Fallon 2017a.

Study characteristics
Methods	Purpose of the study: reducing cancer‐related pain that was unalleviated by an optimised maintenance dose of Step 3 opioid therapy Study setting: 101 centres in Belgium, Bulgaria, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, Poland, Romania, UK and US Study period: not reported Study design: double‐blind, randomised, placebo‐controlled, parallel‐group design Study duration: 6 weeks (2 weeks' double‐blind individual titration, 3 weeks' double‐blind stable individual dose, 1‐week follow‐up)
Participants	Type of cancer: not reported Inclusion criteria: aged ≥ 18 years; cancer‐related pain that was unalleviated by an optimised maintenance dose of Step 3 opioid therapy. Opioid therapy was considered optimised if 1. a dose increase was clinically inappropriate due to opioid‐related adverse effects or 2. further efficacy benefit was not expected at higher doses (for the second definition, participants had to be receiving ≥ 90 mg morphine equivalents/day, inclusive of maintenance and breakthrough opioids). ≤ 4 opioid breakthrough analgesic episodes per day (mean over the 3 days), a stable maintenance opioid therapy dose, mean pain ≥ 4 and ≤ 8 on a 0–10 NRS and mean pain scores on the NRS that did not change by > 2 points from the beginning to end of screening (i.e. no more than a 2‐point difference between the highest and lowest scores, with all scores remaining between 4 and 8). Exclusion criteria: baseline use of morphine at > 500 mg morphine equivalents/day (inclusive of maintenance and breakthrough opioids), current use of > 1 type of breakthrough opioid analgesic, planned clinical interventions that would affect pain, and history of schizophrenia or substance abuse including recreational use of cannabis product. Any planned clinical interventions that would have affected their pain (e.g. chemotherapy or radiotherapy where, in the clinical judgement of the investigator, these would be expected to affect pain). The participant was using or had used cannabis or CB‐based medications within 30 days of study entry and was unwilling to abstain for the duration of the study. The participant had experienced myocardial infarction or clinically significant cardiac dysfunction within the last 12 months or had a cardiac disorder that, in the opinion of the investigator, would have put the participant at risk of a clinically significant arrhythmia or myocardial infarction. Impaired renal or hepatic function. THC/CBD: 200 participants; 53% men; mean age 60.0 (SD 11.0) years; Caucasian 97%; type of cancer pain: neuropathic (13.5%), somatic (4.5%), visceral (10.5%), mixed (55.5%), bone (16.0%), other (0%); mean pain baseline 5.7 (SD 1.2); daily morphine equivalent maintenance 170.4 (SD 118.7) mg/day; daily breakthrough morphine equivalent 28.8 (SD 40.2) mg/day; previous cannabis use: not reported Placebo: 199 participants; 49% men; mean age 59.6 (SD 11.0) years; Caucasian 91%; type of cancer pain: neuropathic (11.6%), somatic (8.5%), visceral (11.1%), mixed (58.3%), bone (10.6%), other (0%); mean pain 5.8 (SD 1.1); daily morphine equivalent maintenance 182.4 (SD 124.3) mg/day; daily breakthrough morphine equivalent 25.3 (SD 38.1) mg/day; previous cannabis use: not reported
Interventions	THC/CBD extract, oromucosal spray; flexible dosage: THC 2.7 mg and CBD 2.5 mg, both per 100 µL (which equalled 1 pump action). Treatment was initiated as a single spray in the evening of the first day of treatment and was gradually increased by 1 additional spray/day (15 minutes apart) according to a prespecified dose escalation protocol until participants experienced/ unacceptable adverse effects, received acceptable pain relief or reached the maximum allowed daily dosage of 10 sprays/day (participants were advised to reach ≥ 3 sprays/day). Mean 6.3 sprays/day Placebo, oromucosal spray: mean 7.4 sprays/day Rescue medication: opioids Allowed cotherapies: not reported
Outcomes	Proportion of participants reporting no worse than mild pain on treatment at 14 days after start of treatment (typically < 30/100 mm on a 100‐mm VAS or < 3 on an 11‐point NRS): not assessed Participant impression to be much or very much improved: Subject Global Impression of Change Withdrawal due to adverse events: no details of assessment reported except that participants completed the Columbia Suicide Severity Rating Scale at every visit and that laboratory tests and vital signs reading were performed at every study visit. Combined responder: not assessed Pain relief ≥ 30%: NRS 0–10, last 24 hours. Calculated by imputation method Pain relief ≥ 50%: NRS 0–10, last 24 hours. Calculated by imputation method Mean pain intensity: NRS 0–10, last 24 hours Sleep problems: sleep disruption score 0–10, last 24 hours Depression: not assessed Anxiety: not assessed Maintenance opioid therapy dose: – Breakthrough opioid therapy dose: – Withdrawals due to lack of efficacy: not reported in detail Nervous system disorders adverse effects: no details of assessment reported except that participants completed the Columbia Suicide Severity Rating Scale at every visit and that laboratory tests and vital signs reading were performed at every study visit. Psychiatric disorders adverse effects: no details of assessment reported except that participants completed the Columbia Suicide Severity Rating Scale at every visit and that laboratory tests and vital signs reading were performed at every study visit. Any serious adverse event: no details of assessment reported except that participants completed the Columbia Suicide Severity Rating Scale at every visit and that laboratory tests and vital signs reading were performed at every study visit.
Notes	Funding: Otsuka Pharmaceutical Development & Commercialisation, Inc, Rockville, Maryland, USA Conflicts of interest: authors declared no conflicts of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details reported.
Allocation concealment (selection bias)	Unclear risk	No details reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Active product peppermint flavoured, placebo coloured and peppermint flavoured.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	ITT analysis; no details reported.
Selective reporting (reporting bias)	Low risk	Data reported as outlined in NCT01361607.
Selection bias	Low risk	No differences in demographic and clinical variables between the study groups at baseline.