Thorne 2008.

Methods	Randomized, double‐blind, cross‐over RCT Setting: clinic
Participants	100 participants (45 men and 55 non‐pregnant, non‐nursing women) ages ≥ 18 years, diagnosed with OA and requiring the use of acetaminophen, anti‐inflammatory agents or combination opioid and non‐opioid analgesics for ≥ 3 months. 77/100 randomly assigned participants (36 men and 41 women with a mean age 59.4 (SD 9.6) years were evaluable for efficacy of the 8‐week cross‐over study.
Interventions	Active group: conventional release tramadol 150 mg/day Control group: placebo Treatment was titrated weekly to 200 mg, 300 mg or a maximum of 400 mg once daily over 4 weeks, at which point participants were crossed over to the alternate treatment for another 4 weeks. Analgesic washout for 2–4 days except acetaminophen before start of randomly selected treatment.
Outcomes	Pain: PI in a diary, twice per day (08:00 and 20:00), using 5‐point ordinal scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = excruciating) and 100‐mm VAS bounded by 'no pain' and 'excruciating pain.' PI over the previous 24 hours and over the previous week was assessed using the 100‐mm VAS and 5‐point ordinal scales. WOMAC Pain, Stiffness and Physical Function subscales. Other: pain‐related disability using the PDI, which consists of 7 × 11‐point ordinal subscales. Impact of pain on sleep (since the last evaluation) assessed with 8‐item Pain and Sleep Questionnaire. SF‐36 benefits of treatment assessed by participant and investigator using a 4‐point categorical scale (not effective, slightly effective, moderately effective, highly effective). Overall treatment phase preference assessed by participant and investigator at end of study, without unblinding the treatment allocation, clinical benefit and adverse events. No extractable pain or physical function outcomes as it appeared that authors combined time periods for this cross‐over study
Notes	Funding source not reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "randomized treatment phase." (p.95) Quote: "All patients were randomly assigned to receive either active or placebo CR tramadol." (p.95) No mention of how the randomization process was carried out.
Allocation concealment (selection bias)	Unclear risk	No mention of allocation concealment.
Blinding of personnel	Low risk	Quote: "Both patients and investigators rated CR tramadol in a blinded manner…" (p.100)
Blinding of participants	Low risk	Quote: "Medications included oral CR tramadol 150 mg, 200 mg, 300 mg and 400 mg tablets and matching placebo tablets." (p.95)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Overall treatment phase preference was assessed by the patient and the investigator at the end of the study, without unblinding the treatment allocation, by answering the question: 'Which treatment period did you prefer in the management of your pain?' (treatment period 1; treatment period 2; no preference)." (p.95)
Incomplete outcome data for pain and physical function	Low risk	Quote: "The full analysis set (intent‐to‐treat [ITT]) was used to confirm the results of the primary efficacy variables, the WOMAC and overall treatment preference." (p.96) Quote: "Seventy seven patients (36 men, 41 women) were evaluable for efficacy (Figure 1), with an average age of 59.4 ± 9.6 years and a mean weight and height of 91.0 ± 21.4 kg and 167 ± 10.9 cm, respectively." (p.96) Composite scores for pain and physical function of the WOMAC Osteoarthritis Index reported. 75/100 participants completed full 8 weeks of treatment. In Phase 1, % withdrawals due to reasons other than adverse events: 8% with tramadol vs 6% with placebo.
Incomplete outcome data for adverse effects All outcomes	Low risk	Quote: "The full analysis set (intent‐to‐treat [ITT]) was used to confirm the results of the primary efficacy variables, the WOMAC and overall treatment preference." (p.96) Quote: "Seventy seven patients (36 men, 41 women) were evaluable for efficacy (Figure 1), with an average age of 59.4 ± 9.6 years and a mean weight and height of 91.0 ± 21.4 kg and 167 ± 10.9 cm, respectively." (p.96) Composite scores for pain and physical function of the WOMAC Osteoarthritis Index reported. 75/100 participants completed full 8 weeks of treatment. In Phase 1, % withdrawals due to reasons other than adverse events: 8% with tramadol vs 6% with placebo.
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes (pain, physical function and stiffness, and sleep quality) 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 detected. Was use of a cross‐over design appropriate? Yes, OA was stable. Was it clear that the order of receiving treatments was randomized? Unclear, randomized but no details on randomization procedure. Can it be assumed that the trial was not biased from carry‐over effects? Yes, 2–7‐day washout (tramadol can take about a day and a half for the drug to completely exit the body). Are unbiased data available? Yes, paired t‐test and tested for carry‐over effect which was not statistically significant. *We did not combine the data for pain or physical function outcomes since the authors combined time periods for this cross‐over study.