Simons 2003.

Study characteristics
Methods	Randomised double‐blind placebo‐controlled trial in 2 NICUs
Participants	150 ventilated neonates Inclusion criteria: all neonates admitted to NICU who required mechanical ventilation; postnatal age < 3 days; ventilation < 8 hours Exclusion criteria: severe asphyxia; severe IVH; major congenital malformations; facial malformations; neurological disorders; continuous or intermittent treatment with neuromuscular blockers
Interventions	Morphine group (n = 73): loading dose 100 mcg/kg followed by 10 mcg/kg/hour continuous infusion Placebo group (n = 77): sodium chloride in 5% glucose Masked treatment was continued for 7 days or less (as for clinical conditions); after 7 days, study medication was weaned or stopped, or was replaced by open‐label morphine infusion During study period, additional morphine was allowed if patients from either group were judged to be in pain or distress based on decisions of the attending physician
Outcomes	Primary outcomes: pain response: PIPP, NIPS, and visual analogue scale at standardised time points Secondary outcomes: incidence of all grades of IVH and poor neurological outcome (severe IVH, PVL, or death); duration of MV; length of NICU stay; incidence of comorbidity (chronic lung disease; sepsis; necrotising enterocolitis; PDA); number of painful procedures; MAP; administration of volume expanders and vasopressor drugs; number of infants with hypotensive MAP measurements as compared with "normal" values of BP; concentrations of adrenaline and noradrenaline in arterial blood plasma Primary and secondary outcomes were measured during hospital stay and were reported by Simons 2003 and Simons 2005 Follow‐up outcomes: At 5 years (reported by de Graaf 2011 and de Graaf 2014): IQ score (measured by short version of the Revision Amsterdam Child Intelligence Test); visual motor integration (assessed with the Beery‐Buktenica Developmental Test of Visual‐Motor Integration); T‐scores from Child Behavior Checklist (CBCL) completed by parents and teachers; chronic pain (assessed by the Dutch Chronic Pain Questionnaire completed by parents); health‐related quality of life (by Health Utility Index scores); diurnal rhythm of cortisol concentration At 8 or 9 years (reported by de Graaf 2013 and Valkenburg 2015): IQ score (measured by short version of the Wechsler Intelligence Scale for Children III); visual motor integration (assessed with the Beery‐Buktenica Developmental Test of Visual‐Motor Integration); T‐scores from CBCL completed by parents and teachers; executive function skills; reaction time 1‐ and 5‐choice; spatial span forward and backward; rapid visual information processing; spatial planning and spatial working memory test; ability to acquire rules and adjust to set shifting; ability to inhibit a response; executive function behaviour in daily life. Thermal sensitivity, chronic pain, and minor neurological dysfunction were also evaluated
Notes	Data on duration of ventilator days were presented for the first period (NICU stay) and as total duration of ventilator days during admission. Data from the first period were used for the meta‐analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Method of randomisation: computer‐generated randomisation list to select 10 random permuted blocks stratified into 5 groups of gestational age ranges
Allocation concealment (selection bias)	Low risk	Allocation concealment was ensured
Blinding of participants and personnel (performance bias)	Low risk	Blinding of caregivers was attained
Blinding of outcome assessment (detection bias)	Low risk	Blinding of assessors was attained
Incomplete outcome data (attrition bias)	Low risk	There was no loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Trial not registered; protocol not available
Other bias	Low risk	Study appears to be free of other sources of bias