Venipuncture is among the most common neonatal painful procedures. While several analgesic interventions (non-pharmacologic and pharmacologic) have been studied in the last two decades, their comparative efficacy is unknown.
Objective:
To compare the efficacy and safety of different interventions for analgesia during venipuncture in neonates by a systematic review and network meta-analysis (NMA).
Data sources:
Medline, the Cochrane Central Register of Controlled Trials, Embase, and CIHAHL were searched from inception until March 2023.
Study selection:
Randomized and quasi-randomized clinical trials that evaluated different pharmacological and non-pharmacological interventions for analgesia during venipuncture were included.
Data extraction and synthesis:
Data from the included trials were extracted in duplicate. An NMA with frequentist random-effects model was used for data synthesis. Certainty of evidence (CoE) was assessed using GRADE.
Main outcomes and measures:
Pain scores during and 30 s after the venipuncture.
Results:
Of 95 full texts, 37 trials comparing 18 different analgesic measures were included. Three trials had a low risk of overall bias, 21 had some concerns and 13 had a high risk of overall bias. Among the 18 interventions for pain during the venipuncture, breastfeeding (including breastmilk; SMD −1.9 (−0.83, −3)) followed by non-nutritive sucking (SMD −1.69 (−0.27, −3.1)) had a high certainty of evidence (CoE) to reduce pain scores when compared to no intervention. Glucose and swaddling had low certainty of evidence to reduce pain scores.
Conclusions and relevance:
Among various non-pharmacological and pharmacological analgesics to reduce pain during and after the venipuncture in neonate, breastfeeding (including breast milk) was the best intervention to reduce pain during venipuncture, followed by NNS. Both these are feasible interventions in all settings.
ShahidSFlorezIDMbuagbawL. Efficacy and safety of EMLA cream for pain control due to venipuncture in infants: a meta-analysis. Pediatrics2019; 143: e20181173.
2.
CourtoisEDroutmanSMagnyJF, et al. Epidemiology and neonatal pain management of heelsticks in intensive care units: EPIPPAIN 2, a prospective observational study. Int J Nurs Stud2016; 59: 79–88.
3.
CarbajalRRoussetADananC, et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA2008; 300: 60–70.
4.
CruzMDFernandesAMOliveiraCR. Epidemiology of painful procedures performed in neonates: a systematic review of observational studies. Eur J Pain2016; 20(4): 489–498.
5.
LeeSJRalstonHJPDreyEA, et al. Fetal pain: a systematic multidisciplinary review of the evidence. JAMA2005; 294: 947–954.
6.
ChauCMYRangerMBichinM, et al. Hippocampus, amygdala, and thalamus volumes in very preterm children at 8 years: neonatal pain and genetic variation. Front Behav Neurosci2019; 13: 51.
7.
HallRWAnandKJS. Pain management in newborns. Clin Perinatol2014; 41(4): 895–924.
8.
American Academy of Pediatrics. Prevention and management of procedural pain in the neonate: an update. Pediatrics2016; 137(2): e20154271.
9.
MangatAKOeiJLChenK, et al. A review of non-pharmacological treatments for pain management in newborn infants. Children2018; 5(10): 130.
HuttonBSalantiGCaldwellDM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions. Ann Intern Med2015; 162(11): 777–784.
12.
OuzzaniMHammadyHFedorowiczZ, et al. Rayyan: a web and mobile app for systematic reviews. Syst Rev2016; 5(1): 210.
13.
SterneJACSavovićJPageMJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ2019; 366: l4898.
14.
R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing. https://www.R-project.org/ (2021, accessed 8 August 2025).
15.
RosenbergerKJDuanRChenY, et al. Predictive P-score for treatment ranking in Bayesian network meta-analysis. BMC Med Res Methodol2021; 21: 53.
16.
Luis Aguayo-AlbasiniJFlores-PastorBSoria-AledoV. GRADE system: classification of quality of evidence and strength of recommendations. Cirugía Española2014; 92: 82–88.
17.
AcharyaABBustaniPCPhillipsJD, et al. Randomised controlled trial of EMLA cream for venepuncture in healthy preterm infants. Arch Dis Child Fetal Neonatal Ed1998; 78(2): F138–F142.
18.
AcharyaABAnnamaliSTaubNA, et al. Oral sucrose analgesia for preterm infant venepuncture. Arch Dis Child Fetal Neonatal Ed2004; 89(1): F17–F18.
19.
AlemdarDKFernandesFK. Effect of recorded maternal voice, breast milk odor, and incubator cover on pain and comfort during peripheral cannulation in preterm infants. Appl Nurs Res2018; 40: 1–6.
20.
AlemdarDKÖzdemirFK. Effects of covering the eyes versus playing intrauterine sounds on premature infants’ pain and physiological parameters during venipuncture. J Pediatr Nurs2017; 37: e30–e36.
21.
AyaziMBazziAVashhaniHB, et al. Effect of ear protector on heart rate and pain due to intravenous sampling in premature infants. J Babol Univ Med Sci2017; 19(9): 13–19.
22.
MekkaouiNIssefIKabiriM, et al. Analgesic effect of 30% glucose, milk and non-nutritive sucking in neonates. J Pain Res2012; 5: 573–577.
23.
BasnetSShresthaLShresthaPS. Sucrose as an analgesic in relieving procedural pain in neonates. J Neonatal Perinatal Med2010; 3(4): 325–331.
24.
BaudessonDeChanvilleABrevaut-MalatyVGarbiA, et al. Analgesic effect of maternal human milk odor on premature neonates: a randomized controlled trial. J Hum Lact2017; 33(2): 300–308.
25.
BauerKKettelerJHellwigM, et al. Oral glucose before venepuncture relieves neonates of pain, but stress is still evidenced by increase in oxygen consumption, energy expenditure, and heart rate. Pediatr Res2004; 55(4): 695–700.
26.
BekenSHirfanoğluIMGücüyenerK, et al. Cerebral hemodynamic changes and pain perception during venipuncture: is glucose really effective?J Child Neurol2014; 29(5): 617–622.
27.
BiranVGourrierECimermanP, et al. Analgesic effects of EMLA cream and oral sucrose during venipuncture in preterm infants. Pediatrics2011; 128(1): e63–e70.
28.
CakirliMAcikgozA. Effect of own mother’s breast milk odor and another mother’s breast milk odor on pain level of newborn infants. Breastfeed Med2021; 16(1): 75–81.
29.
CarbajalRChauvetXCoudercS, et al. Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term neonates. BMJ1999; 319(7222): 1393–1397.
30.
CarbajalRVeerapenSCoudercS, et al. Analgesic effect of breastfeeding in term neonates: randomised controlled trial. BMJ2003; 326(7379): 13.
31.
ChenYLiYSunJ, et al. The effect of maternal voice on venipuncture-induced pain in neonates: a randomized study. Pain Manag Nurs2021; 22(5): 668–673.
32.
DilenBElseviersM. Oral glucose solution as pain relief in newborns: results of a clinical trial. Birth2010; 37(2): 98–105.
33.
EfeESevimS. Effect of two different methods during peripheral venous blood collection on pain reduction in neonates, https://www.researchgate.net/publication/6080542 (2007, accessed 8 August 2025).
34.
Collados-GómezLFerrera-CamachoPFernandez-SerranoE, et al. Randomised crossover trial showed that using breast milk or sucrose provided the same analgesic effect in preterm infants. Acta Paediatr2018; 107(3): 436–441.
35.
GradinMErikssonMHolmqvistG, et al. Pain reduction at venipuncture in newborns: oral glucose compared with local anaesthetic cream. Pediatrics2002; 110(6): 1053–1057.
36.
HoarauKPayetMLZamidioL, et al. Holding–cuddling and sucrose for pain relief during venepuncture in newborn infants: a randomized controlled trial (CÂSA). Front Pediatr2021; 8: 607900.
37.
HowardCPowellASPavlidisE, et al. No effect of a musical intervention on stress response to venepuncture in a neonatal population. Acta Paediatr2020; 109(3): 511–517.
38.
JainARutterN. Does topical amethocaine gel reduce the pain of venepuncture in newborn infants? A randomised double blind controlled trial. Arch Dis Child Fetal Neonatal Ed2000; 83: F207–F210.
39.
JebreiliMNeshatHSeyyedrasouliA, et al. Comparison of breastmilk odor and vanilla odor on mitigating premature infants’ response to pain during venipuncture. Breastfeed Med2015; 10(7): 362–365.
40.
LopezOSubramanianPRahmatN, et al. Effect of facilitated tucking on procedural pain among premature babies. J Clin Nurs2015; 24(1–2): 183–191.
41.
OgawaSOgiharaTFujiwaraE, et al. Venepuncture is preferable to heel lance for blood sampling in term neonates. Arch Dis Child Fetal Neonatal Ed2005; 90(5): F432–F436.
42.
ÖzdemirFEvginDGördeles BeşerN. Effect of prone position, pacifier and smelling breast milk on pain and stress parameters among term neonates during venipuncture: randomized controlled trial. J Pediatr Res2022; 9(2): 146–156.
43.
RazaghiNAemmiSZSadat HoseiniAS, et al. Effectiveness of lavender scent and glucose on pain of blood sampling in term neonates: randomized trial. Complement Ther Med2020; 49: 102289.
44.
ReddyHVRRajanARao AroorA. Eutectic mixture of prilocaine and lignocaine (2.5%) vs 5% lignocaine vs placebo for pain relief in newborns undergoing venipuncture: double blind RCT. Int J Contemp Pediatr2019; 6(3): 1014–1020.
45.
RoofthooftDWESimonsSHPVan LingenRA, et al. Single doses of intravenous paracetamol for PICC placement in preterm infants: randomized trial. Neonatology2017; 112(2): 150–158.
46.
RoshanrayARayyaniMDehghanM, et al. Comparative effect of mother’s hug and massage on neonatal pain behaviors caused by blood sampling: randomized clinical trial. J Trop Pediatr2020; 66(5): 479–486.
47.
SahooJPRaoSNesargiS, et al. Expressed breast milk vs 25% Dextrose in procedural pain in neonates: a double blind randomized controlled trial. Indian Pediatr2012; 50: 203–207.
48.
TaddioAShahVStephensD, et al. Effect of liposomal lidocaine and sucrose alone and in combination for venipuncture pain in newborns. Pediatrics2011; 127(4): e940–e947.
49.
TaddioAShahVHancockR, et al. Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures. CMAJ2008; 179(1): 37–43.
50.
TalebiMAmiriSRJRoshanPA, et al. Concurrent use of swaddle and sucrose on pain intensity during venous blood sampling: clinical trial. BMC Pediatr2022; 22: 323.
51.
TangLWangHLiuQ, et al. Effect of music intervention on pain responses in premature infants during PICC insertion. Eur J Integr Med2018; 19: 105–109.
52.
YıldızdaşHYErdemBKarahanDY, et al. Whole body massage versus oral dextrose and kangaroo care for pain during venous puncture: randomized clinical study. J Perinatol. 2023. DOI: 10.21203/rs.3.rs-1925790/v1. PMID: 36450853.
53.
RajaSNCarrDBCohenM, et al. The revised IASP definition of pain: concepts, challenges, and compromises. Pain2020; 161(9): 1976–1982.
54.
ZhangSSuFLiJ, et al. Analgesic effects of maternal milk odor on newborns: a meta-analysis. Breastfeed Med2018; 13(5): 327–334.
55.
ShahPSTorgalkarRShahVS. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database Syst Rev2023; 8: CD004950.
56.
BuenoMYamadaJHarrisonD, et al. Nonsucrose sweet solutions for pain relief in neonates: systematic review and meta-analyses. Pain Res Manag2013; 18(3): 153–161.
57.
JinLZhangJYangX, et al. Maternal voice reduces procedural pain in neonates: meta-analysis. Medicine (Baltimore)2023; 102(12): e33060.
58.
Pillai RiddellRRBucseaOShiffI, et al. Non-pharmacological management of infant and young child procedural pain. Cochrane Database Syst Rev2023; 6: CD006275.
59.
De Clifford-FaugereGLavalléeAKhadraC, et al. Systematic review and meta-analysis of olfactive stimulation interventions for managing procedural pain in neonates. Int J Nurs Stud2020; 110: 103697.
60.
JohnstonCCampbell-YeoMDisherT, et al. Skin-to-skin care for procedural pain in neonates. Cochrane Database Syst Rev2017; 2: CD008435.
61.
StevensBYamadaJOhlssonA, et al. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev2016; 7: CD001069.
62.
FosterJPTaylorCSpenceK. Topical anaesthesia for needle-related pain in newborn infants. Cochrane Database Syst Rev2017; 2: CD010331.
63.
YamadaYKitamuraMInayamaE, et al. Acoustic stimulation for relieving pain during venipuncture: systematic review and network meta-analysis. BMJ Open2023; 13(12): e077343.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
