Clinical trial NCT01938092
Conditions: Pelvic Floor Disorders Pelvic Pain
Keywords: High-tone pelvic floor dysfunction Spasm Pelvic pain Diazepam Female Randomized trial
Sponsor: Raymond Foster
Start date: 2013-09-01; Completion date: 2017-07-01
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine the efficacy of intravaginal diazepam for the treatment of pelvic pain associated with pelvic floor hypertonic disorder.

Detailed description:
Women who are asked to participate will already be receiving a standard conservative therapy consisting of a psyllium-based bowel regimen, heat therapy, pelvic stretching exercises, and Kegel exercises. Participants will randomly be assigned by a computer-derived random number sequence (after pregnancy is ruled out) to either the treatment group (intravaginal diazepam) or the placebo group Investigators and patients will be blinded to group assignment. The placebo or diazepam tablet will be distributed to the participant in the examining room on the day of allocation. The participant will be instructed to insert the diazepam or placebo tablet into her vagina at home. The treatment group will insert the diazepam 10 mg vaginal tablet 1-2 times daily as needed in addition to the standard conservative therapy. The placebo group will receive the standard conservative therapy, and an intravaginal tablet (visually indistinguishable from diazepam) commercially produced by the university pharmacy. After 4 weeks, patients from either group will have the option of enrolling into a standard routine program (not research) of comprehensive pelvic floor rehabilitation therapy. The Visual Analog Pain Scale, Pelvic Floor Distress Inventory-20 Questionnaire, McGill Pain Questionnaire and Global Response Assessment will be completed by the participant at the initial visit, 4 weeks, 8 weeks and 12 weeks. Participants will be given the option of choosing one or more methods for returning questionnaires: electronic mail, self-addressed home envelope, or telephone call.

Arms: arm 1: Participated will be instructed to insert one 10mg tablet vaginally 1-2 times per day as needed for pain. arm 2: Participated will be instructed to insert one 10mg tablet vaginally 1-2 times per day as needed for pain.
Interventions: intervention 1: Diazepam intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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Unique Protocol ID: 1208827 
Brief Title: Vaginal Diazepam for the Treatment of Female 
Pelvic Pain   
Official Title: Intravaginal Diazepam for the Treatment of Pelvic 
Pain Among Women With Pelvic Floor Hypertonic 
Disorder: a Double Blind, Randomized, Placebo 
Controlled Trial   
Version: 5 
Date: 08/18/2016 
 
 


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Intravaginal diazepam for the treatment of pelvic pain among women 
with pelvic floor hypertonic disorder: a double blind, randomized, 
placebo controlled trial 
Michael Holland, DO2, John S. Joyce, MD1, Julie A. Starr, BSN, MS, FNP-BC2, 
Erma Z. Drobnis, PhD2, Sarah Hwang, MD3, Jonathan Thomas, MD2, Breton F. 
Barrier, MD2,and Raymond T. Foster, Sr., MS, MD, MHSc2 
 
1. Department of Obstetrics, Gynecology and Women’s Health, Scott and White Memorial 
Hospital, Temple, TX 
2. Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of 
Medicine, Columbia, MO 
3. Department of Physical Medicine and Rehabilitation, University of Missouri School of Medicine, 
Columbia, MO 
ABSTRACT 
OBJECTIVE:  To determine the efficacy of intravaginal diazepam for the treatment of pelvic pain 
associated with pelvic floor hypertonic disorder.  
METHODS:  After informed consent, women 18 years of age or older presenting with pelvic pain and 
physical exam findings of levator spasm will be scheduled to receive a standard therapy consisting of a 
bowel regimen, heat therapy, kegel exercises, and pelvic stretching exercises for 4 weeks.  Subjects will 
then be randomized by a computer-derived random number sequence to receive either a self-
administered program of intravaginal diazepam 10 mg one-two times daily, or a placebo vaginal tablet 
during the 4 weeks of their standard therapy.  At the end of the 4 weeks, patients will be allowed to 
enroll in a program of comprehensive pelvic floor rehabilitative therapy (CPRFT) we have described 
previously [3].   Pelvic floor pain and response to treatment will be evaluated by the Visual Analog Scale 
for Pain (VAS-P) and validated questionnaires.   Using improvement in the VAS-P as our primary 
outcome, seventeen women in each group will be required to achieve 80% power to detect a difference 
of patient’s perceived level of improvement of symptoms.  In order to account for patients lost to 
follow-up, 25 patients will be enrolled in each group.  Outcomes will be assessed at baseline, 4 weeks, 
12 weeks, and 24 weeks.  Patients, care-givers and those assessing the outcomes will be blinded to 
group assignment.   
ANTICIPATED RESULTS AND CONCLUSIONS:  These authors predict that the initial group of patients 
randomized to receive intravaginal diazepam will demonstrate a significant improvement in their Visual 
Analog Scale for Pain scores (VAS-P) from baseline.  We also predict that women from either group who 
enroll in the program of CPFRT will have superior outcomes than those who do not enroll in CPFRT.     
 


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TRIAL REGISTRATION:  This trial will be registered at clinicaltrials.gov pending IRB approval 
FUNDING:  The primary investigator will be using his faculty start-up funding for miscellaneous expenses 
related to this project 
 
INTRODUCTION 
Pelvic floor hypertonic disorder, (a.k.a. high-tone pelvic floor dysfunction, levator spasm, pelvic floor 
muscle spasm, myofascial pelvic pain, etc.) represents a neuromuscular condition characterized by 
involuntary levator spasm and reproducible pain upon vaginal penetration and internal examination [1].   
It may manifest as a primary pain generator, a singular component of chronic pain, or a dysfunction of 
viscera (bladder or bowel) controlled by the pelvic floor musculature.   Clinical syndromes associated 
with pelvic floor hypertonic dysfunction are numerous and include childhood elimination disorder, 
idiopathic urinary retention, vaginismus, constipation, pelvic floor dyssynergia, bladder pain 
syndrome/interstitial cystitis, vulvodynia, colorectal pain, and chronic pelvic myofascial pain syndrome 
[2].    
Although a number of non-surgical treatment options are described in the literature (pelvic floor 
physical therapy and rehabilitation, botulinum toxin injections, pharmacological therapy, off-labeled use 
of intravaginal diazepam), data describing their efficacy is limited [2].   For example, a recent 
retrospective review we recently published, analyzing the efficacy of a comprehensive pelvic floor 
rehabilitation program (CPFRP) on pelvic floor disorders demonstrated an 80% improvement in urinary, 
defecatory, and pain disorders throughout a 5-session course of rehabilitation [3].   Unfortunately, this 
treatment modality has limitations due to its cost and accessibility to geographically isolated patients.   
Previously, a randomized controlled trial comparing Botulinum Toxin Type A to placebo did not 
demonstrate any statistically significant improvement in either the Visual Analog Pain Scale or quality of 
life in patient’s treated with Botulinum Toxin [4].    
Intravaginal diazepam has generated interest as a viable alternative to traditional pelvic floor physical 
therapy.  A retrospective study in patients receiving diazepam vaginal suppositories in adjunct to pelvic 
physical therapy and intramuscular trigger point injections reported a clinically significant, but not 
statistically significant level of subjective improvement in 25 of 26 patients [5].  Recently, a randomized 
controlled trial by Crisp et al. using a nightly dose of 10 mg intravaginal diazepam, failed to demonstrate 
a significant improvement in resting EMG parameters or subjective outcomes when compared with 
placebo.   However, this study has limitations with sample size and dosing schedule.   
The purpose of this study is to evaluate the efficacy of intravaginal diazepam in the treatment of pelvic 
pain among women with hypertonic pelvic floor disorder.  Secondary outcomes will include assessment 
of CPFRT efficacy as adjunctive or stand-alone therapy for the treatment of hypertonic pelvic floor 
disorder.  We hypothesize that patients receiving self-administered intravaginal diazepam, one to two 
times daily, in addition to a standard conservative therapy consisting of a psyllium-based bowel 
regimen, heat therapy, pelvic stretching and kegel exercises, will demonstrate a significant improvement 


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in pain scores after 4 weeks compared to those patients receiving the standard conservative therapy 
alone.    We then hypothesize that patients enrolling in a program of comprehensive pelvic floor 
rehabilitation therapy will increase their pain improvement scores after 12 and 24 weeks compared to 
those patients receiving intravaginal diazepam plus standard conservative therapy alone.  Additional 
secondary outcomes of interest include sexual function, pain, and health-related quality of life as 
measured by validated questionnaires. 
METHODS 
This is a double blind, randomized, placebo controlled trial.  This is a single site study that will include 
women being seen at a MU Health Clinic site with complaints of acute or chronic pelvic pain will be 
approached for enrollment into this research protocol. 
Inclusion criteria: 
1. Age 18 years or older 
2. Primary complaint of acute or chronic pelvic pain with or without dyspareunia 
3. Physical exam findings consistent with levator muscle spasm 
 
Exclusion criteria: 
1. Chronic narcotic use 
2. Non-English speaking 
3. Currently serving a prison sentence 
4. Stage III or greater vaginal prolapse 
5. Allergies or contraindications to benzodiazepines 
6. Pregnant or breastfeeding 
7. Current or previous treatment with CPFRT and/or vaginal valium therapy 
 
Participating women will be scheduled to receive a standard conservative therapy consisting of a 
psyllium –based bowel regimen, heat therapy, pelvic stretching exercises, and kegel exercises [3].  
Patients will be randomly assigned (after pregnancy is ruled out by a urine pregnancy test performed in 
the office) to either the treatment group (intravaginal diazepam) or the placebo group (investigators and 
patients will be blinded to group assignment by use of sequential opaque envelopes).  The diazepam 
capsules will be created by the investigational pharmacy by embedding hard size 1 gelatin capsules with 
manufactured diazepam 10mg tablets (Teva Pharmaceuticals) and cellulose filler.  Identical appearing 
gelatin capsules filled only with cellulose will be used for the placebo group.  
The diazepam, capsules, and filler will be funded by the primary investigator.  The treatment group will 
receive a self-administered regimen of 10 mg diazepam vaginal capsules to be used one to two times 
daily as needed in addition to the standard conservative therapy.   The placebo group will receive the 
standard conservative therapy, and an inactive intravaginal tablet.  The participants will acknowledge 


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during the consent process that they will only take the placebo or diazepam capsules vaginally.  .  After 4 
weeks, patients from either group will have the option of enrolling into a program of comprehensive 
pelvic floor rehabilitation therapy as described previously by Starr et al. 
 
A review of the literature does not report any adverse events from intravaginal diazepam (1,5), and the 
onset of action and half-life of intravaginal diazepam has not been determined [1].  We will diligently 
monitor for any unexpected adverse events that may be result of medication.    
 
The primary outcome of interest will be the patient’s improvement of pain as measured by the Visual 
Analog Scale for Pain (VAS-P) at 4 weeks.  Secondary outcomes of interest will be the patients’ perceived 
level of sexual function, pain and health-related quality of life as measured by validated questionnaires 
such as PFDI-20.  The VAS-P and questionnaires (PFDI-20, McGill Pain Questionnaire, and Global 
Response Assessment) will be completed at baseline, 4, 12, and 24 weeks.  Patients will be given the 
option of choosing one or more of the following methods for follow-up contact and data collection:  
electronic mail, self-addressed home envelope, or telephone call.  Case report forms will be utilized by 
investigators to record data provided by the patients. 
The investigational pharmacy will perform the computer-derived randomization and create a log book to 
track and un-blind the participants in case of an adverse eventThe log book and capsules will be 
transferred to the dispensing pharmacy, (in-patient pharmacy at Women’s and Children Hospital, 
Columbia, MO) for including the participants.  A co-investigator will write a prescription for a 4-week 
supply (60 capsules).  A clinic nurse will take the prescription to the dispensing pharmacy and return 
with the capsules and give to the participant.  Participants will also have the option of having the 
dispensing pharmacy mail a 4-week supply of capsules directly to the participants. 
    
STATISTICAL METHODS 
 
We will be using a non-parametric 2 sample t-test to compare pain scores between placebo and 
diazepam groups.  Chi-squared analysis will be performed to calculate the proportion of patients 
analyzed in each of four CPFT groups (CPFT alone, CPFT + diazepam, CPFT + placebo, placebo alone). 
In order to determine the treatment response and variance for use in power calculation for our primary 
outcome of VAS pain scale at 4 weeks, 4 placebo-controlled studies were evaluated that used VAS-P to 
assess the response of pelvic pain to treatment.  Results from those using a 10 point VAS were 
converted to a 100 point scale.  
Paper 
Baseline 
Placebo 
Treatment 
Difference (mm) 
Harada et al [6] 
78 ± 13 
53 ± 6 
27 ±  13 
26 
Bergqvist et al [7] 
58 ± 12 
43 ± 8 
08 ± 10 
35 
Abbott et al [2] 
52 ± 19 
40 ± 20 
25 ± 20 
15 
Seracchioli et al [8] 
40 ± 38 
30 ±   49 
0 ± 11 
30 
Results are mean +SD or median + interquartile range.  Values were estimated by measurements from 
the published graph when exact values were not presented. 
 
Assuming a difference in VAS between treatment and placebo of 20 mm with a SD of 20 mm, 17 women 
in the diazepam and placebo groups will be required to give 80% power and a two-sided 5% significance 


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level.  In order to account for patients lost to follow-up, we will enroll 25 patients per treatment group.  
To recruit this number of patients, a 6 month inclusion period is anticipated.  Fifty patients will be 
allocated by sealed opaque envelopes according to a computer-derived random number sequence 
consisting of 25 groups of 2 choices (random.org).    
 
Patients, care-givers and those assessing the outcomes will be blinded to group assignment.   
Upon completion of enrollment, data analysis will begin.  The investigational pharmacist will provide un-
blinded information to the study statistician only.  This information will be communicated through a 
secure password protected file.   
EXPECTED RESULTS 
Patients randomized to receive intravaginal diazepam will not differ from those randomized to placebo 
in terms of patient age, duration of pain, psychological and medical history, gynecology problem list, 
body mass index, and physical exam findings.  Patients randomized to receive intravaginal diazepam will 
have significantly higher improvement scores compared to placebo on the VAS-P.  It is anticipated that 
more patients from the placebo group than the intravaginal diazepam group will enroll into the 
comprehensive pelvic floor rehabilitation therapy program.  It is anticipated that the patients in the 
comprehensive pelvic rehabilitation therapy group will have higher VAS-P scores then patients receiving 
either intravaginal diazepam or placebo alone.    
             
REFERENCES: 
1. Crisp CC, Vaccaro CM, Estanol MV, Oakley SH, Kleeman SD, Fellner AN, Pauls RN.  Intra-vaginal 
diazepam for high-tone pelvic floor dysfunction: a randomized placebo-controlled trial.  Int 
Urogynecol J.  2013. epublished 17 May 
2. Butrick CW.  Pelvic floor hypertonic disorders: identification and management.  Obstet Clin 
North Am.  2009;36(3):707-22 
3. Starr JA, Drobnis EZ, Lenger S, Parrot J, Barrier B, Foster RT.  Outcomes of a comprehensive 
nonsurgical approach to pelvic floor rehabilitation for urinary symptom, defecatory dysfunction, 
and Pelvic Pain.  Female Pelvic Medicine & Reconstructive Surgery.  2013 
4. Abbot JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG.  Botulinum toxin type A for chronic pain 
and pelvic floor spasm in women, a randomized controlled Trial.  Obstet Gynecol.  2006;108 
(4)915-23. 
5. Rogalski MJ, Kellogg-Spadt S, Hoffmann AR, Fariello JY, Whitmore KE.  Retrospective chart 
review of vaginal diazepam suppository use in high-tone pelvic floor dysfunction.  Int Urogynecol 
J.  2010;21:895-9. 
6. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral contraceptive pill for 
dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized 
trial. Fertil Steril. 2008;90: 1583-8. 
7. Bergqviat A, Bergh T, Hogström L, Mattsson S, Nordenskjöld F, Rasmussen C.  Effects of  


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triptorelin versus placebo on the symptoms of endometriosis.  Fertility and Sterility.  1998; 
69(4):702-8. 
8. Seracchioli R, Mabrouk M, Frascà C, Manuzzi L, Savelli L, Venturoli S. Long-term oral 
contraceptive pills and postoperative pain management after laparoscopic excision of ovarian 
endometrioma: a randomized controlled trial. Fertil Steril. 2010;94: 464-71.  
Flow diagram of patient disposition throughout the study. 


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Women screened for 
eligibility 
Excluded for not 
meeting criteria,     
Declined to 
participate 
Randomized 
Allocated to 
intravaginal diazepam 
and conservative 
therapy 
Enrolled in CPRT
Lost to follow-up or   
Discontinued 
intervention 
Analyzed 
Abstained from CPRT 
Lost to follow-up or  
Discontinued 
intervention 
Analyzed 
Allocated to placebo 
and conservative 
therapy
Enrolled in CPRT 
Lost to follow-up or 
Discontinued 
intervention 
Analyzed  
Abstained from CPFRT
Lost to follow-up   
Discontinued 
intervention 
Analyzed