Lichtman 2018.

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: 114 centres in the 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: 5–14 days' screening, 4 weeks' double‐blind (2 weeks' titration, 3 weeks' stable dosage)
Participants	Type of cancer: not reported Inclusion criteria: advanced cancer, aged ≥ 18 years, clinical diagnosis of 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). The maintenance opioid was preferably a sustained‐release formulation, but a 24‐hour immediate‐release formulation was acceptable. To be eligible, participants also had to fulfil the following criteria on each of 13 consecutive days during the screening period: ≤ 4 opioid breakthrough analgesic episodes/day (mean over 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 (i.e. ≤ 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 any history of schizophrenia or substance abuse. 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: 199 participants; 55.8% men; mean age 59.2 (SD 12.0) years; Caucasian 93.0%; type of cancer pain: neuropathic (13.1%), somatic (5.0%), visceral (13.1%), mixed (48.2%), bone (19.6%), other (1.0%); mean pain 5.6 (SD 1.2); daily morphine equivalent maintenance 167.5 (SD 118.8) mg/day; daily breakthrough morphine equivalent 25.4 (SD 38.3); previous cannabis use: not reported Placebo: 198 participants; 52.0% men; mean age 60.7 (SD 11.1) years; Caucasian 93.4%; type of cancer pain: neuropathic (12.6%), somatic (3.0%), visceral (14.1%), mixed (54.0%), bone (16.2%), other (0%): mean pain 5.6 (SD 1.2); daily morphine equivalent maintenance 159.7 (SD 121.2) mg/day; daily breakthrough morphine equivalent 26.4 (SD 40.4); 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). Mean spray in nabiximols group: 6.4 sprays/day Placebo, oromucosal spray: mean spray in nabiximols group: 7.3 sprays/day Rescue medication: opioids Allowed cotherapies: (quote) "Whenever possible, stable doses of other prescribed pain medications were continued during the study period."
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 Patient impression to be much or very much improved: PGIC 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 Pain relief ≥ 30%: 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: mg/day Breakthrough opioid therapy dose: mg/day. SD calculated from P value Withdrawals due to lack of efficacy: 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. 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	Sponsor: Otsuka Pharmaceutical Development & Commercialisation, Inc, Rockville, Maryland, USA. The efforts of AH Lichtman were supported by the Virginia Commonwealth University School of Pharmacy start‐up funds. 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	Unclear risk	No details reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	ITT analysis by last observation carried forward method.
Selective reporting (reporting bias)	Low risk	All outcomes reported as outlined in NCT01262651.
Selection bias	Low risk	No differences in demographic and clinical variables between the study groups at baseline.