Böhme 2003.

Methods	Design: Randomised, double‐blind, parallel group trial Year: Not reported Country: Austria, Germany, and Hungary
Participants	Patients: 189 patients entered the run‐in phase, of these 38 were excluded and 151 patients were randomised to one of the following 4 groups: Placebo: N = 37, 18 females/19 males, mean age (SD) = 54.9 (11.5) years; 20 had malignant pain origin/17 had non‐malignant pain origin; frequency of additional analgesic, anti‐inflammatory agent and anti‐pyretic use (WHO step 1) = 54% of patients; number of patients prematurely withdrawn from the study = 3. Buprenorphine 35 μg/h: N = 35, 18 females/17 males, mean age (SD) = 60.6 (12.2) years; 22 had malignant pain origin/13 had non‐malignant pain origin; frequency of additional analgesic, anti‐inflammatory agent and anti‐pyretic use (WHO step 1) = 71% of patients; number of patients prematurely withdrawn from the study = 2. Buprenorphine 52.5 μg/h: N = 41, 21 females/20 males, mean age (SD) = 60.5 (13) years; 22 had malignant pain origin/19 had non‐malignant pain origin; frequency of additional analgesic, anti‐inflammatory agent and anti‐pyretic use (WHO step 1) = 63% of patients; number of patients prematurely withdrawn from the study = 5. Buprenorphine 70 μg/h: N = 38, 24 females/14 males, mean age (SD) = 62.7 (11) years; 19 had malignant pain origin/19 had non‐malignant pain origin; frequency of additional analgesic, anti‐inflammatory agent and anti‐pyretic use (WHO step 1) = 63% of patients; number of patients prematurely withdrawn from the study = 3. 90 to 93% of the patients in the treatment arms had been prescribed strong opioids (WHO step 3), 0 to 8% in each treatment arm used weak opioids (WHO step 2). Inclusion criteria: "The main inclusion criteria for the double‐blind phase was chronic pain that was at least satisfactorily relieved (according to a verbal rating scale) with 0.8‐1.2 mg/day sublingual buprenorphine after a 5‐day run‐in phase." Exclusion criteria: "Exclusion criteria were alcohol or drug abuse, hypersensitivity towards opioids, compromised respiratory function, a history of convulsions, raised intracranial pressure, and previous extensive damage to the dermis in the patch application area (subclavicular chest or upper back regions). Also excluded were patients receiving local radionucleotide therapy, opioids other than sublingual buprenorphine, or MAO‐inhibitors."
Interventions	Buprenorphine arms (3): Drug: Buprenorphine. Dose/dosing: 35 μg/h or 52.5 μg/h or 70 μg/h buprenorphine administered in 2 patches applied consecutively for 72 hours each to the subclavicular chest or upper back region of each patient. "Because of the delayed onset of analgesia due to patch technology with buprenorphine TDS, patients continued to take prescribed sublingual buprenorphine on the first day of the double‐blind treatment phase, day 6. Formulation: TD. Route of administration: TD patch. Length of treatment: 6 days (study days 6 to 11; study days 12 to 15 comprised the washout phase). Titration schedule: "Patients first entered an open run‐in phase (days 1‐5), during which they took sublingual buprenorphine 0.8‐1.2 mg/day at prescribed doses and times....If this analgesic regimen produced satisfactory pain relief (VRS), patients were randomised to one of four study arms and entered the double‐blind phase (days 6‐15)." Rescue medication: "From day 7 onwards, patients took 0.2 mg sublingual buprenorphine tablets only as required for the relief of breakthrough pain." Other medication: "Opioids other than the study medication were prohibited, while non‐excluded concomitant medications were continued at fixed doses." Comparison arm: Drug: Placebo Apart from study drug everything else was similar to the buprenorphine arms.
Outcomes	Pain intensity: Assessed by patients at 8.00 and 20.00 and during interviews on days 1, 6, 9, 12 and 15 on a 5‐point verbal rating scale. Pain intensity was categorised as absent, slight, moderate, severe or very severe. Pain relief: Assessed by patients during interviews on days 1, 6, 9, 12 and 15 on a 4‐point verbal rating scale. "Pain relief was categorised as unsatisfactory, satisfactory, good or complete. Duration of sleep uninterrupted by pain the previous night: Assessed by patients at 8.00 and 20.00 on a 4‐point verbal rating scale with the following categories: > 6, 3 to 6, 2 to 3, or < 2 hours. Responding patients "defined as those whose pain relief was at least satisfactory at all determination points (excluding the final examination) and who took a mean of 0.2 mg/day or less of sublingual buprenorphine on days 7‐12. Patients who prematurely withdrew from the study due to adverse events, unsatisfactory pain relief or for unclear reasons were classed as non‐responders." Adverse events: Systemic AE recorded throughout the trial, patch‐related AE assessed at patch change (including swelling, erythema, pruritus, signs of infection, other dermal damage).
Notes	Study free of commercial funding? "This study was supported by Grunenthal GmbH, Aachen, Germany." Groups comparable at baseline? "There were no significant differences at baseline between treatment groups in demographic parameters, although patients in the placebo group were younger than those in the other treatment groups (p = 0.0079)". ITT analyses undertaken? Unclear.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information reported.
Allocation concealment (selection bias)	Unclear risk	No information reported.
Blinding of participants and personnel (performance bias) Pain	Unclear risk	Study described as double‐blind. Unclear who is blinded.
Blinding of participants and personnel (performance bias) Adverse events	Unclear risk	See cell above.
Blinding of outcome assessment (detection bias) Pain	Low risk	See cell above. Pain is patient reported. Probably reasonable to assume that patients were blinded.
Blinding of outcome assessment (detection bias) Adverse events	Unclear risk	Study described as double‐blind. Unclear who is blinded and whether this outcome is assessed by healthcare professionals also.
Incomplete outcome data (attrition bias) Pain	Low risk	The analyses appear to include 149/151 patients.
Incomplete outcome data (attrition bias) Adverse events	Low risk	The analyses appear to include 151/151 patients.
Selective reporting (reporting bias)	Low risk	All obvious outcomes appear to be reported.
Other bias	Low risk	No other obvious biases were observed.
Were the patients adequately titrated?	Low risk	Probably.
For cross‐over trials: Are data available for both time periods?	Unclear risk	NA.