A Two-Arm Study Comparing the Analgesic Efficacy and Safety of Tramadol HCl Once-a-Day Versus Placebo for the Treatment of Pain Due to Osteoarthritis

The purpose of this study is to compare the analgesic efficacy, safety and clinical benefit of Tramadol OAD tablets versus Placebo.

Inclusion Criteria for Open-Label phase:

1. Males or females

2. Must be between the ages of 40-80

3. Must meet the American College of Rheumatology (ACR) Clinical Classification Criteria for Osteoarthritis 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

4. Must have a history of exposure to treatment (for pain due to osteoarthritis (OA) of the knee) with Non-steroidal anti-inflammatory drugs (NSAIDs), COX II inhibitors or tramadol.

5. Must be taking one of the above medications on a regular basis in the 30 days prior to Visit 2 (S0).

6. Must meet the following criteria for severity of pain at Visit 2 (Day S0):

   • Have a score of ≥ 4 on the 11-point Numerical Rating Scale (PI-NRS; range: 0-10)
   • Have a total increase of ≥ 2 points on the 11-point Numerical Rating Scale (range: 0-10) compared to the rating at Visit 1 (Day SX)

7. Must have a erythrocyte sedimentation rate (ESR) < 40 mm/hr

8. Must have oral and written language comprehension at a level sufficient to comply with the protocol and complete study-related materials

9. Must have signed and dated an approved written Informed Consent form in French, Spanish, English or Romanian, which has also been signed and dated by the Investigator (unless otherwise required by the ethics committee), prior to study participation

Exclusion Criteria for Open-Label phase:

1. Has known rheumatoid arthritis or any other rheumatic disease
2. Has secondary arthritis i.e. any of the following: septic arthritis; inflammatory joint disease; gout; pseudogout; Paget's disease; target joint fracture; acromegaly; fibromyalgia; Wilson's disease; Ochronosis; Haemochromatosis; Osteochondromatosis; heritable arthritic disorders; or collagen gene mutations
3. Has a history of bursitis of the knee (target knee)
4. Has a history of pain in the ipsilateral hip (target knee)
5. Has had a meniscal tear in the target knee within the last 12 months
6. Has had cartilage reconstruction procedure in the target knee
7. Has had a therapeutic arthroscopy procedure in the target knee within the last 12 months
8. Has a Body Mass Index (BMI) greater than 37
9. Has had a major illness, requiring hospitalisation during the 3 months before commencement of the screening period
10. Is unwilling to stop taking pain medication other than the study medication (for arthritis or other types of pain) or is unwilling to stop taking other medications for the treatment of OA
11. Has previously failed treatment with tramadol or discontinued treatment with tramadol due to adverse events
12. Has been taking other opioids (e.g. codeine, oxycodone, hydromorphone, etc.) for treatment of OA or other chronic conditions
13. Has received Corticosteroid Injections in the target knee within the last 3 months or Viscous injections in the target knee within the last 6 months
14. Has had 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; serotonin-norepinephrine reuptake inhibitors or any other drug that reduces seizure threshold
15. Has had treatment with another investigational agent within the last 30 days
16. Has a history of seizure disorder other than Infantile Febrile Seizures
17. Has a previous or current opioid dependency
18. Has a bowel disease causing malabsorption
19. Is pregnant, lactating or of childbearing potential and is unwilling to utilise a medically approved method of contraception during participation in this clinical trial
20. Has significant liver disease, defined as active hepatitis or elevated liver enzymes >3 times the upper boundary of the normal range
21. Has significant renal disease (defined as creatinine clearance <30 mL/min
22. Has a history of current or past substance abuse or dependence, other than nicotine
23. Has a known and documented allergy to tramadol or any structurally similar drugs (e.g. opiates)
24. Has a known and documented allergy to acetaminophen or any structurally similar drugs
25. Has any other condition that, in the opinion of the Investigators, would adversely affect the patient's ability to complete the study or its measures.

Inclusion criteria for the double-blinded phase:

• Patients must continue to meet the open-label eligibility criteria and
• Must have a score of ≥ 4 on the Numerical Rating Scale (NRS) with a total increase of ≥ 2 points on the NRS compared to Visit 3(Day R14) and
• Must not have taken any of the prohibited medications during the Open-label Phase.

Exclusion criteria for the double-blinded phase:

• Patient Request
• Adverse Events that contraindicate further administration of the study medication
• Any other situation where in the opinion of the Investigator continued participation in the study would not be in the patient's best interest.