Transcutaneous Genital Nerves Stimulation for the Treatment of Refractory Chronic Pelvic and Genital Pain in Women.

GNS-PAIN is a prospective, multicenter, single-arm proof-of-concept study investigating transcutaneous perivulvar electrical stimulation in adult women with treatment-refractory chronic genital pain, deep visceral pelvic pain, or both. The study aims to estimate the proportion of participants experiencing clinically meaningful pain improvement and to assess feasibility, safety, and tolerability.

Eligible participants have experienced pain for at least six months despite appropriate conventional medical management. A diagnostic evaluation must exclude an active condition requiring specific causal treatment, such as active endometriosis adequately explaining the current symptoms, pelvic malignancy, infection, or identifiable pelvic nerve entrapment or injury. Previous endometriosis or pelvic surgery does not itself preclude participation. Participants must have an average baseline pain intensity of at least 4 on a numerical rating scale from 0 to 10 in their designated main pain domain.

Genital pain and visceral pelvic pain will be assessed separately. Before treatment begins, each participant will have an index pain domain designated as either genital or visceral pelvic pain. For participants with both types of pain, the more burdensome domain will be selected. This designation will remain unchanged throughout the study and will determine the primary outcome.

Following screening and informed consent, participants will complete a 14-day baseline period, recording daily pain intensity and analgesic medication use. They will then receive training in device operation, electrode placement, stimulation intensity adjustment, and safety precautions before beginning 12 weeks of home-based treatment.

Stimulation will be delivered using a portable transcutaneous electrical nerve stimulation (TENS) device and two self-adhesive electrodes placed on intact skin approximately 2-3 cm lateral to the vulva. Neither electrode will be placed on the clitoris or vulvar or vaginal mucosa. The intervention involves no intracavitary electrode, skin penetration, or implantation.

The stimulation frequency will be 20 Hz. Participants will gradually increase the intensity until a mild tingling sensation is perceived and then slightly reduce it to maintain comfortable stimulation. Treatment sessions will last 30 minutes and will be performed twice daily, in the morning and evening. Device use and electrode placement will be standardized across participating centers through a dedicated stimulation manual.

The primary endpoint is the proportion of participants achieving at least a 30% reduction in mean daily pain intensity in their prospectively designated index pain domain at Week 12. The mean score from the final seven days of treatment will be compared with the mean score from the 14-day baseline period.

Secondary outcomes include the proportion achieving at least 50% pain reduction, changes in mean and worst pain intensity, pain interference with daily activities, Patient Global Impression of Change, analgesic medication use, and health-related quality of life. Associated urinary, bowel, and sexual symptoms will also be assessed. Exploratory analyses will examine responses separately in participants with predominantly genital pain, predominantly visceral pelvic pain, and mixed genital-visceral pain.

Follow-up assessments will take place three and six months after completion of treatment, without continued study stimulation, to assess persistence or loss of any observed benefit. Adverse events, including skin irritation, stimulation-related discomfort, and worsening pain or pelvic symptoms, will be monitored throughout treatment and follow-up. Stimulation will be discontinued if clinically significant or intolerable treatment-related adverse effects occur.

The proposed rationale is that stimulation of sensory pathways in the genital region may influence pelvic pain processing. However, recruitment of specific deep pelvic autonomic structures has not been demonstrated with this skin-electrode configuration, and analgesic efficacy in the study population remains unproven.

There is no control or sham-stimulation group. Accordingly, observed improvements cannot be conclusively attributed to stimulation rather than placebo effects, natural symptom fluctuations, or regression to the mean. The findings will provide preliminary response estimates and feasibility information to inform the design of a subsequent randomized, sham-controlled trial.

• Transcutaneous Genital Nerves Stimulation (Device): Transcutaneous genital nerve stimulation (GNS) will be administered using an external electrical nerve stimulation device connected to bilateral adhesive skin electrodes positioned approximately 2-3 cm lateral to the vulva on intact perivulvar skin. Stimulation will be delivered at a frequency of 20 Hz for approximately 30 minutes twice daily. The stimulation intensity will be individually adjusted to produce a comfortable tingling sensation and then slightly reduced to maintain tolerability. Following initial instruction, participants will self-administer the treatment at home according to the study protocol. No vaginal or mucosal electrodes, surgical procedures, or implanted devices will be used.

Primary outcomes

• Change in Genital and/or Visceral Pelvic Pain Intensity [Baseline and 12 weeks after initiation of treatment]: Change in patient-reported pain intensity from baseline, assessed using a 0-10 Visual Analog Scale (VAS), where 0 represents no pain and 10 represents the worst imaginable pain. Genital and visceral pelvic pain will be assessed separately, according to the symptoms present at baseline. Higher scores indicate greater pain intensity. A reduction in score indicates improvement.

Secondary outcomes

• Patient Global Impression of Improvment (PGI-I) [Baseline and 12 weeks after initiation of treatment]: Patient-reported overall improvement assessed using the 7-point PGI-I scale, ranging from 1 (very much better) to 7 (very much worse).
• Change in Sitting Tolerance [Baseline and 12 weeks after initiation of treatment]: Change in the maximum duration of sitting tolerated before pain becomes intolerable, measured in minutes and compared with baseline.
• Change in Health-Related Quality of Life assessed by the EQ-5D-5L Visual Analogue Scale (EA VAS) [Baseline and 12 weeks after initiation of treatment]: Change from baseline in self-reported health status assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), specifically its visual analogue scale (EQ VAS). The EQ VAS ranges from 0 (worst imaginable health) to 100 (best imaginable health). Higher scores indicate better self-reported health status. The outcome is the change in EQ VAS score from baseline to 12 weeks.
• Proportion of Participants Achieving at Least 50% Pain Reduction [Baseline and 12 weeks after initiation of treatment]: Percentage of participants achieving a reduction of at least 50% in their prespecified target pain score compared with baseline, measured on a 0-10 pain scale.
• Incidence of Treatment-Related Adverse Events [Baseline and 12 weeks after initiation of treatment]: Number and proportion of participants experiencing treatment-related adverse events, including skin irritation, discomfort during stimulation, or worsening of pelvic or genital pain.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* All of the following must be met:

  1. Female sex, age ≥18 years
  2. Chronic pelvic pain persisting ≥6 months
  3. Average baseline NRS ≥4/10 in the prospectively designated index pain domain
  4. Persistent genital pain and/or deep visceral pelvic pain, including a mixed phenotype, with a clinically meaningful average NRS ≥4/10 in at least one domain during baseline
  5. Pain refractory to appropriate conventional medical management
  6. Completed diagnostic evaluation without identification of a structural or surgically correctable pathology adequately explaining the current pain
  7. Stable analgesic treatment before enrolment
  8. Ability to understand the study procedures and complete electronic or written pain diaries
  9. Written informed consent A history of endometriosis and/or prior pelvic surgery, including hysterectomy, does not constitute an exclusion criterion, provided that currently active pathology adequately explaining the pain has been excluded.

Exclusion Criteria:

* Participants with a history of spinal cord injury or clinically significant spinal cord lesions are not eligible. This explicit exclusion applies regardless of the presence or absence of prior autonomic dysreflexia.

Participants will be excluded in the presence of:

1. Active endometriosis considered sufficient to explain the current pain
2. Pelvic malignancy
3. Active pelvic infection or inflammatory disease
4. Predominant pudendal neuralgia
5. Identifiable sacral radiculopathy
6. Identifiable pelvic nerve entrapment or injury
7. Predominant ilioinguinal, iliohypogastric or genitofemoral neuropathy
8. Predominant pelvic-floor myofascial pain
9. Spinal, musculoskeletal or hip pathology considered sufficient to explain the symptoms
10. Another identifiable condition requiring specific causal treatment
11. Pregnancy
12. Contraindication to electrical stimulation
13. Inability to comply with the study protocol
14. Spinal Cord Injured peoples