VestibulodyniaPhase 2NCT03844412
Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments
A Phase 2 study testing 5% lidocaine/5 mg/ml 0.02% estradiol compound cream and Nortriptyline in people with Vestibulodynia and Temporomandibular Disorder, run by Duke University at 2 sites in United States.
Trial summary
Vestibulodynia (VBD) is a complex chronic vulvar pain condition that impairs the psychological, physical, and sexual health of 1 in 6 reproductive aged women in the United States. Read more about this study
- Who is it for?
- Ages 18 to 50 years, women only
- Conditions the study is for
- Vestibulodynia, Temporomandibular Disorder, Fibromyalgia Syndrome
- What is being tested?
- 5% lidocaine/5 mg/ml 0.02% estradiol compound cream and Nortriptyline
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 209 participants
- Where
- 2 sitesUnited States
- Study dates
- 4 Nov 2019to 30 May 2024
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Female
- Age 18-50 years
- English-literate
- Willingness to provide informed consent
- Meeting criteria for diagnosis of VBD based on:
- self-report of 3 continuous months of insertional (entryway) dyspareunia, and/or pain to touch/tampon insertion
- pain score of ≥ 3 on the tampon insertion test
Who cannot join
- Use of daily topical lidocaine, or estradiol, or lidocaine/estradiol to the vulvar vestibule within the past three months
- Use of nortriptyline or other TCA medications within the past three months
- Use of pregabalin or gabapentin within the past three months
- Presence of active dermatologic vulvar disease or vaginal infection
- Untreated atrophic vaginitis (participants may undergo treatment and re-evaluation for enrollment if the condition is resolved)
- Previous vestibulectomy
Show all 21Show fewer
- Pregnant or planning on becoming pregnant during the study period. Within the first six months of the postpartum period. Currently breastfeeding/lactating, or within three months of discontinuing breastfeeding/lactation.
- Active incarceration
- Cancer within the past year.
- Chemotherapy and/or radiation treatment within the past year.
- Unstable medical condition (e.g., renal impairment, significant hematological disease, cardiovascular disease, hepatic insufficiency, neurological disorder, autoimmune disease, or respiratory illness)
- Clear inflammatory states (e.g., morbid obesity)
- Use of immunosuppressant medications
- History of intolerance to nortriptyline, topical lidocaine, or topical estradiol
- Contraindications to use of nortriptyline: current use, or use within the past 3 months, of MAOIs, SSRIs, SNRIs, NDRIs; recent (within the past year) myocardial infarction, active psychotic or suicidal thoughts, narrow angle closure glaucoma
- Contraindications to the use of lidocaine or local anesthetics
- Contraindications to the use of topical estrogen therapy
- Post-menopausal, defined as no menses for 12 consecutive months or surgical removal of both ovaries. (Hysterectomy is not an exclusion)
- Have not had Botox of the pelvic floor muscles in the last 12 months, or pelvic nerve blocks in the last three months.
- Are not currently enrolled or planning to enroll in another clinical trial during the course of this trial.
- Are not currently receiving pelvic physical therapy
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27278
University of California, Los Angeles
Los Angeles, California, 90095
About this study
Vestibulodynia (VBD) is a complex chronic vulvar pain condition that impairs the psychological, physical, and sexual health of 1 in 6 reproductive aged women in the United States. Here, the investigators plan to conduct a randomized, double-blinded, placebo-controlled clinical trial to 1) compare the efficacy of peripheral (lidocaine/estradiol cream), centrally-targeted (nortriptyline), and combined treatments in alleviating pain and improving patient-reported outcomes and 2) determine cytokine and microRNA biomarkers that predict treatment response in women with distinct VBD subtypes. Positive findings from this study will readily translate to improved patient care, permitting the millions of women with VBD, their partners, and their clinicians to make more informed decisions about pain management.
Read the detailed description
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 0.02% 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.
- Conditions
- Vestibulodynia, Temporomandibular Disorder, Fibromyalgia Syndrome, Irritable Bowel Syndrome, Migraines, Tension Headache
- Being tested
- 5% lidocaine/5 mg/ml 0.02% estradiol compound cream, Nortriptyline, Placebo cream, Placebo pill
- Keywords
- Pelvic pain, Lidocaine, Estradiol, Nortriptyline, Chronic pain
- Medical subject headings
- Vulvodynia, Temporomandibular Joint Disorders, Fibromyalgia, Irritable Bowel Syndrome, Migraine Disorders, Tension-Type Headache, Endometriosis, Cystitis, Interstitial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
5% lidocaine/5 mg/ml 0.02% estradiol compound creamDrug
Lidocaine/estradiol cream targets peripheral nerves and tissues affected in VBD. Participants will be provided with a diagram and written instructions, detailing how to apply the cream to the vaginal vestibule daily for weeks 1-16. Treatment with lidocaine/estradiol or placebo cream will be terminated at week 16 (end of month 4).
NortriptylineDrug
Nortriptyline is a centrally-acting tricyclic antidepressant that is FDA-approved for treatment of neuropathic pain. Dosing will begin with one 10 mg pill nightly for week 1, then two 10 mg pills nightly for week 2, three 10 mg pills nightly for week 3, four 10 mg pills nightly for week 4, and five for weeks 5 -16. Treatment with nortriptyline or placebo pill will be tapered off over weeks 16-18, decreasing the dose by 10 mg every 4 days. Participants will be provided with a list of drugs to avoid that are known to interact with nortriptyline.
Placebo creamDrug
Also called Moisturel cream
The comparison treatment will be an identical-appearing placebo Moisturel™ cream
Placebo pillDrug
The comparison treatment will be an identical-appearing placebo pill
| Study group | Role | What they receive |
|---|---|---|
| peripheral treatment | Active comparator | 5% lidocaine/5 mg/ml 0.02% estradiol compound cream Receives: Drug: 5% lidocaine/5 mg/ml 0.02% estradiol compound cream; Drug: Placebo pill |
| central treatment | Active comparator | tricyclic antidepressant nortriptyline pill Receives: Drug: Nortriptyline; Drug: Placebo cream |
| combined peripheral and central treatments | Active comparator | 5% lidocaine/5 mg/ml 0.02% estradiol compound cream and tricyclic antidepressant nortriptyline pill Receives: Drug: 5% lidocaine/5 mg/ml 0.02% estradiol compound cream; Drug: Nortriptyline |
| placebo | Placebo comparator | placebo cream and placebo pill Receives: Drug: Placebo cream; Drug: Placebo pill |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pain Score During the Tampon Test
The Tampon Test will provide a self-reported numeric rating scale of pain with self-tampon insertion, performed by the patient and reported to the research nurse. Participants will be asked to verbally rate the pain on a scale of 0-10, with 0 meaning no pain and 10 meaning the worst possible pain.
Measured: Baseline, 16 weeks
Change in Self-reported Pain Via the Short Form- McGill Pain Questionnaire (SF-MPQ)
The SF-MPQ consists of 15 descriptors which are rated on an intensity scale as 0 = none, 1 = mild, 2 = moderate or 3 = severe. The total score ranges from 0 to 45, where a higher score indicates greater pain. A negative change score indicates a decrease in pain over time.
Measured: Baseline, 16 weeks
Self-reported Physical Health Via SF-12 Health Survey (SF12v2)
The SF-12 physical health score has a mean of 50 and a standard deviation of 10 in the general population. Scores above 50 indicate a better-than-average health-related quality of life, while scores below 50 suggest below-average health.
Measured: Prior to randomization
Self-reported Mental Health Via SF-12 Health Survey (SF12v2)
The SF-12 mental health score has a mean of 50 and a standard deviation of 10 in the general population. Scores above 50 indicate a better-than-average health-related quality of life, while scores below 50 suggest below-average health.
Measured: Prior to randomization
Sexual Health Via Patient-Reported Outcomes Measurement Information System (PROMIS)
The PROMIS score is based on a 96-item form developed by the NIH that measures 11 domains of biopsychosocial function and includes an assessment of sexual function measures (e.g., desire, frequency, fear, and pain) related to sexual intercourse. The PROMIS Sexual Function and Satisfaction (SexFS) measures produce a T-score that summarizes a person's sexual health. The T-score is a standardized score that ranges from 0 to 100, where 50 indicates the population mean with a standard deviation of 10. Higher scores indicate greater satisfaction.
Measured: Baseline, 16 weeks
Secondary outcomes (7)
Change in Pain Level as Measured by Vaginal Vestibule Pressure Pain Intensities (PPI)
Vaginal Vestibule PPIs will be determined using a cotton swab applied to externally-accessed sites (at 10, 6, and 2 o'clock on the vestibule) for 1-2 seconds. Upon application of cotton swab at each site, participants will rate their pain intensity on a scale from 0-10, where 0 = no pain and 10 = the worst pain possible. Reported as a composite mean score.
Measured: Baseline, 8 weeks, and 16 weeks
Change in Levator Muscle Complex Pressure Pain Threshold (PPT)
Levator Muscle Complex PPTs will be determined using a digital vestibular algometer applied internally to the left puborectalis levator muscles site (7 o'clock) just lateral to the perineum. The test determines the amount of pressure over a given area in which a steadily increasing nonpainful pressure stimulus turns into a painful pressure sensation.
Measured: Baseline, 16 weeks
Change in Pain Level as Measured by Remote Bodily PPTs
Remote Bodily PPTs will be determined by applying the algometer to 3 'neutral' non-pelvic body sites (deltoid, shin, and trapezius), right and left, beginning at 1N and increasing until the participant's first sensation of pain. PPT scores are rated on a scale of 0-10, where 0 meaning no pain and 10 meaning the worst pain possible. Reported as a composite mean score.
Measured: Baseline, 8 weeks, and 16 weeks
Somatic Awareness Via Pennebaker Index of Limbic Languidness (PILL)
Pennebaker Index of Limbic Languidness (PILL) is used to create a summary score of somatic symptoms (e.g., itchy eyes, dizziness). Symptom frequency is recorded on a five-point Likert scale ranging from "never" (0) to "more than once a week" (4). The total score ranges from 0 to 216, where greater scores indicate greater frequency of symptoms.
Measured: Baseline, 8 weeks, and 16 weeks
Change in Sleep as Measured by the Sleep Scale
The sleep scale is a 12-item scale that measures amount of sleep and ease/difficulty of initiating and maintaining sleep.
Measured: Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in Perceived Stress Via Perceived Stress Scale (PSS)
The Perceived stress scale (PSS) is a 10-item scale that measures the impact of personal stress on thoughts and feelings.
Measured: Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in Mood as Measured by the Symptom Checklist-27 (SCL-27)
Symptom Check List 27 (SCL-27) questionnaire will be used to measure a broad range of psychological symptoms (e.g., anxiety and depression).
Measured: Baseline, 8 weeks, 16 weeks, and 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Feb 2019
- Study start4 Nov 2019
- Primary completion13 Mar 2024
- Study completion30 May 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for VestibulodyniaStudies of the same condition, open and under way.
- More trials run by Duke UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Model description
- Two-center, randomized, double-blind, placebo-controlled 2x2 factorial study enrolling 400 women to participate for 24-week duration.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 209 participants (actual)
Sponsor and investigators
- Lead sponsor
- Duke University
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- Andrea Nackley, PhD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03844412
- Sponsor's protocol ID
- Pro00100678
- Other IDs
- 1R01HD096331-01
- Status last verified
- Feb 2026
- First submitted
- 15 Feb 2019
- Last updated
- 19 Mar 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The investigators will share data in a manner consistent with NIH's policy NOT-OD-14-124, found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html, released August 28, 2014. Genotypic data (e.g. microRNA and protein expression) and relevant phenotypic data (e.g. pain scores) from 400 participants will be posted on the dbGaP website.
Publications
Shudt C, Carey ET, Geller EJ, Rapkin A, Farb D, Cutting H, Akaninwor J, DeLaRosa J, Stirling C, Bortsov A, Rowe P, Luo S, Klein ME, Nackley AG. Testing peripheral and central therapies for provoked vestibulodynia: results from the UPDATe trial. Ann Med. 2026 Dec;58(1):2732293. doi: 10.1080/07853890.2026.2732293. Epub 2026 Oct 10.
PubMed 42857927Carey ET, Geller EJ, Rapkin A, Farb D, Cutting H, Akaninwor J, Stirling C, Bortsov A, McNulty S, Merrill P, Zakroysky P, DeLaRosa J, Luo S, Nackley AG. Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe). Ann Med. 2022 Dec;54(1):2885-2897. doi: 10.1080/07853890.2022.2132531.
PubMed 36269028