A Systematic Review of Lidocaine-Prilocaine Cream (EMLA) in the Treatment of Acute Pain in Neonates

Abstract

Objective. Neonates routinely undergo painful cutaneous procedures as part of their medical treatment. Lidocaine-prilocaine 5% cream (EMLA) is a topical anesthetic that may be useful for diminishing the pain from these procedures. EMLA is routinely used in children and adults. There is substantial apprehension about its use in neonates because of concerns that it may cause methemoglobinemia. The objective of this review was to determine the efficacy and safety of EMLA as an analgesic for procedural pain treatment in neonates and provide evidence-based recommendations for clinical practice. Methods. Systematic review techniques were used. Studies were identified using manual and computer-aided searches (Medline, EMBASE, Reference Update, personal files, scientific meeting proceedings). Behavioral (eg, facial action, crying) and physiologic (eg, heart rate, oxygen saturation, blood pressure, respiratory rate) outcome data from prospective nonrandomized controlled studies and randomized controlled trials in full-term and preterm neonates were accepted for inclusion to establish efficacy of EMLA. The risk of methemoglobinemia (defined as methemoglobin concentration >5% and requiring medical intervention) was estimated from all prospective studies. Results. Eleven studies of the efficacy of EMLA were included in the analysis. Infant gestational age at the time of delivery ranged from 26 weeks to full-term. Two studies included data from both neonates and older infants. The following procedures were studied: circumcision (n = 3), heel lancing (n = 4), venipuncture (n = 1), venipuncture and arterial puncture (n = 1), lumbar puncture (n = 1), and percutaneous venous catheter placement (n = 1). Nine studies were randomized controlled trials. The total sample size for each study ranged from 13 to 110 neonates. The dose of EMLA used was 0.5 g to 2 g in 9 studies, and was not specified in the others. The duration of application ranged from 10 minutes to 3 hours. The three studies that investigated the efficacy of EMLA for decreasing the pain of circumcision used a randomized controlled trial design. All of them demonstrated significantly reduced crying time during the procedure in the infants in the EMLA group compared with the infants in the control group. Facial grimacing, assessed in two of the studies, was also significantly lower in the EMLA group. Using meta-analytic techniques, the heart rate outcome data for two studies was summarized. Increases in heart rate compared with baseline values were 12 to 27 beats per minute less for the EMLA group than in the placebo group during various stages of the surgical procedure. Three studies that investigated the pain from heel lancing were randomized controlled trials; the other was a nonrandomized controlled study. None demonstrated a significant benefit of EMLA for any of the outcome measures used to assess pain (ie, behavioral pain scores, infant crying, heart rate, blood pressure, respiratory rate, oxygenation parameters). One randomized controlled study of the pain from venipuncture showed that infants treated with EMLA had significantly lower heart rates and cry duration compared with infants treated with a placebo. In one nonrandomized study, a significantly lower behavioral pain score was observed for infants treated with EMLA compared with the control group. Infant heart rate, however, did not differ between the groups. In one randomized controlled study of pain from percutaneous venous catheter placement, EMLA resulted in a significantly lower increase in heart rate and respiratory rate. Behavioral pain scores were significantly lower during arterial puncture in one nonrandomized controlled study. EMLA did not reduce physiologic changes or behavioral pain scores in one randomized controlled trial in infants undergoing lumbar puncture. Meta-analytic techniques revealed that methemoglobin concentrations did not differ between EMLA-treated and placebo-treated infants (weighted mean difference, −0.11%; 95% confidence interval, −0.31% to 0.10%). The incidence of clinically important methemoglobinemia from all prospective studies was 0% (95% confidence interval, 0.0% to 0.2%). There was insufficient data to assess the risk with multiple doses of EMLA. Four studies measured concentrations of lidocaine in the plasma of neonates who had been treated with EMLA. In all cases, concentrations were <0.3 μg/mL. Three studies that measured prilocaine detected <0.1 μg/mL. Conclusions. EMLA diminishes pain during circumcision. It may also diminish the pain from venipuncture, arterial puncture, and percutaneous venous catheter placement; however, efficacy data for these procedures are limited. EMLA does not diminish the pain from heel lancing. Based on available data, EMLA is recommended for the treatment of pain from circumcision but not heel lance. There is insufficient data to recommend its use for other procedures. Single doses do not cause methemoglobinemia. Additional research is recommended in neonates before EMLA is used routinely for procedures other than circumcision and to determine the safety of repeated administration.