Schnitzer 1999.

Methods	Parallel, multicenter, double‐blind RCT Setting: clinic
Participants	Participants ages ≥ 45 years with symptomatic OA of knee. % women: naproxen responders tramadol group: 55.6%; naproxen responders placebo group: 57.4%; naproxen non‐responders tramadol group: 61.5%; naproxen non‐responders placebo group: 70.6%
Interventions	2 phases, and we evaluated the 8‐week double‐blind phase. Participants whose pain did not resolve with 500 mg of naproxen were randomized. Randomization was stratified based on response to naproxen 1000 mg (responders and non‐responders). Active group: tramadol plus naproxen for 54 days. Control group: placebo plus naproxen for 54 days. During the double‐blind phase the naproxen dose was reduced to 250 mg every 2 weeks. Dosage of tramadol (200 mg/day) or placebo remained constant during the double‐blind phase.
Outcomes	Primary aim to determine whether tramadol decreased naproxen requirements. No data on PI during the double‐blind phase. Number of participants who discontinued therapy due to adverse events was reported Pain data not reported for double‐blind phase Physical function data not reported for double‐blind phase
Notes	Supported by research grant from Ortho‐McNeil Pharmaceutical, Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The randomization was stratified based on the patient's baseline VAS score" (p.1371) Unknown if the sequence was computer‐generated. No mention of sequence generation.
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment.
Blinding of personnel	High risk	Quote: "During the 8‐week double‐blind phase, the initial dosage of naproxen in the double‐blind phase was 750 mg/day. This dosage was reduced by 250 mg every two weeks. The naproxen dosage reduction was accomplished in a single‐blind manner (i.e. the patients did not know what dosage of naproxen they were receiving). The dosage of tramadol or placebo remained constant during the double‐blind phase." (p.1372) Authors did not describe blinding of personnel, and the quote provided above suggests that they may have known which participants were taking naproxen once the dosage started being reduced.
Blinding of participants	Low risk	Quote: "patients were randomly assigned to treatment with tramadol 200 mg/day or matching placebo" (p.1372)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Personnel interacting with participants with regard to outcome assessment were not explicitly reported to be blinded.
Incomplete outcome data for pain and physical function	Low risk	Quote: "Four patients (3 taking tramadol, 1 taking placebo) were randomized but were not included in the efficacy analysis because they did not have an efficacy assessment or they did not take the study medication. A total of 236 patients were evaluated." (p.1373) 236/240 randomized participants were analyzed for benefits. % withdrawals due to adverse events: 22% with tramadol vs 13% with placebo. Total number of withdrawals in each treatment group unknown.
Incomplete outcome data for adverse effects All outcomes	Low risk	Quote: "Twenty‐two percent of tramadol patients and 13% of placebo patients discontinued due to an adverse event during the double‐blind phase." (p.1374) Outcome data for withdrawals due to adverse events were likely included in the analysis since there were only 4 participants in total not included in the benefits analysis.
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes (pain) 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.