Peeva 2010.

Methods	Randomized, double‐blind, placebo‐controlled, 3‐period cross‐over study
Participants	Participants ages ≥ 45 years with knee OA > 6 months based on clinical and radiographic criteria and had an American Rheumatological Association functional class of I–III. Eligible participants had PI while standing ≤ 5 on a 0–10 NRS. % women (active and control group combined): 63.6%.
Interventions	Cross‐over trial Comprised 3 × 3‐day periods. Participants randomized to naproxen, tramadol/acetaminophen and placebo for 3 days with a 4–7‐day washout period between the 3 phases of treatment. Tramadol/acetaminophen period: participants received total daily doses of tramadol 75 mg/acetaminophen 650 mg on day 1 and tramadol 112.5 mg/acetaminophen 975 mg on day 2 and tramadol 75 mg/acetaminophen 650 mg administered as a single dose on day 3. Naproxen period: participants received 1000 mg total daily dose of naproxen on days 1 and 2 and 500 mg on the morning of day 3.
Outcomes	Pain: change from baseline in TWA PI for both postdose self‐pace walks on day 3, with TWA reflective of pain across the entire walk. Key secondary endpoints included TWA PI for all self‐pace walks on day 1 and for each individual walk on days 1 and 3, TTMP using a 4‐point Likert scale (none, slight, moderate, severe), and if applicable, TTSP. WOMAC questionnaire VAS 3.0 (100‐mm VAS) collected at end of days 1 and 3 after the completion of the last timed walks, with participants reporting pain, physical function and stiffness results for the preceding 24 hours. Other: the incidence of overall adverse events, serious adverse events, drug‐related adverse events and discontinuation due to adverse events collected to evaluate tolerability and safety. No extractable pain or physical function outcomes as authors combined time periods for this cross‐over study.
Notes	ClinicalTrials.gov Identifiers: NCT00772967 and NCT00565084. sponsored by Merck & Co., Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Allocation to balanced treatment sequences was determined according to a computer‐generated schedule by the study statistician." (p.647)
Allocation concealment (selection bias)	Low risk	Quote: "Numbered containers were used to implement allocation." (p.647)
Blinding of personnel	Low risk	Quote: "All study personnel, including investigators, study site personnel, patients, monitors, and central laboratory personnel, were blinded to treatment allocation throughout the study; the code was revealed to the researchers once recruitment, data collection, and laboratory analyses were complete." (p.647)
Blinding of participants	Low risk	Quote: "Study medication was administered in double‐dummy fashion with over‐encapsulated pills." (p.647)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All those involved in study were blinded, as noted above.
Incomplete outcome data for pain and physical function	Low risk	Quote: "Only observed data were analyzed; no data were imputed." (p.648) Quote: "Nineteen patients (86.4%) completed the study, and all 19 were included in both the primary efficacy analysis and safety analysis. Two patients discontinued due to protocol violations, and one patient discontinued due to an adverse event (acute gouty attack), which was not considered to be drug‐related." (p.648) Unknown what treatment (naproxen 500 mg twice daily, tramadol/acetaminophen or placebo) the participant was receiving when they withdrew. ClinicalTrials.gov indicated that the 22 participants were randomized to 6 groups corresponding to a different order of treatment administration (e.g. placebo, naproxen, tramadol/acetaminophen; or naproxen, tramadol/acetaminophen, placebo, etc.). However, the percentage of total withdrawals in both groups combined was only 13.6% and reasons for withdrawal were included. % of withdrawals due to adverse events in both groups combined was 4.5%.
Incomplete outcome data for adverse effects All outcomes	Low risk	Quote: "Only observed data were analyzed; no data were imputed." (p.648) Quote: "Nineteen patients (86.4%) completed the study, and all 19 were included in both the primary efficacy analysis and safety analysis. Two patients discontinued due to protocol violations, and one patient discontinued due to an adverse event (acute gouty attack), which was not considered to be drug‐related." (p.648) Unknown what treatment (naproxen 500 mg twice daily, tramadol/acetaminophen or placebo) the participant was receiving when they withdrew. ClinicalTrials.gov indicated that the 22 participants were randomized to 6 groups corresponding to a different order of treatment administration (e.g. placebo, naproxen, tramadol/acetaminophen; or naproxen, tramadol/acetaminophen, placebo, etc.). However, the percentage of total withdrawals in both groups combined was only 13.6% and reasons for withdrawal were included. % of withdrawals due to adverse events in both groups combined was 4.5%.
Selective reporting (reporting bias)	Low risk	Outcomes listed in earliest iteration of protocol were consistent with those reported as results in the article (ClinicalTrials.gov Identifier: NCT00772967).
Other biases	Low risk	No other sources of bias. Was use of a cross‐over design appropriate? Yes, OA was stable. Was it clear that the order of receiving treatments was randomized? Yes, randomized "computer generated schedule." Can it be assumed that the trial was not biased from carry‐over effects? Yes, 4–7‐day washout period; "there were only slight period effects." Were unbiased data available? Yes, analysis of variance model for a 3‐period cross‐over design.