Study reference 

Study characteristics 

Patient characteristics   

Intervention (I) 

Comparison / control (C)  

Follow-up 

Outcome measures and effect size  

Comments 

Foster ea 2017 

PS., study characteristics and results are extracted from the SR (unless stated otherwise) 

Type of study:  

SR and meta-analysis of RCTs and quasi-RCTs 

Literature search from 1990 to April 2015. 

7/8 studies included in the meta-analysis 

A: Bonetto 2008 

B: Jain 2000a 

C: Kaur 2003 

D: Larsson 1995 

E: Larsson 1998 

F: Long 2003 

G: Shah 2008 

H: Stevens 1999 

Setting and country: 

A: Single-centre study in Argentina 

B: Single-centre study in UK 

C: Single-centre study in India 

D: Single-centre study in Sweden 

E: Single-centre study in Sweden 

F: Single-centre study in UK 

G: Single-centre study in Canada 

H: Double-centre study in Canada 

Funding and conflicts of interest (derived from studies directly):  

A: Not reported 

B: Funded by the Higher Education Funding Council 

C: Not reported 

D: Not accessible 

E: ASTRA pharmaceuticals prepare and supplied EMPA and placebo for the study 

F: Not reported 

G: Funded by ‘Striving for Excellence Fund’ Mount Sinai Hospital 

H: Not reported 

Inclusion criteria SR: 

RCTs or quasi-RCTs, cluster and cross-over randomised trials. 

Newborn term or preterm (or both) infants up to a postnatal age of one month requiring an invasive procedure involving puncture of skin and other tissues with a needle. 

Type of interventions included: 

EMLA vs placebo 

EMLA vs amethocaine 

EMLA vs other topical anaesthetic 

Amethocaine vs placebo 

Amethocaine vs other topical anaesthetic 

Exclusion criteria SR: 

Infants previously exposed to a topical anaesthetic.  

Topical anaesthetica during circumcision. 

N total at baseline (derived from the studies directly): 

A: 76 total 

B: I 19, C 20 

C: I 30, C 30 

D: Not accessible 

E: I 55, C 56 

F: I 17, C 17 

G: I 55, C 55 

H: Phase 1; 

I 31, C 29 

Phase 2; 

I 25, C 21 

Important prognostic factors2 (derived from studies directly): 

Age: 

A: 4.3 days ± 1.3  

B:  

I 7 days (3-17),  

C 6 days (2-17) 

C:  

I 3.5 days,  

C 3.2 days 

D: Not accessible 

E:  

I 5 days (3-8),  

C 5 days (3-7) 

F: 

I 6 days (3-18) 

C 6 days (5-10) 

G:  

I 53 min (35-151) 

C 51 min (32-95) 

H: Phase 1;  

I 3.7 days ± 1.0 

C 3.9 days ± 1.0 

Phase 2; 

I 4.7 days ± 1.2 

C 4.6 days ± 1.5 

Gender (% males): 

A: 57% total 

B: Not reported 

C: I 63%, C: 43% 

D: Not accessible 

E: I 56%, C 48% 

F: I 40%, C 23% 

G: I 55%, C 42% 

H: 60% total 

Groups comparable at baseline? (derived from the studies directly) 

A: Not reported 

B: Yes 

C: Not reported 

D: Not reported 

E: Not reported 

F: Not reported 

G: Not reported 

H: Yes, except for postnatal age, but this was not considered clinically important 

Describe intervention (treatment/procedure/test): 

A: EMLA cream to the skin and under occlusion for 60 minutes, then removed with a dry cloth with the procedure being performed 10 minutes later. 

B: Infants in the study group received 4% 

amethocaine gel a 1.5 g to the skin and 

occlusion for 60 minutes with the procedure being performed 

five minutes later. 

C: Infants received a EMLA cream 1 g 

cream to one square in at the site of the procedure and covered 

with an occlusive dressing for 60 to 90 minutes before the 

scheduled time of the procedure 

D: Infants received EMLA cream 1 g  

at the site of the procedure and covered with an occlusive 

dressing for 10, 20, 30, 40, 50, 60, 90 or 120 minutes before the 

scheduled time of the procedure 

E: Infants received a EMLA cream 0.5 g on the dorsal aspect of the hand and covered with 

an occlusive dressing for 60 minutes before the scheduled time of 

the procedure 

F: : Infants received a tetracaine patch formulated 

from hydroxypropyl cellulose discs of uniform area (0.283 cm2 

) 

were cut from the dried tetracaine film which, because of the 

formulation method, was calculated to contain tetracaine base 

0.283 mg. The discs were positioned onto pressure-sensitive 

adhesive film to sandwich the tetracaine discs between the 

adhesive film and the release liner. Patches of 16 mm diameter 

were cut with the 6-mm disc of tetracaine film at the centre. The 

tetracaine patch applied on the dorsal 

aspect of the hand for 30 minutes before venepuncture. 

G: Infants in the study group received 

amethocaine gel 4% to the skin and covered with an 

adhesive Tegaderm occlusive dressing for 30 minutes before the 

scheduled time of the procedure. 

H: 1st phase infants receive EMLA 0.5 g on an occlusive dressing for 30 minutes. Five minutes before heel 

lancing, the dressing was removed. 2nd phase the method was the same as phase one except a larger automated lancet was used 

because of a change in unit policy. 

Describe control (treatment/procedure/test): 

A: Placebo cream, same procedure as intervention 

B: Placebo cream, same as procedure as intervention 

C: Placebo cream, same procedure as intervention 

D: Placebo cream, same procedure as intervention 

E: Placebo cream, same procedure as intervention 

F: Placebo device, same procedure as intervention 

G: Placebo gel, same procedure as intervention 

H: 1st pase Glaxal base 0.5 g, 2nd phase placebo cream containing all ingredients of EMLA except lidocaine and prilocaine. Same procedure as intervention 

Length of follow-up (derived from the studies directly): 

A: Not reported 

B: Not reported 

C: 24 hours after the procedure 

D: Not accessible 

E: Not reported 

F: Not reported 

G: 2 minutes after removal of the gel 

H: 8 hours after application 

Loss-to-follow-up (derived from the studies directly): 

A: Not reported 

B: Not reported 

C: I 0, C 0 

D: Not accessible 

E: I n=5 (9.1%); screaming before skin puncture, video-equipment failure 

C n=4 (7.1%); screaming before skin puncture, video-equipment failure, parents withdraw consent 

F: I 2 (10.5%), C 0; parents withdrew consent after randomisation 

G: Not reported 

H: 14 infants withdrawn after randomization but before data collection; discharged or transferred. 

Incomplete outcome data (derived from the studies directly):  

A: Not reported  

B: Not reported 

C: I 0, C 0 

D: Not accessible 

E: Not reported 

F: Not reported 

G: I 2 (3.6%), C 3 (5.5%); reasons not reported 

H: Not reported 

Outcome measures and effect size (include 95%CI and p-value if available): 

Efficacy 

Pain: 

A: PIPP score from insertion of heel lance and up to three minutes; MD 0.27, 95% CI -1.45 to 1.99 (no statistical difference).  

During heel lancing; MD 0.27, 95% CI -0.75 to 1.29 (no statistical difference) 

B: Five seconds after insertion of the needle; median 3 amethocaine and median 16 placebo, significant difference in favour of amethocaine. 

Insertion of the needle; 

16 of 19 (84%) amethocaine-treated 

infants showed little or no pain in response to insertion of the needle compared with six of 20 (30%) in the placebo group (P = 0.001). 

C: Neonatal Facial Coding System (NFCS) during lumbal puncture; mean 4.0 ± SE 0.3 with EMLA versus mean 5.0 ± SE 2.7 with placebo; P = 0.004  

Needle withdrawal; 

mean 1.8 ± SE 0.3 with EMLA versus mean 3.9 ± SE 0.3 with placebo; P < 0.001 

D: ‘Pain cry’ 

I: 54 out of 56 

C: 52 out of 54 

RR 1.0, 95% CI 0.9 to 1.1, P=.9705 

E: 0 to 15 seconds post venepuncture; median 287 with EMLA versus median 374 with placebo; P = 0.016 

60 to 70 seconds post venepuncture; median 288 

with EMLA versus median 407 with placebo 

F: Significant difference in pain score during venepuncture between amethocaine group (median 0) compared to the placebo group (median 12.5) (P = 0.0002; n = 32) during venepuncture (this is defined as clinically effective anaesthesia (p=0.01)). 

G: MD -5.00, 95% CI -17.34 to 7.34; no statistically significant difference. 

H: PIPP score EMLA applied for 30 minutes; mean 10.19, SD 4.09 with EMLA versus mean 9.45, SD 4.01 with placebo; P = 0.48 

EMLA applied for 60 minutes; mean 

13.08, SD 4.35 with EMLA versus mean 13.33, SD 3.49 with placebo; P = 0.83 

Pain cry: 

D: No statistical difference; (54 out of 56 infants uttered a ’pain cry’ with EMLA versus 52 out of 54 infants uttered a ’pain 

cry’ with placebo; P = 0.97) 

Total cry duration: 

B: No significant difference; amethocaine (33 seconds, range 9 to 79; n = 4) and placebo (68 seconds, range 9 to 122. 

E: No difference for median total duration of crying between EMLA and placebo during venepuncture (p=0.89) 

Number of attempts for successful venepuncture: 

B: typical RR 1.21, 95% CI 0.82 to 1.81; typical RD 0.14, 95% CI -0.14 to 0.42 (no difference). 

C: Lumbar puncture 

was traumatic on the first attempt in two cases with EMLA and three cases with placebo. No case required more than two attempts. 

E: Typical RR 0.98, 95% CI 0.93 to 1.03; typical RD -0.02, 95% CI -0.07 to 0.03; n = 111 (no statistical difference). 

Time required for successful completion of procedure: 

E: Median 145 

seconds with EMLA versus median 125 seconds with placebo; P = 0.01 (significantly less time to complete venepuncture in placebo group) 

Safety 

Symptoms of MetHb: 

D: No clinical symptoms of MetHb. 

Methaemoglobin levels of ≥ 5%: 

B, F, and G: did not report number of infants with methaemoglobin levels ≥5%. 

H: No methaemoglobin levels of ≥ 5%. Mean methaemoglobin concentration for all infants who received EMLA was 1.19% 

Transcutaneous oxygen saturation: 

C: Comparable between EMLA and placebo groups during lumbar puncture, with maximum dip at needle insertion. 

Adverse events 

Adverse events: 

Measured by meta-analysis, based on D, C, and H; 

Typical RR 1.65, 95% CI 1.24 to 2.19; typical RD 0.17, 95% CI 0.09 to 0.26; n = 272; NNTH 6, 95% CI 4 to 11. I2 = 92% 

Measured by meta-analysis based on G; 

Typical RR 2.00, 

95% CI 0.64 to 6.26; typical RD 0.04, 95% CI -0.03 to 0.12 

Skin reactions: 

D: local pallor and redness 

C and H: temporary blanching 

C: temporary blanching of the skin during removal of the occlusive dressing. 

All skin irritation and blanching dissipated within one hour. 

B and F: reported no difference in local skin reactions. 

Other adverse events: 

No studies reported episodes of apnoea. 

No studies reported episodes of bradycardia. 

No studies reported neurodevelopmental disability. 

I cannot access Larsson 1995 to extract the necessary baseline characteristics. 

Shahid ea 2019 

PS., study characteristics and results are extracted from the SR (unless stated otherwise) 

Type of study:  

SR and meta-analysis 

Literature search from inception to August 2017 

10/10 studies included in meta-analysis 

A: Abad 2001, 41 

B: Acharya 1998, 20 

C: Aziznejad 2013, 42 

D: Biran 2011, 49 

E: Brisman 1998, 50 

F: Gradin 2002, 51 

G: Lindh 2000, 22 

H: Marcatto Jde 2011, 43 

I: Noori-Sadkam 2008, 52 

J: Larsson 1998, 21 

K: Lindh, 2000 

Setting and country (derived directly from study article): 

A: Single-centre study in Spain 

B: Single-centre study in United Kingdom 

C: Iran 

D: Multi-centre study in France 

E: Single centre study in Sweden 

F: Multi-centre study in Sweden 

G: Single-centre study in Sweden 

H: Brazil 

I: Single-centre study in Iran 

J: Single-centre study in Sweden 

Funding and conflicts of interest (derived directly from study article):  

A: Not reported 

B: Not reported 

C: Not accessible 

D: No financial relationships relevant to article 

E: Not reported 

F: The study was supported by grants from the Research Committee of Örebro County Council, from the Örebro Medical Center Research Foundation, and from the Sven Johansson Memorial Foundation. 

G: Not reported 

H: Not reported 

I: 

J: ASTRA pharmaceuticals prepare and supplied EMPA and placebo for the study 

Inclusion criteria: 

RCTs studying the effectiveness of EMLA cream were included.  

Population of interest: infants who are at term or preterm up to a postnatal age of 3 months who  

required venipuncture for blood  

drawing or venous catheter insertion,  

from both inpatient and outpatient  

settings. 

Possible nonpharmacological comparators: 

placebo, no  

EMLA (no treatment at all), sucrose,  

breastfeeding, and skin-to-skin care 

Exclusion criteria: 

Not reported 

N total at baseline (derived directly from study article): 

A: I 11 C 40 

B: In total 20 patients 

C: Not accessible 

D: I 39, C 37 

E: I 24, C 23 

F: I 99, C 102 

G: I 28, C 28 

H: EMLA + placebo 9 

Glucose + placebo cream 12 

EMLA + glucose 9 

I: I 115, C 115 

J: I 55, C 56 

Important prognostic factors2 (derived directly from study article): 

Postnatal age: 

A: I 1.8 days ± 1.2  

Placebo 1.7 ± 1.0 

Sucrose 1.9 ± 1.3 

EMLA + sucrose 2.0 ± 0.9 

B: 21 days (3-65) 

C: Not accessible 

D: I 14.3 days ± 13.9 

C 17.1 days ± 13.7 

E: I 40 days (1-74), C 34 (1-71) 

F: I 4 days (1-30), C 4.5 days (1-28) 

G: I 80 hours ± 11 

C 84 hours ± 16 

H: Not reported 

I: I 4 days (2-15) 

C 4.2 (2-15) 

J: I 5 days (3-8),  

C 5 days (3-7) 

Gender (% males): 

A: I 55% 

Placebo 80% 

Sucrose 75% 

EMLA + sucrose 79% 

B: 50% 

C: Not accessible 

D: I 48.7 % 

C 70.2% 

E: 77% in total 

F: I 51%, C 56% 

G: I 43%, C 46% 

H: Not reported 

I: I 55%, C 48.5% 

J: I 56%, C 48% 

Groups comparable at baseline (derived directly from study article)?  

A: Yes for weight at birth, weight at time of procedure, and postnatal age. No for gestational age but clinical value is doubtful. 

B: Not reported 

C: Not accessible 

D: Yes 

E: Not reported 

F: Yes 

G: Yes, except that mean gestational age was different between groups (40 weeks in placebo and 39 weeks in EMLA) 

H: Not reported 

I: Yes 

J: Not reported 

Describe intervention (treatment/procedure/test): 

A: 1 g of EMLA 

B: 0.5 mL of EMLA 

C: 1 g of EMLA 

D: 0.5 g of EMLA and 0.5 mL of sucrose 

E: 1 g of placebo 

F: 0.5 g of EMLA cream and 1 mL of water 

G: 1 g of EMLA 

H: 0.6 g of EMLA and 2 mL of water 

I: 0.5 g of EMLA cream with 1 mL of water 

J: 0.5 mL of EMLA 

Describe control (treatment/procedure/test): 

A: 2 mL of spring water, 2 mL of sucrose 24%, and 1 g of EMLA + 2 mL of sucrose 

B: 0.5 mL of placebo cream 

C: No treatment, sucrose, breast milk 

D: 0.5 mL of sucrose + placebo cream (0.5 g) 

E: 1 g of placebo cream 

F: 0.5 g of placebo and 1 mL of sucrose 

G: 1 g of placebo 

H: 0.6 g of placebo and 2 mL sucrose 

I: 0.5 g of placebo cream and 1 mL of sucrose 

J: 0.5 mL of placebo 

Length of follow-up (derived directly from study article): 

A: 4 minutes after venepuncture 

B: 2.5 minutes after needle removal 

C: Not accessible 

D: 30 seconds after needle removal 

E: 18 hours 

F: 3 minutes after venepuncture 

G: 80 seconds 

H: 15 minutes after completing procedure 

I: Two minutes 

J: Not reported 

Loss-to-follow-up (derived directly from study article): 

A: Not reported how many loss-to-follow-up; impossible to obtain a fully awake state at time of oral administration or venepuncture. 

B: I C ; discharged early and had venepuncture with only one cream. 

C: Not accessible 

D: Not reported 

E: Not reported 

F: I 1, C 4; <36 weeks, antibiotic treatment, seizures during procedure, and parents did not want to proceed. 

G: I 2, C 0; technical failure and baby cried vigorously during baseline sequence and was impossible to soothe. 

H: Not reported 

I: Not reported 

J: I n=5 (9.1%); screaming before skin puncture, video-equipment failure 

C n=4 (7.1%); screaming before skin puncture, video-equipment failure, parents withdraw consent 

Incomplete outcome data (derived directly from study article):  

A: Not reported 

B: Not reported 

C: Not accessible 

D: Not reported 

E: Not reported 

F: Not reported 

G: Not reported 

H: Not reported 

I: I 9, C 1; reasons not provided 

J: Not reported 

Outcome measures and effect size (include 95%CI and p-value if available): 

Efficacy 

Pain during venipuncture: 

J, C, H, D, F, and I: 

SMD: 0.14; 95% CI:  

−0.17 to 0.45; 6 trials, n = 742; I2 = 71%; moderate-quality evidence. 

Little to no reduction in pain when EMLA cream was compared with placebo, sucrose, and breastfeeding. 

Pain at end of venipuncture: 

B, J, D, and H: 

SMD: −0.26; 95% CI:  

−0.59 to 0.07; 4 trials, n = 226; I2 = 25%; moderate-quality evidence. 

Minimal-to-moderate reduction in pain score  

Total duration of crying: 

B, J, A, D, F, and I: 

MD: 3.32; 95% CI:  

−1.19 to 7.84, 6 trials, n = 624; I2 = 9%; moderate-quality evidence. 

Duration of crying was comparable in both groups 

Incidence of crying: 

K 

I: 9 of 28 

C: 14 of 28 

RR 0.64, 95% CI 0.33 to 1.24, P=.1850.  

Subgroup analysis based on gestational age at birth for pain: 

B, J, G, and A: 

There was small-to-moderate effect size in reduction in pain favouring EMLA in comparison with placebo or no treatment (SMD: −0.34; 95% CI: −0.67 to −0.00; 2 trials, n = 149; I2 = 0%) 

There was no effect in  

reduction of pain with sucrose or  

breastfeeding when compared with  

EMLA in both preterm and term  

infants (SMD: 0.28; 95% CI: −0.02 to 0.58; 5 trials, n = 593; I2 = 59%) 

EMLA was inferior for term infants  

SMD: 0.44; 95% CI: 0.22 to 0.58; 3 trials, 5 trials, n = 496; I2 = 0%) 

Subgroup analysis by pain scale revealed no effect when using the DAN and PIPP scale, but when using  

NIPS, EMLA was inferior to control (MD: 0.80; 95% CI: 0.39 to 1.20; n = 241; I2 = 0%) 

Sensitivity analysis pain: 

Small-to-moderate  

reduction in pain with placebo, sucrose, or breast milk (SMD: 0.42;  

95% CI: 0.20 to 0.64; 3 trials, n = 361; I2 = 0%). 

Low-risk bias studies revealed no reduction  

to moderate reduction in pain with EMLA cream when compared with  

placebo or sucrose (SMD: −0.14; 95% CI: −0.66 to 0.37; 3 trials, n = 381;  

I2 = 83%). 

Safety 

Methemoglobinemia: 

B and I: 

MD 0.35%; 95% CI: 0.04% to 0.66%, 2 trials, n = 134; I2 = 58%; low-quality evidence.  

Moderate effect size favouring placebo over EMLA. 

Did not report methaemoglobin levels of >5% or any clinical symptom. 

Subgroup analysis based on different time periods of serum methaemoglobin levels (<8 hours or 8-24 hours after EMLA application): 

B, J, G, and A: 

Placebo favoured over EMLA, with low-quality evidence. 

Heart rate during venipuncture: 

B, G, A, H, and F: 

MD: −1.22; 95% CI: −9.85 to 7.41; 5 trials, n = 330; I2 = 75%; low-quality evidence. 

No difference in reduction in heart rate during venipuncture between groups 

Heart rate after venipuncture: 

B, G, A, H, and F: 

MD: 3.74; 95% CI: −5.74 to 13.22; 3 trials, n = 254; I2 = 50%, very low-quality evidence. 

No difference in reduction in heart rate after venipuncture between groups 

Oxygen saturation: 

B and A: 

MD: 0.35; 95% CI: −0.77 to  

1.47; 2 trials, n = 57; I2 = 20%; very low–quality evidence. 

No difference in oxygen saturation between groups. 

Skin-blanching: 

D and E: 

RR: 2.63; 95% CI: 1.58 to 4.38; 2 trials, n = 123; I2 = 84%, very low–quality  

evidence 

EMLA increased risk of skin blanching 

They also performed a meta-analysis under random effects model, this revealed no statistical difference. Due to counterintuitive results, a new analysis was performed with a fixed model. 

Larsson 1998 is also reported in Foster ea 2017. 

Full text article from Aziznejad ea 2013 is in Iran language.