Bono 1997.

Methods	Design: Randomised cross‐over trial Year: Not reported Country: Italy
Participants	Patients: 60 patients (with the following types of cancer: lung (N = 9), urological (N = 11), gynaecological (N = 3), blood‐based (N = 2), ENT (N = 14), thoracic/oesophageal (N = 8), skin (N = 1), gastrointestinal (N = 12)) were randomised to one of the following 2 groups (order of treatment): Tramadol‐Buprenorphine: N = 30, 8 females/22 males, mean age (SD) = 62.6 (9.9) years; mean duration of cancer (SD) = 16.3 (16.6) months, mean pain intensity (SD) = 58 (28.3), mean Karnofsky performance status (SD) = 62.3 (19.6). Buprenorphine‐tramadol: N = 30, 8 females/22 males, mean age (SD) = 60.2 (10.7) years; mean duration of cancer (SD) = 16.9 (15.3) months, mean pain intensity (SD) = 67.3 (25.3), mean Karnofsky performance status (SD) = 59.3 (19.1). Inclusion criteria: "Sixty adults presenting with advanced tumours no longer responsive to NSAIDs were included". Exclusion criteria: Uncooperative patients, those with known intolerance to the test drugs, with renal, respiratory or hepatic failure, associated chronic pathology, and women in pregnancy or breast‐feeding.
Interventions	Buprenorphine arm: Drug: Buprenorphine. Dose/dosing: 0.2 mg tablets 3 times a day to 0.6 mg buprenorphine per day. Formulation: SL. Route of administration: Oral Length of treatment: 7 days for each arm. Titration schedule: After a period of 7 days free of analgesic intake, the patients took the study medications. No further information reported. Rescue medication: Patients could receive an additional study drug dose, if necessary. Other medication: "Any concomitant medicinal products has been reported in medical patient case file, specifying the name of the drug, the dose and duration of treatment. Patients were not permitted to take morphine or monoamineoxidase inhibitors but could take NSAIDs." Comparison arm: Drug: Tramadol. Dose/dosing: 100 mg tablets 3 times a day to 300 mg/day. Formulation: Oral. Route of administration: Oral. Length of treatment: 7 days for each arm. Titration schedule: After a period of 7 days free of analgesic intake, the patients took the study medications. No further information reported. Rescue medication: Patients could receive an additional study drug dose, if necessary. Other medication: "Any concomitant medicinal products has been reported in medical patient case file, specifying the name of the drug, the dose and duration of treatment. Patients were not permitted to take morphine or monoamineoxidase inhibitors but could take NSAIDs." For cross‐over trials: Cross‐over schedule: There was a 24‐hour washout period between the treatments.
Outcomes	Pain severity: Assessed by patients at baseline, at 15 mins, 30 mins, 1, 2, 3 and 4 hours after first drug administration and then every day at 1 hour after drug intake, and every hour(?) on a 1‐cm VAS (no pain on extreme left through to maximum pain on extreme right) and on a comparative (to the previous day) pain scale (0 = almost disappeared, 1 = slightly decreased, 2 = same, 3 = higher, 4 = much higher). Time spent asleep, including the quality of sleep (deep, good, bad; patient‐assessed). Adverse events. Global treatment efficacy/tolerability: Assessed the end of each of the two periods of treatment by the investigator (overall assessment of efficacy) and patients (overall assessment of tolerance of treatment) using a VAS (zero efficacy/tolerability on extreme left through to maximum efficacy/tolerability on extreme right).
Notes	Study free of commercial funding? No information reported. Groups comparable at baseline? The groups appeared to be comparable at baseline in terms of age, weight, gender distribution, illness duration and performance status, but baseline pain severity appears to be higher in the buprenorphine‐tramadol group. ITT analyses undertaken? The analyses do not appear to be conducted as ITT. The study was published in French and lay translated by MSH.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information reported apart from that it is a randomised study.
Allocation concealment (selection bias)	Unclear risk	See cell above.
Blinding of participants and personnel (performance bias) Pain	Unclear risk	No information reported.
Blinding of participants and personnel (performance bias) Adverse events	Unclear risk	See cell above.
Blinding of outcome assessment (detection bias) Pain	Unclear risk	See cell above.
Blinding of outcome assessment (detection bias) Adverse events	Unclear risk	See cell above.
Incomplete outcome data (attrition bias) Pain	High risk	Nine and 23 of the 60 patients discontinued treatment during treatment with tramadol and buprenorphine, respectively.
Incomplete outcome data (attrition bias) Adverse events	Low risk	Data are reported for all included patients.
Selective reporting (reporting bias)	Low risk	All major outcomes are reported.
Other bias	Unclear risk	It is unclear if the study is subject to high risk of other biases.
Were the patients adequately titrated?	Unclear risk	It is unclear whether the patients were adequately titrated based on the available information.
For cross‐over trials: Are data available for both time periods?	High risk	The pain intensity data did not appear to be inferentially analysed collapsed over phases for (any of) the study days, apart from for the first 4 hours of treatment, where no differences were observed between the treatments.