The purpose of this study is to determine the efficacy of ADL5859 versus placebo and ADL5747 versus placebo in relieving pain in participants with osteoarthritis of the knee.

Key Inclusion Criteria:

• a man or woman between 18 and 75 years of age, inclusive
• for women of childbearing potential, be using an insertable, injectable, transdermal, or combination oral contraceptive deemed highly effective by the United States Food and Drug Administration from the first dose of study medication through the end of the study and have negative findings on pregnancy tests performed at screening and randomization (women who are surgically sterile [for example, hysterectomy, tubal ligation] or postmenopausal [if ≥55 years old, no menses for at least 2 years; if <55 years old, follicle-stimulating hormone concentrations within the postmenopausal range of >40 milli-international units per milliliter (mIU/mL) and 17 β-estradiol levels of <37 picograms per milliliter (pg/mL)] are also eligible to participate)
• for male participants, be surgically sterile or agree to use an appropriate method of contraception (that is, use a barrier method in conjunction with spermicide or have a sexual partner who is surgically sterile, postmenopausal, or using an insertable, injectable, transdermal, or combination oral contraceptive deemed highly effective by the United States Food and Drug Administration) from the first dose of study medication through the end of the study
• have a body weight between 45 and 150 kilograms (kg), inclusive
• have had pain in the index knee for at least the past 6 months
• meet the following criteria for osteoarthritis of the knee established by the American College of Rheumatology (radiographs must have been taken within the last year; if none is available, a radiograph must be taken and the diagnostic criteria must be confirmed before the participant is enrolled in the study): have index knee pain plus at least 1 moderate or definite osteophyte on radiographs. Must also have at least 1 of the following: be more than 50 years old, have morning stiffness for less than 30 minutes, or have crepitus on active motion
• have an average weekly pain score of at least 4.00 on the numeric pain rating scale (NPRS) for the index knee during the baseline week before randomization (to be eligible for randomization, participants must report their NPRS score via the interactive voice-response system (IVRS) for at least 4 of the 7 days immediately before randomization, with the first score being recorded on Day -6)
• if receiving nonselective or selective cyclooxygenase (COX) inhibitors, have a stable daily dose regimen for at least 4 weeks before screening; if receiving nonselective or selective COX inhibitors on an as needed basis, have discontinued use by Day -14; if receiving angiotensin-converting enzyme (ACE) inhibitors, have a stable dose regimen for at least 4 weeks before screening

Key Exclusion Criteria:

• have undergone arthroscopy on the index knee within 6 months before study entry
• have other severe pain that, in the opinion of the investigator, may impair the assessment of the pain due to osteoarthritis
• have a history of hypersensitivity or intolerance to opioids (including tramadol and tapentadol)
• have, as determined by the investigator or the sponsor's medical monitor, a history or clinical manifestations of significant renal, hepatic, hematologic, cardiovascular, metabolic, gastrointestinal, neurologic, psychiatric, or another condition that would preclude participation in the study or affect the outcome of the study
• have taken oral or intramuscular corticosteroids within 30 days before study entry (inhaled or topical corticosteroids are permitted)
• have received intra-articular injections of corticosteroids into the index joint within 12 weeks before screening
• have received intra-articular injections of hyaluronic acid into the index joint within 24 weeks before screening
• currently taking medications other than nonsteroidal anti-inflammatory drugs prescribed for chronic pain (such as duloxetine or pregabalin)