Comparison 1. Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Pain (PIPP)	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1.1 < 12 hours after infusion	2	50	Mean Difference (IV, Fixed, 95% CI)	‐5.74 [‐6.88, ‐4.59]
1.1.2 ≥ 12 and < 48 hours after infusion	3	963	Mean Difference (IV, Fixed, 95% CI)	‐0.98 [‐1.35, ‐0.61]
1.1.3 Multiple time points (e.g. during endotracheal suctioning)	1	150	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.73, 0.93]
1.2 Pain (NFCS)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.2.1 < 12 hours after infusion	1	22	Mean Difference (IV, Fixed, 95% CI)	0.19 [‐1.15, 1.53]
1.3 Pain (NIPS)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.3.1 Multiple time points (e.g. during endotracheal suctioning)	1	150	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.72, 0.34]
1.4 Pain (COMFORTneo)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.4.1 ≥ 12 and < 48 hours after infusion	2	65	Mean Difference (IV, Fixed, 95% CI)	‐3.33 [‐4.98, ‐1.68]
1.5 Duration of ventilation (days)	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.5.1 All studies	7	1259	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.38, 0.83]
1.5.2 With no dose adjustments or open‐label boluses	3	111	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.62, 0.67]
1.5.3 Very preterm infants only	3	1003	Mean Difference (IV, Fixed, 95% CI)	0.17 [‐0.47, 0.80]
1.6 Neonatal mortality	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.6.1 All studies	5	1189	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.80, 1.55]
1.6.2 With no dose adjustments or open‐label boluses	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.32, 4.98]
1.6.3 Very preterm infants only	2	943	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.82, 1.68]
1.7 Mortality to discharge	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.7.1 All studies	4	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.52, 1.88]
1.7.2 With no dose adjustments or open‐label boluses	2	67	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.47, 4.32]
1.8 Neurodevelopmental outcome at 18 to 24 months (moderate to severe disability)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.8.1 All studies	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [0.39, 10.29]
1.8.2 Very preterm infants only	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [0.39, 10.29]
1.9 Neurodevelopmental outcome at 5 to 6 years (disability)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.9.1 All studies	1	95	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.56, 4.56]
1.10 Weight gain at discharge (g/kg per day)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.10.1 All studies	1	45	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.64, 0.28]
1.10.2 Very preterm infants only	1	45	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.64, 0.28]
1.11 Days to reach full enteral feeding	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.11.1 All studies	3	974	Mean Difference (IV, Fixed, 95% CI)	1.68 [0.12, 3.25]
1.11.2 With no dose adjustments or open‐label boluses	1	31	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐3.52, 3.52]
1.11.3 Very preterm infants only	2	943	Mean Difference (IV, Fixed, 95% CI)	2.10 [0.35, 3.85]
1.12 Length of stay in hospital (days)	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.12.1 All studies	3	131	Mean Difference (IV, Fixed, 95% CI)	1.85 [‐6.88, 10.57]
1.12.2 With no dose adjustments or open‐label boluses	1	31	Mean Difference (IV, Fixed, 95% CI)	‐2.00 [‐26.74, 22.74]
1.12.3 Very preterm infants only	1	45	Mean Difference (IV, Fixed, 95% CI)	‐1.40 [‐18.48, 15.68]
1.13 Oxygen at 28 days of life (BPD any grade)	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.13.1 All studies	4	262	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.73, 1.92]
1.13.2 With no dose adjustments or open‐label boluses	2	57	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.36, 3.37]
1.14 Oxygen at 36 weeks' postmenstrual age (BPD moderate or severe)	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.14.1 All studies	4	964	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.80, 1.23]
1.14.2 With no dose adjustments or open‐label boluses	2	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.03, 0.92]
1.14.3 Very preterm infants only	2	924	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.85, 1.31]
1.15 Necrotising enterocolitis	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.15.1 All studies	5	1278	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.61, 1.76]
1.15.2 With no dose adjustments or open‐label boluses	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.07, 16.41]
1.15.3 Very preterm infants only	2	1029	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.56, 2.10]
1.16 Any intraventricular haemorrhage (IVH)	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.16.1 All studies	8	515	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.65, 1.09]
1.16.2 With no dose adjustments or open‐label boluses	4	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.51, 1.49]
1.16.3 Very preterm infants only	2	176	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.53, 1.33]
1.17 Severe intraventricular haemorrhage (Papile grade 3/4)	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.17.1 All studies	6	1299	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.71, 1.34]
1.17.2 With no dose adjustments or open‐label boluses	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 7.32]
1.17.3 Very preterm infants only	3	1074	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.78, 1.52]
1.18 Periventricular leukomalacia (PVL)	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.18.1 All studies	7	1345	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.57, 1.21]
1.18.2 With no dose adjustments or open‐label boluses	2	66	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.48, 2.42]
1.18.3 Very preterm infants only	3	1074	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.47, 1.19]
1.19 Hypotension requiring medical treatment	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.19.1 All studies	3	1083	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [1.13, 1.72]
1.19.2 With no dose adjustments or open‐label boluses	1	41	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.32, 4.98]
1.19.3 Very preterm infants only	1	898	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [1.25, 2.11]