Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments

Vestibulodynia (VBD) is a chronic pelvic pain condition that affects 1 in 6 reproductive aged
women, yet remains ineffectively treated by standard trial-and-error approaches. The
investigators have identified two distinct VBD subtypes that may benefit from different types
of treatment: 1) VBD peripheral (VBD-p) subtype characterized by localized pain specific to
the vulvar vestibule, and 2) VBD central (VBD-c) subtype characterized by pain at both
vaginal and remote body regions. Preliminary data further demonstrate that VBD-p and VBD-c
subtypes differ with respect to patient reported outcomes (e.g., physical and mental health),
production of cytokines (intracellular proteins that regulate the activity of pain nerves and
inflammatory processes), and expression of microRNAs (small non-coding RNA molecules that
regulate gene expression). Women with VBD-p exhibit normal psychological profiles; balanced
circulating pro- and anti-inflammatory cytokines; and dysregulation in microRNAs that
regulate the expression of genes in estrogen pathways. In contrast, women with VBD-c report
decreased functional status and increased somatization; increased pro-inflammatory but not
anti-inflammatory cytokines; and dysregulation in microRNAs that regulate the expression of
genes relevant to muscle, nerve, and immune cell function. Based on these data, the
investigators hypothesize that two VBD-p and VBD-c subtypes will preferentially respond to
peripheral, central, or combined treatments and can be distinguished by cytokine and microRNA
profiles. These hypotheses will be tested in a phase III clinical trial that evaluates
diverse treatment strategies in women with VBD-p and VBD-c. Participants will be randomly
assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml
estradiol compound cream, 2) central treatment with the tricyclic antidepressant
nortriptyline, 3) combined peripheral and central treatments, or 4) placebo. The treatment
phase will last 4 months (with a 6-week titration at treatment initiation and 2-week taper
period at 4 months), with outcome measures and biomarkers assessed at 4 time points (0, 2, 4,
and 6 months). First, the investigators will compare the efficacy of treatments in
alleviating pain among women with VBD-p and VBD-c using standardized tampon insertion with a
numeric rating scale and self-reported pain on the McGill Pain Questionnaire. Next, the
investigators will compare the efficacy of treatments in improving perceived physical,
mental, and sexual health among women with VBD-p and VBD-c using standardized questionnaires.
Finally, investigators will measure cytokines and microRNAs in women with VBD-p versus VBD-c
using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to
predict treatment response. Successful completion of the proposed work will provide new
insights into the mechanisms that drive pain perception and treatment response in two
distinct VBD subtypes, and determine the efficacy of peripheral, central, and combined
therapies in reversing this pain. Such findings will readily translate to improved patient
care, permitting the millions of women with VBD, their partners, and clinicians to make more
informed decisions about pain management.

Inclusion Criteria:

1. Female

2. Age 18-50 years

3. English-literate

4. Meeting criteria for diagnosis of VBD based on:

1. self-report of 3 continuous months of insertional (entryway) dyspareunia, and/or
pain to touch/tampon insertion

2. pain score of > 4 on the tampon insertion test

5. Willingness to provide informed consent

Exclusion Criteria:

1. Use of daily topical lidocaine, or estradiol, or lidocaine/estradiol to the vulvar
vestibule within the past year

2. Use of nortriptyline or other TCA medications within the past year

3. Presence of active dermatologic vulvar disease or vaginal infection

4. Untreated atrophic vaginitis (participants may undergo treatment and re-evaluation for
enrollment if the condition is resolved)

5. Previous vestibulectomy

6. Pregnant, breastfeeding, or planning on becoming pregnant during the study period.

7. Active incarceration

8. Cancer within the past year.

9. Chemotherapy and/or radiation treatment within the past year.

10. Unstable medical condition (e.g., renal impairment, significant hematological disease,
cardiovascular disease, hepatic insufficiency, neurological disorder, autoimmune
disease, or respiratory illness)

11. Clear inflammatory states (e.g., morbid obesity)

12. History of intolerance to nortriptyline, topical lidocaine, or topical estradiol

13. Contraindications to use of nortriptyline: current use of MAOIs, SSRIs, SNRIs, recent
(within the past year) myocardial infarction, active psychotic or suicidal thoughts,
narrow angle closure glaucoma

14. Contraindications to the use of lidocaine or local anesthetics

15. Contraindications to the use of topical estrogen therapy

16. Post-menopausal, defined as no menses for 12 consecutive months