A Pilot Study on the Efficacy of Oral Low Dose Naltrexone for Vulvodynia

Vulvodynia is a chronic vulvar pain condition characterized by persistent vulvar pain or discomfort without an identifiable cause. The condition can substantially affect quality of life, including sexual function, emotional well-being, and social functioning. The etiology of vulvodynia is multifactorial and may involve peripheral nerve dysfunction, hormonal factors, pelvic floor dysfunction, and altered central pain processing.

Available treatments for vulvodynia include topical medications, pelvic floor physical therapy, systemic medications, behavioral interventions, injections, and other procedural therapies. Treatment response is variable, and some participants continue to experience clinically significant symptoms despite conventional management. Additional treatment options with acceptable tolerability are therefore needed.

Low-dose naltrexone (LDN) is a low-dose formulation of naltrexone that has been investigated for the management of several chronic pain conditions. Proposed mechanisms include modulation of neuroinflammatory pathways and reduction of inflammatory signaling within the central nervous system. The potential effects of LDN on vulvodynia-related pain remain insufficiently characterized, supporting further clinical investigation.

This pilot study will evaluate the safety, tolerability, and potential effectiveness of oral LDN for the treatment of vulvodynia. The study will enroll approximately 20 adult female participants with vulvodynia. Participants will receive oral LDN at a dose of 4.5 mg once daily for four weeks.

The study will consist of screening, a four-week treatment period, and post-treatment follow-up. Screening procedures will include confirmation of eligibility, collection of demographic and clinical information, medication review, pregnancy testing when applicable, assessment of baseline pain and symptoms, and laboratory testing. Baseline assessment will include a comprehensive clinical evaluation and validated measures of pain and vulvodynia-related symptoms. A pelvic floor and vulvar assessment will be performed as clinically appropriate and according to the study protocol.

Before initiation of LDN, participants will record daily vulvar pain scores for seven consecutive days using the Numerical Rating Scale (NRS). The average baseline NRS score will be calculated from the seven-day recording period. Validated questionnaires will also be administered at baseline and during follow-up to assess vulvar pain, symptom severity, treatment-related improvement, and central sensitization.

Following completion of baseline assessments, LDN will be dispensed through a mail-order pharmacy. Participants will take 4.5 mg orally once daily for four weeks. Medication instructions and information regarding potential adverse effects will be provided before treatment initiation.

Safety monitoring will occur throughout the treatment period. Participants will be instructed to discontinue study medication and contact the study team promptly in the event of significant or concerning adverse reactions. A study coordinator will conduct an adverse-event and adherence assessment approximately two weeks after treatment initiation. A follow-up clinical assessment will occur approximately four weeks after treatment initiation.

Safety laboratory testing will include a complete blood count and comprehensive metabolic panel at screening and at the end of treatment. Hepatic enzymes, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, will be assessed at baseline and at the end of treatment and may be repeated when clinically indicated. Treatment-emergent liver enzyme elevations will be followed until resolution or stabilization, as clinically appropriate. Other treatment-emergent adverse events will be monitored until resolution or stabilization.

Participants will be counseled regarding the potential risks associated with naltrexone, including dizziness, somnolence, fatigue, gastrointestinal symptoms, hypersensitivity reactions, mood-related adverse effects, and potential hepatic injury. Counseling will also address the importance of avoiding opioid-containing medications during treatment and the potential risk of opioid withdrawal and opioid overdose following naltrexone exposure. Participants of childbearing potential will receive pregnancy and contraception counseling consistent with the study eligibility requirements and protocol.

The study will include assessment of adherence, treatment-related adverse effects, and changes in pain and symptom measures from baseline to follow-up. Patient-reported treatment improvement will be assessed using the designated global treatment improvement measure. Changes in average NRS and vulvar pain questionnaire scores will also be evaluated.

The study will use descriptive statistics to characterize baseline participant and clinical data. Pre-treatment and post-treatment pain and symptom scores will be compared using appropriate statistical methods. A two-sided alpha level of 0.05 will be used to define statistical significance for inferential analyses. Given the pilot nature and anticipated sample size of approximately 20 participants, analyses will primarily provide estimates of treatment response, variability, and tolerability to inform the design of future studies.

Research procedures will be distinguished from standard clinical care. Routine medical history, physical examination, and clinically indicated pelvic or vulvar evaluation may occur as part of standard clinical care. Study-specific procedures include administration of oral LDN, study-specific questionnaires and assessments, systematic adverse-event monitoring, study-specific follow-up assessments, and collection and analysis of research data.

Study data will be collected and maintained in accordance with applicable institutional policies, regulatory requirements, and privacy protections. Research data will be coded or de-identified as appropriate. Data shared with collaborating investigators at Mayo Clinic may include coded or de-identified demographic, clinical, treatment-response, and adverse-event information. Direct identifiers will not be included in data sets intended for research analysis unless specifically permitted under applicable institutional and regulatory requirements. Data transfers will occur through secure institutional systems, and access will be limited to authorized research personnel. Data retention and destruction will follow institutional requirements, applicable regulations, and the approved study data-management plan.

The study is planned to recruit approximately 20 participants. Recruitment and data collection are anticipated during Quarters 1 through 3 of 2027, followed by data analysis during Quarter 4 of 2027. The anticipated deliverable is a pilot assessment of the safety, tolerability, and potential effectiveness of LDN for vulvodynia. Findings from the pilot study are intended to provide preliminary data regarding treatment response and adverse events and may inform the design and feasibility of a subsequent larger clinical trial.