1. Overview of included studies, listed by type of comparison.
| Author | Country | No. of infants in intervention and control group, respectively | GA in intervention and control group, respectively | Procedure | Intervention | Comparison |
| Comparison 1: Opioids versus no treatment or placebo | ||||||
| Carbajal 2005 | France, USA | 21/21 | 27.3 (1.8)/27.2 (1.7)a | Heel lances | Morphine 100 μg/kg loading dose and 10 to 30 μg/kg/h continuous infusion (intravenously) | Placebo 5% dextrose (intravenously) |
| Hartley 2018 | UK | 15/16 | 28.1 (26.3 to 30.1)/28.6 (27.9 to 29.7)b | Heel lances and ROP screening examination | Morphine 100 μg/kg single dose (orally) | Placebo (orally) |
| Manjunatha 2009 | UK | 6/6 | NR | ROP screening examination | Morphine 200 μg/kg single dose (orally) | Placebo (orally) |
| Fallah 2016 | Iran | 23/22 | 37.4 (0.8)/37.6 (0.6)a | Lumbar puncture | Fentanyl 2 μg/kg single dose (intravenously) | Placebo normal saline (intravenously) |
| Sindhur 2020 | India | 56/55 | 30.7 (1.7)/31.0 (1.7)a | ROP screening | Fentanyl 2 μg/kg single dose (intranasal) | Placebo normal saline (intranasally) |
| Lago 2008 | Italy | 27/27 | 28 (2)/29 (2)a | PICC insertion | Remifentanil 0.03 μg/kg/min continuous infusion (intravenously) | Placebo 5% dextrose continuous infusion (intravenously) |
| Pokela 1994 | Finland | 42/42 | 31.6 (25 to 40)/32.9 (24 to 41)c | Daily routine care proceduresd and tracheal suction | Meperidine 1 mg/kg single dose (intravenously) | 0.9% saline single dose (intravenously) |
| Comparison 2: Opioids versus oral sweet solution or non‐pharmacological intervention (skin‐to‐skin contact, music exposure, non‐nutritive sucking, swaddling, etc.) | ||||||
| Gitto 2012 | Italy | 50/50/50 | NR | Heel lances | Fentanyl 1 to 2 μg/kg bolus injection (intravenously) | Facilitated tucking/sensorial saturation |
| Sethi 2020 | India | 29/29 | 30.3 (2.2)/30.3 (2.4)a | Laser for ROP | Fentanyl 1 μg/kg/h continuous infusion (intravenously) | 24% oral sucrose single dose |
| Comparison 3: Opioids versus other analgesics (e.g. paracetamol) and sedatives (e.g. midazolam and other benzodiazepines) | ||||||
| Manjunatha 2009 | UK | 6/6 | NR | ROP screening examination | Morphine 200 μg/kg single dose (orally) | Paracetamol 20 mg/kg single dose (orally) |
| Cordero 1991 | USA | 15/14 | 28 (2)/27 (2)a | Broviac catheter placement | Fentanyl 2 μg/kg single dose (intravenously) | Secobarbital 1 mg/kg single dose (intravenously) |
| Madathil 2021a | India | 51/46 | 29.7 (1.9)/29.8 (1.5)a | Laser for ROP | Fentanyl 2 μg/kg followed by a continuous infusion of 1 μg/kg/h increased to a maximum of 3 µg/kg/h (intravenously) | Ketamine 0.5 mg/kg, followed by further intermittent intravenous bolus doses of 0.5 mg/kg to a maximum of 2 mg/kg (intravenously) |
| Madathil 2021b | India | 13/14 | 30.3 (1.3)/30.5 (2.4)a | Laser for ROP | Fentanyl 2 μg/kg followed by infusion of 2 μg/kg/h to a maximum of 5 μg/kg/h (intravenously) | Ketamine 1 mg/kg followed by intermittent bolus doses of 0.5 mg/kg to a maximum of 4 mg/kg (intravenously) |
| Taddio 2006 | Canada | 38/42 | 29.6 (4.9)/30 (5.1)a | PICC placement | Morphine 100 μg/kg single dose (intravenously) | Tetracaine 0.5 g 4% gel applied to the insertion site |
| We included no studies for the following comparisons: head‐to‐head comparison of different opioids; different routes of administration of the same opioid. | ||||||
GA: gestational age; NR: not reported; PICC: peripherally inserted central catheter; ROP: retinopathy of prematurity aMean (standard deviation). bMedian (interquartile range). cMean (range). dWeighing, washing, temperature measurement, chest roentgenogram.