Short title: EMLA to reduce circumcision pain
Reviewer(s): Taddio A, Ohlsson A
Date of most recent amendment: 25/08/1997
Date of most recent substantive amendment: 21/08/1997
Date next stage expected: / /
Contact
Anna Taddio
Pharmacologist
Division of Clinical Pharmacology and Toxicology
The Hospital for Sick Children
555 University Avenue
Toronto, Ontario
CANADA
M5G 1X8
Telephone 1: +1 416 813 4927
Telephone2:
E-mail: anna.taddio@utoronto.ca
Sources of support for the review
The Hospital for Sick Children
Women's College Hospital
Acknowledgements
We acknowledge Dr. C. Johnston et al. for providing additional
information about their study.
Conflict of interest
None
To determine the effectiveness of EMLA compared to placebo or no treatment as an analgesic for circumcision in male newborns.
The guidelines of the Cochrane Neonatal Review Group were followed. No language restrictions were applied. Two reviewers (AT, AO) agreed through a consensus process on the inclusion of a specific study.
Randomized controlled trials assessing the efficacy/effectiveness of EMLA to prevent circumcision associated pain. Behavioral and physiological outcome data were accepted for efficacy/effectiveness.
Data abstracted from each report included gestational age at birth, timing and dosage regimen of EMLA, control group treatment and outcomes. Abstracted data were verified by the two investigators (AT, AO).
During the different stages of the surgical procedure for circumcision, the increase in heart rate was 12 - 27 beats per minute less for the EMLA group compared to placebo. In a single study, neonates treated with EMLA showed a higher oxygen saturation. Although the data from two studies could not be combined, facial action and crying during circumcision was reported as less in the EMLA treated groups.
EMLA reduces pain response during circumcision in newborn male infants. EMLA is recommended for circumcision in the neonate when other techniques such as dorsal penile nerve block are not available.
Hospitalized full-term and preterm neonates routinely undergo tissue-damaging interventions as part of their medical treatment. The skin is the site of noxious stimulation for many procedures, including circumcision. Analgesics are not routinely administered in clinical practice due to the relatively short duration of the intervention, perceived lack of importance of the pain, and concerns of toxicity from currently available agents. This practice is being questioned by recent evidence that neonates are capable of both perceiving and exhibiting reproducible responses to noxious stimulation. The immediate pain response is complex, involving behavioral changes such as facial grimacing and body movements, as well as physiologic, metabolic and hormonal changes. Preliminary data suggest that pain in neonates may have long-term effects such as pain memories (Taddio 1995; Taddio 1997a).
EMLA 5% cream (eutectic mixture of local anesthetics; lidocaine and prilocaine, Astra Pharma Inc.) is a topical anesthetic used in children and adults to diminish pain from cutaneous procedures. EMLA represents a therapeutic breakthrough as it is the first topical anesthetic preparation which penetrates intact skin to provide reliable anesthesia. The usual dose for children and adults is 1-2 g applied under an occlusive dressing for approximately 1 hour prior to the procedure.
The efficacy of EMLA for treatment of procedural pain in children and adults is well established. In neonates, however, there has been no systematic evaluation of its efficacy/effectiveness. In children and adults, adverse effects are limited to transient local skin reactions such as blanching and redness. There has been substantial apprehension about using EMLA in neonates due to the potential risk of methemoglobinemia from prilocaine metabolites which can oxidize hemoglobin. As compared to children and adults, neonates are believed to be at increased risk of methemoglobinemia. Neonates have a deficiency in the enzyme which reduces methemoglobin (MetHb), NADH cytochrome b5 reductase (Taddio 1995). In addition, the higher body surface area to weight ratio in infants may result in higher systemic exposure from the same dose relative to adults. Preterm infants may be at even greater risk of toxicity due to immaturity in skin barrier properties which enhances percutaneous absorption of drugs (Taddio 1995). In a recent systematic review/meta-analysis, EMLA was proved to be safe for single applications in term and preterm (from 30 weeks gestational age) infants (Taddio 1997b).
The purpose of this review was to systematically evaluate the efficacy/effectiveness of EMLA as an analgesic for circumcision in neonates, to provide evidence based recommendations for clinical practice and to identify areas for future research. The specific question asked was: In newborn male infants does the use of EMLA reduce physiologic and/or behavioral responses to pain?
Types of studies
Randomized controlled trials in which EMLA was compared to
placebo treatment or no treatment.
Types of participants
Male infants undergoing circumcision in the neonatal period.
Types of intervention
The application of EMLA to the foreskin prior to circumcision.
Types of outcome measures
Behavioral (e.g. facial action score(s), per cent time crying)
or physiologic (e.g. changes in heart rate, oxygen saturation,
blood pressure, respiratory rate).
The standard method for the Cochrane Neonatal Group was used to search the literature. MEDLINE was searched for relevant articles published from January 1, 1966 to July 31, 1997; EMBASE from 1993-1996; and Reference Update from January 1, 1995 to July 31, 1997 with the following MeSH terms or text words; "infant-newborn, pain, analgesia, anesthesia, EMLA, lidocaine-prilocaine, local anesthetics". The Cochrane Library was searched in early August, 1997. In addition, manual searches of bibliographies, personal files, scientific meeting proceedings, and recent issues of key journals were performed. Language restrictions were not applied. Attempts were made to obtain additional data from investigators of published studies. No attempts were made to obtain unpublished studies.
The standard method of the Cochrane Collaboration for conducting a systematic review was used.
Only reports with information on neonates (for this study defined as up to 1 month of age) were included. All randomized controlled trials that included a placebo/unexposed group were included for the determination of efficacy/effectiveness. Since neonates respond to noxious stimuli with behavioral, physiologic, hormonal and metabolic changes, all randomized controlled studies that reported data on any of these variables were included. The inclusion/exclusion of a specific study was decided by the two investigators (AT, AO) and disagreement was resolved by consensus.
The quality of the trials was assessed independently by the two researchers (AT,AO) according to the methods used by the Cochrane Neonatal Group (Blinding of randomization, blinding of intervention, complete follow up, blinding of outcome measurement).
Data abstraction: Data abstracted from each report included the procedure studied, study design, gestational age (GA), sample size, dosage regimen, control group treatment, and outcomes. Abstracted data were verified by two investigators (AT, AO).
Statistical methods: A priori, a decision was made that if there were at least 2 randomized controlled trials that evaluated the efficacy of EMLA for circumcision and using the same outcome measure, study results would be pooled to obtain an overall estimate of effect size. The statistical tests for categorical and continuous data as recommended by the Cochrane Neonatal Group were used.
The efficacy of EMLA for the treatment of circumcision pain was investigated in three studies which included a total of 139 neonates.
Double-blind randomized controlled studies:
Taddio (1997c) randomly assigned 59 male neonates to 1 g of EMLA or a cosmetically identical placebo cream on the outside of the prepuce for 60-80 minutes prior to circumcision.
Randomized controlled studies:
Benini (1993) administered 0.5 g of EMLA or petrolatum jelly placebo for 45-65 minutes prior to circumcision to 28 male neonates.
Lander et al (1996) studied the efficacy of 2 g of EMLA applied for 90 minutes prior to circumcision. Fifty-two male infants were randomized to four groups: no treatment, EMLA, dorsal penile nerve block, or penile ring block.
For details regarding studies see the Table: Characteristics of Included Studies.
The three studies included in this meta-analysis Benini (1993), Taddio (1997c) and Lander are randomized controlled trials, but only the study by Taddio (1997c) was double-blinded with an identical looking placebo. An element of detection bias cannot be excluded in the study by Benini (1993). None of the authors describe whether there was blinding of randomization. There was complete follow up in the studies by Benini (1993) and Taddio (1997c). The study by Lander (1996) has only been published in abstract form and a full quality assessment must await its peer reviewed publication. Change in heart rate data was available for a subset of patients from the study by Benini (1993) (n=24) and the study by Taddio (1997c) (n=39).
Taddio (1997) found that infants pre-treated with EMLA had lower (p<0.05) facial action pain scores [assessed using the Neonatal Facial Coding System (NFCS) (Grunau & Craig 1987)], percent crying time, and heart rate during surgery as compared to placebo. Facial activity scores were 12 to 49% lower during various stages of the procedure. The average difference in percentage crying time and heart rate between the groups compared to baseline values was 55% and 10 beats per minute, respectively. Blood pressure was lower in the EMLA group compared with controls, but the difference did not reach statistical significance.
Benini (1993) found that for all outcome measures [heart rate, transcutaneous O2 saturation, cry duration and NFCS], EMLA was associated with a significantly (p<0.05) reduced response compared to placebo during the painful phases of the procedure (e.g., clamping, incision of foreskin, lysis, and application of Gomco clamp). The average heart rate (HR) for the EMLA group compared with the control group was 25 beats per minute less and the average O2 saturation was 5% higher. Twenty percent less facial activity and 15% less crying was also observed in the EMLA-treated infants. Cry features such as maximum fundamental frequency, peak spectral energy, and dysphonation, however, were not significantly different between groups.
Lander (1996) reported that although the EMLA group had lower mean HR during foreskin retraction than did the no treatment group (169 vs 200 beats per minute), HR values were even lower for the two block groups (151 beats per minute). These investigators did not report the standard deviation and p-values among treatment groups. All three intervention groups cried significantly less than the no treatment group (data and p-values were not provided).
Meta-analysis of the results of two trials (Benini 1993 and Taddio 1997c) shows that the use of EMLA results in a significantly lower increase in heart rate (from baseline) during the various phases of circumcision surgery [weighted mean difference, forceps application -12.9 (95% CI -23.4, -2.5); lysis of adhesions -12.4 (-20.3,-4.5); dorsal incision -27.1 (-37.1,-17.0); application of clamp (Gomco) -27.2 (-36.0,-18.5); foreskin cutting -12.1 (-20.8,-3.3); removal of clamp (Gomco) -11.7 (-19.9,-3.4)]. Although the results for facial action and time crying from the studies by Benini (1993) and Taddio (1997c) could not be combined (results presented in graph format), the individual studies showed that the EMLA group had significantly less facial activity scores and less crying during at least some of the phases of the circumcision procedure. Benini (1993) reported on a significantly higher oxygen saturation in the EMLA group. Taddio (1997c) found no statistically significant difference in systolic or diastolic blood pressure as a response to circumcision in the EMLA compared to the placebo group. Benini (1993) found no differences between groups in the spectral crying parameters.
There are currently few therapeutic classes of drugs available for the management of acute procedural pain in neonates. The severity of potential adverse effects from opioid analgesics have discouraged clinicians from using them in neonates and, until recently, no commercially available local anesthetic preparation has been available that was suitable for use on intact skin. EMLA cream is considered a breakthrough in topical analgesia. Two randomized controlled studies (Benini 1993; Taddio 1997c), including one double-blind study (Taddio 1997c), demonstrate that EMLA diminishes pain response during circumcision. An additional randomized controlled trial that has been published in abstract form supports these results (Lander 1996).
A factor that may influence the observed efficacy of EMLA is the outcome measure used to assess pain. Although there is no consensus regarding the most suitable way to measure neonatal pain, there are many 'accepted' methods. Validated behavioral pain scales such as the Neonatal Facial Coding System (NFCS) (Grunau 1987) and cry duration have been used. In addition to behavioral approaches, physiologic indicators such as heart rate, blood pressure and respiratory rate, and biochemical markers such as stress hormone concentrations have been used. Finally, composite pain measures are also currently available. With the abundance of choice in outcome measures, it is no wonder that investigators who have evaluated the efficacy of EMLA in neonates have utilized very diverse pain indicators in their studies. These differences limit direct comparisons between studies and the use of meta-analytic techniques. Moreover, the sensitivity and specificity of these measures as indicators of neonatal pain are not clear.
Co-interventions may have also contributed to the variability in the results.
In a recent meta-analysis the risk of methemoglobinemia was shown to be low following single dose application of EMLA (Taddio 1997b). In full-term neonates, single doses ranging from 0.5 to 2 g applied for 10 to 180 minutes have not been reported to cause methemoglobinemia. In preterm neonates, single doses ranging from 0.5 to 1.25 g applied for 30 to 180 minutes have not been reported to cause methemoglobinemia. Concentrations of lidocaine and prilocaine are considerably lower than those considered toxic (>5 mcg/mL) using these dosage regimens. There are currently insufficient data to determine the safety of repeated EMLA administration (Taddio 1997b).
The current data provide sufficient evidence to recommend routine use of EMLA for neonatal circumcision pain management in settings where no analgesics are routinely administered. EMLA cannot be recommended over other analgesic techniques with proven efficacy, such as regional nerve block with lidocaine. Single doses of EMLA are safe for application to the skin of neonates.
Additional research is needed before EMLA can be recommended for other painful procedures and for repeated administration. In order to facilitate systematic evaluations, investigators are encouraged to devise their research studies with similar outcomes, and to provide results in a consistent fashion (as described by The Standards of Reporting Trials Group (1994).
Further research is necessary to determine the relative and combined efficacy of different analgesic techniques for circumcision and the most appropriate dosage regimens.
Study: Benini 1993
Methods: Randomized, placebo controlled study.
Blinding of randomization - cannot tell
Blinding of intervention - no
Complete follow up - yes
Blinding of outcome measure - no
Participants: 28 male neonates of 37-42 weeks gestation.
Interventions: 0.5 g of EMLA or sterile petroleum jelly
applied to the penis 45-65 minutes prior to circumcision.
Outcomes: Heart rate, transcutaneous oxygen saturation,
facial expression, crying were measured at baseline and at time
of restraint, clamping, incision, lysis of adhesions, application
of Gomco, foreskin cutting, removal of Gomco and unrestrained.
Results were presented in graph form only. Means and SD were obtained
from the authors for heart rate during the different phases of
circumcision. Spectral features of crying were reported.
Notes: Facial expression [Facial-Action-Coding System,
Grunau & Craig (1990)] was coded from videotape by assistants
who were blinded to the design of the study. Crying was recorded
into an audi recorder via a microphone. Percentage of time crying
was calculated for each phase.
Study: Lander 1996
Methods: Randomized controlled trial of three interventions
to relieve infant distress during circumcision.
Blinding of randomization - cannot tell
Blinding of intervention - no
Complete follow-up - cannot tell
Blinding of outcome measure - cannot tell
As the study has been published only in abstract form a full quality
assessment must await its peer-reviewed publication.
Participants: 52 male infants undergoing circumcision.
Interventions: No treatment, EMLA, dorsal penile nerve
block or penile ring block.
Outcomes: Heart rate, duration of cry, and infant behaviour.
Notes: To date this study has been published in abstract
form only.
Study: Taddio 1997c
Methods: Randomized, placebo controlled, double-blind study.
Blinding of randomization - yes.
Blinding of intervention - yes.
Complete follow-up - yes.
Blinding of outcome measure - yes.
Participants: 59 male neonates of 37-42 weeks gestational
age.
Interventions: 1 g of EMLA applied to the penis 60-80 minutes
prior to circumcision.
Outcomes: Heart rate at the time of lysis of adhesions,
longitudinal incision, application of Gomco, clamping/tightening,
foreskin cutting, removal of clamp. Facial expression was scored
from videotapes using the Neonatal Facial Coding System (Grunau
& Craig, 1987). The duration of crying was calculated from
the videotape as the percentage of time an infant cried during
each phase of the circumcision. Systolic blood pressure was measured
in each infant at base line and during lysis of adhesions. The
authors provided mean and SD for heart rate data for the different
phases that were reported as summary values in the original paper.
Notes: Randomization was performed by the pharmaceutical
company (Astra) and investigators were unaware of group allocation
until after the analysis of the data.
None
Benini F, Johnston CC, Faucher D, Aranda JV. Topical anesthesia during circumcision in newborn infants. JAMA 1993;270:850-3
Lander J, Brady-Fryer B, Nazarali S, Muttitt S. Three interventions for circumcision pain. International Association for the Study of Pain. 8th World Congress on Pain, Vancouver, Canada; 1996:186 (Abstract 256).
Taddio A, Stevens B, Craig K, Rastogi P, Ben-David S, Shennan A. Mulligan P, Koren G. Efficacy and safety of lidocaine-prilocaine cream for pain during circumcision. N Engl J Med 1997;336:1197-201.
Grunau RVE, Craig KD. Pain expression in neonates: facial action and cry. Pain 1987;28:395-410.
Grunau RVE, Craig KD. Facial activity as a measure of neonatal pain expression. In: Tylor DT, Krane EJ, eds. Advances in Pain Therapy and Research. New York, NY: Raven Press; 1990;15:147-156.
The Standards of Reporting Trials Group. A proposal for structured reporting of randomized controlled trials. JAMA 1994;272:1926-1931
Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain response during vaccination in boys. Lancet 1995;345:291-2.
Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 1997;349:599-603.
Taddio A, Ohlsson A, Einarson TR, Stevens B, Koren G. Efficacy and safety of lidocaine-prilocaine (EMLA) cream in the management of acute pain in neonates: a systematic review. Pediatrics 1997 (in press).
01.00.00 EMLA vs placebo
01.01.00 Change in heart rate at time of forceps application
01.02.00 Change in heart rate at time of lysis of adhesions
01.03.00 Change in heart rate at time of dorcal incision
01.04.00 Change in heart rate at time of application of clamp (Gomco)
01.05.00 Change in heart rate at time of foreskin cutting
01.06.00 Change in heart rate at time of removal of clamp (Gomco)