Sucrose for analgesia in newborn infants undergoing painful procedures

Bonnie Stevens; Janet Yamada; Arne Ohlsson; Sarah Haliburton; Allyson Shorkey

doi:10.1002/14651858.CD001069.pub5

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

Sucrose for analgesia in newborn infants undergoing painful procedures

Bonnie Stevens ^1,^2,^3,⁴, Janet Yamada ^5,^✉, Arne Ohlsson ⁶, Sarah Haliburton ⁷, Allyson Shorkey ⁷

Editor: Cochrane Neonatal Group

PMCID: PMC6457867 PMID: 27420164

Abstract

Background

Administration of oral sucrose with and without non‐nutritive sucking is the most frequently studied non‐pharmacological intervention for procedural pain relief in neonates.

Objectives

To determine the efficacy, effect of dose, method of administration and safety of sucrose for relieving procedural pain in neonates as assessed by validated composite pain scores, physiological pain indicators (heart rate, respiratory rate, saturation of peripheral oxygen in the blood, transcutaneous oxygen and carbon dioxide (gas exchange measured across the skin ‐ TcpO₂, TcpCO₂), near infrared spectroscopy (NIRS), electroencephalogram (EEG), or behavioural pain indicators (cry duration, proportion of time crying, proportion of time facial actions (e.g. grimace) are present), or a combination of these and long‐term neurodevelopmental outcomes.

Search methods

We used the standard methods of the Cochrane Neonatal. We performed electronic and manual literature searches in February 2016 for published randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 1, 2016), MEDLINE (1950 to 2016), EMBASE (1980 to 2016), and CINAHL (1982 to 2016). We did not impose language restrictions.

Selection criteria

RCTs in which term or preterm neonates (postnatal age maximum of 28 days after reaching 40 weeks' postmenstrual age), or both, received sucrose for procedural pain. Control interventions included no treatment, water, glucose, breast milk, breastfeeding, local anaesthetic, pacifier, positioning/containing or acupuncture.

Data collection and analysis

Our main outcome measures were composite pain scores (including a combination of behavioural, physiological and contextual indicators). Secondary outcomes included separate physiological and behavioural pain indicators. We reported a mean difference (MD) or weighted MD (WMD) with 95% confidence intervals (CI) using the fixed‐effect model for continuous outcome measures. For categorical data we used risk ratio (RR) and risk difference. We assessed heterogeneity by the I² test. We assessed the risk of bias of included trials using the Cochrane 'Risk of bias' tool, and assessed the quality of the evidence using the GRADE system.

Main results

Seventy‐four studies enrolling 7049 infants were included. Results from only a few studies could be combined in meta‐analyses and for most analyses the GRADE assessments indicated low‐ or moderate‐quality evidence. There was high‐quality evidence for the beneficial effect of sucrose (24%) with non‐nutritive sucking (pacifier dipped in sucrose) or 0.5 mL of sucrose orally in preterm and term infants: Premature Infant Pain Profile (PIPP) 30 s after heel lance WMD ‐1.70 (95% CI ‐2.13 to ‐1.26; I² = 0% (no heterogeneity); 3 studies, n = 278); PIPP 60 s after heel lance WMD ‐2.14 (95% CI ‐3.34 to ‐0.94; I² = 0% (no heterogeneity; 2 studies, n = 164). There was high‐quality evidence for the use of 2 mL 24% sucrose prior to venipuncture: PIPP during venipuncture WMD ‐2.79 (95% CI ‐3.76 to ‐1.83; I² = 0% (no heterogeneity; 2 groups in 1 study, n = 213); and intramuscular injections: PIPP during intramuscular injection WMD ‐1.05 (95% CI ‐1.98 to ‐0.12; I² = 0% (2 groups in 1 study, n = 232). Evidence from studies that could not be included in RevMan‐analyses supported these findings. Reported adverse effects were minor and similar in the sucrose and control groups. Sucrose is not effective in reducing pain from circumcision. The effectiveness of sucrose for reducing pain/stress from other interventions such as arterial puncture, subcutaneous injection, insertion of nasogastric or orogastric tubes, bladder catherization, eye examinations and echocardiography examinations are inconclusive. Most trials indicated some benefit of sucrose use but that the evidence for other painful procedures is of lower quality as it is based on few studies of small sample sizes. The effects of sucrose on long‐term neurodevelopmental outcomes are unknown.

Authors' conclusions

Sucrose is effective for reducing procedural pain from single events such as heel lance, venipuncture and intramuscular injection in both preterm and term infants. No serious side effects or harms have been documented with this intervention. We could not identify an optimal dose due to inconsistency in effective sucrose dosage among studies. Further investigation of repeated administration of sucrose in neonates is needed. There is some moderate‐quality evidence that sucrose in combination with other non‐pharmacological interventions such as non‐nutritive sucking is more effective than sucrose alone, but more research of this and sucrose in combination with pharmacological interventions is needed. Sucrose use in extremely preterm, unstable, ventilated (or a combination of these) neonates needs to be addressed. Additional research is needed to determine the minimally effective dose of sucrose during a single painful procedure and the effect of repeated sucrose administration on immediate (pain intensity) and long‐term (neurodevelopmental) outcomes.

Plain language summary

Sucrose for analgesia (pain relief) in newborn infants undergoing painful procedures

Review question

Cochrane reviewers investigated how well sucrose (table sugar) works as a reliever of pain in newborn babies who are having painful procedures (e.g. an injection, or heel lance, or insertion of a needle to obtain a blood sample (venipuncture), or eye examinations). The babies' pain responses (e.g. crying, grimacing) were assessed by scoring systems for pain used by health care professionals to measure the pain that babies are experiencing. In addition, the reviewers wanted to investigate whether the level of pain relief is related to the dose of sucrose, or the method of delivery (e.g. as a solution squirted into the mouth, or on a pacifier (also called a soother or dummy), and whether there are any safety concerns about using sucrose to relieve pain.

Background

Although there are ways to manage the pain of surgery, medical illness and major procedures, ways of preventing or reducing pain from minor medical procedures (e.g. heel lance and venipuncture) have, until relatively recently, been lacking. Sucrose has been examined for its calming effects in crying newborns and its pain‐relieving effects for invasive procedures in full‐term and premature newborns.

Study characteristics

We searched the medical literature widely up to February 2016 for studies that investigated the pain‐relieving effect of sucrose for minor medical procedures in newborn full‐term and premature babies. We included randomised controlled trials only, as these provide the most reliable medical evidence. We identified 74 studies that reported on a total of more than 7000 infants in this Cochrane Review.

Thirty‐eight studies included full‐term babies only, 31 included premature babies only, and five included both full‐term and premature babies. Heel lance was the painful procedure in 38 studies, and venipuncture in nine; the remaining studies investigated a wide variety of other minor painful procedures.

The studies used a variety of delivery methods for the sucrose solution (oral syringe, dropper or sucrose‐dipped pacifier), as well as a range of concentrations and volumes of dose. Sucrose treatment was compared with giving the babies a similar volume of water, a pacifier, routine care, breastfeeding, 'facilitated tucking' (holding the infant in a flexed position with arms close to the body and hands placed to promote sucking), laser acupuncture, swaddling, warmth, anaesthetic cream for the skin (EMLA), or a combination of these. The studies used a range of pain assessment scales to measure their results.

Study funding sources

We did not identify any studies that received funding from the industry.

Key results

There was high‐quality evidence that sucrose reduces different measures of newborn pain during heel lance, venipuncture and intramuscular injection. However, sucrose does not provide effective pain relief during circumcision. There is conflicting evidence for whether sucrose reduces pain for other minor painful procedures and further research is needed to investigate these more thoroughly.

Twenty‐nine studies reported on adverse events (harms of the sucrose and other treatments) and found that the number of minor adverse events (e.g. choking or gagging) was very low, and was similar in the different groups (so not attributable to the sucrose treatment). No major adverse events were reported.

Quality of evidence

Although sucrose has been widely studied as a pain reliever for newborn babies, most studies have included few babies and have used many different measures of pain to assess its effectiveness. We identified high‐quality evidence that sucrose reduces pain for heel lance, venipuncture and intramuscular injection. The quality of evidence was low or moderate in favour for the use of sucrose for other painful procedures.

Summary of findings

for the main comparison.

Sucrose (20% to 33%) compared with water for pain associated with heel lance
Patient or population: neonates with heel lance‐associated pain Settings: hospital Intervention: sucrose (20% to 33%) Comparison: water
Outcomes	Illustrative comparative risks (mean and range)		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Water	Sucrose (20% to 33%)
PIPP at 30 s after heel lance Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA. A lower score = less pain (Stevens 1996)	The mean for PIPP ranged across control groups from  8.5 to 9.62	The WMD for PIPP in the intervention groups was lower: ‐1.42 (95% CI ‐2.86 to 0.01)	105  (2)	⊕⊕⊝⊝  low	Bias: there were some concerns about bias in both studies (see RoB tables) Consistency: there was moderate inconsistency between the study point estimates (1² = 51 %) Precision: there was low precision in the point estimate with wide 95% CIs) Indirectness: all trials were conducted in the target population (no concern about indirectness)
PIPP at 60 s after heel lance Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants >3 6 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean for PIPP in the control group was 8.59	The mean for PIPP in the intervention groups was lower: ‐1.80 (95% CI ‐3.81 to 0.21)	31 (1)	⊕⊕⊝⊝  low	Bias: there were concerns about allocation concealment and performance bias in this single study Consistency: N/A as there was only one study Precision: there was lack of precision due to small sample size Indirectness: the study was conducted in the target population
PIPP score during heel lance (1st heel lance) Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean for PIPP in the control group was  7.3	The mean for PIPP in the intervention group was the same as in the control group: 0.00 (95% CI ‐1.52 to 1.52)	107  (1)	⊕⊕⊕⊝  moderate	Bias: there were no concerns about bias in this study Consistency: as there was only one study in this analysis concerns about consistency were N/A Precision: this was a relatively large single study (no lack of precision) Indirectness: the study was conducted in the target population
DAN score at 30 s after heel lance Range of scale 0‐10 A lower score = less pain (Carbajal 1997)	The mean DAN score in the control group was 9.5	The mean DAN score in the intervention group was lower: ‐1.90 (95% CI ‐8.58 to 4.78)	32  (1)	⊕⊕⊝⊝  low	Bias: concerns about blinding of performance and detection bias Consistency: as there was only one study in this analysis concerns about consistency were not N/A Precision: small sample size Indirectness: the study was conducted in the target population
NIPS during heel lance Range of scale 0‐7 A lower score = less pain Lawrence 1993	The mean NIPS score in the control group was  3	The mean NIPS score in the intervention group was lower: ‐2.00 (95% CI ‐2.42 to ‐1.58)	56 (1)	⊕⊕⊕⊝  moderate	Bias: no concerns about bias Consistency: as there was only one study in this analysis concerns about consistency were N/A Precision: small sample size Indirectness: the study was conducted in the target population (no concern about indirectness)
The basis for the assumed risk* was 'The mean PIPP, DAN and NIPS scores across control groups according to the values reported in the Assumed risk column. The corresponding risk was the mean in the intervention groups for the PIPP, DAN and NIPS scores with their 95% CI'.  CI: confidence interval; DAN: Douleur Aiguë du Nouveau‐né Scale; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; N/A: not applicable; NIPS: Neonatal Infant Pain Scale; WMD: weighted mean difference
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with breastfeeding for heel lance‐associated pain
Patient or population: neonates with heel lance‐associated pain Settings: hospital Intervention: sucrose 24% Comparison: breastfeeding
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Breastfeeding	Sucrose (24%)
PIPP ‐ Preterm infants	The mean PIPP score in the breast feeding group was 7 Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score in the sucrose group was lower: ‐1.75 (95% CI ‐2.22 to ‐1.28)	47 (1)	⊕⊕⊝⊝  low	Bias: there were concerns about performance and detection bias Consistency: as there was only one study in this analysis concerns about consistency were N/A Precision: small sample size Indirectness: the study was conducted in the target population (no concern about indirectness)
The basis for the assumed risk* was 'The mean PIPP score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the PIPP score with its 95% CI'.  CI: confidence interval; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; N/A: not applicable
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) + NNS compared with water + NNS or pacifier dipped in sucrose compared with pacifier dipped in water for heel lance‐associated pain
Patient or population: newborns with heel lance‐associated pain Settings: hospital Intervention: sucrose (24%) + NNS Comparison: water + NNS
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Water + NNS	Sucrose + NNS
NFCS Range of scale 0‐10 in term infants 0‐9 in preterm infants A lower score = less pain Grunau 1987	The mean NFCS score in the water + NNS groups was 2.1	The mean NFCS score in the sucrose + NNS group was lower than in the water + NNS group: ‐0.60 (95% CI ‐1.47 to 0.47)	100 (1)	⊕⊕⊝⊝  low	Bias: many items scored 'unclear' on the RoB assessment Consistency: as there was only one study in this analysis concerns about consistency were N/A Precision: relatively large sample size (no lack of precision) Indirectness: the study was conducted in the target population (no concern about indirectness)
PIPP 30 s after heel lance (term and preterm infants) Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score ranged across control groups from 6.3 to 10.19	The WM PIPP score in the sucrose + NNS group was lower than in the control group: ‐ 1.70 (95% CI ‐2.13 to ‐1.26)	278  (3)	⊕⊕⊕⊕  high	Bias: there was low risk of bias in all three studies. Consistency: the findings of the three studies were consistent, I² = 0% (no heterogeneity). Precision: large sample size (no lack of precision). Indirectness: the studies were conducted in the target population (no concern about indirectness).
PIPP 60 s after heel lance Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score ranged across control groups from 10.54 to 11.2	The WM PIPP score in the sucrose + NNS group was lower than in the control group: ‐ 2.14 (95% CI ‐3.34 to ‐0.94)	164 (2)	⊕⊕⊕⊕  high	Bias: there was low risk of bias in both studies Consistency: the findings of the two studies were consistent, I² = 0% (no heterogeneity) Precision: large sample size (no lack of precision) Indirectness: the studies were conducted in the target population (no concern about indirectness)
The basis for the assumed risk* was 'The mean NFCS and PIPP scores across control groups according to the values reported in the Assumed risk column. The corresponding risk was the mean in the intervention groups for the NFCS and PIPP scores with their 95% CI'.  CI: confidence interval; RoB: risk of bias; N/A: not applicable;NFCS: Neonatal Facial Coding System;NNS: non‐nutritive sucking; WM: weighted mean
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) + NNS + NIDCAP compared with breast milk (by breastfeeding) for heel lance‐associated pain
Patient or population: neonates with heel lance‐associated pain Settings: hospital Intervention: sucrose (24%) + NNS + NIDCAP Comparison: breast milk (by breastfeeding)
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Breast milk (by breastfeeding)	Sucrose (24%) + NNS + NIDCAP
PIPP score Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score in the breast milk (by breast feeding) group was 7	The mean PIPP score in the sucrose (24%) + NNS + NIDCAP group was lower than in the control group: ‐ 1.75 (95% CI ‐4.03 to 0.53)	47 (1)	⊕⊕⊝⊝  low	Bias: there was a high risk of performance and detection bias as the interventions could not be blinded Consistency: as there was only one study in this analysis concern about consistency was N/A Precision: small sample size (lack of precision) Indirectness: the study was conducted in the target population (no concern about indirectness)
The basis for the assumed risk* was 'The mean PIPP score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the PIPP score with its 95% CI'.  CI: confidence interval; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; N/A not applicable; NIDCAP: Newborn Individualized Developmental Care and Assessment Program;NNS: non‐nutritive sucking
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) + NNS + NIDCAP support compared with breast milk (by syringe) for heel lance‐associated pain
Patient or population: neonates with heel lance‐associated pain Settings: hospital Intervention: sucrose (24%) + NNS + NIDCAP support Comparison: breast milk (by syringe)
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Breast milk (by syringe)	Sucrose (24%) + NNS + NIDCAP support
PIPP score Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score in the breast milk (by syringe) group was 5.38	The mean PIPP score in the sucrose (24%) + NNS + NIDCAP support group was lower than in the control group: ‐0.13 (95% CI ‐2.41 to 2.15)	47 (1)	⊕⊕⊝⊝  low	Bias: there was a high risk of performance and detection bias as the interventions could not be blinded Consistency: as there was only one study in this analysis concern about consistency was N/A Precision: small sample size (lack of precision) Indirectness: the study was conducted in the target population (no concern about indirectness)
The basis for the assumed risk* was 'The mean PIPP score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the PIPP score with its 95% CI'.  CI: confidence interval; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; N/A not applicable; NIDCAP: Newborn Individualized Developmental Care and Assessment Program;NNS: non‐nutritive sucking
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with laser acupuncture for pain associated with heel lance
Patient or population: neonates with pain associated with heel lance Settings: hospital Intervention: sucrose (24%) Comparison: laser acupuncture
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Laser acupuncture	Sucrose (24%)
NIPS score Range of scale 0‐7 A lower score = less pain Lawrence 1993	The mean NIPS score was 4.52 in the laser acupuncture group	The mean NIPS score in the sucrose group was lower than in the laser group: ‐0.86 (95% CI ‐1.43 to ‐0.29)	42 (1)	⊕⊕⊝⊝  low	Bias: There was high risk of selection bias and performance bias in this study Outcome assessments were made from video tapes (low risk of bias) Consistency: As there was only one study in this analysis concern about consistency was N/A Precision: small sample size (lack of precision) Indirectness: the study was conducted in the target population (no concern about indirectness)
The basis for the assumed risk* was 'The mean NIPS score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the NIPS score with its 95% CI'.  CI: confidence interval; N/A: not applicable; NIPS: Neonatal Infant Pain Scale
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with sucrose (24%) + NNS for pain associated with heel lance
Patient or population: neonates with pain associated with heel lance Settings: hospital Intervention: sucrose (24%) Comparison: sucrose (24%) + NNS
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Sucrose (24%) + NNS	Sucrose (24%)
Revised NFCS Range of scale 0‐10 in term infants 0‐9 in preterm infants A lower score = less pain Grunau 1987	The mean NFCS score in the sucrose (24%) + NNS group was 0.02	The mean NFCS score in the sucrose (24%) only group was higher than in the sucrose (24%) + NNS group: 0.43 (95% CI 0.23 to 0.63)	343 (1)	⊕⊕⊕⊝  moderate	Bias: there was a risk of performance and detection bias in this study as the coder could have distinguished the different groups Consistency: as this was a single study a rating of consistency was N/A Precision: this study had a very large sample size with a narrow 95% CI (no concerns about precision) Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean NFCS score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the NFCS score with its 95% CI'.  CI: confidence interval; N/A: not applicable; NFCS: Neonatal Facial Coding System; NNS: non‐nutritive sucking.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (20%) compared with facilitated tucking for pain associated with repeated heel lances
Patient or population: neonates with pain associated with repeated heel lances Settings: hospital Intervention: sucrose (20%) Comparison: facilitated tucking
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Facilitated tucking	Sucrose (20%)
Total Bernese Pain Scale for Neonates (BPSN) during heel lance Range: The BPSN contains 9 items; 3 physiologic (HR, RR, oxygen saturation) and 6 behavioural (grimacing, body movements, crying, skin colour, sleeping patterns, consolation) items. Each item is scored on a 3 point scale (0‐3) points. Higher scores for the behavioural items and greater changes in the physiological items indicate increased pain, whereas a total score of < 11 is considered nonpainful. Cignacco 2004	The mean Total Bernese Pain Scale in the control group was 9.75	The mean Total Bernese Pain Scale was lower in the in the intervention group: MD ‐2.27 (95% CI ‐4.66 to 0.12)	48 (1)	⊕⊕⊕⊝  moderate	Bias: there was some risk of bias in this study as the intervention was not blinded Consistency: as this was a single study consistency was N/A Precision: this was a small study and the CI was wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
Total Bernese Pain Scale for Neonates during recovery from heel lance Range: See comments above. Cignacco 2004	The mean Total Bernese Pain Scalein the control group was 5.18	The mean Total Bernese Pain Scale was lower in the intervention group: MD ‐0.31 (95% CI ‐1.72 to 1.10)	48  (1)	⊕⊕⊕⊝  moderate	Bias: There was some risk of bias in this study as the intervention was not blinded. Consistency: As this was a single study consistency was N/A. Precision: This was a small study and the CI was wide around the point estimate. Directness: The study was conducted in the target population ‐ no concerns about indirectness.
The basis for the assumed risk* was 'The mean Total Bernese Pain Scale for Neonates score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the mean Total Bernese Pain Scale for Neonates score with its 95% CI'.  CI: confidence interval; MD mean difference;N/A not applicable
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (12%) compared with water for pain associated with venipuncture
Patient or population: neonates with pain associated with venipuncture Settings: hospital Intervention: sucrose (12%) Comparison: water
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Water	Sucrose (12%)
NIPS score in term and preterm infants Range of scale 0‐7 A lower score = less pain Lawrence 1993	The mean NIPS score was 3.8 in the water group	The mean NIPS score in the sucrose group was lower than in the water group: 0.90 (95% CI ‐1.81 to 0.01)	111 (1)	⊕⊕⊕⊝  moderate	Bias: it is uncertain if outcome assessors were blinded Consistency: as this was a single study a rating of consistency was N/A Precision: this study had a relatively large sample size with a narrow 95% CI (no concerns about precision) Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean NIPS score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the NIPS score with its 95% CI'.  CI: confidence interval; N/A: not applicable; NIPS: Neonatal Infant Pain Scale
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24% to 30%) compared with control (sterile water or no treatment) for pain associated with venipuncture
Patient or population: neonates with pain associated with venipuncture Settings: hospital Intervention: sucrose (24% to 30%) Comparison: sterile water or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Sterile water or no treatment	Sucrose (24% to 30%)
PIPP score during venipuncture Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score ranged across control groups from 8.9 to 9.2	The WM PIPP score in the intervention group was lower than in the control group: 2.79 (95% CI‐3.76 to ‐1.83)	213 (2 groups in 1 study)	⊕⊕⊕⊕  high	Bias: low risk of bias Consistency: this study reported on two groups of infants; one group was born to non‐diabetic mothers and the other group to diabetic mothers. There was no heterogeneity for the results of the two groups I² = 0% Precision: this study (with the two groups combined) had a large sample size with a narrow 95% CI (no concerns about precision) Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean PIPP score in the control groups according to the values reported in the Assumed risk column. The corresponding risk was the mean in the intervention groups for the PIPP score with its 95% CI'.  CI: confidence interval; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; N/A: not applicable; WM weighted mean
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24% to 30%) compared with sucrose (24% to 30%) + EMLA/liposomal lidocaine cream on the skin for pain associated with venipuncture
Patient or population: neonates with pain associated with venipuncture Settings: hospital Intervention: sucrose (24% to 30%) Comparison: sucrose (24% to 30%) + EMLA/liposomal lidocaine cream on the skin
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Sucrose (24% to 30%) + EMLA/liposomal lidocaine cream on the skin	Sucrose (24% to 30%)
PIPP score Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score was 7.2 in the control group	The mean PIPP score in the intervention group was higher than in the control group: 1.30 (95% CI ‐0.12 to 2.72)	76 (1)	⊕⊕⊕⊝  moderate	Bias: low risk of bias Consistency: as this was the only study consistency was N/A Precision: this was a relatively small study and the CIs were wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
PIPP score during post‐injection period Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score was 7.1 in the control group	The mean PIPP in the intervention group was higher than in the control group: 0.60 (95% CI ‐0.73 to 1.93)	76 (1)	⊕⊕⊕⊝  moderate	Bias: low risk of bias Consistency: as this was the only study consistency was N/A Precision: this was a relatively small study and the CIs were wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
DAN score during venipuncture (preterm infants) Range of scale 0‐10 A lower score = less pain (Carbajal 1997)	The mean DAN score was 6.4 in the control group	The mean DAN score in the intervention group was higher than in the control group: 1.30 (95% CI 0.26 to 2.34)	76 (1)	⊕⊕⊕⊝  moderate	Bias: low risk of bias Consistency: as this was the only study consistency was N/A Precision: this was a relatively small study and the CIs were wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
DAN score during the post‐injection period Range of scale 0‐10 A lower score = less pain (Carbajal 1997)	The mean DAN score in the control group was 5.7	The mean DAN score in the intervention groups was higher than in the control group: 1.40 (95% CI 0.03 to 2.77)	76 (1)	⊕⊕⊕⊝  moderate	Bias: low risk of bias Consistency: as this was the only study consistency was N/A Precision: this was a relatively small study and the CIs were wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean PIPP scores and the DAN scores in the control groups according to the values reported in the Assumed risk column. The corresponding risk was the means in the intervention groups for the PIPP scores and the DAN scores with their 95% CI'.  CI: confidence interval; DAN: Douleur Aiguë du Nouveau‐né Scale; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; N/A: not applicable
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Study	Participants	Procedure	Interventions	Outcomes	Metrics used	Results
Ogawa 2005	100 healthy full‐term infants: Heel lance + water group: GA 40 weeks (range 38 to 42 weeks) Heel lance + sucrose group: GA 39 weeks (range 37 to 41 weeks) Venipuncture + water group: GA 39 weeks (range 37 to 41 weeks) Venipuncture + sucrose group: GA 39 weeks (range 37 to 41 weeks)	Heel lance or venipuncture	2 min before procedure: Heel lance + 0.1 mL sterile water on infant's tongue via syringe (n = 25) Heel lance + 0.1 mL 50% sucrose on infant's tongue via syringe (n = 25) Venipuncture + 0.1 mL sterile water on infant's tongue via syringe (n = 25) Venipuncture + 0.1 mL 50% sucrose on infant's tongue via syringe (n = 25)	Duration of first cry (s), first crying time/total procedure time (%) and the ratio of crying: no crying NFCS score: 1 min after oral administration of water/sucrose disinfection of skin before heel lance or venipuncture during skin puncture during blood sampling during compression to stop bleeding during application of plaster, and 1 min after application of plaster	Reported medians, range and mean, SD Reported in graph form, median and IQR	Significant reduction in duration of first cry in heel lance group given sucrose compared to heel lance alone (P < 0.001) Significantly reduced NFCS scores in sucrose group during heel lance (median 47, IQR 31 to 60) and during compression to stop bleeding (median 32, IQR 8 to 54) compared to the water group (median 58, IQR 54 to 65, median 52, IQR 41 to 61, respectively) (P < 0.001) Sucrose did not significantly reduce NFCS scores during or after venipuncture We included data for sucrose vs water for heel lance and for venipuncture for duration of first cry

Study	Participants	Procedures	Intervention	Outcomes	Metrics used	Results
Rogers 2006	83 infants ≤ 90 days of age requiring bladder catheterization. 3 infants were withdrawn after randomisation as a result of inappropriate enrolment or withdrawal of consent Subgroup analysis performed: infants 1 to 30, 31 to 60 and 61 to 90 days of age	Bladder catheterization	2 min before procedure: 2 mL sterile water via syringe (n = 40) 2 mL 24% sucrose (0.48 g) via syringe (n = 40)	% of subjects crying at maximal insertion Change in DAN scores	Change in mean (SD) for DAN score	Subgroup analysis of youngest infants (1 to 30 days) in sucrose group showed smaller changes in DAN score compared to water group (2.86 vs. 5.29; P = 0.035) Subgroup analysis of infants (1 to 30 days) showed infants in sucrose group were significantly less likely to cry during maximal catheter insertion compared to water group (28.6% vs. 78.6%; P = 0.008) Change in DAN score and number of infants crying at maximal catheter insertion used in meta‐analysis

Study	Participants	Procedure	Interventions	Outcomes	Metrics used	Results
Al Qahtani 2014	90 full‐term newborn males who underwent circumcision. PMA 38 weeks or more, 5‐min Apgar score of 8 or higher, PNA of 12 h or more, birthweight > 2500 g and free from jaundice, anomalies of the penis and analgesia or sedation in the previous 48 h	Circumcision	EMLA group (n = 30): 1 g of a topical mixture of lidocaine (2.5%) and prilocaine (2.5%) cream was applied to the shaft of the penis with an occlusive dressing 1 h before the procedure Sucrose group (n = 30): 2 mL oral sucrose (24% weight by volume) given through a dropper onto the tongue 2 min before the procedure EMLA + sucrose group (n = 30): infants given both EMLA cream and oral sucrose as above	N‐PASS used to assess the severity of pain and neonatal response to pain, 5 min before, during and 5 min after the circumcision for all newborns. The scale measures both physiologic (HR, RR, blood pressure and oxygen saturation) and behavioural (crying irritability, behaviour state, facial expression and extremities tone) responses to pain	Mean, SD (Abstract says median) (Tables state mean and SD)	N‐PASS scores were significantly lower in  EMLA + sucrose group (median EMLA + sucrose group = 5.2, EMLA group = 5.8, sucrose group = 8.5; P < 0.001). The endogenous response to pain  in terms of escalation of heart rate and reduction in O₂ saturation were minimal among EMLA + sucrose group (P < 0.0001)  Duration of crying was comparable among all the groups Data used in RevMan‐analyses
Herschel 1998	120 healthy male newborns, ≥ 38 weeks PMA	Circumcision	Control group (n = 40): no treatment DPNB group (n = 40): 0.8 mL 1% lidocaine without epinephrine injected into dorsolateral penile root 3 min before procedure Sucrose group (n = 39): pacifier dipped in 50% sucrose with a gauze pad moistened with sucrose inside the nipple 2 min before procedure	HR at baseline, restraint, skin preparation for procedure, lateral clamping, lysis of adhesions, dorsal clamping, dorsal cut, retraction, application of Gomco bell and clamp, tightening of clamp, excision of foreskin, removal of clamp, removal of bell, placement of dressing and overall change in HR from baseline SpO₂ at baseline and throughout procedure; change from baseline during the circumcision procedure	Mean, SD, mean differences and 95% CI	Mean change in HR from baseline through all follow‐up times were significantly different between groups (P < 0.001) Mean (95% CIs) HR differences: control vs. DPNB: 27.1 beats/min (17.6 to 36.6) control vs. sucrose: 9.7 beats/min (0.1 to 19.3) sucrose vs. DPNB: 17.4 beats/min (7.8 to 27.0) Sucrose had a statistically significant effect compared to the no treatment controls (P < 0.001) Significant differences between groups in changes in SpO₂ from baseline to circumcision (P < 0.001) Mean (95% CI) SpO₂ differences between the 3 groups from baseline: Control: ‐2.5 (‐15.8 to 3.12) DPNB: ‐0.8 (‐4.3 to 5.5) Sucrose: 0.7 (‐6.8 to 12.5) Differences between both the DPNB and sucrose groups compared to control were significant (P < 0.05) Control vs. sucrose: ‐3.3 (‐5.0 to ‐1.6) was statistically significant (P < 0.001) Data used in RevMan‐analyses
Kaufman 2002	57 term infants, mean age at time of procedure 30 h to 43 h	Circumcision	Gomco + water group (n = 14): Gomco method (of circumcision) and pacifier dipped in water Gomco + sucrose group (n = 14): Gomco method and pacifier dipped in 24% sucrose Mogen + water group (n = 15): Mogen method (of circumcision) and pacifier dipped in water Mogen + sucrose group (n = 14): Mogen method and pacifier dipped in 24% sucrose All infants had EMLA cream applied 1 to 3 h before procedure	Time spent crying during procedure Time spent grimacing Procedure stages: Table to restraint Restraint to forceps Forceps to excision Excision to unrestraint Unrestraint to end	Median and means, graphically Not reported	Cumulative mean time crying for forceps to unrestraint interval in the Gomco + sucrose group was 56 s (median = 53 s) compared to 86 s (median = 78 s) in the Gomco + water group (P = 0.0001) Crying time in Mogen + sucrose and Mogen + water groups were not significantly different Overall, mean crying time significantly decreased in infants treated with sucrose compared to infants treated with water (P = 0.0001) Significantly less time spent grimacing in the Gomco + sucrose group compared to the Gomco + water group (P = 0.0001) No significant differences between Mogen + sucrose and the Mogen + water groups Overall, mean time grimacing was significantly reduced in infants treated with sucrose compared to infants treated with water (P = 0.0001) No data were presented that could be used in RevMan‐analyses
Stang 1997	80 healthy, term, newborn male infants, mean PMA 39.5 weeks	Circumcision	DPNB + NNS group (n = 20): 0.8 mL lidocaine and 0.2 mL saline plus pacifier dipped in water and using new padded restraint chair Buffered DPNB + NNS group (n = 20): 0.8 mL lidocaine and 0.2 mL sodium bicarbonate and pacifier dipped in water DPNB + sucrose group (n = 20): 0. 8 mL lidocaine and 0.2 mL saline and pacifier dipped in 24% sucrose Control group (n = 20): DPNB (0.8 mL lidocaine and 0.2 mL saline) and pacifier dipped in water, rigid chair	Plasma cortisol level 30 min after beginning circumcision Behavioural arousal and behavioural distress scores were recorded at five scoring periods: baseline injection immediate post injection (2 min) delayed post injection (the next 2 min) circumcision	Mean, SD	Plasma cortisol levels not significantly different between groups Data used in RevMan‐analyses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total crying time (s)	1	42	Mean Difference (IV, Fixed, 95% CI)	‐48.09 [‐93.04, ‐3.14]
1.1 Term infants	1	42	Mean Difference (IV, Fixed, 95% CI)	‐48.09 [‐93.04, ‐3.14]
2 Percentage change in heart rate 1 min after heel lance	1	30	Mean Difference (IV, Fixed, 95% CI)	6.4 [‐13.69, 26.49]
2.1 Term infants	1	30	Mean Difference (IV, Fixed, 95% CI)	6.4 [‐13.69, 26.49]

Sucrose (20% to 25%) compared with water or no intervention for pain associated with intramuscular injection
Patient or population: neonates with pain associated with intramuscular injection Settings: hospital Intervention: sucrose (20% to 25%) Comparison: water or no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Water or no intervention	Sucrose (20% to 25%)
NIPS during 1‐2 minutes after IM injection Range of scale 0‐7 A lower score = less pain Lawrence 1993	The mean NIPS score in the control group was 5.2	The mean NIPS score in the intervention group was lower than in the control group: ‐2.30 (95% CI ‐2.93 to ‐1.67)	60 (1)	⊕⊕⊝⊝  low	Bias: concerns about bias for random sequence generation, allocation concealment and lack of blinding for performance and detection Consistency: as this was the only study consistency was N/A Precision: this was a relatively small study and the CIs were wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
PIPP during IM injection (term infants) ‐ Infants of non‐diabetic and diabetic mothers Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score ranged across control groups from 7.2 to 8.5	The WM PIPP score in the intervention groups was lower than in the control group: ‐1.05 (95% CI ‐1.98 to ‐0.12)	232 (2 groups in 1 study)	⊕⊕⊕⊕  high	Bias: no concerns about bias Consistency: there was high consistency between the two groups in this study. I² = 0% Precision: this was a large study and the CIs were narrow around the point estimates Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean NIPP score and the PIPP scores in the control groups according to the values reported in the Assumed risk column. The corresponding risk was the mean in the intervention groups for the NIPP score and the PIPP scores with their 95% CI'.  CI: confidence interval; IM: intramuscular; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; N/A: not applicable; WM: weighted mean
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (25%) compared with glucose (25%) for pain associated with intramuscular injection
Patient or population: neonates with pain associated with intramuscular injection Settings: hospital Intervention:sucrose (25%) Comparison: glucose (25%)
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Glucose (25%)	Sucrose (25%)
NIPS during 1‐2 minutes after immunization Range of scale 0‐7 A lower score = less pain Lawrence 1993	The mean NIPS score was 3 in the control group	The mean NIPS score in the intervention group was lower than the mean score in the control group: ‐ 0.10 (95% CI ‐0.89 to 0.69)	60 (1)	⊕⊕⊝⊝  low	Bias: concerns about bias for random sequence generation, allocation concealment and lack of blinding for performance and detection Consistency: no concerns as this was the only study Precision: this was a relatively small study and the CIs were wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean NIPS score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the NIPS score with its 95% CI'.  CI: confidence interval; N/A: not applicable; NIPS: Neonatal Infant Pain Scale
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with sterile water for pain associated with bladder catheterization
Patient or population: neonates with pain associated with bladder catheterization Settings: hospital Intervention: sucrose (24%) Comparison: sterile water
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Sterile water	Sucrose (24%)
Change in DAN score Range of scale 0‐10 A lower score = less pain (Carbajal 1997)	The mean change in DAN score in the control group was 5.29	The mean change in DAN score was lower in the intervention group than in the control group: ‐ 2.43 (95% CI ‐4.50 to ‐0.36)	33 (1)	⊕⊕⊕⊝  moderate	Bias: There was a low risk of bias in this study Consistency: as this was a single study concerns about consistency were N/A Precision: this was a small study and the CI was wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean Change in DAN score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the NIPS score with its 95% CI'.  CI: confidence interval;DAN: Douleur Aiguë du Nouveau‐né Scale; N/A: not applicable
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with distilled water for pain associated with orogastric tube insertion
Patient or population: neonates with pain associated with orogastric tube insertion Settings: hospital Intervention: sucrose (24%) Comparison: distilled water
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Distilled water	Sucrose (24%)
PIPP score intra procedure Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score was 7.9 in the control group	The mean PIPP score in the intervention group was lower than in the control group: ‐0.30 (95% CI ‐1.33 to 0.73)	105 (1)	⊕⊕⊕⊕  high	Bias: there was a low risk of bias in this study. The protocol for the study was available to us and there were no deviations Consistency: as this was a single study concerns about consistency were N/A Precision: this was a moderately sized study and the CI was narrow around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
PIPP score 30 seconds post procedure Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score was 5.6 in the control group	The mean PIPP score in the intervention group was lower than in the control group ‐1.30 (95% CI ‐2.31 to ‐0.29)	105 (1)	⊕⊕⊕⊕  high	Bias: there was a low risk of bias in this study. The protocol for the study was available to us and there were no deviations Consistency: as this was a single study concerns about consistency were N/A Precision: this was a moderately sized study and the CI was narrow around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
PIPP score 1 min post procedure Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score was 4.6 in the control group	The mean PIPP score in the intervention group was lower than in the control group: ‐0.50 (95% CI ‐1.40 to 0.40)	105 (1)	⊕⊕⊕⊕  high	Bias: there was a low risk of bias in this study. The protocol for the study was available to us and there were no deviations Consistency: as this was a single study concerns about consistency were N/A Precision: this was a moderately sized study and the CI was narrow around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean PIPP scores in the control group according to the values reported in the Assumed risk column. The corresponding risk was the mean in the intervention groups for the PIPP scores with their 95% CI'.  CI: confidence interval; N/A: not applicable; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) by syringe + swaddled +pacifier compared with water by syringe + swaddled + pacifier for pain/distress associated with retinopathy of prematurity (ROP) examination
Patient or population: neonates with pain/distress associated with ROP examination Settings: hospital Intervention: sucrose (24%) by syringe + swaddled + pacifier Comparison: water by syringe + swaddled + soother
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Water by syringe + swaddled + pacifier	Sucrose (24%) by syringe + swaddled +pacifier
PIPP during exam Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score was 14 in the control group.	The mean PIPP score in the intervention group was neither lower nor higher than in the control group: 0.00 (95% CI ‐2.08 to 2.08	32  (1)	⊕⊕⊝⊝  low	Bias: the authors did not describe how the random sequence was generated, nor did they describe how allocation concealment was achieved Consistency: as this was the only study concerns about consistency were N/A Precision: this was a small study and the CI were wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean PIPP score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the PIPP scores with its 95% CI'.  CI: confidence interval; N/A not applicable; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; ROP: retinopathy of prematurity examination
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24% to 33%) (sucrose or sucrose + NNS) compared with water (or water + NNS) for pain/distress associated with retinopathy of prematurity (ROP) examination
Patient or population: neonates Settings: hospital Intervention: sucrose (24% to 33%) (sucrose or sucrose + NNS) Comparison: water (or water + NNS)
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Water (or water + NNS)	Sucrose (24% to 33%) (or sucrose + NNS)
PIPP score during eye examination Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score ranged across control groups from 11.4 to 16.4	The WM PIPP score in the intervention groups was lower than in the control group: ‐2.15 (95% CI ‐2.86 to ‐1.43)	134 (3)	⊕⊕⊕⊝  moderate	Bias: there were some concerns about risk of bias in these studies for random sequence generation and allocation concealment Consistency: the findings were consistent with each other; I² = 46% (low heterogeneity) Precision: this was a moderately sized meta‐analysis and the CI was narrow around the typical point estimate Directness: the studies were conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean PIPP score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the PIPP scores with its 95% CI'.  CI: confidence interval; N/A: not applicable; NNS: non‐nutritive sucking; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age; ROP: retinopathy of prematurity examination; WM: weighted mean
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with EMLA for pain associated with circumcision
Patient or population: neonates undergoing circumcision Settings: hospital Intervention: sucrose (24%) Comparison: EMLA
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	EMLA	Sucrose (24%)
N‐PASS score during circumcision Range of scale 0‐13 A lower score = less pain (Hummel 2010)	The mean N‐PASS score in the control group was 5.8	The mean N‐PASS score in the intervention group was higher: MD 2.40 (95% CI 1.85 to 2.95)	60  (1)	⊕⊕⊝⊝  low	Bias: there were concerns about risk of bias in this study for random sequence generation (unclear risk) and high risk of performance and detection bias Consistency: as this was the only study concerns about consistency were N/A Precision: this was a small study and the CI was wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
N‐PASS score after 5 min Range of scale 0‐13 A lower score = less pain (Hummel 2010)	The mean N‐PASS score in the control group was 3.1	The mean N‐PASS score in the intervention group was higher: MD 1.40 (95% CI 0.74 to 2.06)	60  (1)	⊕⊕⊝⊝  low	Bias: there were concerns about risk of bias in this study for random sequence generation (unclear risk) and high risk of performance and detection bias Consistency: as this was the only study concerns about consistency were N/A Precision: this was a small study and the CI was wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean N‐PASS score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the N‐PASS score with its 95% CI'.  CI: confidence interval; EMLA: eutectic mixture of local anaesthetic; MD mean difference; N/A not applicable; N‐PASS: Neonatal Pain Agitation and Sedation Scale
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with EMLA + sucrose (24%) for pain associated with circumcision
Patient or population: neonates undergoing circumcision Settings: hospital Intervention: sucrose (24%) Comparison: EMLA + sucrose (24%)
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	EMLA + sucrose (24%)	Sucrose (24%)
N‐PASS score during circumcision Range 0‐13 A lower score = less pain (Hummel 2010)	The mean N‐PASS score in the control group was 5.2	The mean N‐PASS score in the intervention group was higher: MD 3.00 (95% CI 2.42 to 3.58)	60  (1)	⊕⊕⊝⊝  low	Bias: there were concerns about risk of bias in this study for random sequence generation (unclear risk) and high risk of performance and detection bias Consistency: as this was the only study concerns about consistency were N/A Precision: this was a small study and the CI was wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
N‐PASS score after 5 min Range 0‐13 A lower score = less pain (Hummel 2010)	The mean N‐PASS score in the control group was 3.3	The mean N‐PASS score in the intervention group was higher: MD 1.20 (95% CI 0.49 to 1.91)	60  (1)	⊕⊕⊝⊝  low	Bias: there were concerns about risk of bias in this study for random sequence generation (unclear risk) and high risk of performance and detection bias Consistency: as this was the only study concerns about consistency were N/A Precision: this was a small study and the CI was wide around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean N‐PASS score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the N‐PASS score with its 95% CI'.  CI: confidence interval; EMLA: eutectic mixture of local anaesthetic; MD mean difference; N/A not applicable; N‐PASS: Neonatal Pain Agitation and Sedation Scale
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with for water stress associated with echocardiography
Patient or population: neonates undergoing echocardiography Settings: hospital Intervention: sucrose (24%) Comparison: water
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	No intervention	Sucrose (24%)
PIPP	The mean PIPP score was 7.4 in the control group Range of scale 0‐21 for infants < 28 weeks PMA and 0‐18 for infants > 36 weeks PMA A lower score = less pain (Stevens 1996; Stevens 2014a)	The mean PIPP score in the intervention group was lower than in the control group: ‐ 2.15 (95% CI ‐3.30 to ‐1.00)	104 (1)	⊕⊕⊝⊝  low	Bias: there were concerns about allocation concealment bias and performance blinding in this study Consistency: as this was a single study concerns about consistency were N/A Precision: this was a moderately sized study and the CI was narrow around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean PIPP score in the control group according to the value reported in the Assumed risk column. The corresponding risk was the mean in the intervention group for the PIPP scores with its 95% CI'.  CI: confidence interval; N/A: not applicable; PIPP: Premature Infant Pain Profile; PMA: postmenstrual age
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Sucrose (24%) compared with water for potentially painful procedures for a period of seven days
Patient or population: neonates with pain associated with potentially painful procedures for 7 days Settings: hospital Intervention: sucrose (24%) Comparison: water
Outcomes	*Illustrative comparative risks (95% CI)**		No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Water	Sucrose (24%)
Motor development and vigor (MDV) domain of the NAPI tool Normative mean and SD at 36 weeks PMA 63 (14.5) Higher scores are associated with more mature behaviour (Snider 2005)	The mean MDV score at 40 weeks PMA was 76.48 in the control group	The mean MDV score at 40 weeks PMA in the intervention group was lower than in the control group: ‐1.83 (95% CI ‐8.59 to 4.93)	93 (1)	⊕⊕⊕⊕  high	Bias: there were no concerns about bias in this study Consistency: as this was a single study concerns about consistency were N/A Precision: this was a moderately sized study and the CI was narrow around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
Alertness and orientation (AO) domain of the NAPI tool Normative mean and SD at 36 weeks PMA 54 (19.4) Higher scores are associated with more mature behaviour (Snider 2005)	The mean AO score at 40 weeks PMA was 67.77 in the control group	The mean AO score at 40 weeks PMA in the intervention group was higher than in the control group: 3.09 (95% CI ‐6.49 to 12.67)	93 (1)	⊕⊕⊕⊕  high	Bias: there were no concerns about bias in this study Consistency: as this was a single study concerns about consistency was N/A Precision: this was a moderately sized study and the CI was narrow around the point estimate Directness: the study was conducted in the target population ‐ no concerns about indirectness
The basis for the assumed risk* was 'The mean MDV and the mean AO scores in the control group according to the values reported in the Assumed risk column. The corresponding risk was the means in the intervention groups for the MDV and AO scores with their 95% CI'.  AO: 'alertness and orientation' CI: confidence interval; MDV: 'motor development and vigor'; N/A: not applicable; PMA post menstrual age; SD: standard deviation
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

PERMALINK

Sucrose for analgesia in newborn infants undergoing painful procedures

Bonnie Stevens

Janet Yamada

Arne Ohlsson

Sarah Haliburton

Allyson Shorkey

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

for the main comparison.

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Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Quality of evidence

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

1.

Included studies

Painful procedures

1. Trials assessing pain during heel lances.

2. Trials assessing pain during venipunctures.

3. Trials assessing pain during heel lances and venipunctures.

4. Trials assessing pain during arterial puncture.

Date	Event	Description
31 March 2016	New citation required but conclusions have not changed	Authors' conclusions are not changed with the inclusion of additional studies.
15 March 2016	New search has been performed	This review was updated in 2016. An additional 20 studies were accepted for inclusion for a total of 74 studies. The total number of infants included in the review is now 7049. We converted 95% confidence intervals to standard deviations. We performed the comparisons based on the different concentrations of sucrose used and on the different control interventions. This resulted in a large number of comparisons and RevMan‐analyses. Most comparisons and outcomes included a limited number of studies and infants. Although we included a total of 37 comparisons, we include 'Summary of findings' tables for primary outcomes (validated pain scales) and GRADE assessments based on the GRADE assessment tables that are available in RevMan.
17 February 2012	New citation required but conclusions have not changed	For the purpose of the current updated review, the inclusion criteria were expanded to include all minor painful procedures (rather than heel lance and venipuncture only). The updated review criteria included studies that assessed the efficacy of repeated doses of sucrose.
17 February 2012	New search has been performed	This updates the review "Sucrose for analgesia in newborn infants undergoing painful procedures" published in The Cochrane Library, Issue 3, 2010 (Stevens 2010). Thirteen new studies were added in the current update.
3 February 2008	Amended	Converted to new review format.
20 April 2004	New citation required and conclusions have changed	Substantive amendment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 PIPP at 30 s after heel lance	2	105	Mean Difference (IV, Fixed, 95% CI)	‐1.42 [‐2.86, 0.01]
1.1 Term infants	1	44	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐4.96, ‐0.44]
1.2 Preterm infants	1	61	Mean Difference (IV, Fixed, 95% CI)	‐0.56 [‐2.42, 1.30]
2 PIPP at 60 s after heel lance	1	31	Mean Difference (IV, Fixed, 95% CI)	‐1.80 [‐3.81, 0.21]
2.1 Preterm infants	1	31	Mean Difference (IV, Fixed, 95% CI)	‐1.80 [‐3.81, 0.21]
3 PIPP score during heel lance (1st heel lance)	1	107	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐1.52, 1.52]
3.1 Newborns of diabetic mothers	1	107	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐1.52, 1.52]
4 DAN score at 30 s after heel lance	1	32	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐8.58, 4.78]
4.1 Term infants	1	32	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐8.58, 4.78]
5 NIPS during heel lance	1	56	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐2.42, ‐1.58]
5.1 Term infants	1	56	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐2.42, ‐1.58]
6 Duration of first cry (s)	2	142	Mean Difference (IV, Fixed, 95% CI)	‐8.63 [‐19.88, 2.61]
6.1 Term infants	1	32	Mean Difference (IV, Fixed, 95% CI)	‐5.0 [‐17.40, 7.40]
6.2 Preterm infants	1	110	Mean Difference (IV, Fixed, 95% CI)	‐25.41 [‐52.06, 1.24]
7 Total crying time	2	88	Mean Difference (IV, Fixed, 95% CI)	‐22.11 [‐32.52, ‐11.70]
7.1 Term infants	2	88	Mean Difference (IV, Fixed, 95% CI)	‐22.11 [‐32.52, ‐11.70]
8 Heart rate (beats/min) during heel lance	2	96	Mean Difference (IV, Fixed, 95% CI)	‐0.81 [‐8.57, 6.94]
8.1 Term infants	2	96	Mean Difference (IV, Fixed, 95% CI)	‐0.81 [‐8.57, 6.94]
9 Percentage change in heart rate 1 min after heel lance	2	86	Mean Difference (IV, Fixed, 95% CI)	0.90 [‐5.81, 7.61]
9.1 Term infants	2	86	Mean Difference (IV, Fixed, 95% CI)	0.90 [‐5.81, 7.61]
10 Respiratory rate (breaths/min) during heel lance	1	56	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐7.64, 5.64]
10.1 Term infants	1	56	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐7.64, 5.64]
11 Oxygen saturation (%) during heel lance	1	56	Mean Difference (IV, Fixed, 95% CI)	‐5.0 [‐12.79, 2.79]
11.1 Term infants	1	56	Mean Difference (IV, Fixed, 95% CI)	‐5.0 [‐12.79, 2.79]
12 Skin blood flow during heel lance (perfusion units (PU))	1	56	Mean Difference (IV, Fixed, 95% CI)	‐32.0 [‐68.87, 4.87]
12.1 Term infants	1	56	Mean Difference (IV, Fixed, 95% CI)	‐32.0 [‐68.87, 4.87]
13 Nociceptive‐specific brain activity (mean weight)	1	44	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.05, 0.09]
13.1 Term infants	1	44	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.05, 0.09]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of first cry (s)	2	80	Mean Difference (IV, Fixed, 95% CI)	‐63.20 [‐79.20, ‐47.19]
1.1 Term infants	2	80	Mean Difference (IV, Fixed, 95% CI)	‐63.20 [‐79.20, ‐47.19]
2 Percentage change in heart rate 1 min after heel lance	1	30	Mean Difference (IV, Fixed, 95% CI)	2.60 [‐11.43, 16.63]
2.1 Term infants	1	30	Mean Difference (IV, Fixed, 95% CI)	2.60 [‐11.43, 16.63]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 PIPP	1	47	Mean Difference (IV, Fixed, 95% CI)	‐1.75 [‐2.22, ‐1.28]
1.1 Preterm infants	1	47	Mean Difference (IV, Fixed, 95% CI)	‐1.75 [‐2.22, ‐1.28]
2 Comfort score	1	47	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐3.06, ‐2.14]
2.1 Preterm infants	1	47	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐3.06, ‐2.14]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 NFCS	1	100	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐1.47, 0.27]
1.1 Term infants	1	100	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐1.47, 0.27]
2 PIPP 30 s after heel lance (mainly preterm infants)	3	278	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐2.13, ‐1.26]
2.1 New subgroup	3	278	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐2.13, ‐1.26]
3 PIPP 60 s after heel lance	2	164	Mean Difference (IV, Fixed, 95% CI)	‐2.14 [‐3.34, ‐0.94]
4 Crying time (s)	2	142	Mean Difference (IV, Fixed, 95% CI)	‐1.41 [‐9.87, 7.04]
4.1 Term infants	2	142	Mean Difference (IV, Fixed, 95% CI)	‐1.41 [‐9.87, 7.04]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Crying time (s)	1	35	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐21.07, 5.07]
1.1 Term infants	1	35	Mean Difference (IV, Fixed, 95% CI)	‐8.0 [‐21.07, 5.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 PIPP score	1	47	Mean Difference (IV, Fixed, 95% CI)	‐1.75 [‐4.03, 0.53]
2 COMFORTneo score	1	47	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐4.84, ‐0.36]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 PIPP score	1	47	Mean Difference (IV, Fixed, 95% CI)	‐0.13 [‐2.41, 2.15]
2 COMFORTneo score	1	47	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐2.74, 1.74]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total Bernese Pain Scale for Neonates during heel lance	1	48	Mean Difference (IV, Fixed, 95% CI)	‐2.27 [‐4.66, 0.12]
2 Total Bernese Pain Scale for Neonates during recovery	1	48	Mean Difference (IV, Fixed, 95% CI)	‐0.31 [‐1.72, 1.10]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total Bernese Pain Scale for Neonates during heel lance (preterm infants)	1	47	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐2.16, 2.06]
2 Total Bernese Pain Scale for Neonates during recovery (preterm infants)	1	47	Mean Difference (IV, Fixed, 95% CI)	0.64 [‐0.73, 2.01]