Injection With OnabotulinumtoxinA (Botox) for the Treatment of Chronic Pelvic Pain

BACKGROUND AND RATIONALE: Chronic pelvic pain affects 15-20% of the female population aged
18-50 years and accounts for up to 10% of gynecologic visits each year resulting in a cost
of 2.8 billion dollars annually to the health care system. It is defined as non-menstrual
(non-cyclic) pain that occurs on an average of two weeks per month for at least six months'
duration; localized to the anatomic pelvis, anterior abdominal wall below the umbilicus,
buttocks, or lumbosacral back. Many affected patients are noted to have severely short and
tight pelvic floor muscles on examination (termed MPP), resulting in pelvic floor trigger
points which may cause associated pelvic symptoms, including: dyspareunia, urinary urgency
and frequency, symptoms of a urinary tract infection, and pelvic discomfort or heaviness.As
a result of the constant, severe pain and associated symptoms, women with chronic pelvic
pain are more likely to experience a decrease in their quality of life, depression, and
anxiety towards their condition. The difficulty in treating chronic pelvic pain is that the
etiology can be varied and multifactorial. Frequently associated with an abnormal response
to an acute injury such as a pelvic infection, traumatic birth, and endometriosis or
repetitive insult like chronic constipation, chronic pelvic pain can also result from
prolonged pelvic floor muscle spasm and muscular hypertonicity. Specialized examination of
the pelvic floor musculature in patients with chronic pelvic pain will often reveal MPP as
well as 'trigger points'.11 This pain is perpetuated as a result of modifications in the
neuronal pathways which maintain a set pattern of pain sensations including increased pain
sensitivity (hyperalgesia), referred pain, and even changes in tissue make-up. The treatment
of MPP must therefore treat the inciting injury and modify the tissue response. The effects
of onabotulinumtoxinA on painful muscle were first suggested by the effects of toxin
injection in patients with migraine headache. While undergoing onabotulinumtoxinA injection
for cosmetic purposes, patients also suffering from migraine headaches found symptom
improvement. Further follow-up studies demonstrated a 51% complete resolution and 38% a
partial response noted of migraine symptoms within in 1 to 2 hours of treatment among true
migraine patients. Although the mechanism of action remains unclear, onabotulinumtoxinA is
believed to act by denervating autonomic nerves, thereby altering peripheral sensory nerve
function and interrupting the migraine cycle of pain. The trigeminal neurovascular theory of
migraine pain suggests that onabotulinumtoxinA acts not only causing muscle paralysis, but
also inhibiting the transmission of any vesicles from the synaptic junction, including
vasoactive intestinal peptide. This blockage of any neuromuscular junction transmission
inhibits any muscle activity or efferent pain signals. Interestingly, though muscle
paralysis takes about one week to manifest, pain relief occurs in 1 to 2 hours and although
flaccid paralysis last for approximately 3 months, benefits for migraine pain last much
longer.

STUDY RATIONALE: In MPP syndrome, prolonged muscle contraction, spasm, and inappropriately
high muscle tone are thought to diminish blood supply and increase oxygen demand of the
muscles of the pelvic floor. Ischemic muscle may secrete pain-producing substances, which
further sensitize muscle nociceptors, alter receptor field properties, and convert wide-band
mechanoreceptors to nociceptors. OnabotulinumtoxinA can directly block cholinergic
neuromuscular transmission and interrupt the cascade of events that lead to hyperalgesia and
allodynia. onabotulinumtoxinA plays a direct role by blocking the alpha- and gamma-motor
neurons, thereby preventing the abnormal pattern of muscle contraction (eg, spasm, dystonia)
that activates muscle nociceptors and sensitizes the muscle pain system through
mediators.The investigators division has been utilizing pelvic floor injections of
onabotulinumtoxinA as an off-label treatment for MPP in conjunction with pelvic floor
physical therapy for more than 6 years. In patients with severe MPP, who often unable to
tolerate any vaginal exam, or those receiving no further reduction in pelvic pain with
extensive physical therapy, the investigators have been utilizing the injection of 100 U of
onabotulinumtoxinA into pelvic floor trigger points with significant success. Anecdotally,
treated patients report a 30-40% reduction in their pain complaints 7-10 days post-treatment
which lasts for approximately 3 months. Even when the pain recurs, it is not as severe as it
was pre-treatment and patients take the opportunity of the window of reduced pain to
maximize further progress with pelvic floor physical therapy. Two to four weeks after pelvic
floor injection, patients with severe MPP reported statistically significant changes in VAS
scores before and after onabotulinumtoxinA treatment with a median reduction in VAS of -3.9
(CI for changed score -2.2, -5.6, p<0.001). Eighty percent of patients reported significant
subjective improvement in their pelvic pain lasting more than 4 weeks and anecdotally
lasting up to 3 to 4 months in duration. Adverse events were reported by 22% of patients and
were mild, limited to: pelvic heaviness, increased pain, urinary irritation, and
nausea/vomiting. However, despite these encouraging results, there is no definitive evidence
that onabotulinumtoxinA is an effective treatment modality in patients with severe MPP. In
their evidence-based review of the literature regarding the treatment of refractory pain
with onabotulinumtoxinA, Jabbari and Machado found only level C evidence (possibly
effective, may be used at discretion of clinician) when investigated the role of
onabotulinumtoxinAs in the treatment of MPP. Moreover, less is known regarding the potential
side effects of onabotulinumtoxinA injected into the pelvic floor muscles. Therefore,
stronger randomized controlled studies are necessary to investigate the efficacy and
possible side effects of pelvic floor injections of onabotulinumtoxinA in the treatment of
MPP syndrome and this is actually our research proposal. It is our hope that our study will
significantly change current clinical treatment protocols for MPP syndrome.

STUDY DESIGN: This is a phase I study in which participants will be randomized 1:1
(onabotulinumtoxinA:placebo), double-blinded, placebo-controlled clinical trial. Potential
participants are women seeking treatment for MPP as diagnosed by the participating clinical
investigators based on the following criteria: MPP is defined by at least 4 to 5 palpable
trigger points on transvaginal and/or transrectal examination of the pelvic floor, which
reproduces the pain for which they are seeking medical care. A trigger point is defined as
an extremely tender focus of muscle causing pain radiating to other areas specific for each
trigger point. A trigger point is termed 'active' if pain occurs spontaneously, and 'latent'
if palpation and pressure are required to elicit pain, which may replicate symptoms or
radiate to surrounding lower extremity, pelvic and abdominal sites. This study will have two
arms:* Treatment group: 20 patients randomly assigned to receive 100 U onabotulinumtoxinA
reconstituted in 20 ml saline sequentially injected bilaterally into the pubococcygeus,
iliococcygeus, coccygeus, obturator internus, and piriformis muscles. * Placebo group: 20
patients randomly assigned to receive 20 ml of saline bilaterally into the same pelvic floor
muscles. All injections will be performed using a pudendal injection tray in the clinical
treatment area after obtaining consent. The patients will be randomized using a
computer-generated randomization sequences in balanced blocks of four. Both the patients and
physicians will be blinded to the first injection assignment. All participants with
inadequate symptom control (VAS score 7 or more) at 1 months after the injection will have
their treatment unblinded. Those who received placebo (saline) will be offered injection
with open label onabotlulinumA. Those who previously received onabotlulinumA will not be
eligible for reinjection. All patients will be followed for 6 months after the initial
injection or for 6 months following the second injection. All patients who opt for a second
injection will once again begin the outlined injection follow-up visit schedule.

STUDY PROCEDURES:

Screening - A detailed medical and surgical history, demographic information and review of
medications will be taken from all patients suspected of having MPP. Then, a physical exam
and a pelvic floor examination for myofascial trigger points will be performed. It will
include an assessment of VAS at the bilateral pubococcygeus, iliococcygeus, coccygeus,
obturator internus, and piriformis muscles. All VAS scores will be recorded. Post residual
Void (PVR) will be recorded. Patients will have an assessment of their post residual void
(PVR) and the volume will be recorded. Patients who meet inclusion criteria will be offered
study participation. Patients who agree to participate will be formally consented and
complete all pertinent questionnaires: * Short Form 12 (SF-12) for quality of life
assessment * Patient Global Impression Index (PGI-I) for degree of bother from pelvic pain *
Pelvic Floor Distress Inventory (PFDI) and Pelvic Floor Impact Questionnaire (PFIQ - short
form 7) to assess the bladder and bowel functions * Female Sexual Function Index (FSFI) for
sexual function assessment. Currently no validated questionnaire for symptoms of MPP exists.

Procedure - A pudendal block type needle is gently advanced along the outstretched fingers.
Holding the needle in a near horizontal plane, the pelvic floor muscles are injected in a
systematic fashion starting on the levator ani and then marching backward all the way down
back to the piriformis muscle including the obturator internus muscle. The following muscles
are sequentially injected with 2 cc of diluted onabotulinumtoxinA: pubococcygeus (this
muscle is felt as a sling around the vagina, just proximal to the hymenal ring),
iliococcygeus (palpated superiorly and laterally to pubococcygeus muscle), obturator
internus (on the sidewalls of the pelvis just superior to the arcus tendineus levator ani),
coccygeus (half distance between the ischial spine and sacrum), and piriformis (these
muscles are palpated filling the posterolateral pelvic walls and are injected lateral to the
sacrum). Careful attention is made to withdraw prior to injection to ensure no intravascular
injection of the diluted onabotulinumtoxinA. Once the injection had been performed on one
side of the pelvis, pressure is held for good hemostasis. The same procedure is then
performed on the other side. Peri-procedural adverse events are recorded.

Post Procedure Instructions - Post treatment, all patients will be monitored for 15 minutes.
Standardized post-injection instructions are given to the participant verbally and in
written form. Patients will be contacted by telephone within 24-48 hours after the procedure
for safety assessment. The first follow-up evaluation will be scheduled 1 month after pelvic
floor injection.

Follow-Up Visits 3, 4, 5, 6, 7 & Visit 8 (Visit 8, only if Patient Received 2nd Injection) -
Follow-up clinic evaluations will occur 1, 2, 3, 4 and 6 months after injection,
respectively. A history will be taken and a physical examination that includes PVR
assessment will be performed at each follow-up visit. VAS scores of pelvic floor muscles
will be recorded. PGI-I, PFDI, PFIQ, and FSFI forms will be collected at each follow-up
visit. Adverse events will be carefully monitored and recorded.

Inclusion Criteria:

1. Females age 18 years to 65 years

2. MPP for at least 6 months with pain ranked > 7/10 by VAS

3. Able to make medical decisions for herself

4. Ability to speak and understand English

5. Ability to follow study instructions and likely to complete all required visits 6
.Must give written informed consent before enrolment in this study

Exclusion Criteria:

1. Pelvic onabotulinumA injections within the last 6 months

2. Pelvic floor physical therapy (PFPT) within the last 1 months

3. Pelvic surgery within the last 1 year

4. PVR greater than 150 ml

5. Presence of interstitial cystitis/ painful bladder syndrome (IC/PBS) by the current
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria
37.

6. Evidence of pelvic pathology or other active diagnoses of acute or chronic pain
syndromes including endometriosis, chronic cystitis, acute urinary tract infection,
vaginitis, pelvic inflammatory disease, etc.

7. Breastfeeding, pregnant or contemplating pregnancy in the next 1 year or not on a
current reliable form of birth control

8. Patients with known neurological diseases involving impaired neurotransmission,
including myasthenia gravis and Charcot-Marie-Tooth disease

9. Patients who are on ambulatory anticoagulant therapy, including aspirin, who are
unable to discontinue this treatment for 24 hours prior to the bladder injection

10. Women taking aminoglycosides at the time of injection (i.e. Cipro)

12. Uncontrolled clinically significant medical condition other than the condition under
investigation 13. Known allergy or sensitivity to any of the components in the study
medication 14. Concurrent or past (within 1 months) participation in another
investigational drug or device study 15. Any condition or situation that, in the
investigators opinion, may put the patients at significant risk, confound the study
results, or interfere significantly with the patients participation in the study