Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments

NCT ID: NCT03844412

Last Updated: 2024-06-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 223 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-04
• Study Completion Date: 2024-05-30

Brief 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. 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.

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; Endometriosis; Interstitial Cystitis; Back Pain; Chronic Fatigue Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

peripheral treatment

5% lidocaine/5 mg/ml 0.02% estradiol compound cream

Group Type: ACTIVE_COMPARATOR

5% lidocaine/5 mg/ml 0.02% estradiol compound cream

Intervention Type: DRUG

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).

Placebo pill

Intervention Type: DRUG

The comparison treatment will be an identical-appearing placebo pill

central treatment

tricyclic antidepressant nortriptyline pill

Group Type: ACTIVE_COMPARATOR

Nortriptyline

Intervention Type: DRUG

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 cream

Intervention Type: DRUG

The comparison treatment will be an identical-appearing placebo Moisturel™ cream

combined peripheral and central treatments

5% lidocaine/5 mg/ml 0.02% estradiol compound cream and tricyclic antidepressant nortriptyline pill

Group Type: ACTIVE_COMPARATOR

5% lidocaine/5 mg/ml 0.02% estradiol compound cream

Intervention Type: DRUG

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).

Nortriptyline

Intervention Type: DRUG

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

placebo cream and placebo pill

Group Type: PLACEBO_COMPARATOR

Placebo cream

Intervention Type: DRUG

The comparison treatment will be an identical-appearing placebo Moisturel™ cream

Placebo pill

Intervention Type: DRUG

The comparison treatment will be an identical-appearing placebo pill

Interventions

5% lidocaine/5 mg/ml 0.02% estradiol compound cream

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).

Intervention Type: DRUG

Nortriptyline

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.

Intervention Type: DRUG

Placebo cream

The comparison treatment will be an identical-appearing placebo Moisturel™ cream

Intervention Type: DRUG

Placebo pill

The comparison treatment will be an identical-appearing placebo pill

Intervention Type: DRUG

Other Intervention Names

Moisturel cream

Eligibility Criteria

Inclusion Criteria

1. Female

2. Age 18-50 years

3. English-literate

4. Willingness to provide informed consent

5. 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 ≥ 3 on the tampon insertion test

Exclusion Criteria

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

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

3. Use of pregabalin or gabapentin within the past three months

4. Presence of active dermatologic vulvar disease or vaginal infection

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

6. Previous vestibulectomy

7. 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.

8. Active incarceration

9. Cancer within the past year.

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

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

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

13. Use of immunosuppressant medications

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

15. 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

16. Contraindications to the use of lidocaine or local anesthetics

17. Contraindications to the use of topical estrogen therapy

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

19. Have not had Botox of the pelvic floor muscles in the last 12 months, or pelvic nerve blocks in the last three months.

20. Are not currently enrolled or planning to enroll in another clinical trial during the course of this trial.

21. Are not currently receiving pelvic physical therapy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andrea Nackley, PhD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Locations

University of California, Los Angeles

Los Angeles, California, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Countries

United States

References

Carey 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.

Reference Type: DERIVED

PMID: 36269028 (View on PubMed)

Other Identifiers

1R01HD096331-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Pro00100678

Identifier Type: -

Identifier Source: org_study_id