical procedure, 
administration of drugs, etc.) or collection of data (e.g., survey, questionnaire, 
etc.).
Subject enrollment and treatment may both occur at the initial visit.  If desired, these 
visits may also be scheduled as separate visits within a 7-14 day period of time.   
The first arm (Group 1) will receive TPI with a steroid and a local anesthetic followed by 
saline and the second arm (Group 2) will receive a local anesthetic followed by a 
mixture of 200u of Onabotulinumtoxin A and saline.   Each group will receive injections 
globally throughout the pelvic floor at 1, 3, 5, 7, 9, 11 o’clock (Figure 1). See below.
Intralevator trigger point injections will then be performed as follows:  With the subject in 
lithotomy position and blinded by a drape, the clinician will perform a pelvic exam to 
palpate the muscles of the levator complex.  Pain scores from 0-10 on the VAS will be 
recorded according to positions on a clock as rated by the patient.  The pharmacy will 
provide the injection medications in dark syringes in the following solutions:  For 
patients randomized to group 1, a mixture of 40mg/1 ml of triamcinolone (40 mg) and 
29cc of ropivicaine 0.5% (5cc/6 sites) will be used first followed by 6 cc of saline 
(1cc/injection site).  In Group 2, patients will receive an injection of 30 cc of ropivicaine 
(5cc/6 sites) followed by a mixture of 200 u of onabotulinumtoxinA and 6cc of saline.  In 
patients weighing less than 58kg, the ropivicaine dose will be adjusted to a maximum of 
2.5mg/kg/dose.  A 7 inch 22 gauge spinal needle and a needle guide will be used to 
administer the injections.  A tampon will be inserted following the injection for 
approximately 5 minutes and then removed.
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Subjects will be monitored for at least 30 minutes following TPI.  An ice pack to the 
vulva, warm blanket and water or juice will be provided as needed for patient comfort.  
Side effects will be monitored by assessing vital signs (Blood pressure, pulse, 
respirations) within 10 minutes of the injection by the clinical staff (medical assistants) 
and monitoring subject-reported symptoms such as those most commonly noted with 
trigger point injection such as pain, hematoma, light-headedness, and hypertension (all 
<1 %).  Vital signs and any adverse effects will be reported to the study physician 
performing the injections.  An overall pelvic pain score (0-10) prior to departure will be 
obtained
For in office follow up visits the following will take place:
30 days (+/- 7 days) following the first TPI, the subjects will return to the WUC for a 
follow up visit.  Follow up questionnaires will be given (VAS, BPI, GRA) and subjects will 
have an office visit with one of the study clinicians.  A pelvic exam will be performed and 
levator pain scores from 0-10 on the VAS will be recorded according to positions on a 
clock as rated by the patient.  The subject’s symptoms will be assessed and other 
treatments will be initiated as needed.
90 days (+/- 30 days) following the initial TPI, patients will return to the WUC for a follow 
up visit.  Pelvic pain scores will be assessed using the VAS and BPI.  GRA will also be 
determined.  Patients will be asked to fill out a questionnaire regarding other treatments 
they have had since the initial TPI (Appendix 4).  A pelvic exam will be performed by the 
study clinician and levator pain scores from 0-10 on the VAS will be recorded according 
to positions on a clock as rated by the patient.
At 180 days (+/- 30 days) following the initial TPI, patients will return to the WUC for a 
follow up visit and a study exit interview.  The VAS, BPI, GRA and additional treatments 
questionnaires will be obtained.  A pelvic exam will again be performed by the study 
clinician and pain scores from 0-10 on the VAS will be recorded according to positions 
on a clock as rated by the patient.
* While in-person study visits are preferable, the follow up visits may be completed as a 
phone call visit, if the participant is otherwise unable or unavailable. The questionnaires 
will be collected via mail.
In the event the follow up study visit is not conducted in-person, the visit may be 
conducted by phone and/or mail and Research Staff will:

Send the follow up questionnaires to the participant for completion with a self-
addressed Stamped envelope for questionnaire return

Review the questionnaires and completion dates with the participant
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
Request and verify the completed questionnaires have been returned to the 
research office

Contact the participant for clarification and/or to address questions regarding the 
completed questionnaires, if needed

Assess concomitant medication changes

Assess for adverse events
Subjects may be permitted to withdraw from the study if they have poor resolution of 
their pain or worsening of their symptoms.  If they feel that they need other therapy 
during the first 30 days that is not permitted by the study (additional physical therapy, 
higher or more frequent doses of vaginal valium or  pain medications, repeat TPI, etc.) 
they may be withdrawn and will be evaluated by the clinician for other treatment options. 
Patients who withdraw from the study will be asked if they are willing to fill out post 
questionnaires. Either group can get additional therapy following the first 30 days 
following the TPI.  Furthermore, either group may have repeat TPI with kenalog one 
month following the original injection but patients may not undergo TPI with 
onabotulinumtoxinA following the original injection unless they withdraw from the study 
and are unblinded to prevent overdose of onabotulinumtoxinA.  If additional TPIs with 
kenalog and ropivicaine are indicated at any of the follow up visits, the injections will be 
prepared and administered in the Woman’s Urology Center, per routine standard of 
care.  In no way will their withdrawal from the study impact what treatments will be 
offered to them.  Subjects may also withdraw from the study without any reason given.   
If they do not feel comfortable continuing treatment by the study clinicians or at the 
WUC, they will be referred to another provider/site not involved in the study.  
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Schedule of Activities
Initial Visit
Screening
Consent
Treatment Visit
Baseline 
Questionnaires and 
physical exam
(May be done at initial 
visit)
30 days
90 days
180 days
Screening
X
Consent
X
Intake medical history form
X
X (If not done at initial 
visit)
Urine pregnancy testa
X
Q tip test 
X
X
Xb
Xb
Xb
Vaginal pH and wet mount
X
X (As needed)
Xb (As needed)
Xb (As needed)
Xb (As needed)
Assess concomitant meds
X
X
X
X
X
Vaginal exam assessment 
for high tone pelvic floor 
dysfunction with record of 
patient reported levator pain 
scores
X
X
Xb
Xb
Xb
Vital signs
X
X
Xb
Xb
Xb
Total overall pelvic pain 
score on VAS
X
X (done pre and post 
TPI)
X
X
X
BPI
X 
X
X
X
Trigger point injection
X
As needed
As needed
As needed
Assess side effects
X
X
X
X
GRA
X
X
X
Assess concomitant 
treatments
X 
X
X
X
aPremenopausal women that have not had a tubal ligation or hysterectomy
bOnly applies to follow up visits completed in office
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Risks and Benefits
The benefit of this study is that it will guide clinicians to make an evidenced based 
decision on the clinical efficacy as well as cost effectiveness of two different means of 
intravaginal trigger point injections for patients with PFD.  We hope that identification of 
successful therapies will improve patient’s quality of life, decrease the requirement for 
narcotic pain medications and decrease medical costs to the patient.
In this patient population, pain during the exam and trigger point is common and 
expected.  However, the goal of this treatment is to decrease the pain long term.  
Anecdotally, patients are able to put up with temporary pain during the treatment to gain 
the benefit of prolonged relief that comes with injections.  
Potential risks to the subject include:
Risks of Trigger Point Injections:
Most Frequent (occurring more than 10% of the time):

Slight discomfort during the vaginal exam

Light bleeding at the trigger point injection site

Pain during the trigger point injection
Rare (occurring less than 1% of the time):

Vaginal hematoma (collection of blood in the tissue)

Infection
Risks of OnabotulinumtoxinA:
Less Frequent (occurring from 1% to 10% of the time):

Transient urinary retention (temporary inability to urinate)

Transient flatal incontinence (temporary accidental passing of gas)

Transient fecal incontinence (temporary accidental loss of stool) 

Slight temporary fatigue 
Rare (occurring less than 1% of the time):

Botox toxicity/intolerance 

Lower extremity weakness 

Lower extremity numbness
Risks of Kenalog:
Rare (occurring less than 1% of the time):

Headache 

Dizziness 

Weight gain 

Hyperglycemia (high blood sugar)

Trouble Sleeping 
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Risks of Ropivacaine:
Rare (occurring less than 1% of the time):

Hypertension (high blood pressure) 

Hypotension (low blood pressure)

Arrhythmia (abnormal heart rate)

Tachycardia (rapid heart rate)

Headache 

Rash 

Lower extremity weakness 

Urinary retention (inability to urinate)

Urinary incontinence (accidental loss of urine)

Local anesthetic toxicity (numbing medication could be absorbed through the 
bloodstream into the rest of the body affecting your breathing, heartbeat, blood 
pressure)
There is a risk of an allergic reaction from any medication. Symptoms may include 
swelling, skin rash and/or headache, difficulty swallowing or talking, trouble breathing, 
muscle weakness. Symptoms can occur days to weeks after injection. There may be 
unknown side effects or problems that could result in serious illness or even death.
Inclusion Criteria

Provide informed consent

Healthy women > age 18 regardless of menopausal status

Willing and able to fill out study questionnaires.  In patients that are unable to 
read, the research nurse will be available to assist.

High-tone pelvic floor dysfunction on vaginal exam

A pelvic pain score of  > 4  on screening VAS

Pain perceived to be in the pelvis that has been present for at least 3 months.  
 Exclusion Criteria

Patients that have had Botox to the bladder within the last 8 months

Patients that have had Botox outside the bladder of > 160 u within the last 12 
weeks.

Patients that have had transvaginal trigger point injections of any form (Botox or 
steroid) in the last 3 months

Pregnancy

Concomitant use of any narcotic drug, alcohol, or any illicit drug use during the 
study period that could be deemed unsafe in combination with study medication 
as judged by the investigators.

Any evidence of vaginitis on wet mount slide at initial visit that is untreated.

Subject with any other vaginal epithelial disorder that could affect absorption of 
medication as deemed by the investigators.
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
Any indication/condition/medication that the investigators identify as 
contraindicated in conjunction with study medication.

Systolic blood pressure > 160 mm Hg on screening blood pressure

Heart rate > 110 beats/minute on screening heart rate
Randomization
Subjects will be randomized to one of the two trigger point injection types by a sealed 
randomization envelopes (or similar randomization) created by our biostatistician. 
Patients will be randomized in a 1:1 pattern in varied randomized block design.
Recruitment
We anticipate recruitment will come from volunteers with pelvic pain both within and 
outside the Beaumont health care system urology and gynecology practices by 
physician referral and word of mouth. 
Data Analysis
This study is an exploratory pilot study. Descriptive statistics, which will be provided for 
all variables, will be the main focus of the analysis because of the small sample size. 
Descriptive statistics will consist of frequency tables and bar charts for categorical 
variables, as well as summary statistics tables and boxplots for continuous variables. 
Exploratory data analysis will be conducted on the data, particularly focusing on 
comparisons between the two treatment groups. Formal significance testing will be 
done to analyze group differences in terms of the baseline variables and clinical 
characteristics at time of treatment.
Since both the VAS and the BPI scores are given on ordinal scales, the marginal 
distributions of each of these scores will be provided for both time of treatment and 30 
days after. For each subject, the difference in their score from pre to post will be 
calculated. Frequencies will be tabulated for the number of subjects whose pain score 
improved the number whose pain score stayed the same, and the number whose pain 
score worsened. The proportion of subjects in these categories will be compared 
between groups. Bar graphs will be created to illustrate the distribution of this variable. 
Nonparametric tests may be used to compare groups based on the distribution of the 
outcome variables. 
Data Safety Monitoring Plan
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An independent physician (not connected with the study, but familiar with the use of 
trigger point injections) will review study records at the half-way point of enrollment for 
each arm of the study to ensure the safety of subjects and lack of significant adverse 
effects.  As an on-going plan, any adverse effects (prolonged bleeding, hemodynamic 
changes, significant patient pain, or other deemed significant by clinicians) will be 
reported to the research nurse and then to the PI at the time of the event. Adverse 
events, serious adverse events, and unanticipated problems not listed in the risks 
section of this protocol will be reported per federal regulations and IRB guidelines.
Stipend 
Participants will receive a check for $15 from William Beaumont Hospital following each 
of the five study visits. A total stipend of $75 will be paid to those who complete all study 
visits. 
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IRB NUMBER: 2015-008
IRB APPROVAL DATE: 09/12/2017