6. Opioids.

RCT ID	Population	Intervention	Comparison	Outcomes	Notes
Anand 1999	67 preterm infants; 24 to 32 GA; intubated and required ventilatory support for less than 8 h; ostnatal age ≤ 72 h Mean GA ± SD: 28.6 ± 2.5 in midazolam group, 29.2 ± 2.2 in morphine group, 28.1 ± 2.2 in PLA group Mean BW ± SD: 1245 ± 445 in midazolam group; 1230 ± 475 in morphine group; 1049 ± 419 in PLA group	Group 1: morphine sulfate (0.05 mg/mL in 10% dextrose) as infusion. N = 24	Group 2: midazolam hydrochloride (0.1 mg/ml in 10% dextrose). N = 22 Group 3: placebo (10 % dextrose). N = 21	Level of sedation, PIPP after 24 h of continued infusion and at 10 to 12 h after stopping infusion. ITT analyses for: neonatal death (poor neurologic outcomes at 0 to 28 days of age without discharge from the NICU); germinal matrix hemorrhage‐intraventricular hemorrhage (GMH‐IVH) grade III or IV, PVL; severity of illness (with Neonatal Medical Index Grade). Secondary outcomes: analgesia and sedation, weight gain, incidence of pneumothorax, duration of respiratory support (ventilatory support, continuous positive airway pressure, oxygen), length of NICU stay and hospital stay, neurobehavioral assessment scores (NAPI) at 36 weeks after conception. Outcomes related to enteral feeding (full strength, full‐volume NG and PO). Number of children receiving additional doses of morphine sulfate analgesia on day 1, 2, 3, 4 and 14 after starting the drug infusion.	All (morphine, midazolam and PLA) were received as infusion. Additional analgesia provided with intravenous morphine doses was allowed. All study population included in this overview.
Anand 2004	898 ventilated preterm neonates (23 to 32 wk of GA), intubated within 72 h of birth, and ventilated for less than 8 h. Mean/median GA not reported.	Morphine (n = 449): loading dose 100 mcg/kg infused over 1 h, followed by a continuous infusion of 10, 20 or 30 mcg/kg/h for infants of GA 23 to 26, 27 to 29, or 30 to 32 weeks, respectively; continued as long as clinically justified (maximum 14 days).	Unspecified placebo N = 449	Primary outcomes: GMH‐IVH (grade III or IV); PVL, neonatal death, composite outcome (sIVH, PVL, and/or neonatal death.	Analgesia with bolus doses of the study drug or increases in the infusion rate were not permitted. All study population included in this overview.
Ancora 2013	131 newborns (≤ 32 + 6 wk of GA; 22 to 32 weeks), mechanically ventilated through an endotracheal tube during first 72 hours of life. Median GA with range: 26 (22 to 32 in PHE group; 26 (22 to 31 in PLA group. Infants with sIVH and intraparenchymal hemorrhage according to the Volpe classification, cystic periventricular leukomalacia were excluded.	Fentanyl (intravenous loading dose of 1 µg/kg in 30 min, followed by a continuous intravenous infusion of 1µg/kg/h Infants treated with a bolus of fentanyl for endotracheal intubation did not receive the loading dose if fentanyl had to be initiated within 1 hour after intubation. N = 64	Placebo (continuous infusion of placebo) N = 67	Primary outcome: analgesic efficacy of continuous fentanyl infusion with pain scale. Safety measures: use of mechanical ventilation at 1 wk of age; duration of the first cycle of mechanical ventilation (hrs), age at full enteral feeding, age at first meconium passage (hours); GMH‐IVH, cystic periventricular leukomalacia, or death within 28 days of life; chest wall rigidity; and bladder size during the first week of life; diuresis, blood pressure, and the use of vasopressors.	Additional treatment: open‐label boluses of fentanyl.
Chen 2015	30 neonates who received mechanical ventilation (28 to 39 wks of GA; birth weight 1050 to4070 g); ventilated for more than 24 h; with diseases including neonatal pneumonia, neonatal respiratory distress syndrome, neonatal aspiration pneumonia, and neonatal wet lung. Median/mean GA not reported. Age at the time of intervention not specified.	Fentanyl (an intravenous bolus injection, 2 μg/kg for > 10 min, followed by continuous intravenous infusion, 2 μg/kg per hour (dose according to the degree of pain). N = 15 Additionally, the drug intervention group received fentanyl as the analgesic treatment.	Control group: no analgesics given N = 15	HR, respiratory rate, blood pressure changes, and PIPP score measured before treatment and at 30 min, 2 h, and 4 h after treatment; mental development index and psychomotor development index measured at 3, 6, 9 and 12 mo after discharge.
Dyke 1995	26 preterm infants (29 to 36 wks of GA) with hyaline membrane disease requiring ventilatory assistance on the first day after birth.	Morphine (1 mg/ml in 5% dextrose; a loading dose 100 µg/k over 30 min followed by continuous intravenous infusion at 10 µg/kg per h). N=12	Placebo (5% dextrose, infused as intervention) N=14	Primary outcomes: HR, blood pressure, respiratory rate and interaction of spontaneous respiration with mechanical ventilation. Secondary outcomes: duration of oxygen therapy, ventilator therapy, hospitalization, incidence of bronchopulmonary dysplasia, periventricular hemorrhage and pneumothorax.	Infusion continued until weaning from MV or for a maximum of 48 h therapy. Pancuronium allowed for infants not stabilized by ventilatory adjustment and markedly asynchronous with their ventilator. All study population included in this overview.
e Silva 2008	20 premature neonates (28 to 34 wks) with respiratory distress syndrome, mechanically ventilated; requiring elective tracheal intubation and surfactant therapy. Mean GA ± SD: 31.35 ± 1.67 in morphine group; 31.27 ± 1.46 in remifentanil group Infants with birth weight < 1000 g were excluded.	Morphine (intravenous bolus 150 µg/kg‐1) N = 10	Remifentanil (intravenous bolus 1 µg/kg‐1) N = 10	The length of time to awaken and extubate the neonate after interrupting opioid administration; stress (COMFORT scale), pain response (NIPS), hemodynamic and ventilatory variables; adverse effects secondary to infusion of the specific opioid.	Additional treatment: midazolam 200 µg/kg‐1.
Guinsburg 1998	22 preterm infants (≤ 32 wks; postnatal age of 12 to 48 h), intubated and mechanically ventilated since birth; with an indwelling arterial umbilical line. Mean GA ± SD: 31 ± 1 in fentanyl group; 30 ± 2 in PLA group. Infants with grade III to IV intraventricular hemorrhage were excluded.	Fentanyl (single dose, 3 µg/kg) N = 11	Placebo (0.2 ml of normal saline) N = 11	HR, blood pressure, arterial blood gases, ventilator settings, and behavioral measures (Neonatal Facial Coding System and Modified Postoperative Comfort Score) at 30 and 60 min after drug administration; blood cortisol, growth hormone, glucose, and lactate were measured before and at 60 min after analgesia; behavioral measures were assessed at the bedside and from video films recorded during each observation period.	Both fentanyl and placebo were injected slowly over 2 min. All study population included in this overview.
Ionides 1994	25 MV infants Mean GA ± SD: 33.9 ± 1.8 in fentanyl group; 32.9±1.6 in morphine group	Fentanyl citrate (single intravenous dose, 3 µg/kg) N = 10	Morphine sulfate (single intravenous dose, 0.1 mg/kg) N = 12	Plasma Β‐endorphin level, HR, blood pressure.	In our analysis, only preterm groups (fentanyl and morphine) were included. 9 infants received pancuronium, and 6 of these infants also received opiates.
Lago 1998	55 preterm infants (26 to 34 wks GA), requiring intermittent mandatory ventilation for hyaline membrane disease with indwelling catheters, first 24 hours of life. Mean GA ± SD: 31(2) in fentanyl group, 31 (2) in control group	Fentanyl (given at 0.5 to 2.0 µg/kg/h and adjusted to render the neonate sedated) N = 26	No treatment N = 27	Behavioral sedation score, urinary metanephrine, the normetanephrine: creatinine molar ratio measured at 0, 24, 48 and 72 h; ventilatory indexes; need for surfactant replacement, evidence of clinically significant patent ductus arteriosus, incidence of air leak (pulmonary emphysema and pneumothorax), bronchopulmonary dysplasia, GMH‐IVH, periventricular leukomalacia, days of ventilatory support and oxygen treatment, days of exclusive enteral feeding, growth and hospital stay.	All study population included in this overview.
Lago 1999 (conference abstract)	27 preterm (> 28 wks GA) with RDS and conventionally ventilated Mean/median GA not reported Age at the time of intervention not specified.	Fentanyl (continuous venous infusion 1.5 µg/kg/h, scaled down by 0.5 µg/kg/h every 24 h, for a total 72 h of infusion) N = 13	Placebo (infusion of 5% glucose solution) N = 14	Peak inspiratory pressure, respiratory rate, tidal volume and minute ventilation, along with arterial blood gas and electromyographic activity, a sedation score.	All study population included in this overview.
Liem 1999	8 preterm infants (29.9 to 32.1 wks GA) who needed MV Ranges of GA: 30.7 to 32 in midazolam group; 29.9 to 32.1 in morphine group. Age at the time of intervention not specified.	Morphine (a loading dose of 0,05 mg/kg, maintenance 0.001 mg/kg/h) N = 4	Midazolam (a loading dose 0.2 mg/kg, maintenance 0.2 mg/kg/h) N = 4	Concentration changes of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin in the brain, changes in cerebral blood flow velocity in the internal carotid artery (in %) determined before and at 15, 30, and 60 min after sedation.
Naderi 2017	32 newborns (26 to 38 wks of GA) undergoing intubation and mechanical ventilation (for at least 24 h); following RDS, bacterial pneumonia, viral pneumonia, and other respiratory problems for at least 24 h during a period of 12 months. Mean GA ± SD: 31.6 ± 4.7 in fentanyl group; 31.0 ± 4.2 in morphine group	Morphine (a loading dose of 100 mcg/kg in the first hour, and a maintenance dose of 12 mcg/kg/h for the next 24 h, injected intravenously) n = 16	Fentanyl (loading dose of 2 mcg, and with a maintenance dose of 0.25 mcg/kg/h, intravenously injected slowly) n = 16	Ultrasonographic measurements of gallbladder dimensions (length, width, depth and volume) as well as the occurrence of hydrops of gall bladder.
Orsini 1996	20 premature infants undergoing MV for RDS in the first 24 h of life, with indwelling arterial catheter, > 1000 g BW Mean GA ± SD: 31.6 ± 2.8 in fentanyl group, 29.9 ± 3.2 in PLA group	Fentanyl (continuous infusion; a 5 mcg/kg bolus infused for 20 min, followed by 2 mcg/kg/h for 72 h, then decreased to 1 mcg/kg/h for the next 24 h and 0.5 mcg/kg/h for the final 24 h; then the infusion was discontinued; total: 5 days) N=11	Placebo (5% dextrose in water; volume‐matched infusion) N = 9	Behavioral state score, cortisol and 11‐deoxycortisol levels, 24‐h urine collection for 3‐methyl histidine/creatinine molar ratio and urea excretion, arterial blood gases, heart rate, IMV, PIP, PEEP	Other analgesics, sedatives, and muscle relaxants were precluded from being administered. All study population included in this overview.
Qiu 2019	60 preterm infants (< 32 wks of GA), admitted in the first 72 h after birth and mechanically ventilated Mean GA ± SD: 31.08 ± 2.02 in fentanyl group; 30.32 ± 2.03 in PLA group Infants with significant parenchymal brain injury (grade IV GMH‐IVH or PVL) were excluded.	Fentanyl (an intravenous loading dose of 1 μg/kg in 30 min, followed by a continuous intravenous infusion of 1 μg/kg/h, immediately after using MV) n = 30	Placebo (continuous infusion of 5% glucose at the same rate as fentanyl) n = 30	Gas analysis (pH, PaO2, PaCO2, SaO2), cardiovascular parameters (MABP, HR, cardiac output), ventilatory parameters (PIP, positive end‐expiratory pressure, MAP and FiO2) before administration, and 1, 12, 24, 48 and 72 h after start of infusion. PIPP, cerebral blood flow velocity, neuron‐specific enolase concentrations in plasma samples, cerebral function monitoring.	Dose of fentanyl/glucose was decreased to 0.5 mcg/kg/hour when default parameters for MV were as follows: FiO2 < 25%, RR < 25 bpm, and MAP < 7 cmH2O. 30 minutes later, MV was stopped after discontinuation of infusion.
Quinn 1992	95 premature newborns (≤ 34 wks of GA), with hyaline membrane disease, RDS requiring MV; postnatal age > 4 h and < 48 h; no prior treatment with narcotic analgesics or neuromuscular blocking agents; struggling against the ventilator. Median GA with range: 29 (24 to 34) in morphine group; 28 (24 to 32) in pancuronium group; 28 (24 to 33) in morphine+pancuronium group	Group 1: morphine (continuous infusion at a dose of 50 mcg/kg/h, increased to 100 mcg/kg/h if infant continued to struggle after 2 h on lower dose) N = 29	Group 2; pancuronium (100 mcg/kg/h, given as required to inhibit spontaneous respiration) N = 28 Group 3: morphine with pancuronium (morphine by infusion at a dose of 50 mcg/kg/h and intermittent pancuronium 100 mcg/kg as required; dosage of morphine was not increased) N = 38	Plasma catecholamine levels, BP, HR. ventilatory requirements (peak inspiratory pressure and oxygen concentration), at entry and at 6 h. Outcomes: GMH‐IVH, air leak, patent ductus arteriosus, duration of mechanical ventilation in days, drug therapy, death of the infants.	Babies in morphine group who continued to ‘light the ventilator’ after 4 h on the morphine infusion (2 h at 50 pg/kg per h + 2 h at 100 kg per h ) were allowed to be given pancuronium (N = 7). Babies in pancuronium group were given morphine analgesia if a painful procedure was performed (N = 4). Drug therapy continued until FiO2 < 0.45; 1 infant stopped treatment within 24 h because FiO2 fell below 0.45. Group 3 (morphine with pancuronium) was not included in our review.
Quinn 1993	41 MV infants (≤ 34 wks of GA) who were treated with surfactant (Curosurf) for hyaline membrane disease (clinically and radiologically confirmed), and have arterial line in situ, and an arterial/alveolar oxygen ratio below 0.22.	Morphine (in 5% dextrose; 2 mL per h for each kg birthweight for 2 h as a loading infusion, then 0 to 5 mL per h for each kg birthweight as a continuous infusion; 100 mcg/kg/h for 2 h, followed by 25 mcg/kg/h of continuous infusion) N = 21	Placebo (5 % dextrose) N = 20	Pain assessment (with validated score); GMH‐IVH, pneumothorax, patient ductus arteriosus, duration of intubation in completed days, death during the first 6 months of life. Blood pressure, HR and ventilator settings (i.e. peak inspiratory pressure, oxygen concentration), and catecholamine, adrenaline, noradrenaline concentrations were reported.	Infusion of both started 1h after first dose of Curosurf. All study population included in this overview. Treatment until the baby had recovered sufficiently to be weaned from ventilation.
Saarenmaa 1999	163 newborns (≥ 24 wks of GA) who underwent intubation and MV after birth (for at least 1 day), an indwelling arterial line, no chromosomal aberrations or major abnormalities, during first days of life Median GA with IQR: 31.7 (29.4 to 37.0) in fentanyl group, 31.0 (28.9 to 35.3) in morphine group	Fentanyl (a loading dose of 10.5 mcg/kg over 1 h, followed by a maintenance rate of 1.5 mcg/kg/h for at least 24 h) N = 83	Morphine (a loading dose of 140 mcg/kg over 1 h, followed by a maintenance rate of 20 mcg/kg/h for at least 24 h) N = 80 .	The severity of pain, behavioral pain (adapted NIPS scale), stress hormone concentrations (catecholamines; beta‐endorphin) before and 2 and 24 h after start of intervention; decreased gastrointestinal motility, necrotizing enterocolitis, retention.	Additional analgesia with opioid boluses was allowed. The bolus, equal to a 1‐h maintenance infusion dose, could be given 4 times a day at the most. Muscle relaxation could be used if the infant was struggling against the ventilator despite analgesia. All study population included in this overview.
Simons 2003	150 newborns who had received ventilatory support, postnatal age < 3 d and ventilation for less than 8 h, indwelling (peripheral or umbilical) arterial catheter, admitted to NICU. Median GA (IQR) of 29.1 wks (27.4 to 31.6) in morphine group; and 29.2 wks (27.3 to 31.4) in placebo group Infants with sIVH were excluded.	Morphine (intravenous; a loading dose of 100 mcg/kg, followed by continuous infusion of 10 mcg/kg per h) N = 73	Placebo (sodium chloride infusion, the same dosages as morphine) N = 77	Primary outcome: analgesic effect (measured before, 30 min after loading dose and twice daily at a standardized time point before, during and after endotracheal suctioning; NIPS, Visual Analogue Score and PIPP). Secondary outcomes: poor neurologic outcome defined as sIVH, PVL, or death within 28 days and the incidence of all grades of GMH‐IVH. Other: duration of artificial ventilation, length of NICU stay, incidence of comorbidity, number of painful procedures.	Both morphine and PLA were dissolved in 5% glucose, and both were given for 7 days (or less because of clinical necessity in severe cases). Additional morphine based on physician decision was allowed. All study population included in this overview.
Siwiec 1999 (conference abstract)	20 infants (26 to 35 wks of GA), receiving MV, BW 810 to 2750 g Mean/median GA not reported.	Morphine (loading dose 100 mcg/kg over 30 min followed by continuous infusion of 20 mcg/kg/h for 1 to 5 days) N = 10 (reported in the Cochrane Review)	Control: no treatment N = 10 (reported in the Cochrane Review)	Pain (PIPP), comfort score, assessed prior to the treatment then at 6, 12, 24 hrs of age, HR, blood pressure, and ventilatory parameters assessed more frequently. Mean airway pressure, ventilatory rate or FIO2, pneumothorax, GMH‐IVH, PVL, bronchopulmonary dysplasia.	All study population included in this overview.
Wood 1998	88 preterm neonates (< 35 wks of postconceptional age at birth), 2 to 48 h of postnatal age at trial entry, requiring IPPV and sedation; indwelling intra‐arterial access. Median GA with IQR: 28 (26 to 30) in morphine group; 27 (26 to 29) in diamorphine group	Morphine (a loading dose of 200 mcg/kg over 2 h, followed by maintenance infusion of 25 mcg/kg/h) N = 44	Diamorphine (120 mcg/kg over 2 h, followed by maintenance infusion of 15 mcg/kg/h) N = 44	Arterial blood pressure, HR, PaO2 (or SaO2), temperature, intermittent arterial blood gas sampling; mean arterial blood pressure recorded when starting infusion and at 2, 6, 24 h. The use of initiation of inotropic support over the first 24 h of infusion.

BW = birth weight; CPAP = continuous positive airway pressure; FiO₂ = fraction of inspired oxygen; GA = gestational age, in weeks; GMH‐IVH = germinal matrix hemorrhage‐intraventricular hemorrhage; h = hour; HR = heart rate; IMV = intermittent mechanical ventilation; IPPV = intermittent positive pressure ventilation; IQR = interquartile range; ITT= intention to treat; MAP = mean airway pressure; MABP = mean arterial blood pressure; min = minute; mo = months; MV = mechanical ventilation; NAPI = neurobehavioral assessment scores; NG = nasogastric; NICU = neonatal intensive care unit; NIPS = Neonatal Infant Pain Scale; PEEP = positive end‐expiratory pressure ; PIP = peak inspiratory pressure; PIPP = premature infant pain profile; PLA = placebo; PO = per os; PVL = periventricular leukomalacia; RCT = randomized controlled trial; RDS = respiratory distress syndrome; RR = respiratory rate; SaO₂ = oxygen saturation; sIVH = severe intraventricular hemorrhage; wk = week.