Cubero 2010.

Methods	Randomised, double‐blind, placebo‐controlled, parallel group study Participants switched (stop/start) from oral morphine to equivalent dose of oral methadone plus either oral paracetamol or placebo Treatment for 1 week
Participants	Cancer patients (mainly colorectal, prostate, breast) on stable dose morphine ≥ 1 week Excluded: receiving radiotherapy, severe hepatic or renal dysfunction, cognitive alterations, use of paracetamol within 48 hours N = 49 (all completing) M 26, F 23 Median age 59 (19 to 81) Median baseline PI: 5/10 (paracetamol), 3.5/10 (placebo) PI range 0 to 10 Median dose of oral morphine 60 mg (40 mg to 540 mg)
Interventions	In addition to calculated dose of methadone: Paracetamol 4 x 750 mg daily, n = 24 Placebo, n = 25 NSAIDs, tricyclic antidepressants, neuroleptics, dipyrone etc. allowed if dose stable ≥ 1 week Extra methadone (25% daily dose not more frequently than 2 hours) for breakthrough pain
Outcomes	Daily PI (NRS 0 to 10 and 6‐faces scale) Time to return to baseline PI Adverse events (symptoms) Additional analgesia Quality of life at baseline and end of study
Notes	NCT00525967; completed, no results
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"generated aleatory numbers"
Allocation concealment (selection bias)	Low risk	"envelopes … handled by a pharmacist in charge of giving medications to patients"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Method used to blind participants and personnel not described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Method used to blind outcome assessment not described
Incomplete outcome data (attrition bias) All outcomes	High risk	6/49 (12%) withdrew; do not appear to be included in analyses
Selective reporting (reporting bias)	Low risk	NCT record available, no results posted. All relevant specified outcomes reported
Size	High risk	< 50 participants per treatment arm