Fleischmann 2001.

Methods	Multicenter, outpatient, randomized, double‐blind, placebo‐controlled, parallel‐group clinical trial
Participants	129 participants ages 35–75 years, with symptomatic (painful) OA of knee for ≥ 1 year, who had used NSAIDS ≥ 3 months before study entry and were otherwise in good health. Participants were required to have at least moderate pain (PI ≥ 2 on a scale of 0 to 4, with 0 being the least and 4 being the greatest PI) in the target knee when their current analgesic was discontinued. Number of participants: tramadol group: 63; control (placebo) group: 66 % women: active group: 65.1%; control group: 59.1%
Interventions	10‐day analgesic washout period Active group: tramadol in 50 mg increments every 2 days, titrated to a target 200 mg after 7 days (1 capsule 4 times daily). Participants were permitted to increase their dose up to 400 mg/day if needed for 84 days. 91‐day treatment period. Control group: placebo identical in appearance for 91 days.
Outcomes	PI (5‐point Likert scale) Pain relief: measure of change in pain relative to the end of the washout phase (7‐point Likert Scale Overall WOMAC score; subscores for pain, stiffness and physical function Global Assessment of Efficacy Number of participants in each group with who reported adverse events Withdrawals due to adverse events We reported on: WOMAC Pain and Physical Function subscales, adverse events and withdrawals due to adverse events Extracted pain outcome: PI score (5‐point Likert scale) at 91 days, with lower values indicating benefit Extracted physical function outcome: WOMAC Disability score (0–10) at 91 days, with lower values indicating benefit
Notes	Funded by OrthoMcNeil Pharmaceutical, Raritan (NJ)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients (…) were randomly assigned in a 1:1 ratio to receive tramadol or placebo. Study medications were randomly assigned by a computer to a numerical list for each site, and patients were enrolled sequentially using the list" (p.117)
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: "tramadol 50‐mg capsules were identical in appearance to the placebo capsules." (p.117)
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: "All analyses included all randomized patients who took ≥ 1 dose of study medication and for whom an efficacy measurement was available (the intent‐to‐treat population)." (p.118) Unknown how many of the 129 randomized participants were included in the analyses. Withdrawals due to adverse events: 22.2% with tramadol vs 15.2% with placebo. Total withdrawals from study: 68.3% with tramadol vs 74.2% with placebo. The high withdrawal rate impacts the validity of the imputed data used for the ITT analysis.
Incomplete outcome data for adverse effects All outcomes	High risk	Quote: "All analyses included all randomized patients who took ≥ 1 dose of study medication and for whom an efficacy measurement was available (the intent‐to‐treat population)." (p.118) Unknown how many of the 129 randomized participants were included in the analyses. Total withdrawals from study: 68.3% with tramadol vs 74.2% with placebo. The high withdrawal rate impacts the validity of the imputed data used for the ITT analysis.
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes (PI, WOMAC Osteoarthritis Index) 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