Study to Evaluate the Efficacy of Milnacipran in the Treatment of Pain Due to Osteoarthritis

The study design is a Double-Blind, Placebo-Controlled, Enriched Enrollment Randomized
Withdrawal Study. This means that, upon entry into the study, all subjects will enter an
open-label period during which they will take milnacipran for 4 weeks. Subjects will taper
their dose up to one 100mg tablet twice daily for a total of 200mg per day. After 4 weeks,
the subject will return to the clinic and be re-evaluated.

Only subjects who meet certain criteria are then randomized to continue in the double-blind
period of the study. Once a subject is randomized, he or she will take either milnacipran or
placebo for another 4 weeks. Following the double-blind period, subjects will be tapered off
the study medication and will receive a phone call once each week for 2 weeks for follow-up
assessments.

Throughout the study, subjects will complete various questionnaires and other test
procedures aimed at sub-typing subjects based on pain mechanisms.

Inclusion Criteria:

- Be 21-75 years of age and in good general medical and psychological health

- Be able to speak, read, write, and understand English, understand the consent form,
complete study related procedures, and communicate with the study staff

- Have a negative urine pregnancy test at screening, and use appropriate birth control

- Have documented painful Osteoarthritis (OA) of at least one knee for at least 6
months; OA should be of Class I-III and meet the American College of Rheumatology
(ACR) clinical classification criteria, defined as:

1. Knee pain and at least 3 of the following 6:

- Age > 50

- Morning stiffness < 30 minutes

- Crepitus on active motion

- Bony tenderness

- Bony enlargement

- No palpable warmth of synovium

2. The target joint must not contain any type of orthopedic and/or prosthetic
device

- Have a target joint pain average of 5 days per week and have an average pain
intensity of at least 4/10 on the 0-10 NRS over the last 24 hours prior to screening

- Have stable treatment modalities, e.g. acupuncture, physical therapy

- Be willing to stop taking Non-steroidal Anti-inflammatory drugs (NSAIDs) and opioids
for the duration of the study

Exclusion Criteria:

- Are allergic or intolerant to SNRI; have a previous poor response to a SNRI for OA
pain; are currently taking an SNRI or tricyclic antidepressant

- Have a body mass index (BMI) >40 kg/m2

- Have an Hospital Anxiety and Depression Scale (HADS) score >12 on either subscale or
has an established history of major depressive disorder not controlled with
medication

- Have significant pain outside the target knee, including significant hip or back
pain. (Bilateral knee OA allowed.)

- Have pain affecting the target knee that is due to any other etiology than OA

- Have documented history of inflammatory arthritis including rheumatoid arthritis

- Have had local injections in target joint within the past 3 months prior to screening

- Have had oral or intramuscular corticosteroids within the past 30 days

- Have had worker's compensation claim, disability, or litigation

- Have a known history of uncontrolled narrow-angle glaucoma

- Have a known history of suicidal ideation

- Use monoamine oxidase inhibitors (MAOI) concomitantly

- Are allergic or intolerant to acetaminophen

- Using opioids 4 or more days per week during the month preceding the screening visit

- Have significant history or renal impairment/failure.