Eissa 2021.

Study characteristics
Methods	RCT, parallel groups
Participants	15 infants enrolled at 7 trial sites in a global setting Inclusion criteria: Patients < 2 years undergoing routine surgery that, in the investigator’s opinion, would reliably produce moderate‐to‐severe pain requiring opioid treatment. The medication used in these trials was either tapentadol oral solution, to treat subjects from birth with a gestational age of ≥ 37 weeks, or tapentadol IV formulation, to include treatment of preterm neonates (≥ 24 weeks gestational age). Exclusion criteria: Patients with previous exposure to tapentadol, concomitant disease or disorder that could affect or compromise subject's safety during the trial, a history of seizure disorder or brain injury, clinically relevant abnormal pulmonary function, clinically relevant abnormal findings in laboratory, ECG, or vital signs assessment and history or present condition of moderate‐to‐severe renal or hepatic impairment
Interventions	Tapentadol oral solution, 0.75 mg/kg body weight for patients aged 6 months to < 2 years, 0.6 mg/kg for patients aged 1 month to < 6 months, and 0.5 mg/kg for neonates  Tapentadol intravenous Infusion, 0.3 to 0.4 mg/kg depending on the gestational week
Outcomes	Efficacy: total amount of supplemental opioid analgesic medication administered via nurse‐controlled analgesia pump within the first 12 to 24 hours after the first dose of trial medication; time to first administration of supplemental opioid analgesic medication; changes from baseline in pain intensity (FLACC scale) over the treatment period; ratings regarding the patients' overall improvement Safety/tolerability: adverse events
Notes	Authors were paid or employed by Grünenthal GmbH. Funding source: Grünenthal GmbH
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported Quote: "Patients were randomly allocated (2:1) to receive either tapentadol OS or a matching placebo OS".
Allocation concealment (selection bias)	Unclear risk	Not reported Quote: "Patients were randomly allocated (2:1) to receive either tapentadol OS or a matching placebo OS".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Reported as double‐blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Reported as double‐blinded; unclear if outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	All included patients accounted for in the results
Selective reporting (reporting bias)	Low risk	All planned outcomes/endpoints were reported.
Other bias	Low risk	None