Park 2012.

Methods	Randomized, multicenter, open comparative study in outpatients at 6 sites Setting: outpatient clinic at 6 sites.
Participants	Ages 40–75 years. 143 participants (women 121, men 22) enrolled, mean age 61.15 (SD 7.80). With symptomatic moderate knee OA pain (≥ 5 on NRS) for > 1 year despite treatment with stable doses of NSAIDs (meloxicam 7.5 mg or 15 mg once daily or aceclofenac 100 mg twice daily) for ≥ 4 weeks. Investigators used the 1986 ACR clinical and radiographic criteria for classification of idiopathic knee OA and checked standing anteroposterior view of knee joints. Participants with moderate knee joint pain (≥ 5 on NRS) in last 48 hours of the screening/washout phase eligible to enter study. % women: active group: 84%; control group: 87%.
Interventions	During the 14‐day screening/washout phase, participants discontinued cyclobenzaprine, antidepressant or anticonvulsant therapy and underwent clinical and radiologic exam. During the 4‐week tramadol/acetaminophen add‐on period, participants maintained their existing NSAID dose and tramadol/acetaminophen was titrated from 1 pill at bedtime for 3 days, 1 pill twice/day for 4 days, 1 pill 3 times/day for 3 days, and thereafter as needed from 3 to 8 pills per day. On day 29, participants with reduced pain (< 4 on NRS) were randomized to continue with either tramadol/acetaminophen or NSAID for a further 8 weeks.
Outcomes	Major benefits measure was the Korean version of the WOMAC Osteoarthritis Index score; minor outcome measures included PI on NRS, pain relief score, and overall medication assessment by participants and investigators. Benefits evaluations were performed on days 29 and 57 during monotherapy. Safety assessments comprised adverse event monitoring, changes from baseline in vital signs, physical examination at every visit and clinical laboratory tests at the end of study. Extracted pain outcome: PI on NRS (0–8) for 4 weeks, with lower values indicating benefit Extracted physical function outcome: WOMAC Physical Function subscale (0–1700 mm) for 4 weeks, with lower values indicating benefit
Notes	Specific sites involved were not listed in the paper. All authors based in South Korea. Supported by a grant from Janssen Korea, Ltd, Seoul, Korea. ClinicalTrials.gov identifier: NCT00635349.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomized, but randomization procedure not described by authors.
Allocation concealment (selection bias)	High risk	No mention of allocation concealment.
Blinding of personnel	High risk	Quote: "This was a randomized, multicenter, open comparative study in out‐patients at six sites." (p.318) Study described as "open," author confirmed that personnel were not blinded.
Blinding of participants	High risk	Quote: "This was a randomized, multicenter, open comparative study in out‐patients at six sites." (p.318) Study described as "open," author confirmed that participants were not blinded.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "This was a randomized, multicenter, open comparative study in out‐patients at six sites." (p.318) Study described as "open," author confirmed that outcome assessors were not blinded.
Incomplete outcome data for pain and physical function	High risk	Quote: "Efficacy analyses were performed on the intent‐to‐treat population, defined as patients who took at least one dose of study medication and had available efficacy measurements." (p.319) Quote: "Ninety‐one of the 97 randomized subjects were included in the ITT population (44 in tramadol/APAP [acetaminophen] group; 47 in NSAID group)…" (p.319) For ITT population, 3 excluded in each group. Total discontinued: 19% (23% with tramadol vs 14% with NSAID); reasons for discontinuation differed between 2 groups.
Incomplete outcome data for adverse effects All outcomes	Unclear risk	Quote: "The population evaluable for safety was used for above safety analyses…" (p.319) Safety population not specified.
Selective reporting (reporting bias)	Unclear risk	Outcome measures listed in 'Methods' were adequately reported, with 1 exception: secondary measure "overall medication assessment by patients and investigators" (p.319). This measure was reported as follows: "Although NSAID monotherapy tended to be superior to tramadol/APAP with respect to pain relief score and overall assessment by participants and investigators, the differences failed to reach statistical significance" (p.320), with no data to support this conclusion. ClinicalTrials.gov identifier: NCT00635349.
Other biases	Low risk	No other sources of bias.