Greenberg 2017.

Methods	Study design: randomized controlled trial (2 arms) Study duration: Febuary 2012 to September 2015 Study setting: hospital, single centre, USA
Participants	Adults undergoing craniotomy of > 2 hours duration (n = 140) Inclusion criteria Adults undergoing craniotomy of > 2 hours duration Exclusion criteria Opioid or tramadol use daily for > 7 days before study medication administration Chronic pain Hypersensitiviy to opioids or acetaminophen Known or suspected history of alcohol or drug misuse in the 2 years before the proposed surgery Impaired liver function (aspartate aminotransferase/alanine aminotransferase/bilirubin abnormality, Clinically significant liver disease or any other disease suggestive of increased susceptibility to hepatotoxicity with acetaminophen) Taking NSAIDs Taking certain herbal supplements within 14 days of surgery Significant medical disease or laboratory abnormality that in the investigator's judgment could compromise the subject's welfare Mean age, range (years) 58 (18 to 90) Numbers allocated to each arm Group intervention (n = 66) Group control (n = 65) Male gender Group intervention = 26/66 Group control = 29/65
Interventions	Technique and timing Immediately upon the beginning of closure (time 0), 1000 mg of IV acetaminophen (in 100 mL) or 100 mL of IV placebo (normal saline) was administered. The study drug or placebo was then administered every 6 hours thereafter (for a total of 3 additional doses, at 6, 12, and 18 hours). Dosage 1000 mg
Outcomes	Primary Number of participants requiring no hydromorphone equivalents in the first 24 hours Secondary Time to rescue analgesia Total hydromorphone equivalents in the first 24 hours Patient satisfaction Intensive care unit length of stay Hospital length of stay Pain intensity in the first 24 hours (measured at 8, 16 and 24 hours) Delirium Sedation Successful neurological examination Temperature
Notes	Funding Funding in the amount of USD 9000 was provided by Mallinckrodt Pharmaceuticals.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The participants were randomized to receive either placebo (saline) or acetaminophen using a computer‐generated randomization code.
Allocation concealment (selection bias)	Low risk	Quote: ''individual group assignments were concealed in opaque envelopes''.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: ''the clinical providers administering placebo or IV acetaminophen were blinded to the group to which patients were assigned''.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Those assessing outcomes were not aware of treatment received.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	4 participants in the acetaminophen group and 5 participants in the control group did not receive the intervention as intended and were excluded from the final analysis.
Selective reporting (reporting bias)	Low risk	Outcomes were reported as specified.
Other bias	High risk	Study likely not adequately powered, long study duration and multiple outcomes