Anand 1999.

Methods	Multi‐centre, randomised, double‐blind, placebo‐controlled pilot study (NOPAIN trial) 1. Blinding of randomisation ‐ yes 2. Blinding of intervention ‐ yes 3. Complete follow‐up ‐ yes 4. Blinding of outcome measure ‐ yes
Participants	Preterm infants from 24 to 32 weeks' gestational age at ≤ 72 hours' postnatal age who were ventilated for < 8 hours were eligible for inclusion. Exclusion criteria: major congenital anomalies, severe intrapartum asphyxia (5‐minute Apgar score ≤ 3), participation in other studies interfering with the NOPAIN trial procedures 67 infants were randomised. Demographic data: values presented as means (SDs) Midazolam group (n = 22) Gestational age: 28.6 weeks (2.5 weeks) Birth weight: 1245 grams (445 grams) Entry weight: 1224 grams (491 grams) Male: 54.5% Duration of infusion: 122.2 hours (122.1 hours) CRIB score: 5.7 (3.5) Morphine group (n = 24) Gestational age: 29.2 weeks (2.2 weeks) Birth weight: 1230 grams (475 grams) Entry weight: 1265 grams (501 grams) Male: 46.2% Duration of infusion: 81.0 hours (94.1 hours) CRIB score: 4.5 (3.1) Placebo (10% dextrose) group (n = 21) Gestational age: 28.1 weeks (2.2 weeks) Birth weight: 1049 grams (419 grams) Entry weight: 1188 grams (524 grams) Male: 57.1% Duration of infusion: 121.1 hours (120.8 hours) CRIB score: 6.6 (4.0)
Interventions	Midazolam was given as 200 microgram/kg loading dose followed by infusion of 20 microgram/kg/h, 40 microgram/kg/h or 60 microgram/kg/h for those whose gestational age was 24 to 26 weeks, 27 to 29 weeks or 30 to 33 weeks, respectively. Morphine was given as 100 microgram/kg loading dose, followed by infusion of 10 microgram/kg/h, 20 microgram/kg/h or 30 microgram/kg/h for those whose gestational age was 24 to 26 weeks, 27 to 29 weeks or 30 to 33 weeks, respectively. Additional analgesia was given, as needed, by intravenous morphine boluses at the discretion of the clinical team. The amount and frequency of additional morphine were recorded as an outcome measure. Infusions were weaned according to a set protocol. Maximum duration of study treatment was 14 days.
Outcomes	Severity of illness was measured by the CRIB score (The International Neonatal Network) and the NMI (Korner 1993). Primary outcome Incidence of adverse neurological events (neonatal death, grade III or IV IVH, PVL) Secondary outcomes Level of sedation, as measured by the COMFORT score (Ambuel 1992). Pain response to tracheal suctioning, as assessed by the PIPP (Stevens 1996). All of these scores were assessed before the start of study treatment, after 24 hours of infusion and at 10 to 12 hours after discontinuation of treatment. Incidence of pneumothorax, days of ventilatory support, continuous positive airway pressure and oxygen, length of intensive care unit and hospital stay and neurodevelopmental outcomes were measured by NAPI cluster scores (Korner 1991) at 36 weeks' corrected gestational age.
Notes	Balanced randomisation by blocks stratified by each participating centre. Randomisation was performed by a 24‐hour automated telephone response system. Reasons for non‐enrolment were provided. Finnegan Neonatal Abstinence Scale (Finnegan 1975) was administered at 12 and 24 hours after discontinuation of study infusion, then daily. This study was supported by industry: Astra Pain Control, Södertälje, Sweden.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Balanced randomisation was done in blocks, stratified by each participating centre via a 24‐hour automated telephone response system that was available 24 hours a day for authorised users at each site.
Allocation concealment (selection bias)	Low risk	Following enrolment, randomised group allocation was faxed to the participating NICU and hospital pharmacy. Only 1 pharmacist at each site had access to the codes regarding drug assignment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Physicians, nurses and all NICU staff were masked to the identity of study drug.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Physicians, nurses and all NICU staff were masked to the identity of study drug.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcomes were reported on all infants enrolled in the trial.
Selective reporting (reporting bias)	Unclear risk	The protocol for the study was not available to us, so we cannot ascertain whether deviations from the protocol occurred.
Other bias	Low risk	Trial appears free of other bias.