Beaulieu 2008.

Methods	Randomized, double‐blind, parallel‐group comparison of the benefits, safety and clinical benefits of CR tramadol vs SR diclofenac over a 6‐week treatment period Setting: clinic
Participants	Number of participants: 129: CR tramadol: 62; SR diclofenac: 66 Men and non‐pregnant women ages 35–75 years with chronic pain due to primary knee or hip OA of at least moderate severity
Interventions	Active group: CR tramadol titrated to optimal dose (200 mg/day, 300 mg/day or 400 mg/day) Control group: SR diclofenac packaged and labeled in the same way as the treatment and titrated to their optimal dose (75 mg or 100 mg once daily, or 75 mg twice a day), unless adequate pain control was achieved or adverse effects prevented the dose from being titrated further. All participants were randomly assigned an initial dose of either active CR tramadol 200 mg and placebo SR diclofenac 75 mg each morning, or active SR diclofenac 75 mg and placebo CR tramadol 200 mg each morning. Treatment lasted 6 weeks
Outcomes	The overall PI over the preceding 2 weeks assessed with 100‐mm VAS. The WOMAC Physical Function subscale used to report physical function and pain. Impact of pain on quality and quantity of sleep using the Pain and Sleep Questionnaire Withdrawals due to adverse events Other outcomes included PI while walking on a flat surface, going up or down stairs, at night while in bed, sitting or lying, standing upright, effect of pain on quality and quantity of sleep, global assessment of clinical benefits (participant and investigator) and Drug Liking Index. The effect sizes were assessed in terms of change over the study period. Extracted pain outcome: WOMAC Pain subscale (0–100 mm) during the last 2 weeks of treatment, with lower values indicating benefit Extracted physical function outcome: WOMAC Physical Function subscale (0–1700 mm) at 8 weeks, with lower values indicating benefit
Notes	Study funded by Purdue Pharma, Canada
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Study medication was prepackaged with an assigned randomization number, according to a computer‐generated code, in blocks of four." (p.105)
Allocation concealment (selection bias)	Unclear risk	Quote: "Study medication was prepackaged with an assigned randomization number, according to a computer‐generated code, in blocks of four." (p.105) Not mentioned if packaging was opaque and sealed. Techniques used to implement the sequence not addressed.
Blinding of personnel	Unclear risk	Authors did not explicitly report blinding of personnel
Blinding of participants	Low risk	Quote: "Blinding was maintained using the double‐dummy technique." (p.105)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Patients recorded their pain intensity in a diary." (p.105) Quote: "At the completion of the study, the patient and investigator each provided a global assessment of clinical effectiveness." (p.105) 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	Low risk	Quote: "Safety data are presented using the ITT population and efficacy data are presented using the per protocol population." (p.106) Quote: "All patients who completed the study were included in the per protocol population, with the exception of one patient with a protocol violation." (p.106) Quote: "one patient was excluded from all analyses due to lack of evidence of OA." (p.106) Quote: "Ninety‐seven patients were evaluated for efficacy; 45 in the CR tramadol group and 52 in the SR diclofenac group." (p.106) Only 97/129 (75%) participants were included in the per‐protocol population and evaluated for benefits. The missing 31 people withdrew from the study before completion due to reasons including adverse events and inadequate pain control. Withdrawals due to adverse events were 16.1% (10/62) with tramadol vs 15.2% (10/66) with diclofenac. Percentage of withdrawals for reasons other than adverse events (inadequate pain control, intermittent illness, voluntary withdrawal, etc.) were 11.3% (7/62) with tramadol vs 6.1% (4/66) with diclofenac. Despite the overall withdrawal rates being > 20%, most withdrawals were due to reasons other than adverse events.
Incomplete outcome data for adverse effects All outcomes	Low risk	Quote: "Safety data are presented using the ITT population and data are presented using the per protocol population." (p.106) Quote: "All randomly assigned patients were included in the intent‐to‐treat (ITT) population, with the exception of one patient who did not meet the eligibility criteria." (pp.105–106) 128/129 participants evaluated for safety since they were included in ITT population.
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes (pain, physical function and stiffness, and sleep quality) appeared to have been reported in results but we did not have access to the protocol for verification.
Other biases	Low risk	No other sources of bias detected.