Emkey 2004.

Methods	Multicenter, randomized, double‐blind, placebo‐controlled trial
Participants	Randomized 307 participants with ≥ 1 year of OA of hip or knee, experiencing at least moderate OA pain. ITT population (number of participants): tramadol/acetaminophen: 153; control: 153. % women: active group: 65%; control group: 71.2%
Interventions	Participants randomized after 3‐week screening and washout period of all non‐COX‐2 analgesics Active group: tramadol 37.5 mg/acetaminophen 325 mg combination pills for a total of 13 weeks. Medication titrated by 1 pill every 3 days to a total of 4 pills/day on day 10, and thereafter as needed to a maximum of 8 pills/day Control group: matching placebo for a total of 13 weeks
Outcomes	Major benefits variable was VAS scores, which participants rated from 'no pain' (0 mm) to 'extreme pain' (100 mm). Minor outcomes included pain relief rating scores (scale of 4 to –1: 4 = complete, 3 = a lot, 2 = moderate, 1 = slight, 0 = none, –1 = worse), overall medication assessment by both physicians and participants at final visit, cumulative distribution of time to discontinuation due to lack of benefits, proportion of participants discontinuing due to lack of benefits, WOMAC Osteoarthritis Index questionnaire scores, and SF‐36 Health Survey scores. Extracted pain outcome: pain on VAS (0–100 mm) at 91 days, with lower values indicating benefit Extracted physical function outcome: WOMAC Physical Function subscale (0–10) at 91 days, with lower values indicating benefit
Notes	Supported by Ortho‐McNeil Pharmaceutical, Inc., Raritan (NJ)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "randomized" Quote: "Subjects were recruited from within investigator's medical practices and through advertising." (p.151) No description of randomization process.
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment.
Blinding of personnel	Low risk	Quote: "All subjects, investigators, and clinical personnel were blinded to treatment assignments until the trial was complete and the database had been finalized." (p.151)
Blinding of participants	Low risk	Quote: "Tramadol/APAP [acetaminophen] or matching placebo was titrated…" (p.150)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All subjects, investigators, and clinical personnel were blinded to treatment assignments until the trial was complete and the database had been finalized." (p.151)
Incomplete outcome data for pain and physical function	High risk	Quote: "Efficacy analyses were performed on the intent‐to‐treat population, defined as all randomized subjects who took at least one dose of study medication and for whom a post‐randomization efficacy measurement was available." (p.151) 306/307 randomized participants were included in the ITT and evaluable‐for‐safety populations. 227/307 randomized participants completed treatment. Withdrawal due to insufficient pain relief: 13/153 (8.5%) with tramadol vs 26/154 (16.9%) with placebo. Withdrawals due to adverse events: 13.1% with tramadol vs 3.9% with placebo. Withdrawals for reasons other than adverse events (insufficient pain relief, participant choice, intercurrent illness, other): 21/153 (13.7%) with tramadol vs 54/153 (35.3%) with placebo. There was an imbalance between the groups regarding reasons for withdrawal and an important (> 20%) overall withdrawal rate.
Incomplete outcome data for adverse effects All outcomes	High risk	Quote: "Safety assessments were performed on randomized subjects who took at least one dose of study medication and had at least one available post baseline safety measurement." Withdrawals due to adverse events: 13.1% with tramadol vs 3.9% with placebo. Withdrawals for reasons other than adverse events (insufficient pain relief, participant choice, intercurrent illness, other): 21/153 (13.7%) with tramadol vs 54/153 (35.3%) with placebo. There was an imbalance between the groups regarding reasons for withdrawal and an important (> 20%) overall withdrawal rate.
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes (pain, WOMAC Osteoarthritis Index, SF‐36 Health Survey) 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.