Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe)

Figures & data

Table 1. Study inclusion and exclusion criteria.

Inclusion criteria

Female age 18–50 years

English-literate BMI under 40

Willingness to provide informed consent

>3 continuous months of insertional dyspareunia, pain to touch or tampon insertion

Average pain >3 on a 0–10 numeric rating scale with the tampon test at first study visit, reports pain with sexual contact in the past 3 months involving penetration into the vagina, or pain with touch to the vaginal opening

Exclusion criteria

Presence of active dermatologic vulvar disease or vaginal infection

Untreated atrophic vaginitis (participants may undergo treatment with topical hormone therapy for a minimum of six weeks to be considered for re-evaluation for enrolment)

Previous vestibulectomy – full or partial

Pregnancy or at risk for pregnancy during the study period

Within the first six months postpartum

Currently breastfeeding/lactating, or within 3 months of discontinuing breastfeeding/lactation

Active incarceration

Cancer diagnosis within the past year

Chemotherapy and/or radiation treatment within the past year

Noncontrolled medical condition: significant renal impairment, hematological disease, hepatic insufficiency, cardiovascular disease (cardiac conduction disturbance, congestive heart failure, hypertension), neurological disorder, autoimmune disease, or respiratory illness

Clear inflammatory states (e.g. Rheumatoid Arthritis, Lupus, Ulcerative Colitis, Crohn’s disease, Ehlers-Danlos Syndrome)

Use of immunosuppressant medications

History of intolerance to nortriptyline, topical lidocaine, or topical oestradiol

Contraindications to use of nortriptyline: current use, or use within the past 1-3 months, of MAOIs, some NDRIs, Ethylphenidate (DPH), MDPV (Methylenedioxypyrovalerone), Pipradrol (Meratran), Prolintane (Catovit/ Promotil), myocardial infarction in past year, active psychotic or suicidal thoughts, narrow angle closure glaucoma

Discontinuation of medications for 30-90 days, depending on the medication type, dosage, frequency, duration, and half-life. All concomitant medications will need to be documented at the time of screening so the Principal Investigator and medical doctors at each participating site can determine a conservative window. Medications include, but are not limited to: topical lidocaine, oestradiol, or lidocaine/oestradiol to the vulvar vestibule, nortriptyline or other TCAs, pregabalin, and gabapentin.

Contraindications to the use of lidocaine or local anaesthetics

Contraindications to the use of topical oestrogen therapy

Post-menopausal status, defined as no menses for 12 consecutive months or surgical removal of both ovaries. (Hysterectomy is not an exclusion)

Botulinum toxin A injections of the pelvic floor muscles in the last 12 months, or pelvic nerve blocks in the last three months

Ongoing pelvic floor physical therapy

Not currently enrolled or planning to enroll in another clinical trial during the course of the trial

Figure 1. Study visit overview. All four study visits will consist of four elements: (1) assessment of inclusion criteria related to provoked vulvovaginal pain during the tampon test or by self-report of insertional sexual activity and/or with touch to the vaginal opening, (2) completion of validated questionnaires to measure perceived pain, health, mood, and sexual function, (3) quantitative sensory testing to measure pressure pain thresholds at local and remote body sites, and (4) collection of biologic samples to measure local (vaginal) and systemic (blood) cytokines and miRNAs.

Table 2. Study procedures and assessments in chronological order.

Assessment	Visit 1 Baseline (0 wk)	Visit 2 Treatment (8 wk)	Visit 3 Treatment (16 wk)	Visit 4 Post-treatment (24 wk)
Informed consent	X
Tampon Test	X	X	X	X
Self-reported pain with sex involving vaginal penetration	X	X	X	X
Self-reported pain with touch to vaginal opening	X	X	X	X
Blood collection	X	X	X	X
Participant surveys
Demographics	X
Social history	X
Gynaecologic history	X
VPAQ	X	X	X	X
PROMIS BPSFS-F	X	X	X	X
COPC Inventory	X
COPC follow-up		X	X	X
SF-12v2	X	X	X	X
SCL-27	X	X	X	X
PILL	X	X	X	X
PSS	X	X	X	X
MOS-sleep	X	X	X	X
Vaginal sample collection	X	X	X	X
Pelvic sensory testing	X	X	X	X
Remote bodily PPTs	X	X	X	X
Medication kit distribution	X	X
Medication compliance		X	X	X

Abbreviations: VPAQ: Vulvar Pain Assessment Questionnaire; PROMIS BPSFS-F: Patient-Reported Outcomes Measurement Information System Brief Profile Sexual Function and Satisfaction Female; COPC Inventory: Chronic Overlapping Pain Condition Inventory; SF-12v2: Short Form; SCL-27: Symptom Checklist 27; PILL: Pennebaker Index of Limbic Languidness; PSS: Perceived Stress Scale; MOS Sleep: Medical Outcomes Study Sleep Scale.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.