Hardy 2012.

Methods	Randomised. Double‐blind, but blinding procedure not described. Placebo control. Parallel group Study duration 5 days
Participants	Inpatients aged 18 or older, palliative care patients with refractory chronic pain (BPI average pain score ≥3 despite ongoing treatment with opioids and co‐analgesics at predefined dose levels) secondary to cancer or its treatment N= 185, 93 randomised to ketamine group, 92 randomised to placebo Mean age in ketamine arm: 63 years. Mean age in placebo group: 64.3
Interventions	Participants received either ketamine or placebo (normal saline) as a subcutaneous infusion in a 5‐day schedule, starting at the first dose level (100 mg/24 hrs. If 80% of the study drug had been delivered, and average pain improved by ≥ 2 BPI units, with no more than four breakthrough doses, the dose remained the same. If not, the dose was increased to the next level.
Outcomes	The primary outcome was a positive response, defined as a clinically relevant improvement in pain at the end of the 5‐day study period. A clinically relevant improvement in pain was defined as a reduction in BPI average pain score by ≥ 2 points from baseline in the absence of more than four breakthrough doses of analgesia over the previous 24 hours. Secondary outcomes: pain assessments at days 2‐5. Adverse events.
Notes	Data for patients who discontinued due to reasons unrelated to the intervention were imputed using LOCF. Unclear how data for those who discontinued due to adverse effects or lack of effect were handled. Quality/validity: OPVS: 12 Oxford: 4 Supported by a grant from the Palliative Care Branch, Australian Government Department of Health and Ageing
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised, process of randomisation is described and adequate. "Each site pharmacy used randomization tables from an independent central registry"
Allocation concealment (selection bias)	Low risk	"All non pharmacy study staff, treating clinicians,investigators and participants were unaware of treatment allocation until completion".
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Described as blinded. Blinding procedure not described in final paper but was described in protocol "All syringes will look identical in volume and colour". The authors of this review update felt that blinding could have been compromised due to adverse effects from ketamine.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No specific procedure to check for detection bias. The authors of this review update felt that blinding could have been compromised due to adverse effects from ketamine
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear how missing data were imputed
Selective reporting (reporting bias)	Unclear risk	Total opioid dose was not reported but was mentioned in the protocol
Size	Unclear risk	50 ‐ 199 participants per treatment arm