Wang 2012.

Methods	Design: Randomised, double‐blind, parallel group trial Year: 2005 to 2010 Country: China
Participants	Patients: 163 patients were screened, of these 43 did not meet the inclusion criteria (declined participation, N = 14; adjuvant chemotherapy, N = 11; elevated levels of serum transaminase N = 9; respiratory tract infection, N = 9) while the remaining 120 patients were randomised to one of the following 2 groups (each consisting of two sub‐groups based on the status of P‐gp expression in their tumour tissues): Buprenorphine: B1 [P‐gp+ tumours, defined as specimens with ≥ 10% of positively staining cells]: N = 30, 8 females/22 males, mean age (SD) = 57.4 (10.2) years; cancer type: Oesophageal (N = 8), cardia (N = 3), breast (N = 5), lung (N = 7), colon (N = 3), rectum (N = 4). B2 [P‐gp‐ tumours, defined as specimens with < 10% of positively staining cells]: N = 30, 9 females/21 males, mean age (SD) = 57.5 (9.7) years; cancer type: Oesophageal (N = 8), cardia (N = 3), breast (N = 4), lung (N = 7), colon (N = 4), rectum (N = 4). Morphine: M1 [P‐gp+ tumours, defined as specimens with ≥ 10% of positively staining cells]: N = 30, 9 females/21 males, mean age (SD) = 57.5 (10.4) years; cancer type: Oesophageal (N = 6), cardia (N = 5), breast (N = 4), lung (N = 7), colon (N = 4), rectum (N = 4). M2 [P‐gp‐ tumours, defined as specimens with < 10% of positively staining cells]: N = 30, 10 females/20 males, mean age (SD) = 57.2 (11.1) years; cancer type: Oesophageal (N = 7), cardia (N = 4), breast (N = 5), lung (N = 7), colon (N = 3), rectum (N = 4). Inclusion criteria: "Individual patients with histologically confirmed malignant tumours at stage IV, able to communicate effectively with the healthcare providers, regardless of previous chemotherapy and surgical treatment, were included." Exclusion criteria: "individual tumor patients with opioid intolerance, previous usage of strong opioids, severe renal or hepatic dysfunction, predominantly neuropathic pain, or breakthrough pain; or individuals who needed neural block or neuroablative treatment for pain relief, with impaired sensory or cognitive function, with coma or other mental disorders were excluded."
Interventions	Buprenorphine arm (B1 and B2): Drug: Buprenorphine. Dose/dosing: "All patients with pain due to surgery, tumor progression, or metastases were initially treated orally with 0.05 g of diclofenac sodium suppositories (Jiangsu Yuan Heng Pharmaceutical Company, Nanjing, China) every 8‐12 h, 0.1 g of sustained‐releasing tramadol hydrochloride (Beijing Adorable Pedicle Pharmaceutical Company, Beijing, China), or 0.03 g of sustained‐releasing morphine hydrochloride (Southwest Pharmaceutical Company, Chongqing, China every 12 h. Individual patients, who still suffered with unsustainable pain, received a patient‐controlled intravenous analgesia (PCIA) pump (Dragon Medical Device, Zhangjiagang, China)." "the B1 and B2 groups of patients were treated with a load dose of 0.00015 g BNP" [buprenorphine]. Subsequently, "The B1 and B2 groups of patients were treated with 0.000025 g x kg‐2 BNP and 0.01 g azasetron in 100 ml of saline" with consistent transfusions of 2 ml per h, self‐adjusted with 0.5 ml of PCA solution and a lock time of 20 min. Formulation: Intravenous. Route of administration: Intravenous. Length of treatment: Actual study‐drug treatment length appears to be 36 hours. Titration schedule: See "Dose/dosing" above. Rescue medication: See "Dose/dosing" above. Other medication: See "Dose/dosing" above. No further information reported. Morphine arm (M1 and M2): Drug: Morphine. Dose/dosing: "All patients with pain due to surgery, tumor progression, or metastases were initially treated orally with 0.05 g of diclofenac sodium suppositories (Jiangsu Yuan Heng Pharmaceutical Company, Nanjing, China) every 8‐12 h, 0.1 g of sustained‐releasing tramadol hydrochloride (Beijing Adorable Pedicle Pharmaceutical Company, Beijing, China), or 0.03 g of sustained‐releasing morphine hydrochloride (Southwest Pharmaceutical Company, Chongqing, China every 12 h. Individual patients, who still suffered with unsustainable pain, received a patient‐controlled intravenous analgesia (PCIA) pump (Dragon Medical Device, Zhangjiagang, China)." "The M1 and M2 groups of patients received a load dose of 0.0025 g morphine". "Subsequently, the patients in the M1 and M2 groups were provided with the PCIA solution containing 0.00075 g x kg‐2 morphine and 0.01 g azasetron in 100 ml of saline with consistent transfusions of 2 ml per h, self‐adjusted with 0.5 ml of PCA solution and a lock time of 20 min." One week later, due to poor responses, the M1 group of patients received 0.0011 g x kg‐2 morphine and 0.01 mg azasetron using the same treatment condition." Formulation: Intravenous. Route of administration: Intravenous. Length of treatment: Actual study‐drug treatment length appears to be 36 hours. Titration schedule: See "Dose/dosing" above. Rescue medication: See "Dose/dosing" above. Other medication: See "Dose/dosing" above. No further information reported.
Outcomes	Pain intensity: Assessed by patients at baseline (before treatment), 4 h, 12 h, 24 h and 36 h "using VAS: 0 (no pain feeling and highly satisfactory); 1‐2 (satisfactory), 3‐5 (primary satisfactory), 6‐7 (primary unsatisfactory), 8‐9 (unsatisfactory), and 10 (utmost pain and highly unsatisfactory)."
Notes	Study free of commercial funding? No information reported. Groups comparable at baseline? The baseline characteristics of the four groups were comparable in terms of age, gender, weight, cancer type, baseline VAS and education. ITT analyses undertaken? Unclear. Not enough information reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	No information is reported about the random sequence generation, but 120 patients were randomised into 4 groups with stratification for tumour type, P‐gp expression, and their demographic characteristics, which (due to the relatively large number of stratification factors) increases the risk that the allocation ceases to be random.
Allocation concealment (selection bias)	High risk	See above.
Blinding of participants and personnel (performance bias) Pain	Unclear risk	The study reports that the analgesics effect was tested in "a double blinded manner", but reports no further details.
Blinding of participants and personnel (performance bias) Adverse events	Unclear risk	Outcome not reported.
Blinding of outcome assessment (detection bias) Pain	Unclear risk	The study reports that the analgesics effect was tested in "a double blinded manner", but reports no further details.
Blinding of outcome assessment (detection bias) Adverse events	Unclear risk	Outcome not reported.
Incomplete outcome data (attrition bias) Pain	Unclear risk	It is unclear if data are included from all the patients at all the time points.
Incomplete outcome data (attrition bias) Adverse events	Unclear risk	Outcome not reported.
Selective reporting (reporting bias)	High risk	Adverse events not reported.
Other bias	Unclear risk	It is unclear whether the study is subject to high risk of other bias(es).
Were the patients adequately titrated?	Unclear risk	It is unclear, based on the reported information, whether the patients were adequately titrated.
For cross‐over trials: Are data available for both time periods?	Unclear risk	NA.