Kjaer 1982.

Methods	Design: Randomised, double‐blind, cross‐over trial Year: Not reported Country: Denmark
Participants	Patients: 27 patients were randomised, 26 patients completed the study and were included in the safety analyses (1 patient withdrew to receive treatment for bone metastases), and 25 patients were included in the efficacy analyses (1 patient was excluded due to being remedicated by mistake): 13 males/14 females; mean age (range) = 60 (41 to 71) years; Type of cancer: lung (N = 12), breast (N = 7), female genital system (N = 4), head and neck (N = 3), oesophagus (N = 1). 13/27 received buprenorphine first and 14/27 received morphine first. Inclusion criteria: "None of the patients had previously received regular doses of narcotics. The basis for selection of patients to the study was persistent pain where aspirin, dextro‐propoxyphene or paracetamol were no longer effective in controlling the pain. All patients gave informed consent to participate in the study and agreed to at least 3 full days in hospital." Exclusion criteria: "Patients with severe renal damage (serum creatinine ≥ 120 μmol/L), and severe hepatic damage (serum bilirubin ≥ 17 μmol/L, plasma aspartate aminotransferase ≥ 50 U/L, plasma alkaline phosphatase ≥ 275 U/L, plasma lactate dehydrogenase ≥ 450 U/L) were not included in the study. Neither were patients with marked ventilatory impairment or persistent mental confusion."
Interventions	Buprenorphine arm: Drug: Buprenorphine. Dose/dosing: 0.3 mg buprenorphine in a 1 mL ampoule. Formulation: IM. Route of administration: IM injection. Length of treatment: Single dose. Titration schedule: No titration. Rescue medication: "Seven patients in the buprenorphine group were remedicated with an analgesic agent before 8 h compared with ten patients in the morphine group". No further information provided. Other medication: "No analgesic or sedative was administered less than 6.5 h prior to study medication. Drugs allowed during the test period were the following: ‐ aspirin 1000 mg, paracetamol 1000 mg, diazepam 5 mg. All other medications were recorded."(?) Comparison arm: Drug: Morphine. Dose/dosing: 10 mg morphine in a 1 mL ampoule. Formulation: IM. Route of administration: IM injection. Length of treatment: Single dose. Titration schedule: No titration. Rescue medication: "Seven patients in the buprenorphine group were remedicated with an analgesic agent before 8 h compared with ten patients in the morphine group". No further information provided. Other medication: "No analgesic or sedative was administered less than 6.5 h prior to study medication. Drugs allowed during the test period were the following: ‐ aspirin 1000 mg, paracetamol 1000 mg, diazepam 5 mg. All other medications were recorded."(?) For cross‐over trials: Cross‐over schedule: "The second injection was administered 24 h after the first".
Outcomes	Pain intensity: Assessed by nurse observer/patients immediate before, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours after drug administration on a 4‐point categorical scale (0 = none, 1 = slight, 2 = moderate, 3 = severe). Pain relief: Assessed by nurse observer/patients immediate before, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours after drug administration on a 5‐point categorical scale (0 = none, 1 = slight, 2 = moderate, 3 = good, 4 = complete). Degree of sedation: Assessed by nurse observer/patients immediate before, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours after drug administration on a 4‐point categorical scale (0 = alert, 1 = mildly drowsy, 2 = moderately drowsy, 3 = asleep). Severity of side effects: Assessed by nurse observer/patients immediate before, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours after drug administration on a 3‐point categorical scale (1 = mild, 2 = moderate, 3 = severe), for dizziness, euphoria, nausea, vomiting, blurred vision, thirst, sedation, deep respiration, decreased memory, numbness of hands and feet, headache, perspiration, feeling intoxicated, anxiety, feeling remote.
Notes	Study free of commercial funding? "The authors want to thank the Clinical sciences Department, Pharmaceutical Division, Reckitt & Colman for the supply of drugs and the statistical evaluation of the results". Groups comparable at baseline? "Comparison of the two groups of patients according to randomization sequence with regard to sex, age and weight showed no significant differences". ITT analyses undertaken? The analyses appear to be conducted as ITT.
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	Low risk	Study described as double‐blind. "Individual treatments were supplied in identical coded ampoules (1 ml) containing either buprenorphine (0.3 mg) or morphine (10 mg). Each treatment pack consisted of two ampoules labelled A and B which were administered in alphabetical order. The order of treatments were randomized both within and between patients."
Blinding of participants and personnel (performance bias) Adverse events	Low risk	See cell above.
Blinding of outcome assessment (detection bias) Pain	Low risk	See cell above.
Blinding of outcome assessment (detection bias) Adverse events	Low risk	See cell above.
Incomplete outcome data (attrition bias) Pain	Low risk	The analyses included 25/27 patients for efficacy.
Incomplete outcome data (attrition bias) Adverse events	Low risk	The analyses included 26/27 patients for safety.
Selective reporting (reporting bias)	Low risk	The main expected outcomes are reported, although not in a manner that allow their inclusion in a meta‐analysis.
Other bias	Unclear risk	It is unclear whether the study is subject to other types of bias.
Were the patients adequately titrated?	High risk	There was no titration.
For cross‐over trials: Are data available for both time periods?	Low risk	The data appear to be available for both periods.