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. 2016 Jul 15;2016(7):CD001069. doi: 10.1002/14651858.CD001069.pub5

9. Trials assessing pain during retinopathy of prematurity (ROP) examinations.

Study Participants Procedure Interventions Outcomes Metrics used Results
Boyle 2006 40 preterm infants, median PMA 29 weeks (24 to 34 weeks):

  1. Sterile water group: median PMA 27 weeks (24 to 30 weeks), median PNA 45 days

  2. Sucrose group: median PMA 29 weeks (25 to 34 weeks), median PNA 43 days

  3. Water + NNS group: median PMA 30 weeks (27 to 31 weeks), median PNA 41 days

  4. Sucrose + NNS group: median PMA 29 weeks (24 to 31 weeks), median PNA mean 42 days

 Eye examination for ROP 2 min before start of eye examination:

  1. Sterile water group (n = 10): 1 mL sterile water via a syringe into the mouth

  2. Sucrose group (n = 10): 1 mL 33% sucrose via a syringe into the mouth

  3. Water + NNS group (n = 9): 1 mL sterile water via a syringe into the mouth and pacifier

  4. Sucrose + NNS group (n = 11): 1 mL 33% sucrose via a syringe into the mouth and pacifier


 
 		 PIPP during examination of eye Mean, SD, 95% CI Mean (SD) PIPP scores were: 15.3 (1.9), 14.3 (1.6), 12.3 (2.9), and 12.1 (3.4) for groups the sterile water group, sucrose group, water + NNS group, and sucrose + NNS group, respectively
Significant differences in PIPP scores between the groups, P = 0.023
Infants in pacifier groups scored significantly lower than groups without pacifiers, P = 0.003 (95% CI ‐4.23 to ‐0.96)
No significant differences between groups receiving sucrose vs. groups receiving water (P = 0.321)
Data used in RevMan‐analyses
Dilli 2014 64 infants undergoing ROP eye examination. The groups had similar GA (28.5 ± 2.8 weeks), mean birthweight (1304 g ± 466 g) or corrected GA (35.4 ± 3.7 weeks) at examination Eye examination for ROP Topical anaesthetic (proxymetacaine; Alcaine(®) drop 0.5%: ALCON CANADA Inc., Mississauga, Canada) was applied 30 s before the eye examination in all infants

  1. Sucrose + NNS group (n = 32): 0.5 mL/kg 24% sucrose with a pacifier

  2. Water + NNS group (n = 32): received 0.5 mL/kg sterile water with a pacifier

 Mean PIPP score during examination;
secondary outcome measurements were frequency of tachycardia (>
180 beats/min), bradycardia (<
100 beats/min), desaturations (<
85% for > 10 s) and crying time.		 Mean, SD The intervention group had a significantly lower mean PIPP score during examination of the first eye, following insertion of the speculum (sucrose + NNS group: 13.7 ± 2.1 vs. water + NNS group: 16.4 ± 1.8, P = 0.001).
 Data used in RevMan‐analyses
Gal 2005 23 neonates, PMA mean (SD) 26.4 weeks (1.5) PNA 28 to 93 days Eye examination for ROP

  1. 2 mL sterile water

  2. 2 mL 24% sucrose


Cross‐over design
Mydriatic eye drops (phenylephrine HCl 1%, cyclopentolate HCl 0.2%) and local anaesthetic eye drops (proxymetacaine HCl 0.5%; 2 drops) given to both groups prior to examination		 SpO2 desaturation by ≥ 10% pre‐examination, at eye speculum insertion and postexamination
PIPP scores at 5 and 1 min pre‐examination, eye speculum insertion, and 1 and 5 min postexamination		 Percentage of population
Means, SD reported		 No significant difference in SpO2 desaturation by ≥ 10% pre‐examination, at eye speculum insertion between water group and sucrose group
PIPP score at the eye examination significantly lower in the sucrose group (mean 8.3, SD 4.5) compared to the water group (mean 10.5, SD 4.0), P = 0.01); however, this effect was not sustained at 1 and 5 min post examination
Results for the two groups prior to cross‐over were not reported. No data could be used in RevMan‐analyses
Grabska 2005 32 preterm infants, mean PMA 28 weeks, mean PNA 50.8 days
 		 Eye examination for ROP

  1. Water group (n = 16): sterile water delivered either directly into the mouth or via a nipple 2 min prior to eye examination

  2. Sucrose group (n = 16): 24% oral sucrose delivered either directly into the mouth or via a nipple 2 min prior to eye examination


Doses were adjusted by weight:

  1. < 1 kg = 0.5 mL (0.12 g)

  2. 1 to 1.5 kg = 1.0 mL (0.24 g)

  3. 1.5 to 2 kg = 1.5 mL (0.36 g)

  4. > 2 kg = 2.0 mL (0.48 g)


All infants were swaddled and offered a pacifier
All infants received tropicamide 0.5% and phenylephrine 2.5% eye drops approximately 30 min before examination. Topical tetracaine was instilled into the eyes just prior to the examination		 % of the eye examination the infant spent crying 
 
Mean HR, at baseline, post eye drop instillation, post study drug, during eye examination and post‐eye examination*
RR and SpO2 at baseline, post‐eye drop instillation, post study drug, during eye examination and post‐eye examination*
PIPP at  baseline, during eye examination, post‐eye examination*
*measures were taken at 1‐min intervals and were means for each study period ‐ study period times (in min) were not defined		 Mean, SD No significant difference in crying time between the sucrose and water groups.
Significant increases in HR, in both groups from baseline (P < 0.01)
No differences between the sucrose and water groups in HR at any time point
Significant reduction in SpO2 in sucrose group after the study drug (mean 95%, SD 4%) compared to the water group (mean 97%, SD 3%)
Significant reduction in SpO2 in sucrose group during the eye examination (mean 93%, SD 5%; P < 0.05) compared to the water group (mean 96%, SD 3%; P < 0.05)
No significant difference in RR and SpO2 at 2 min post examination
No significant differences in PIPP scores between the sucrose and placebo groups before, during and after eye examinations
Data for PIPP during examination used in RevMan‐analyses
Mitchell 2004 30 preterm infants:

  1. Water group: mean PMA 27.3 weeks, mean PNA 8.0 weeks

  2. Sucrose group: mean PMA 26.5 weeks, mean PNA 8.5 weeks


 
 		 Eye examination for ROP

  1. Water + NNS group (n = 15): pacifier and 3 doses of 0.1 mL sterile water via syringe into the mouth

  2. Sucrose + NNS group (n = 15): Pacifier and 3 doses of 0.1 mL 24% sucrose via syringe into the mouth


1st dose given 1.5 min before local anaesthetic eye drops, 2nd dose right at placement of the eye speculum, 3rd dose 120 s after 2nd dose
All infants received proxymetacaine hydrochloride 0.5% eye drops and were swaddled before the eye examination		 PIPP at baseline, at eye drop instillation, at examination of left eye and at 30, 60, 90 and 120 s after the examination Mean, SEM Statistically significant differences in mean PIPP scores were found between sucrose group (mean 8.8, SEM 0.7) and the water group (mean 11.4, SEM 0.6) during the eye examination (P = 0.0077). However, this was not sustained after the eye examination
 
Data presented that could be used in RevMan‐analyses
O'Sullivan 2010 40 preterm infants, corrected mean age:

  1. Sucrose group = 33.0 ± 1.1 weeks

  2. Water group = 33.1 ± 1.2 weeks

 Eye examination for ROP

  1. Sucrose + NNS group (n = 20): 0.2 mL sucrose with pacifier soaked in 24% sucrose solution

  2. Water group (n = 20): 0.2 mL sterile water by mouth


Infants were given mydriatic eye drops (cyclopentolate 0.2% and phenylephrine 1%) 60 min and 30 min prior to examination. Every neonate received local anaesthetic eye drops (tetracaine hydrochloride 1%) 30 s prior to examination. The interventions were given 2 min prior to the start of the eye examinations. The infants were swaddled in both groups		 N‐PASS, HR and SpO2 at baseline, number of episodes of bradycardia and desaturation, adverse events Median, range Significantly lower N‐PASS score at speculum insertion in sucrose compared to water group (6.5 vs. 5.0; P = 0.002); during procedure (9.5 vs. 7.5; P = 0.003). No significant differences between sucrose group and water group for episodes of desaturation, bradycardia, and adverse outcomes
Data were not used in RevMan‐analyses
Rush 2005 30 preterm infants < 32 weeks PMA: 

  1. Control group: mean PMA 28.88 weeks (range 25 to 31 weeks)

  2. Sucrose group: mean PMA of 29.57 weeks (range 26 to 32 weeks)

 Eye examination for ROP Prior to examination: instillation of 0.5% proxymetacaine and 1% tropicamide,  then 15 min later eye drop instillation of 0.5% tropicamide, 2.5% phenylephrine and 0.5% tropicamide

  1. Control group (n = 16): no swaddling, no pacifier and no holding

  2. Sucrose treatment group (n = 14): swaddled in warm blanket 15 min prior to examination; given pacifier soaked in 24% sucrose solution and held by nurse until 15 min after examination

 Total crying time out of 5 min starting at the onset of the ROP examination
HR 30 min before eye drop instillation and 5 min before ROP examination, during examination, and 5 min after the ROP examination
SpO2 and RR at 30 min before eye drop instillation, 5 min before the ROP exam, 3 measurements during the ROP exam, and 5 min after the ROP exam		 Reported means and SEM
Not reported
SpO2 means and SEM reported
RR not reported		 No significant differences in crying time between sucrose and water groups (P = 0.127)
 
There was no significant difference in HR between groups
No significant differences between treatment group and the control group for SpO2 and respiratory rate at any point
Transcribed SEM to SD

CI = confidence interval
 GA = gestational age
 HR = heart rate
 NNS = non‐nutritive sucking
 N‐PASS = Neonatal Pain Agitation and Sedation Scale
 PIPP = Premature Infant Pain Profile
 PMA = postmenstrual age
 PNA = postnatal age
 ROP = retinopathy of prematurity
 RR = respiratory rate
 SD = standard deviation
 SEM = standard error of the mean
 SpO2 = oxygen saturation