Savella in Treatment for Provoked Vestibulodynia

This is an 18-week, open-label, flexible-dose "proof of concept" trial where women with a
diagnosis of vestibulodynia will be evaluated at baseline for eligibility. Eligible patients
will be openly treated with 200 mg/d milnacipran (or the maximum tolerated dose) for a total
of 12 weeks. The study design involves 4 phases: screening and washout, baseline assessment,
dose escalation, and stable-dose phase (Figure 1). After completing a 2-week washout of
prohibited medications, patients will enter a 2-week baseline period, where they will be
trained in the use of daily diaries and the tampon test, and baseline safety and efficacy
data will be recorded. Patients who continue to meet the eligibility criteria at the end of
the baseline period will begin a 6-week period of dose escalation. All patients will be
scheduled to receive a total of 12 weeks of stable dose treatment after the 6-week
dose-escalation period for a total of 18 weeks of drug exposure.

Inclusion Criteria:

1. women between 18-54 years of age,

2. 'Friedrich's Criteria' must be met (report greater than six continuous months of
vulvar symptoms including insertional dyspareunia or pain to touch, demonstrate on
physical exam moderate to severe tenderness to light touch, localized to the vulvar
vestibule [positive Cotton Swab Test] and demonstration of variable degrees of
erythema of the vestibule),

3. an average pain level of "4" or greater on the 10-point tampon test and/or an average
pain level of "4" or greater on the sexual intercourse pain scale(0 = no pain at all;
10 = worse pain ever) during the 2-week screening period(see Study Parameters
Section), and

4. willing to use two forms of contraception during the study.

Exclusion Criteria:

1. other vulvar conditions, including dermatoses, vulvitis, vulvar papillomatosis, and
atrophic vaginitis (presence of a maturation index),

2. previous vestibulectomy,

3. active vaginal infection,

4. neuropathology, including seizure disorder or syncopal episodes,

5. pregnancy or at risk for pregnancy and not using a reliable birth control method for
at least 3 months prior to entering the study,

6. breastfeeding,

7. major medical illness including chronic liver disease/hepatic impairment, renal
impairment, narrow-angle glaucoma, or uncontrolled hypertension,

8. major psychiatric illness including substance abuse,

9. multiple allergies (greater than three drugs or environmental agents),

10. use of centrally-acting agents, including monoamine oxidase inhibitors,
benzodiazepines, opiates, muscle relaxants, and antidepressants within 2 weeks of
randomization and during the study, and

11. use of topical lidocaine, within 2 weeks of randomization and during the study, as it
has shown to be an effective treatment in some women, while worsening symptoms in
others. Subjects will be permitted to take acetaminophen, aspirin, or a nonsteroidal
anti-inflammatory drug as rescue medication. They will be provided with a list of
allowable escape medications and those which would constitute a protocol deviation.