Topical anesthesia and pain management before venipuncture

Topical anesthesia and pain management before venipuncture Thomas H. Joyce III, MD From the Department of Anesthesio . University of Cincinnati College of Medicine, CincinnatI, Ohio

Venipuncture is a distressing experience for nearly all children . Reducing the pain of injection and overcoming a child's fear of needles remain serious problems in the medical management of these pat ients. Venipuncture in children is also a problem because it can consume a significant amount of valuable time for medical personnel, including that of the most experienced nurses and anesthetists. Premedication and the use of small-gauge needles are helpful but do not significantly alleviate the problem. The need to reduce the pain and discomfort of venipuncture in pediatric patients has led to the search for a topical preparation that can effectively anesthetize the skin. An eutectic mixture of two local anesthetics, lidocaine and prilocaine, in a dermatologic cream (EM LA) is the only such agent that has been shown in extensive clinical trials to produce effective skin anesthesia. In healthy adults, EMLA has produced skin anesthesia similar to that of lidocaine infiltration and has achieved significant reductions in pain scores compared with placebo.l" The major clinical trials of EMLA for venipuncture in children are reviewed in the following section. None of these trials controlled for the possible effects of age and gender or medical diagnoses. My colleagues and I recently reported on the safety and efficacy of EMLA in age- and gender-matched children with a variety of medical diagnoses; this trial is described in detail after the review of earlier trials.

CLINICAL TRIALS WITH El\ILA IN CHILDREN Review of earlier trials. EMLA has been evaluated in several double-blind. placebo-controlled studies during the

Reprint requests: Thomas H. Joyce III, MD, Professor of Anesthesiology, University of Cincinnati College of Medicine, 231 Bethesda Ave.. Cincinnati. OH 45267-0531. THE JO URNAL OF P EDIATRICS

1993;122:S24-S9.

Copyright (i') 1993 by Mosby-Year Book, Inc. oo22-3476/93/S 1.00 + .10 9/0/45731

S24

past decade in children from 3 to 15 years of age. 4-9 In all these trials, the difference between pain experienced by children receiving applications of EMLA before venipuncture and pain experienced by children receiving a placebo cream was statistically significant as assessed by verbal or visual analog scale ratings made by both the child and an observer (Table I). In clinical trials to date, most children in the EMLA groups have reported no pain or only slight pain with venipuncture. All patients in these studies were being prepared for minor elective surgery, and most children had had premedication. In general, older children, as expected, tended to report pain less often than younger children, although the differences were not significant in those trials in which age groups were compared. No significant differences between boys and girls were observed in these trials. Adverse effects of EMLA consisted of local erythema or pallor , and were mild and transient. Most were thought to have been caused by the occlusive dressing applied over the cream. These trials confirm that EMLA is effective in eliminating the pain of venipuncture and that it is safe and well tolerated. Each trial is briefly reviewed here.

I.....------_J VAS

Visual analog scale

Hallen and Uppfeldt" compared EMLA and placebo in two series of children: one group received an intravenous administration of premed ication for surgery and another group underwent insertion of an intravenous catheter or cannula before surgery. A nurse evaluated pain on a 3-point scale in both series, and the child evaluated pain on the same scale in the second series. The nurse also subjectively evaluated the ease of venipuncture. All pain assessments by both the nurse and the child were significantly better in the EMLA group than in those given placebo. Only I of 49 patients in the EMLA group had severe pa in compared with 6 of 49 in the placebo group in both series as evaluated by the nurse . In the second series, no pain was reported by 14 patients and slight pain by seven in the EMLA group; only

Joyce et af.

The Journal of Pediatrics Volume 122, Number 5, Part 2

825

\ 1, •• , . , ••• 1 " " 1 " " 1 "

o

5

10

15

.• " , •• 1, •• " , •• , 1 , , . , 1 , , •• ,

20

2S

4S

30

B

Fig. 1. Visual scales for subjective evaluation of pain in young children. (From Maunuskela E-L, Korpela R. Doubleblind evaluation of 1ignocaine-prilocaine cream [EMLA] in children. Dr J Anaesth 1986;58:1242-5 . Reprinted with permission.)

Table I. Double-blind, randomized. placebo-controlled studies with EMLA on venipuncture in children No . of

Study Hallen and Uppfeldt," 1982

patients enrolled III

Age· (yr; range) 10 ± 3 (series I) 10 ± 2 (EMLA group; series 2) (4-15)

Results

Comments

Less pain with EMLA on In EMLA group, 44 and 26 of 71 verbal scores by nurse in reported no and slight pain, respectively; no correlation 2 series (p <0.00 I, between age and pain score P
Ehrenstrom Reiz and Reiz,' 1982

60

11.1 ± 3.0 (EMLA group) Less pain with EMLA on 10.1 ± 2.4 (placebo group) verbal scores by both (6-15) nurse and child (p <0.001)

Maunuksela and Korpela.? 1986

60

6.4 ± 1.92 (EMLA group) Less pain with EM LA on In EMLA group, 13 and 9 of 27 patients reported no and slight 7.1 ± 1.86 (placebo group) verbal scores by pain, respectively; a1l older (4-10) anesthetist (p <0.001) and child (p <0 .05); less children reported no or slight pain with EMLA on pain visual scale by child (p <0.05)

Cooper et al.,4 1987

40

7.3 ± 3.1 (EMLA group) 7.0 ± 2.7 (placebo group) (3-13)

Manner et al.,8 1987

40

6.9 ± 1.8 (EMLA group) Less pain with EMLA vs All 20 EMLA patients reported no 6.4 ± 1.5 (placebo group) or slight pain; no significant placebo group on verbal 7.5 ± 1.7 (no-treatment differences between placebo and and visual scores by group) child (p <0 .001 ; no-treatment groups (4-10 [EMLA and placebo P <0.001) and EMLA vs groups]; 5-10 no-treatment group on [no-treatment group]) visual scale (p
·Mean ±

so; range in parentheses.

Less pain with EMLA on verbal and visual scales by child (p <0 .001; P <0.01) and observer (p
In EMLA group, 19 and 10 of 30 reported no and slight-to-moderate pain, respectively

A1I 19 EMLA pat ients reported as "did not hurt" or "hurt a little ." Older children had lower pain scores; technical difficulty of venipuncture significantly easier with EMLA (p <0.05)

S26

Th e Lournul o jPediatrics

Jo vcc et £II .

M ar 149.\

-

14 12 ~ c 0

.:::

~ ..... 0

.

.8

E :2 Z

D

-

-

EMLA

ETIm

ffillilli1

Placebo

o

EMLA

lEI

Placebo

10 8

I-

6 4

l-

2

-

0

_

I

:%.,/.>;:

W~::::: . .~..l'f.:::

TI' 0-1

I ~ z....···..-x-

1-4

IfiEf

~~jf~:

4-10

Position on VisualAnalog Scale 16

(em)

-

12 -

14

101-

I

8:6,-

·....:::x:"::':: ..:::

,-

4

2

-

I I I

0 0-1

1-4

4-10

Position on Visual Analog Scale (cm) Fig. 2. Distri hutiun o f patien ts o n linear visual sca le as recorded hy child (toP ) a nd observer i b o t t o m} . Patient s wer e 40 c hild ren ran dom ly selected to re cei ve EM LA or placebo (p
one child reported severe pain . The ease of venipunctu re was simila r in the EM LA a nd the placebo groups. Ehrenstrom Reiz and Reiz? ra ndomly selected 60 patients to receive EML A or placeb o and as ked each child a nd a nurse to evaluate pain on a 3-point verbal scale . Of the EMLA patie nts. 19 reported no pain, 10 report ed slight to modera te pa in. and one pa tient reporte d severe pain. In the placebo group only three pat ients, one of whom was heavily sedated, had no pain. Eightee n patients had slight to moderat e pa in a nd nine had severe pain. The nurse's assessment

or th e effi cac y of EMLA was bette r tha n that of the c hil-

dre n: there was no differe nce in the nu rse's a nd the child' s assessme nts of placebo. Maun uksela a nd Korpela'!compared EM LA and place bo in 60 children with a verba l rat ing scale used hy the child a nd the a nesthe tist and with two dillc rcnt pictoria l scales used by the child ( Fig. I) . In the EM LA group. the anesthetist rated xr; of childre n as having no or slight pain compa red with 41(.; in the placebo group . T he children 's pain ratings were somewha t greater tha n those of the unes-

The Journal of Pediatri cs Volunn- I ~~. Y UIII !",r ~. Part

J o vce et al .

z

S27

10 9

8 7

VAS Score

6

5 4 3

2

EMLA

N=20

PLACEBO

N=20

CONTROL

N=1a

) on VAS for thr ee trea tm ent g roups. ( h om Ma nne r Fig . 3. Pain a ssessm e nt hy ea c h chil d (each lin« rep re se nts a c h ild 19X7 M un ksSc amI19X 7:.11:7.\:i -9 . Repr inted w it h perm issi on . Copy r il!h t

T. Kant o J.l.i salo R . et a l. Act a Anaesth esiol

) gaurd Inte rn a tional Publis her s. Lt d .. Co pen hagen . Dcnm ur k.

thetist: 11 in the placebo group a nd 4 in the EM LA group reported severe pain. One linear pictor iul sca le used hy the children showed significant differ ences betwee n EM LA a nd placebo . The ratings from the sca le of facia l expressions did not show signifi ca nt difl"eren ces. Cooper et a l." assessed differ ences with a verba l a nd a linea r scale used by both the child a nd the observe r in 40 pati ents rand omly selec ted to receive EM LA or placebo . The ease of venipunctu re by the ane sthet ist was a lso evaluat ed. No suhjec ts were premedica ted in this tr ial. hut the cllicncy results were similar to those of other tr ials . O f t he 20 EM LA pa t ients, 19 reported pain as "did not hurt " ( 15 pat ients) or " hurt a lillie" (4 ). The distribution of rati ng scores by the observe r was similar: 17 pati ent s were rated " no reac tion" in the EM LA group comp are d with Xin the placebo gro up. The EM LA pat ient s also scored much bet ter on the visua l scales (F ig. 2). The anesth etist reported a signilicum improve ment in the Case of venipuncture in the E ML A group (fJ <0 .05 ). Ma nner et al." rand oml y selected 40 pat ients to receive EM Lt\ or placebo crea m a nd compar ed the se groups with a nother IXcontrol pati ent s who received no treatm ent. The a nesthetist assessed each child on a 4-point scale. Eac h pat ient describ ed pain on a VAS . On the 4- point sca le, the a nesthetist rated 15 pati ents as having "no pain" and 5 as having "slight pain" in the EM L. A group. On th e VAS. significant ly less pain was described by children in th e EM LA group compa red with the placebo a nd the " no tre atment " grou ps (F ig. 3). T here was no significant dill'erence bet ween the placebo a nd the control groups. Th e two meth ods of as-

sessmen t a lso correla ted well. Periph eral venous plasma ca techola mi ne a nd arg inine-va so pressin were also mea sured in this study as a possible objective measur e of pain a nd a nxiet y. In this trial. however . the E M LA and the control gro ups had simila r va lues before a nd after venipunctu re. EM LA was compared with stand ard lidoca ine infiltration in 42 c hild ren 7 to 12 yea rs of age (m ean I} . 7 yea rs) by Soliman et al.!" Pain was scored on a VAS by the a nest hesiologist, an independent observe r. and by the chi ld afte r a pplication of EM LA or intrad erma l ad ministra tion of lidocain e with a 30-ga uge needle. The mean rat ing by the ch ildren was 3.0 in t he EM LA group a nd 3.5 in the lidocaine gro up (differe nce not significan t) , Differen ces in rat ings by the ane sthe siologist a nd th e indep endent observe r were also not significa nt. EM LA was thu s as effective as lidocain e inlilt rati on in producing ane sth esia for venipuncture and had the add ed adva ntnge of avoiding the pain of inliltrat ion. E!\lI.A versus placebo in age- and gender- matched subjects, My colleag ues and I assessed the effects of EML A crea m vers us placebo in age- and gender-m at ched subjec ts. which had not been thoroughly eva lua ted in previous studies.? In addition. subjec ts with a va riety of medical diagnoses were selected to assess a ny correlat ion between response to EM LA crea m a nd d isease. We enrolled 96 ch ildr en who had previou sly undergo ne venipun cture one or more times a nd requ ired a second phle botom y as part of his or her evalu ati on at the outpati ent clinics of Texas C hild ren's 1I0spit al. T he stud y was prospecu v«, tri ple blind. ra ndomized . a nd

S28

Joyce et at.

The Journal of Pediatrics May 1993

Table II. Treatment distribution by age and diagnosis Diabetes mellitus

JRA

Other

Group

n

(%)

n

(%)

n

(0/0)

EMLA Placebo Age (yr)

15 20

(31) (42)

17 17

(35) (35)

16 11

(33) (23)

1 5

(8) (42)

4 3

(33)

7 4

(58) (33)

4 6

(31) (50)

7 4

(54) (33)

2 2

(15) (17)

5 4

(45) (33)

5 3

(45) (25)

1 5

(9) (42)

4 6

(33) (50)

6 2

(50) (17)

2 4

(17) (33)

5-6

M

F 7-8

M

F 9-10

M F 11-12

M F

(25)

From Joyce TH III, Skjonsky BS, Taylor BD, et al. Pain Digest 1992;2:137-91. Used with permission from Springer-Verlag.

Table III. Median patient pain assessments by age and observer (first quartile, third quartile) Observer Overall

S

EMlA group 6.0 2.0 2.0

N P

Placebo group 47.0 25.0 \5.0

p' <0.0001 <0.000\ 0.0002

Age (yr)

5-6

S N

7-8

S

P

9-10

11-12

N P S N P S N

P

6.5 3.0 3.5 20.5 2.0 1.0 6.0 2.0 2.0 3.0 3.0 2.5

9.0 14.0 19.5 37.0 8.0 8.0 47.0 21.0 3.0 78.0 48.0 15.5

0.40\ \ 0.1000 0.09 0.3398 0.0234 0.0488 0.0016 0.0770 0.1000 0.0004 0.0007 0.0150

From Joyce TH III, Skjonsky BS, Taylor BD, et a!' Pain Digest 1992;2:137-41. Used with permission from Springer-Verlag, S, Subject (child); N, nurse; P, phlebotomist. ·Wilcoxon's rank sum test.

placebocontrolled. To ensure that subjects with maximum skinsensitivity wereenrolled,weestablished the reaction of each child to sun exposureby using the parent's description. Sunburn skintypeswereclassified as (I) alwaysburn, never tan; (2) always burn, but sometimes tan; (3) sometimes burn, but always tan; (4) never burn, always tan; (5) moderately pigmented,alwaystan; and (6) black. Children with sunburn skin type 4, 5, or 6 were excluded from the study, becausesideeffectssuch as blanchingor erythema could be masked in patients with these skin types. Because methemoglobinemia may be produced by some local anesthetics,children with congenital methemoglobinemia and those with a potential for methemoglobinemia

(i.e., those receiving antihistamines or preparations containing alcohol, dapsone, sulfonarnides, nitrites or nitrates, aniline dyes, acetanilid, or phenacetin) were excluded, Also excluded were patients with a history of sensitivity to local anesthetics. The children weredividedinto four age groups (Table II). Forty-eight of the children received EMLA and 48 received placebo. Independent assessmentsof the clinical efficacy of EMLA during venipuncture were made by a nurse, a phlebotomist, and the child. Pain was measured on a 100 mm VAS, with 0 = no pain and 100 = severe pain. To make the VAS more understandable to a child, a smiling face, a neutral face, and a crying face were placed at points 0, 50, and

The Journal of Pediatrics Volume 122, N umber 5, Part 2

100 on the scale. Using the faces as reference points, the child was instructed to mark the scale according to the degree of pain that he or she had experienced at the time of venipuncture. The nurse and the phlebotomist marked the scale by using their objective evaluation of the child's response to pain. When the study was completed and the randomization code broken, six sets of pain assessment values were compiled from two treatments with the three observers. Each set was divided by gender and sorted into the four age categories. The pain assessment data were treated as ordinal rather than as interval data and were evaluated with nonparametric, rank-based methods. Overall pain assessment differences between EMLA and placebo, and the differences by age and gender, were compared statistically with the Wilcoxon rank-sum test. Differences in treatment effect between EMLA and placebo based on subgroup differences-age, gender, diagnosis, and site of applicationwere tested with the Brown-Forsythe analysis of variance test for statistical interaction. Overall, EMLA alleviated the pain of venipuncture significantly more than placebo, as assessed by the child, a nurse , and a phlebotomist. Although the differences were not significant in every subgroup, the median values for pain in children receiving EMLA were less than the median values for pain in those receiving placebo in an age groups (Table Ill). Statistical differences occurred in pain assessments by the children in the 9- to 10-year-old and 11- to 12-year-old groups. Overall, pain assessment by children (EMLA and placebo groups combined) was significantly greater than that observed by either nurse or phlebotomist (p <0.0001). Pain assessments by the nurses were significantly different in children II to 12 years of age. Differences between the subgroups were not significant (p >0.04), and the differences between the professional observers were not significant (p = 0.05). Overall, the differences between EMLA and placebo in boys and girls were not statistically significant (p = 0.3, Brown-Forsythe analysis). Differences in subject pain assessments by site of application (antecubital fossa or back of the hand) were also not significant (p = 0.8 Brown-Forsythe analysis). Of the 48 children treated with EM LA, four (8%) had a skin reaction at the site of application . Redness occurred in three patients, one of whom was receiving a corticosteroid, and blanching in one; the reactions lasted between 30 and 60 minutes. One additional patient complained of transient "stinging" in the area where the dressing had been sealed against the skin. The cutaneous reactions (3% redness, 1% blanching) in this study were markedly less than the 37% and 18% incidences of redness and 18% incidence of paleness reported by Hallen et al.,2-6 and the 35% incidence of

Joyce et al.

S29

blanching reported by Soliman et al. 10 The reason for fewer skin reactions in this study is not clear, but the fact that these reactions are clinically insignificant is more important than understanding the wide variation in incidence.

CONCLUSIONS Several double-blind, randomized. controlled studies have shown that EM LA is safe and effective in relieving the pain associated with venipuncture in children. EMLA produces skin anesthesia equivalent to that achieved after conventional lidocaine infiltration but avoids the pain associated with the needle stick. Adverse effects are limited to mild and transient local skin reactions. A shorter time of onset than the 60 minutes required for anesthesia might be des irable but can be coordinated with premedication and other preoperative procedures. EMLA is a promising new addition in the care of pediatric patients and can be conveniently included in routine patient care. REFERENCES I . Arendt-Nielsen L, Bjerring P. Laser-induced pain for evalua-

tion of local analgesia: a comparison of topical application (EMLA) and local injection (lidocaine). Anesth Analg 1988; 61:\ \ 5-23. 2. Hallen B, Carlsson P, Uppfeldt A. Clinical study of a Iignocaine-pri\ocaine cream to relievetne pai.n of venipuncture. Hr ] Anaestn \9&5;51 :326-8. 3. Juhlin L, Evers H, Broberg F. A Iidocaine-prilocainecream for superficial skin surgery and painful lesions. Acta Derm Venereol (Stockh) 1980;60:544-6. 4. Cooper eM, Gerrish SP, Hardwick M, et al. EMLA cream reduces the pain of venipuncturein children. Eur J AnaesthesioI1987;4:441-8. 5. Ehrenstrom Reiz GME, ReizSLA. EMLA: a eutectic mixture of localanaestheticsfor topicalanaesthesia. Acta Anaesthesiol Scand 1982;26:596-8. 6. Hallen B, Uppfeldt A. Doeslidocaine-prilocaine cream permit painfree insertion of IV catheters in children? Anesthesiology 1982;57:340-2. 7. Joyce TH Ill, Skjonsky BS, Taylor BD, et al. Dermal anesthesia usinga eutectic mixture of lidocaineand prilocaine (EMLA) for venipunctureinchildren. Pain Digest1992;2:1374\. 8. MannerT, Kanto J, LisaloR, et al. Reductionof painat venous

cannulation in childrenwith a eutectic mixture oflidocaineand prilocaine (EMLA cream): comparison with placebo cream and no local premedication. Acta Anaesthesiol Scand 1987; 31:735-9. 9. Maunuksela E-L, Korpela R. Double-blind evaluation of Iignocaine-prilocainecream (EMLA) in children.BrJ Anaesth 1986;58:1242-5. 10. Soliman IE, BroadmanLM, Hannallah RS, et al. Comparison of the analgesic effects of EMLA (eutectic mixture of local anesthetics) to intradermal lidocaine infiltration prior to venous cannulation in unpremedicated children. Anesthesiology 1988;68:804-6.