Shepherd 2018.

Methods	Study design: randomized controlled trial (2 arms) Study duration: 2015 to 2016 Study setting: hospital, single centre, USA
Participants	Adults participants undergoing transsphenoidal surgery for resection of pituitary tumours Exclusion criteria Allergy or intolerance to acetaminophen, ibuprofen, or opioids Preoperative opioid tolerance, dependence, or abuse Anaphylaxis to opioids History of peptic ulcer disease or recent gastrointestinal bleed requiring surgery Cirrhosis, hepatitis, liver transplant, or abnormal liver function studies Subject unwilling or unable to sign informed consent for the study Pregnancy Incarcerated patients Non‐English speaking and literate or unable to understand the use of a pain scale Body Mass Index < 19 and > 40 kg/m2 Renal failure Mean age (years) 55 Numbers allocated to each arm Group intervention ‐ scheduled IV ibuprofen, scheduled oral acetaminophen, and rescue opioids Group control ‐ scheduled IV placebo, scheduled oral acetaminophen, and rescue opioids Male gender Group intervention: 15/28 Group control: 18/34
Interventions	Technique and timing Intravenous ibuprofen versus placebo Dosage 800 mg every 8 hours with the first dose given intraoperatively
Outcomes	Primary Postoperative pain as measured by the VAS score measured every 4 hours to a max of 48 hours Secondary Breakthrough narcotic requirement Total number of doses and type of any anti‐emetic required postoperatively in both groups The number of patients who did not have a bowel movement during hospitalization in both groups The number of patients in both groups with opioid‐associated adverse events, such as respiratory depression or sedation, using Pasero Opioid‐Induced Sedation Scale Total cost of hospital charges compared between 2 arms Other adverse events Cost of pharmacy charges compared between 2 arms Length of stay in hospital compared between 2 arms Adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote:''Patients were randomised in a 1:1 ratio with blinded treatment assignment. The patients were randomised using a computer‐generated list of random numbers from www.random.org.''
Allocation concealment (selection bias)	High risk	Quotes: ''The randomised list was placed with an ordered list of numbers from 1 to 100. Odd numbers were assigned to Group 1 and even numbers to Group 2.'' ''The research nurse generated the random number sequence and performed the blinded assignment''. This implied that treatment allocation was predictable to the research nurse before the moment of allocation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: ''Patients, family members, bedside nurses, and providers were blinded to treatment assignment. The treatment assignment was known by the research nurse and a research pharmacist''. Blinding was neither well described nor complete.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned in the report who exactly assessed outcomes
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomized patients were included in the analysis.
Selective reporting (reporting bias)	Low risk	Outcomes were reported as specified.
Other bias	High risk	The study was substantially underpowered for its primary outcome. Quote:''Fifty treated patients in each group were required to detect a 2‐point MD on the 11‐point (0–10) VAS, with a standard deviation of 3.2 for the placebo group and 3.5 for the treatment group, with α set at 0.05 and 90% power.''