Taddio 2006.

Study characteristics
Methods	Double‐blind, randomized controlled trial
Participants	132 newborns: the study participants were medically stable neonates who required insertion of a PICC and were receiving ventilatory support in the form of high‐frequency oscillation, conventional ventilation, or continuous positive airway pressure. Exclusion criteria: clinical seizures, concomitant muscle relaxant or inotrope therapy, or skin disorders with visually apparent skin lesions or disruptions in skin integrity. Intravenous morphine group (n = 38; mean GA 29.6 SD 4.9 weeks; BW 1380 SD 900 g) Tetracaine group (n = 42; mean GA 30 SD 5.1 weeks; BW 1450 SD 900 g) Tetracaine and morphine group (n = 31; mean GA 28.9 SD 4.6 weeks; BW 1300 SD 830 g) No analgesia group: not randomized (n = 21; mean GA 27.5 SD 3.4 weeks; BW 900 SD 400 g)
Interventions	Morphine group: 0.1 mg/kg delivered over 20 minutes, single dose, intravenously Tetracaine group: 0.5 g of 4% single dose, gel applied to the insertion site Tetracaine and morphine group: tetracaine: 0.5 g of 4% single dose, gel applied to the insertion site; morphine: 0.1 mg/kg delivered over 20 minutes, single dose, intravenously No analgesia group: not randomized
Outcomes	Facial grimacing (brow bulge) scored in 2‐second intervals for the first 20 seconds of each phase of the procedure, safety assessment (blood pressure and ventilatory support (at 15, 30, and 60 minutes after the beginning of the infusion), local skin reactions)
Funding sources	Funding for this study was provided by the Canadian Society of Hospital Pharmacists. Dr Taddio is supported by the Canadian Institutes of Health Research New Investigator Award. Ms Lee was supported through a studentship by the Ontario Student Opportunity Trust Fund–Hospital for Sick Children Foundation Student Scholarship Program.
Declaration of interest among the primary researchers	The authors did not report any financial disclosures.
Notes	Quote: "Identical‐appearing placebos were available for both tetracaine and morphine (ie, double dummy), so that all neonates received either tetracaine or placebo applied to the insertion site and all neonates received either morphine or placebo infusions prior to the procedure."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "using a computerized random‐number generator" "Concealment of treatment allocation was achieved by having the research pharmacist prepare the randomization assignment before enrollment of neonates using a computerized random‐number generator, stratified by corrected gestational age (30 weeks, 30‐36 weeks, or 36 weeks) and in random block sizes of 6 or 9, with an equal probability of being allocated to each active treatment"
Allocation concealment (selection bias)	Low risk	Quote: "The randomization assignment was stored in a secure location that could not be accessed by study personnel"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Identical‐appearing placebos were available for both tetracaine and morphine (ie, double dummy), so that all neonates received either tetracaine or placebo applied to the insertion site and all neonates received either morphine or placebo infusions prior to the procedure"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The facial grimacing activity of the neonates, expressed as the proportion of time that the neonate had bulging of the brow, was assessed by a trained research assistant who was unaware of treatment assignment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Outcomes are reported for all randomized infants—see Figure Flow of Study Participants"
Selective reporting (reporting bias)	Low risk	Quote: "ClinicalTrials.gov Identifier NCT00213200"
Other bias	Low risk	None

BW: birthweight; CRIES: Crying Requires oxygen Increased vital signs Expression Sleep; DAN: Douleur Aiguë Nouveau‐né; EEG: electroencephalography; GA: gestational age; HR: heart rate; IL6: interleukin 6; IL8: interleukin 8; IQR: interquartile range; NICU: neonatal intensive care unit; NIPS: Neonatal Infant Pain Scale; PICC: peripherally inserted central catheter; PIPP: Premature Infant Pain Profile; PIPP‐R: Premature Infant Pain Profile ‐ Revised; ROP: retinopathy of prematurity; RR: respiratory rate; SaO_²: saturation of oxygen; SD: standard deviation; TNF‐α: tumor necrosis factor alpha