A Four-Arm Study Comparing the Analgesic Efficacy and Safety of Tramadol Once a Day 100, 200 and 300 mg Versus Placebo for the Treatment of Pain Due to Osteoarthritis of the Knee

The purpose of this study is to compare the analgesic efficacy and safety of Tramadol Once a Day 100, 200, 300 mg and Placebo

Inclusion Criteria:

1. Males or Females between the ages of 40-75 with a diagnosis of moderate to severe osteoarthritis of the knee, consistent with the American College of Rheumatology (ACR) Clinical Classification Criteria for Arthritis of the Knee:

   • Current knee pain
   • Less than 30 minutes of morning stiffness with or without crepitus on active motion.
   • Confirmation either by arthroscopy or radiologist's report (X-rays showing osteophytes, joint space narrowing or subchondral bone sclerosis {eburnation}) within five years prior to entry into the study.

2. C-reactive protein (CRP) < 8 ug/ml (if available at local lab) or erythrocyte sedimentation rate (ESR) < 40 mm/hr

3. Total WOMAC (Western Ontario and McMaster University Osteoarthritis Index) Pain Subscale Score of > 150 mm at Baseline corresponding with moderate to severe Osteoarthritis.

4. Oral and written language comprehension at a level sufficient to comply with the protocol and complete study-related materials.

5. Research Ethics Board (REB) approval of the written Informed Consent Form in Spanish or English which was signed and dated by the patient and Investigator, prior to study participation.

Exclusion Criteria:

1. Known rheumatoid arthritis or any other rheumatoid disease.
2. Secondary arthritis i.e. any of the following: septic arthritis; inflammatory joint disease; gout; pseudogout; Paget's disease; joint fracture; acromegaly; fibromyalgia; Wilson's disease; ochronosis; haemochromatosis; osteochondromatosis; or collagen gene mutations.
3. Evidence of effusion greater than 15 cubic centimetre (cc) upon physical examination of the joint at Baseline (Visit 1).
4. Body Mass Index (BMI) ≥ 38.
5. Major illness, requiring hospitalization during the 3 months before commencement of the screening period.
6. The patient was unwilling to stop taking pain medication (for arthritis or other types of pain) or was unwilling to stop taking other medications for the treatment of osteoarthritis (OA).
7. Previous failure or discontinuation (due to adverse events) of tramadol hydrochloride (HCl) therapy.
8. Treatment within the last 3 weeks with any of the following medications: monoamine oxidase inhibitors; tricyclic antidepressants and other tricyclic compounds (e.g. cyclobenzaprine, promethazine); neuroleptics; selective serotonin reuptake inhibitors; or any other drug that reduces seizure threshold.
9. Treatment with another investigational agent within the last 30 days.
10. A history of seizure disorder other than Infantile Febrile Seizures.
11. Previous or current opioid dependency.
12. Bowel disease causing malabsorption.
13. Pregnancy or lactating or childbearing potential and unwilling to utilize a medically approved method of contraception during participation in this clinical trial.
14. Significant liver disease, defined as active hepatitis or elevated liver enzymes >3 times the upper boundary of the normal range.
15. Significant renal disease, defined as creatinine clearance <30 mL/min as estimated by the method of Levey et al., 1999.
16. Current substance abuse or dependence, other than nicotine.
17. Allergy or adverse reaction to tramadol or any structurally similar drugs e.g. opiates.
18. Any other condition, that, in the opinion of the Investigators, would have adversely affected the patient's ability to complete the study or its measures.