DeLemos 2011.

Methods	Phase III, 12‐week, multicenter, randomized, double‐blind, placebo‐controlled, dose‐ranging trial
Participants	1011 participants randomized, 1001 analyzed for safety/benefits; 555 completed study treatment Adults with knee or hip (or both) OA and baseline PI ≥ 40/100 on 100‐mm VAS. Safety/ITT population for 5 groups (number of participants): tramadol 100 mg: 201; 200 mg: 199; 300 mg: 199; celecoxib: 202; placebo: 200 % women: tramadol 100 mg: 58.2%; tramadol 200 mg: 62.3%; tramadol 300 mg: 61.8%; celecoxib: 64.9%; placebo: 68.5%
Interventions	Eligible participants underwent a 2–7‐day washout of prior analgesic therapy. Double‐blind treatment period (12 weeks) Active group 1: tramadol 100 mg Active group 2; tramadol 200 mg Active group 3: tramadol 300 mg Active group 4: celecoxib Control: placebo
Outcomes	Arthritis PI assessed over entire study using 100‐mm VAS (0 = no pain, 100 = extreme pain) WOMAC Pain, Physical Functioning and Stiffness subscales Participant and physician global assessment of disease activity on 100‐mm VAS Sleep assessed with the CPSI (which included 100‐mm VAS) At baseline and at weeks 6 and 12, participants completed the SF‐36 Health Survey Safety assessments included reports of adverse events, either spontaneously or in response to non‐directed questioning, and results of physical exams, vital signs, clinical laboratory tests and electrocardiograms at study visits. Participants completed 49‐item Short Form ARCI questionnaire at baseline and week 12. Participants also completed 16‐item PDQ at baseline, week 12 (or early discontinuation), and week 13 (or 1 week after early discontinuation) Extracted pain outcome: WOMAC Pain subscale (0–100 mm) at 12 weeks, with lower values indicating benefit Extracted physical function outcome: WOMAC Physical Function subscale (0–1700 mm) at 12 weeks, with lower values indicating benefit
Notes	Supported by Biovail Corporation and Ortho‐McNeil Janssen Scientific Affairs, LLC
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "randomized" (p.217) Quote: "Patients (…) were randomly assigned to 12 weeks of study treatment in a 1:1:1:1:1 ratio." (p.217) No mention of how the randomization process was carried out.
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment
Blinding of personnel	Unclear risk	Authors did not explicitly report blinding of personnel
Blinding of participants	Low risk	Quote: "placebo tablets and capsules were matched in size and color to the active tramadol ER tablets and the over encapsulated celecoxib capsules, respectively." (p.218) Quote: "The double‐blind was maintained during the study by each patient taking 3 tablets and 1 capsule once daily." (p.218)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Since this was a participant‐reported outcome and participants were blinded, the outcome assessment was considered blinded.
Incomplete outcome data for pain and physical function	High risk	Quote: "Patients who discontinued early had their last observation carried forward for efficacy analyses" (p.224) 10/1011 (9.9%) randomized participants were not in the safety/ITT population due to "no dose documented" (p.219). Although only 555/1011 (54.9%) participants completed the study, 1001 participants were included in the safety/ITT analysis. Withdrawals due to adverse events: 18.9% with tramadol vs 7.5% with placebo. Withdrawals for reasons other than adverse events (lack of efficacy, participant choice, other): 24.6% with tramadol vs 41% with placebo. The overall high withdrawal rate due to reasons other than adverse events was likely to lead to biased outcome data despite ITT analysis.
Incomplete outcome data for adverse effects All outcomes	High risk	10/1011 (9.9%) randomized participants were not in the safety/ITT population due to "no dose documented" (p.219). Although only 555/1011 (54.9%) participants completed the study, 1001 participants were included in the safety/ITT analysis. Withdrawals due to adverse events: 18.9% with tramadol vs 7.5% with placebo. Withdrawals for reasons other than adverse events (lack of efficacy, participant choice, other): 24.6% with tramadol vs 41% with placebo. The overall high withdrawal rate due to reasons other than adverse events was likely to lead to biased outcome data despite ITT analysis.
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes (pain, physical function and stiffness, and sleep quality) appeared to have been reported in the results, but we did not have access to the protocol for verification.
Other biases	Low risk	No other sources of bias.