The Vulvar Vestibulitis Clinical Trial (VVCT) is an NIH (NICHD)--funded randomized, placebo-controlled, double-blinded clinical trial to study the clinical efficacy of four medical treatments for vulvar vestibulitis (localized vulvodynia): 1) topical lidocaine, 2) oral desipramine, 3) combined lidocaine and desipramine, and 4) placebo cream and tablets. The VVCT was conducted at Strong Memorial Hospital of the University of Rochester between August, 2002, and July, 2007 and the protocol was reviewed and approved by the University of Rochester Research Subjects Review Board (RSRB #8677). A blocked randomization scheme, utilizing a uniform random number generator and employing a block size of 8 ensured the four possible treatment combinations would occur equally or would not be greater than 2 assignments for any given treatment group. The duration of study drugs lasted 12 weeks with post-intervention follow-up at 16, 26, and 52 weeks. Clinical response from randomization to 12 weeks (the end of the randomized, blinded phase of the trial) was assessed by change in pain by Numeric Rating Scale (NRS) of a weekly Tampon Test compared to a number of measures with pre-existing reliability/validity data or prior published experience in vulvodynia clinical trials including: change in overall daily pain intensity (24 hour NRS)(7
), the frequency of sexual intercourse (insertional attempts per week)(10
), the change in intercourse pain NRS(10
), vulvar algesiometer score(11
) and the cotton swab test (CST) pain level by verbal reporting scale (VRS)(12
). In addition, during each study visit subjects completed a battery of pain and health related quality-of- life measures recommended by IMMPACT including: the Brief Pain Inventory, Short Form-McGill Pain Questionnaire (SF-MPQ), Profile of Mood States, and the Beck Depression Inventory.(7
) For the primary outcome analysis of the clinical trial (to be published later), we hypothesized that the response rates would be 20% for the double placebo group, 50% for each treatment used alone and 80% when the two treatments are used together. Therapeutic response of desipramine / lidocaine was estimated from preliminary reported data from our group.(13
) A Bonferroni--corrected 80% power level required a total of 104 subjects to complete the trial for a two-sided test with alpha = 0.05. Assuming a 25% dropout rate we will therefore estimate 130 subjects were needed to be randomized into the trial.
Our present objective is to report data from pre-randomization (Baseline) through the first post-randomization visit (Week 8) in order to demonstrate the utility of the Tampon Test as an outcome measure for vulvodynia clinical trials. Baseline “cross-sectional” comparisons used the mean of the specific outcome variable over three pre-randomization time points as “Baseline” (Week -2, Week -1, Week 0). “Longitudinal” comparisons of outcome change over time used the mean of the specific outcome variable over three pre-randomization time points as “Baseline” (Week -2, Week -1, Week 0) and calculated the change in the respective mean of the outcome variable over three time points ending with Week 8 (Week 6, Week 7, Week 8).
Women were invited to participate if they reported greater than three continuous months' duration of vulvar symptoms of insertional dyspareunia and/or pain with tampon insertion, and were between 18 and 50 years of age. After informed consent, all study candidates completed a standard history and physical exam. To be included in the trial, participants needed to fulfill “Friedrich's Criteria” for the diagnosis of vulvodynia including tenderness localized within the vestibule confirmed by the Cotton Swab Test modified from the technique of Bergeron et al.(12
) The Cotton Swab Test was performed on defined points of the labia majora, minora, and lower vagina. A “positive” Cotton Swab Test was operationally defined as follows. In four
defined points (1:00, 5:00, 7:00, and 11:00) within the vulvar vestibule, the subjects should report mean
score equal to or greater than 4 out of 10
on a Verbal Rating Scale. This modified the criteria of Bergeron et al.(12
) by excluding Cotton Swab Test testing at 12:00 and 6:00 of the vulvar vestibule as defined points. This modification was made with the intent of reducing the chance of inclusion of painful conditions such as Skenitis and vaginal forchette fissures that might evoke a pain response in those respective sites. The localized nature of pain was confirmed by finding all remaining Cotton Swab Test points tested in the lower vagina, labia majora, and labia minora to be non-painful, defined as a mean
score equal to or less than 2 out of 10
in pain on a Verbal Rating Scale. A second clinician-examiner would perform a second independent exam of the candidate and would need to concur with the diagnosis of vulvar vestibulitis. Additionally, eligible candidates did not demonstrate any other specific neuropathology, atrophic vaginitis, dermatitis such as vulvar dystrophy, or pathogens such as culture/smear-proven Candida spp.
or Herpes simplex
Subjects were provided with ORIGINAL REGULAR TAMPAX™ TAMPONS (Proctor & Gamble Corp., Cincinnati, OH) supplied in standard cardboard applicator for insertion. ORIGINAL REGULAR TAMPAX™ TAMPONS are 5.5 cm long and 1.5 cm. in diameter when contained in the cardboard applicator. The cardboard applicator length is 12.8 cm. ORIGINAL REGULAR TAMPAX™ TAMPONS are made of a combination of cotton and rayon, the exact fiber proportions are proprietary to Proctor & Gamble Corp.; the string is made of 100% cotton, and the applicator is made of cardboard.
Detailed instructions concerning the performance and documentation of the weekly Tampon Test, the daily 24 hour pain measure, and intercourse pain measure were given to each subject on the first pre-randomization Visit (Week -2) by the Research Nurse/ Coordinator. Each study participant was verbally instructed to 1) deposit the tampon fully into the vagina above the level of the hymeneal ring via the cardboard applicator, 2) remove the applicator from the vagina, and 3) finally remove the tampon from the vagina via traction on the tampon string. The subject was instructed to remove tampon immediately following vaginal insertion. The subject was instructed not to lubricate the tampon prior to insertion and to insert / deposit the tampon using only the supplied cardboard applicator. On a weekly basis and in a consistent manner, the subject was instructed to insert and immediately remove the tampon and record the degree of pain during the entire insertion/removal experience on a 0 – 10 pain numeric rating scale – 0 meaning “no pain”; 10 meaning the worst possible pain. The subject would then record her level of pain by marking the corresponding number on a linear pain scale printed on the back of the first page of each week in her VVCT logbook. All information was reviewed and recorded during the weekly telephone call by the Research Nurse/Coordinator and later confirmed, following return of the VVCT Logbook on scheduled study visits. During the pre-randomization (Baseline) phase of the trial, eligible subjects were required to demonstrate an adequate baseline level of pain (average 4/10 or greater) on the Tampon Test to proceed to randomization. This criterion was used because lower baseline pain levels on the Tampon Test would limit the ability of the RCT to demonstrate greater improvement with treatment vs. placebo.
On a daily basis during the trial, subjects reported whether they experienced sexual intercourse in the last 24 hours. The possible responses were: #1—“No, too painful” would indicate the subject could not accept an approach to physical intimacy because of pain, #2 –“No, not interested” would indicate that the subject was not in the mood for sexual intimacy, #3—“No, no opportunity” would indicate that her partner was not available, #4—“Yes” would mean an attempt at sexual intercourse was made. If intercourse was attempted, the subject was asked to rate her level of pain during intercourse on a 0 – 10 pain scale – 0 meaning “no pain”; 10 meaning the worst possible pain. She would then record her level of pain by marking the corresponding number on a linear pain scale printed on the front of the daily diary page.
Other than the initial visit (Week -2) when two examiners confirmed the clinical diagnosis of localized vulvodynia, subjects were evaluated consistently during following visits by the same research clinician (DCF) with quantitative sensory tests (Cotton Swab Test and Algesiometer), selective palpation of pelvic muscles for pain, and a battery of psychometric tests. During each study visit of the trial, all components of the exam were performed by a single examiner in identical fashion to the first pre-randomization (Week -2) visit. The Algesiometer, generously supplied by Curnow and Morrison, Plymouth, UK, consisted of a mechanical pulse generator which drove a probe against the mucocutaneous surface of the vulva for a calibrated distance and force ranging from 176 mN to 1868 mN in 8 increments.(14
) A standard 4- anatomic site test of the vestibule was routinely used as described by Eva et al.(11
) We used a “method of limits” with the pain threshold determined as the first consistent verbal report of stimulus pain.(15
) Subjects needed to demonstrate consistently positive responses for two consecutively increasing stimulus intensities. Algesiometer score resulted from the summation of the pain thresholds from the four anatomic sites (0 to 28 score range with higher score corresponding to less vestibular pain). During a pelvic exam conducted at each study visit, selective muscle palpation included digital palpation of the levator ani, obturator internus, and piriformis muscle groups. Notation was made for each muscle group, anatomic side, and pain level on a 0 to 4 scale corresponding to none, mild, moderate, and severe pain, respectively. In addition, the Brief Pain Inventory, Short Form-McGill Pain Questionnaire (SF-MPQ), Neuropathic Pain Scale, Profile of Mood States, Beck Depression Inventory, Sexual and Physical Abuse History, Multidimensional Pain Inventory, Dyadic Adjustment Scale, Communication Pattern Questionnaire, and Index of Sexual Satisfaction were administered and subjects were asked to answer psychometric questions according to their overall pain state.
This report focuses on the Brief Pain Inventory, SF-MPQ, the Neuropathic Pain Scale, the Profile of Mood States, and Beck Depression Inventory for the purpose of validating the Tampon Test based on psychometric measures recommended by IMMPACT for evaluating treatment efficacy and effectiveness.(6
) Outcome domains (in italics)
and recommended measures include: 1) pain intensity
--pain over each 24 hr. period, pain with intercourse (if attempted), Cotton Swab Test, and Algesiometer score, 2) pain quality--
SF-MPQ and Neuropathic Pain Scale, 3) physical functioning
--Brief Pain Inventory Interference Scale score, and 4) emotional functioning
—Beck Depression Inventory and Profile of Mood States.
Over the three pre-randomization (Baseline) Tampon Test assessments, test-retest reliability was assessed with a Kappa statistic, weighted Kappa statistic, and the Shrout-Fleiss intraclass correlation.(16
) To evaluate construct validity, we performed Pearson and Spearman correlations examining associations between Tampon Test scores and the other outcome measures. The Tampon Test and the other outcome measures were analyzed in two ways: cross-sectional baseline values, and longitudinal change in values over time, without reference to treatment group allocation. Subject acceptance of the Tampon Test was evaluated by adherence to the measure compared to the intercourse pain measure. Correlations of the Tampon Test with Cotton Swab Test vaginal pain and with pelvic muscle pain to palpation were included to reflect specificity of the Tampon Test to pain localized to the vestibule compared to superficial vaginal and deep pelvic pain, respectively.