Clinical Therapeutics/Volume 31, Supplement B, 2009

Effectiveness and Tolerability of Pharmacologic and

Combined Interventions for Reducing Injection Pain During
Routine Childhood Immunizations: Systematic Review and
Meta-Analyses
Vibhuti Shah, MD, FRCP, MSC1,2; Anna Taddio, MSc, PhD, RPh 3 ,4; and
MichaelJ. Rieder, MD, PhD, FRCPC, FRCP (Glasgow)5; for the HELPinKIDS Team*
1Department of Paediatrics) Faculty of Medicine) University of Toronto) Toronto) Ontario) Canada;
2Department of Paediatrics) Mount Sinai Hospital) Toronto) Ontario) Canada; 3Division of Pharmacy
Practice) Leslie Dan Faculty of Pharmacy, University of Toronto) Toronto) Ontario) Canada; 4Child Health
Evaluative Sciences) The Hospital for Sick Children) Toronto) Ontario) Canada; and SDepartments of
Paediatrics) Physiology and Pharmacology & Medicine) Schulich School of Medicine & Dentistry, University
of Western Ontario) London) Ontario) Canada
ABSTRACT cluded in meta-analyses. Ten trials, including 1156 in-
Background: Immunization is the most common fants and children, evaluated topical local anesthetics.
cause of iatrogenic pain in childhood. Despite the avail- In a meta-analysis of 2 trials, including 276 children,
ability of various analgesics to manage vaccine injec- child self-reported pain ratings were lower in children
tion pain, they have not been incorporated into clinical who received topical local anesthetics than in those
practice. To date, no systematic review has been pub- who received a placebo. The standardized mean dif-
lished on the effectiveness of pharmacologic and com- ference (SMD) was -0.25 (95% CI, -0.49 to -0.01;
bined interventions for reducing injection pain. P = 0.04). The use of topical local anesthetics was as-
Objectives: The objectives of this article were to as- sociated with less pain than was placebo in 4 trials
sess the effectiveness and tolerability of various phar- (527 infants) based on the difference between Modified
macologic and combined interventions for reducing the Behavioral Pain Scale scores (range, 0-10) before and
pain experienced by children during immunization. after vaccination: the weighted mean difference
Methods: MEDLINE, EMBASE, CINAHL, and (WMD) was -0.79 (95% CI,-1.10 to -0.48; P < 0.001)
the Cochrane Central Register of Controlled Trials and the SMD was -0.43 (95% CI, -0.60 to -0.26;
were searched to identify randomized controlled tri- P = 0.001). Observer-rated pain, using visual analog
als (RCTs) and quasi-RCTs pertaining to pharmaco- scale (VAS) scores (range, 0-100 mm), was signifi-
logic and combined interventions to reduce injection cantly lower (WMD, -16.56 mm; 95% CI, -22.11 to
pain in children 0 to 18 years of age using validated -11.01; P < 0.001; and SMD, -0.75; 95% CI, -1.00
child self-reported pain or observer-reported assess- to -0.49; P < 0.001). The number needed to treat (NNT)
ments of child pain and distress. We included trials to prevent 1 child from having clinically significant
that (1) investigated the effects of pharmacologic pain, measured using the Faces Pain Scale (FPS; score,
interventions (ie, topical local anesthetics, sweet- ::::3), was 3.7 (95% CI, 2.5 to 7.7) from 1 study. Eleven
tasting solutions, vapocoolants, and oral analgesics
*Help ELiminate Pain In Kids (HELPlnKIDS) Team members: Anna
[acetaminophen or ibuprofen]); (2) compared 2 dif-
Taddio, PhD (Team Leader); Mary Appleton; Robert BortolussI, MD;
ferent analgesic interventions; and (3) evaluated Christine Chambers, PhD; Vinita Dubey, MD; Scott Halperin, MD;
combinations of ::::2 analgesic interventions, including Moshe Ipp, MBBCh; Donna Lockett, PhD; Nonl MacDonald, MD;
Deana Mldmer, PhD; PatriCia Mousmanls, MD; Michael Rieder,
breastfeeding. Meta-analyses were performed using
MD;Jeffrey Scott, MD; and V,bhut, Shah, MD.
a fixed-effects model.
Accepted for publicatIOn May 6, 2009
Results: Thirty-two studies, involving 3856 infants dOl:1 0.1 016/J.c1lnthera.2009.08.001
and children 2 weeks to 15 years of age, were included 0149-2918/$ - see front matter
in this systematic review; 23 of these trials were in- © 2009 Excerpta Medica Inc. All rights reserved.

S104 Volume 31 Supplement B


trials (1452 infants and children) evaluated sweet-
tasting solutions. In a meta-analysis of 6 studies (665 in-
fants), administration of sucrose with or without non-
nutritive sucking (NNS; use of a pacifier) was asso-
ciated with less pain than no intervention or sterile
water with or without NNS; the SMD was -0.56
(95% CI, -0.72 to -0.40; P < 0.001). Total cry dura-
tion was lower in infants who received sucrose than in
those who received sterile water (WMD, -9.41 sec;
95% CI,-13.18 to -5.64; P < 0.001; and SMD,-0.43;
95% CI, -0.61 to -0.25; P < 0.001). The NNT to
prevent 1 child from having clinically significant pain,
using the Neonatal Infant Pain Scale (score, >3), was
1.4 (95% CI, 1.0 to 2.5). In 3 trials that evaluated
sweet-tasting solutions longitudinally, administration
of sucrose or glucose (vs sterile water, with or without
NNS) was associated with reduced pain based on cry
duration or the University of Wisconsin Children's
Hospital Pain Scale (all, P < 0.05). Data were pooled
for 2 studies conducted in 100 children who received
a spray with a vapocoolant or placebo at the injection
site before the procedure. Child self-rated pain (4-point
scale) was lower in the group treated with the vapo-
coolant (SMD, -0.43; 95% CI, -0.83 to -0.02; P =
0.04); significant heterogeneity was reported for this
outcome (Z2 = 5.51; P = 0.02; Jl = 82%). In 2 studies
(117 children), no significant difference was found
between vapocoolants and typical care (no treatment)
based on child self-reports; significant heterogeneity
was reported for this outcome (Z2 = 9.89; P = 0.02;
Jl = 90%). None of the studies identified in the litera-
ture search evaluated oral analgesics (acetaminophen
or ibuprofen). Four studies (318 infants and children)
compared 2 different analgesic interventions; there
was insufficient evidence to suggest superiority of
1 intervention over another. Combinations of::::2 anal-
gesic interventions were more effective than the indi-
vidual interventions used alone. Child self-reported
pain ratings were combined for 4 studies (350 chil-
dren); the SMD was -0.52 (95% CI, -0.73 to -0.30;
P = 0.001). Data on cry duration were pooled for
3 studies (229 infants and children); the WMD was
-18.87 seconds (95% CI, -32.05 to -5.69; P = 0.005).
Parent-rated child pain (VAS) scores were combined
for 3 studies (365 infants and children); the WMD was
-15.66 mm (95% CI, -19.74 to -11.57; P < 0.001).
Nurse- or physician-rated child pain (VAS) scores
were combined for 3 studies (368 infants and chil-
dren); the WMD was -17.85 mm (95% CI, -21.43 to
2009
V. Shah et al.
-14.28; P < 0.001). In a meta-analysis of 4 studies
(474 infants), infants who were breastfed before, dur-
ing, and after the procedure had less pain than did
those who were not breastfed (SMD, -2.03; 95% CI,
-2.26 to -1.80; P < 0.001). A meta-analysis of 3 stud-
ies (344 infants) found a shorter cry duration for in-
fants who were breastfed than for those who were not
breastfed (WMD, -38.00 sec; 95% CI, -42.27 to -33.73;
P < 0.001; and SMD, -2.00; 95% CI, -2.27 to -1.73;
P < 0.001). The NNT to prevent 1 infant from having
clinically significant pain, using the Facial Pain Rating
Scale (pain vs no pain), was 7.7 (95% CI, 4.5 to 25.0)
from 1 study.
Conclusion: Topical local anesthetics, sweet-tasting
solutions, and combined analgesic interventions, including
breastfeeding, were associated with reduced pain during
childhood immunizations and should be recommended
for use in clinical practice. (Clin Ther. 2009;31 [Suppl B]:
S104-S151) © 2009 Excerpta Medica Inc.
Key words: infant, child, immunization, pain, anes-
thetic, intervention.
INTRODUCTION
Routine immunization is the most common cause of
iatrogenic pain in childhood. 1 Pharmacotherapy has
been found to be effective in reducing pain from medical
procedures, and promising interventions for immuniza-
tion pain include topical local anesthetics,2-11 sweet-
tasting solutions,11-21 vapocoolantsp-25 and combined
interventions, including breastfeeding. 11 ,24,26-33
We recently documented that only 1% of children
receive pharmacologic interventions to treat pain dur-
ing immunization in clinical practice. 34 One of the
possible reasons for a low level of adoption of phar-
macologic interventions is uncertainty about their ef-
fectiveness and tolerability.
We undertook this systematic review to provide a
summary of the effectiveness and safety profiles of
various pharmacologic and combined interventions
for pain management during routine childhood im-
munizations to guide parents and health care workers
about best clinical practices. Our objectives were to
identify and synthesize randomized controlled trials
(RCTs) and quasi-RCTs that: (1) investigated the ef-
fects of pharmacologic interventions (ie, topical local
anesthetics, sweet-tasting solutions, vapocoolants, and
oral analgesics [acetaminophen or ibuprofen]); (2) com-
pared 2 different analgesic interventions; and (3) evalu-
S105
 Clinical Therapeutics
ated combinations of ;:::2 analgesic interventions, in-
cluding breastfeeding. Breastfeeding was considered a
combined intervention because of its components (lac-
tose [sweet-tasting solution], sucking [pacifier], and
maternal holding/skin-to-skin contact [position]). The
effects of physical interventions (including injection
techniques) and psychological interventions are reported
elsewhere in this supplement. 35 ,36
MATERIALS AND METHODS
Search Strategies
A comprehensive literature search using the OVID
platform was performed in the following databases:
MEDLINE, EMBASE, CINAHL, and the Cochrane
Central Register of Controlled Trials. No language re-
strictions were applied. Search terms used to identify
studies for inclusion were determined by the authors
based on their content expertise in this field and in
consultation with the chief librarian (Elizabeth Uleryk)
at The Hospital for Sick Children (Toronto, Ontario,
Canada), who conducted the searches. A summary of
the search strategies used for the various databases is
provided in the appendix.
The titles and abstracts of the articles were scanned
by 2 reviewers (V.S. and A.T.). Articles selected by the
reviewers were retrieved in full and assessed for eligi-
bility by the 2 reviewers. Reference lists from the identi-
fied trials were reviewed to identify additional studies.
The reviewers were not blinded to the authors or set-
tings of the scanned articles. Experts in this field were
contacted to identify additional articles.
Study Selection
Inclusion Criteria
This review included data from: (1) children 0 to
18 years of age undergoing immunization with a vac-
cine that required injection in any setting (hospital or
community); and (2) RCTs or studies with a quasi-
randomized study design that reported any of the
outcomes of interest in this review. All children must
have been exposed to ;::: 1 pharmacologic intervention,
which must have been compared with a placebo (spe-
cific for that intervention), no intervention, or other
pharmacologic intervention for pain management dur-
ing vaccine injection. The trials had to include the data
necessary for pooling in a meta-analysis, such as means
and SDs, and the outcomes (pain and distress experi-
enced by the child) had to be measured using validated
techniques. Trials were included if they measured pain
S106
within 5 minutes of the injection (or the last injection
if multiple injections were being given during 1 sitting).
We included studies published as full or short reports,
as well as published academic theses.
Exclusion Criteria
Studies in which the analgesic intervention or the
outcome of interest was not clearly defined were ex-
cluded. We also excluded published abstracts, letters,
commentaries, and editorials.
Primary Outcome
The primary outcome was pain or distress experi-
enced by the child during vaccine injection (defined as
needle puncture through the skin and injection of vac-
cine material), as assessed by the child (self-report) or
by others (parent, nurse, physician, or observer) using
validated tools. 37,38 Examples of validated observa-
tional measures were a visual analog scale (VAS), the
Modified Behavioral Pain Scale (MBPS), the Child-
Adult Medical Procedure Interaction Scale-Revised
(CAMPIS-R), and the Neonatal Infant Pain Scale
(NIPS).3 9 --41 Examples of direct measures were VAS
and the Faces Pain Scale-Revised (FPS-R).42
Secondary outcomes included measures of tolera-
bility determined according to the type of intervention
under study. Adverse events for topical local anesthet-
ics were reported based on the type of local anesthetic
evaluated (amide type leg, lidocaine, prilocaine] or
ester type leg, amethocaine]). These included change
in color (pallor or erythema), edema, and alterations
in skin sensation. The frequency of children achieving
protective antibody titers after vaccination was com-
pared between those who received topical local anes-
thetics and those who did not. For sweet-tasting solu-
tions (eg, sucrose, breast milk) and oral analgesics,
episodes of choking and vomiting were evaluated. For
vapocoolants, pain during application and skin reac-
tions were evaluated.
We analyzed results for individual interven-
tions from the same therapeutic class (eg, lidocaine-
prilocaine and amethocaine, sucrose and glucose, ethyl
chloride and Huro-ethyl). For trials using multiple
doses, we included data that were generated from the
most participants for adverse events (eg, topical local
anesthetics). For topical local anesthetics, we analyzed
data for all studies and separately for studies includ-
ing intramuscularly and subcutaneously administered
vaccmes.
Volume 31 Supplement B

Validity Assessment
The included trials were not masked to the review-
ers (\~S. and A.T.). The methodologic quality of the
studies was assessed by the 2 reviewers using the Coch-
rane Collaboration's "Risk of Bias" too1. 43 The in-
cluded domains were sequence generation, allocation
concealment, blinding of outcome assessors and pa-
tients, completeness of outcome data, selective out-
come reporting, and other potential biases. Each of
these domains was assessed and categorized as yes
(low risk of bias), no (high risk of bias), or lInclear
(lack of information or uncertainty about the poten-
tial for bias). An overall summary assessment of the
risk of bias for the individual study was then desig-
nated, based on the following criteria: low (low risk
of bias for all but 1 key item), lInclear (unclear risk
of bias for ::::1 key item), or high (high risk of bias for
::::2 key items). Discrepancies were resolved by consen-
sus and with the assistance of a third reviewer (M.J.R.),
if necessary. The authors rated some of their own
studies.
Data Abstraction
Data from each eligible study were extracted indi-
vidually on custom-made data-collection forms (de-
signed specifically for each intervention) by 2 reviewers
(\~S. or A.T.), and the results were compared. Data were
entered into the database, and the entries were checked
for accuracy by a second reviewer (\~S. or A.T.). The
data were then entered into the data analysis system.
The reviewers resolved any disagreements through dis-
cussion or, if required, consultation with a third person
(M.J.R.). Modification of original data was done as
needed on a predefined, restricted basis according to
established methods. 44 For example, means (SDs) were
calculated from medians, ranges, and 95% CIs.44 Data
were abstracted using an intent-to-treat (ITT) approach;
however, if ITT results were not available, a per-
protocol approach was used for data presentation.
Study Characteristics
We included RCTs and quasi-RCTs that compared
pharmacologic and combined interventions of interest
with a placebo or control group for pain management
°
during immunization in children to 18 years of age.
For children who could provide self-reports, the pri-
mary outcome measure (pain) was child self-reported
pain, using a validated measure (eg, the FPS-R). For
young children who could not self-report pain, assess-
2009
V. Shah et al.
ments of the child's pain were made by a parent,
health care worker, or observer using observational
methods (eg, MBPS, VAS, verbal rating scale [VRS],
FPS-R, cry duration).
Clinical heterogeneity was assessed by noting the
differences among studies in the following variables:
age group (population), country, the intervention and
how it was administered, type of vaccine, route of ad-
ministration (intramuscular vs subcutaneous), injec-
tion technique, other pain-reducing strategies used si-
multaneously (eg, pacifier), and outcome assessments.
Data Synthesis
Data synthesis was performed using qualitative and
quantitative (meta-analytic) methods. All statistical
analyses were conducted using Review Manager (Rev-
Man) version 5.0, the statistical software provided by
the Cochrane Collaboration (Copenhagen, Denmark).43
Data were combined for outcomes that were mea-
sured using the same tool, regardless of who performed
the assessment (eg, nurse, physician, observer), except
for child and parent assessments, which were reported
separately. If data were unavailable for multiple raters
using the same tool, the scores were aggregated for the
same rater(s).
For continuous data, mean differences (MDs) and
weighted MDs (WMDs) were calculated along with
95% CIs. Standardized MDs (SMDs) and 95% CIs
were also computed by combining the results from
different tools measuring the same construct (pain) or
from individual studies to standardize results of stud-
ies to a uniform scale. The SMD expresses the size of
the intervention effect in each study relative to the
variability observed in that study. Values were rated as
follows: <0.40, small; 0.40 to 0.70, moderate; and
>0.70, large. 43 For categorical data, relative risks
(RRs) and risk differences (RDs) were reported. The
number needed to treat (NNT) and the number needed
to harm (NNH) were determined. All meta-analyses
were performed using a fixed-effects mode1. 43
Authors of trials were not contacted for further
details or provision of original data if the published
report contained insufficient information. Missing
data were not imputed. The study findings, as report-
ed by the authors, were included in this review.
Study heterogeneity was assessed using Jl statistic
and '/,2 tests. For Jl, the following template was used
to judge the results regarding heterogeneity: 0% to
40%, may not be important; 30% to 60%, may
S107
 Clinical Therapeutics
be moderate; 50% to 90%, may be substantial; and
75% to 100%, may be considerable. 43 For all Jl
values >40%, the magnitude and accompanying
P value from the '/,2 test were considered in the overall
interpretation. 43 We planned a priori subgroup or
single-study analyses based on the child's age (ie,
younger vs older children, determined by the child's
ability to provide self-reports) to explore possible rea-
sons for heterogeneity only if the number of children
was sufficient for each analysis (arbitrarily defined as
>200 children).
If appropriate, a sensitivity analysis was performed
by including and excluding studies with a high likeli-
hood of bias, as assessed by the Risk of Bias tool. 43
Funnel plots were performed to assess for the possibili-
ty of publication bias if there were sufficient trials
(>10).43
RESULTS
The database searches yielded 480 potentially relevant
articles (Figure 1). All references were stored in an
EndNote library that identified 137 duplicates. The
remaining 343 unique references were screened against
the inclusion criteria, and 311 irrelevant articles were
removed. Thirty-three articles were retrieved for more
detailed evaluation, 32 of which met the criteria for
inclusion in the systematic review. 2- 33 A duplicate
study45 was excluded. Interventions that were evalu-
ated in the 32 trials included: topical local anesthetics
(n = 10)2-11; sweet-tasting solutions (n = 11)11-21;
vapocoolants (n = 4)22-25; comparison of 2 different
analgesic interventions (n = 4)3,4,11,1 9; and combina-
tions of ::::2 analgesic interventions, including breast-
feeding (n = 10).11,24,26-33 None of the trials identified
in the literature search evaluated oral analgesics (ace-
taminophen or ibuprofen) for immunization pain.
Five studies 3,4,1 1,1 9,24 evaluated ::::2 analgesic interven-
tions and were included in >1 category. Twenty-three
of the 32 studies2.5-9,11,14,16,18-20,22-24,26-33 were in-
cluded in meta-analyses.
Two of the 32 included studies 24 ,33 did not contain
information about receiving approval by an institu-
tional review board or ethics committee, or obtaining
informed consent. However, given that many of the
papers were published at a time when reporting ethi-
cal approval and consent was not required, we did not
exclude these trials from analysis.
Characteristics of the included trials, which in-
volved 3856 infants and children 2 weeks to 15 years
S108
of age, are presented in Table I. Results of method-
ologic quality (Risk of Bias )43 assessments of the in-
cluded trials are presented in Table II. The percentage
of agreement on all key items for assessment of the
methodologic quality of the 32 included studies was
89%; disagreements were resolved by consensus.
Topical Local Anesthetics
Nine studies 2- 7 ,9-11 evaluated topical lidocaine-
prilocaine, and 1 study8 evaluated topical amethocaine
gel in 1156 infants and children (Table I). The over-
all risk of bias was low in 3 studies,5,8,9 unclear in
5 studies,2,3,6,7,10 and high in 2 studies 4,11 (Table II).
Topical local anesthetics were compared with a pla-
cebo cream/patch in 7 studies,2.5-l0 sucrose or no in-
tervention in 1 study, 11 typical care (nurse interaction
with the children according to the nurse's routine) in
2 studies,3.4 or distraction (nurse coaching and movie
distraction 3 or nurse-directed movie distraction 4
[1 study each]). Pain and distress were measured in all
of these trials using various tools, including VAS,2--4,9,l0
MBPS,4-6,8,9 the Children's Hospital Eastern Ontario
Pain Scale (CHEOPS),2,11 Child Facial Coding System
(CFCS),2 Faces Pain Scale (FPS),2 VRS/ CAMPIS-R,3
and NIPS. 11 Data could be combined for meta-analysis
for the following pain outcomes: MBPS, VAS, and cry
duration.
Quantitative (Meta-Analytic) Analysis for
Effects on Pain and Distress
Child self-reported pain ratings were combined for
2 studies that included 276 children (data were miss-
ing for 3 children) who received topical local anesthet-
ics or a placebo. V The SMD was -0.25 (95% CI,
-0.49 to -0.01; P = 0.04). Heterogeneity was signifi-
cant for this outcome ('/,2 = 4.64; P = 0.03; Jl = 78%);
thus, data from the individual studies were analyzed
qualitatively. In the study by Cassidy et all in children
4 to 6 years of age, the FPS score (range, 0-6) was
lower in the lidocaine-prilocaine group than in the
placebo group (MD, -1.00; 95% CI, -1.66 to -0.34;
P = 0.003). The SMD was -0.48 (95% CI, -0.79 to
-0.16; P = 0.003). A study by Hansen and S0rensen 7
in children 11 to 15 years of age reported no signifi-
cant difference in the VRS scores between the groups
(MD, 0.04; 95% CI, -0.24 to 0.32).
The differences in MBPS scores before and after
vaccination (range, 0-10) were available from 4 trials
(527 infants; data missing for 18)5,6,8,9; 3 of the
Volume 31 Supplement B
 v. Shah et al.

Potentially relevant articles Identified and screened for

retneval (n ~ 480):
MEDLINE (n ~ 103), EM BASE (n ~ 235), CINAHL(n ~ 33),
Cochrane Central Register ofControlled Tnals (n ~ 109)

Duplicate citations removed (n ~ 13 7)

Potentially relevant articles screened for retneval (n ~ 343)

Irrelevant citations removed (n ~ 311)

Tnals retneved for more detailed evaluation (n ~ 33)

Tnals excluded (n ~ 1)
• Duplicate publication (n ~ 1)

Tnals Included In systematic review (n ~ 32)

Tnals excluded from meta-analysIs (n ~ 9)

• MIssing outcome data (n ~ 2)
• Single study assessing the intervention or
data could not be combined (n ~ 7)

Tnals Included In meta-analysIs (n ~ 23)*

• Topical local anesthetics (n ~ 7)
• Sweet-tasting solutions (n ~ 6)
• Vapocoolants (n ~ 3)
• Companson of 2 analgesIc interventions (n ~ 0)
• Combinations of:2:2 analgesIc interventions, including
breastfeedlng (n ~ 10)

Figure 1. Flow diagram for selection of trials. *Some trials are included in >1 category.

studies 5 ,6,9 used lidocaine-prilocaine, and 1 study8
used amethocaine. The WMD was -0.79 (95% CI,
-1.10 to -0.48; P < 0.001) for the topical local anes-
thetic group compared with the placebo group. The
SMD was -0.43 (95% CI, -0.60 to -0.26; P = 0.001)
(Figure 2). No statistically significant heterogeneity
was noted for this outcome.
Data on observer VAS scores (range, 0-100 mm)
were combined for 2 studies (253 infants and chil-
dren; data missing for 8).2,9 The VAS scores were
significantly lower m the lidocaine-prilocaine
group (WMD, -16.56; 95% CI, -22.11 to -11.01;
P < 0.001). Heterogeneity was not significant for
this outcome. The corresponding SMD was -0.75

2009 S109
 .....
Vl
..... Table I. Baseline characteristics of the included trials on pharmacologic and combined interventions (N = 32). Q
0 I :::l
;:;.
Included ~
-l
Author, Year, in Meta- Population ::r
I'D
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes P:l
"'0
I'D

Topical Local Anesthetics ...;:;.

l:

Cassidy et al, 2 Yes N = 161; children Allergy to local DPTP 1 mL 1M; Lidocaine-prilocaine Pain: Child FPS (no. with
I III

2001, Canada 4-6 y; multicenter anesthetics or prior 2S-gauge, patch 1 g x 1-2 h score :2:3); parent VAS,
(outpatient clinics) use of lidocaine- 1.S-cm needle; (n = 83) or placebo observer VAS,
prilocaine; congenital mid-deltoid; (n = 78); removal CHEOPS, CFCS
or idiopathic 90 0 angle; <10 sec <10 min before Anxiety: Parent VAS
methemoglobinemia; immunization Tolerability: Child, local
active dermatitis; skin reactions;
open wound; fever or observer, local skin
acute illness; sedative, reactions
analgesic, or anesthetic
12 h before procedure;
sulfonamide therapy;
language barrier;
developmental delay
Cohen et al,3t No N = 39; children NR Hepatitis B Typical care (n = 39), Pain and distress:
1999, US 9-11 y; single (3 doses; baseline nurse coaching and Observer CAMPIS-R,
center (school and 1 and 4 mo); distraction (n = 39), or child VAS, nurse VAS
health clinic) method of lidocaine-prilocaine
injection NR cream 2 g x 1 h for
each injection (n = 34);
crossover study; each
participant exposed to
all 3 experimental
~ conditions
i:
3I'D Cohen et al,4t No N = 84; infants Children with chronic Measles-mumps- Typical care (control), Pai n and distress:
.....
(JJ 2006, US 12 mo; single illness requiring rubella; Hib; nu rse-d irected Observer MBPS, parent
Vl center (health multiple injections Varivax; method distraction using toys VAS, nurse VAS
l:
"'0 clinic) of injection NR and a movie, or
"'0
10 lidocaine-prilocaine
3I'D cream 2 g x 1 h (N = NR)
...
:::l

C:l (continued)
g I Table I (continued).
10
Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Halperin et al,5 Yes N = 160; infants Allergy to measles- Measles-mumps- Lidocaine-prilocaine Pain: Observer MBPS
2000, Canada and children':::l y; mumps-rubella vaccine rubella (M-M-R 11 ); patch 1 g x 1-3 h Tolerability: Observer,
single center or amide anesthetics; 0.5 mL SC; (n = 80) or placebo local and systemic
(ambulatory clinic) immune deficiency or 25-gauge, 15-mm patch (n = 80); removal adverse reactions;
immunosuppression; needle; mid-thigh <10 min before antibody response at
congenital or idiopathic immunization 1 mo
methemoglobinemia;
chronic illness; active
dermatitis; open
wound; anesthetic or
analgesic 12 h before
procedure; sulfonamide
or immune globulin
therapy
Halperin et al,6 Yes N = 165; Part A NR Part A: DPTaP-IPV- Part A: Lidocaine- Pain: Observer MBPS
2002,Canada (n = 109): infants Hib (Pentacel) prilocaine patch 1 g x Tolerability: Observer,
6 mo; Part B 0.5 mL 1M, and 1-3 h (n = 54) x 2 doses local skin reactions;
(n = 56): infants hepatitis B (1 for each vaccine) or antibody response at
0-2 mo; multicenter (Recombivax) placebo patch (n = 55) 1 mo
(ambulatory clinics) 0.5 mL 1M; Part B: Lidocaine-
23-gauge, 25-mm prilocaine patch 1 g x
needle 1-3 h (n = 28) or
Part B: DPTaP-IPV- placebo patch (n = 28);
Hib (Pentacel) removal <10 min before
0.5 mL 1M at 2, immunization
4,6 mo, and
hepatitis B
(Recombivax)
0.5 mL 1M at <2,
2, 6 mo; 25- or ::::
VI
23-gauge (6 mo), ::r
~
25-mm needle ::r
.....
VI
.....
...
rtl

..... (continued) ~
 .....
Vl
..... Q
:::l
N ;:;.
~
-l
Table I (continued). ::r
I'D
P:l
Included "'0
I'D
Author, Year, in Meta- Population ...;:;.
l:

Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes III

Hansen and Yes N = 118; children Allergy to lidocaine- Measles-mumps- Lidocaine-prilocaine Pain: Child VRS
Sorensen,? 11-15 y; multicenter prilocaine; analgesic rubella, method cream 5 mL x 1 h (n =
1993, Denmark (outpatient clinics) 24 h before procedure of injection NR 59) or placebo (coconut
oil) x 1 h (n = 59)
O'Brien et ai,s Yes N = 120; infants Allergy to ester Measles-mumps- Amethocaine gel 1 g x Pain: Observer MBPS
2004,Canada >12 mo; multicenter anesthetics; fever or rubella (Priorix) 30-45 min (n = 61) or Tolerability: Observer,
(outpatient clinics) illness that prevented 0.5 mL SC; placebo x 30-45 min local skin reactions;
vaccine administration 25-gauge, 16-mm (n = 59) antibody response
needle; deltoid after 1 mo
muscle
Taddio et al,9 Yes N = 100; infants Sensitivity to amide OPT 0.5 mL 1M; Lidocaine-prilocaine Pai n: Investigator
1994, Canada 4-6 mo; single local anesthetics; use 25-gauge, 16-mm cream 2.5 g x 1-2 h MBPS, VAS, cry
center (outpatient of analgesics 4 h needle; mid-thigh (n = 51) or placebo (latency, duration of
clinic) before the procedure; 2.5 g x 1-2 h (n = 49) first cry, total
fever or illness that duration)
prevented vaccine Tolerability: Observer,
administration crying during dressing
removal; local skin
reactions
Uhari,lO No N = 155; infants NR OPT (98% of Lidocaine-prilocaine Pain: Parent VAS, nurse
1993, Finland 3-28 mo; children),IM cream x 1 h (n = 79) or VAS
~ mu Iticenter placebo cream x 1 h Fear: Parent VAS, nurse
i:
3I'D (outpatient clinics) (n = 76) VAS
Tolerability: Observer,
.....
(JJ

Vl local skin reactions

l:
"'0
"'0 (continued)
1D
3I'D
...
:::l

C:l
N
o
~ I Table I (continued).

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Oilli et al,llt Yes N = 250; infants Intercurrent illness; 1 Injection: Infants <6 mo: breast- Pain: Observer, cry
2009, Turkey and children preterm infants; hepatitis B 0- feeding (30-60 sec duration; infants <1 y
0-48 mo; single inability to tolerate 2 wk, 1 and 6 mo before and during the NIPS; infants and
center (hospital oral fluids; allergy to or measles- procedure [n = 77] or children 13-48 mo
based) any component of mumps-rubella control [n = 85]) CHEOPS
the anesthetic 12 mo Infants and children Except for sign ificance
evaluated; infants Multiple injections: 6-48 mo: sucrose 12% level, pain scores NR
with cerebral palsy BCG 2 mo, 2 mL 2 min before the for infants and
OPTaP-IPVand procedure (n = 34) or children 13-48 mo
Hib 2,4, 6, and lidocaine-prilocaine
16-24 mo; 1M or cream 1 g 1 h before
SC, 16- or 25-mm the procedure; applied
needle on right thigh or deltoid
(n = 24) or no
intervention (n = 30)
Sweet-Tasting Solutions
Allen et al,12 No N = 285; infant Acute or chronic 1 Injection: Sucrose 12% 2 mL or Pain: Observer,
1996, US age categories: illness; if receiving hepatitis B, 2 wk no intervention or percentage oftime
2 wk (n = 50); inoculation >1 mo of and 9 mo; OPT, sterile water 2 mL; crYing
2 mo (n = 44); the recommended age 18 mo sucrose or sterile water
4 mo (n = 50); 2 Injections: OPT administered 2 min
6 mo (n = 46); and Hib, 2 and before the procedure
9 mo (n = 28); 6 mo; measles- (N = NR)
15 mo (n = 30); mumps-rubella
18 mo (n = 37); and Hib, 15 mo
single center 3 Injections: OPT,
(ambulatory clinic) Hib, hepatitis B:
4 months; all SC :<
Vl
in the thigh ::r
~
::r
.....
Vl (continued) ...
I'D
.....
(JJ ~
.....
Vl
..... Q
:::l
.j::o. ;:;.
~
-l
::r
I'D
Table I (continued). P:l
\J
I'D

Included ...;:;.
l:

Author, Year, in Meta- Population III

Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Barr et al,13 No N = 66; infants Fever or present OPT, 1M in the Sucrose 50% 3 doses Pain: Observer,
1995, Canada 2 mo; single center illness; analgesic thigh, 5-10 sec of 250 flL on tongue at percentage oftime
(pediatric practice); before the procedure 30-sec intervals (n = 33) crYing
longitudinal study, or sterile water 3 doses
consecutive (n = 33)
evaluation at
2 and 4 mo
Hatfield et al,14 Yes N = 100; infants Fed 30 min before OPTaP-IPVand Sucrose 24% 0.6 mL/kg Pain: Investigator
2008, US 2 and 4 mo; single immunization; hepatitis B vaccine and NNS using a UWCH Pain Scale
center (ambulatory analgesic on day of followed 3 min pacifier (n = 50) or
pediatric clinic) the procedure; infants later by Hib sterile water 0.6 mL/kg
introduced to solid followed 2 min and NNS using a
food; not used to a later by pacifier (n = 50) x
pacifier pneumococcal 2 min before
conjugate vaccine, immunization
1M
Hatfield,15 No N = 40; infants Fed 30 min before OPTaP-IPV-Hib, Sucrose 24% 0.6 mL/kg Pai n: Investigator
2008, US 2 mo; single center immunization; hepatitis B, and and NNS using a UWCH Pain Scale
(ambulatory analgesic on day of pneumococcal pacifier (n = 20) or
pediatric clinic); immunization; infants conjugate vaccine, sterile water 0.6 mL/kg
~ longitudinal study, introduced to solid 1M; 25-gauge, and NNS using a
i:
3I'D evaluation at food; not used to a 2.54-cm needle pacifier (n = 20) x 2 min
2 and 4 mo pacifier before immunization
.....
(JJ

Vl
l: I (continued)
\J
\J
10
3I'D
...
:::l

C:l
N
o
o
10

Table I (continued).

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Lewindon et al,16 Yes N = 110; infants
1998, Australia 7-38 wk; single
center (ambulatory
clinic)
Lewkowski et No N = 121; children
al,17 9-11 y; multicenter
2003, Canada (school clinics)
Intercurrent illness; Oral polio, OPT, Sucrose 75% 2 mL Pain and distress:
born at <34 wk and Hib, 1M in (n = 54) or sterile water Observer, first cry and
gestation; parental both thighs 2 mL (n = 53),15 sec total cry duration,
request for injection (3 infants withdrawn total cry in first 3 min;
into the arm; infants after randomization) nurse VAS; parent VAS
with cerebral palsy;
unable to tolerate
fluids by mouth;
modification of
standard protocol
Fever or pain present; Hepatitis B 0.25- Sweet gum x 1 min, Pain and distress: Child
receiving analgesia; 0.5 mL 1M in arm; stopped x 1 min FPS, CAS
allergy to gum 26-gauge, 1.59-cm before vaccination
ingredients; blood needle (sweet taste) or
drawn for oncologic unsweetened gum x
investigation 1 min, stopped x 1 min
before vaccination
(control) or sweet
gum x 2 min before
and during vaccination
(sweet + chew) or
unsweetened gum x
2 min before and during
vaccination (no sweet
taste + chew) (N = NR)

(continued)
:<
Vl
::r
~
::r
.....
Vl
..... ...
I'D

til ~
 til
~
~
o
5'
Cl\
n'
~
Table I (continued). -f
:::l"
I'D

Included ~I'D
Author, Year, in Meta- Population ...r::::
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes n'
II>

Mowrey,18 Yes N = 49; infants Infants born <37 wk OPTaP-IPV-Hib Sucrose 50% 2 mL (n = Pain: MBPS; cry (first,
2007, US 2-6 mo; single gestation; and hepatitis B 25) or sterile water total cry duration,
center (hospital hospitalized since Prevnar injections; 2 mL (n = 24); 1 min percentage of time
based) birth; inability to 1M, in 1 sitting crying)
tolerate intraoral
fluids
Ramenghi et Yes N = 184; infants No hospitalization OPT and 3 min Sucrose 25% 2 mL Pain: Observer, cry
al, 19 t 7-25 wk; single since birth later Hib, 1M (n = 46) or sucrose duration
2002, UK center (ambulatory 50% 2 mL (n = 45) or
clinic) hydrogenated glucose
40% 2 mL (n = 46) or
sterile water 2 mL
(n = 47); 1 min before
vaccination
Soriano Faura Yes N = 323; infants Infants born <34 wk Hepatitis B or Sucrose 75% 2 mL Pain: Observer, cry
and Gomez 1-6 mo; gestation; Apgar score OPT, 1M (n = 165) or sterile water duration
Gil,2 0 multicenter <7 at 1 min and <8 at 2 mL (n = 158); orally
2003, Spain (pediatric clinics) 5 min; infant crying 1 min before the
before the procedure; procedure
chronic illnesses; on
oral medications
except for vitamins;
~
i: inability to tolerate
3I'D oral feeds; neurologic
(JJ
~ problems or congenital
til anomalies
r::::
"'0
"'0
i'D (continued)
3
I'D
...
:::l

c:l
N
o
o
10

Table I (continued).

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Thyr et al,21 No N = 110; infants Infants born at Infanrix, polio, Hib; Glucose 30% 2 mL Pain: Observer, cry
2007, Sweden 3 mo; single center <34 wk gestation; 1M in the thigh (0.6 g) (n = 55) or duration and intensity
(ambulatory clinic); modification of sterile water 2 mL
longitudinal study, standard protocol (n = 55) 30 sec before,
evaluation at 3, 5, during, and 10-30 sec
and 12 mo after the procedure
Dilli et al,llt Yes N = 250; infants Intercurrent illness; 1 Injection: Infants <6 mo: Pain: Observer, cry
2009, Turkey and children preterm infants; hepatitis B breastfeeding duration; infants <1 y
0-48 mo; single inability to tolerate 0-2 wk, 1 and (30-60 sec before and NIPS; infants and
center (hospital oral fluids; allergy to 6 mo, or measles- during the procedure children 13-48 mo
based) any component of the mumps-rubella [n = 77] or control CHEOPS
anesthetic evaluated; 12 mo [n = 85]) Except for significance
infants with cerebral Multiple injections: Infants and children level, pain scores NR
palsy BCG 2 mo, 6-48 mo: sucrose 12% for infants and
DPTaP-IPVand 2 mL 2 min before the children 13-48 mo
Hib 2,4, 6, and procedure (n = 34) or
16-24 mo; 1M or lidocaine-prilocaine
SC, 16- or cream 1 g 1 h before
25-mm needle the procedure; applied
on right thigh or
deltoid (n = 24) or no
intervention (n = 30)

(continued)
:<
Vl
::r
~
::r
.....
Vl
..... ...
I'D

'I ~
.....
Vl
..... Q
:::l
00 I Table I (continued). ;:;.
~
-l
Included ::r
I'D
Author, Year, in Meta- Population P:l
\J
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes I'D
...;:;.
l:

Vapocoolants III

Abbott and Yes N = 90; children Skin allergies or OPT Refrigerant topical Pain: Child VAS, parent
Fowler-Kerry,22 4-5.5 y; multicenter conditions; hospitalized anesthetic spray VAS
1995, Canada (health clinics) within the past year; (fluro-ethyl) (n = 30) Anxiety: Parent VAS
inability to understand or placebo topical spray
the concept of pain (n = 30) or no treatment
(n = 30)
Cohen et al,23 Yes N = 58; children NR DPTaP, measles- Vapocoolant (ethyl Pain: Child FPS-R
2009, US 4-6 y; single center mumps-rubella, chloride) (n = 31) or Distress: Caregiver VAS,
(hospital based) and IPV; 25-gauge, typical care (n = 26); nurse VAS
1-in needle in the applied to both legs
thigh
Eland, 24 t 1981, Yes N = 40; children NR OPT 0.5 mL, 1M; Refrigerant topical Pain: Child CAS
US 4.7-5.7 y; single 25-gauge, 5/8-in anesthetic spray Anxiety: Parent VAS,
center (pediatric needle in the (Frigiderm) plus nurse VAS
clinic) thigh cognitive information
or refrigerant topical
anesthetic spray
(Frigiderm) plus no
cognitive information
or aerosol air spray plus
cognitive information
or aerosol air spray plus
~ no cognitive information;
i:
3I'D spray applied 3-5 sec
.....
(JJ on the leg before
Vl vaccination; Frigiderm
l:
\J (n = 20), aerosol air
\J
10 spray (n = 20)
3I'D
...
:::l (continued)
C:l
N
o
o
10

Table I (continued).

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Maikler,25 No N = 60; infants Chronic health OPT 0.5 mL, 1M; Refrigerant topical Pain: Observer MAX,
1991, US 6-30 wk; problems; no previous 2S-gauge, S/8-in anesthetic spray (dichloro- cry attributes (latency
mu Iticenter injections except for needle tetrafluoroethane) to cry, duration of
(ambulatory/ immunizations (n = 30) or compressed crying)
private clinics) air spray (n = 30) for
2-3 sec
Comparison of 2 Analgesic Interventions
Cohen et al,3t No N = 39; children NR Hepatitis B Typical care (n = 39), Pain and distress:
1999, US 9-11 y; single center (3 doses; baseline nurse coaching and Observer CAMPIS-R,
(school health and 1 and 4 mo) distraction (n = 39), or child VAS, nurse VAS
clinic) lidocaine-prilocaine
cream 2 g x 1 h for
each injection;
crossover study; each
participant exposed to
all 3 experimental
conditions
Cohen et al,4t No N = 84; infants Children with chronic Measles-mumps- Typical care (control), Pai n and distress:
2006, US 12 mo; single illness requiring rubella; Hib; nu rse-d irected Observer MBPS,
center (health multiple injections Varivax distraction using toys parent VAS, nurse VAS
clinic) and a movie, or
lidocaine-prilocaine
cream 2 g x 1 h
(N = NR)

(continued)
:<
Vl
::r
~
::r
.....
Vl
..... ...
I'D

10 ~
 .....
Vl
Q
N :::l
o ;:;.
~
-l
::r
I'D
P:l
"'0
I'D
Table I (continued). ...;:;.
l:

III

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Ramenghi et No N = 184; infants No hospitalization OPT and 3 min Sucrose 25% 2 mL Pain: Observer, cry
al, 19 t 7-25 wk; single since birth later Hib, 1M (n = 46) or sucrose duration
2002, UK center (ambulatory 50% 2 mL (n = 45) or
clinic) hydrogenated glucose
40% 2 mL (n = 46) or
sterile water 2 mL;
1 min before
vaccination (n = 47)
Oilli et al,llt No N = 250; infants Intercurrent illness; 1 Injection: Infants <6 mo: breast- Pain: Observer, cry
2009, Turkey and children preterm infants; hepatitis B 0- feeding (during the duration; infants <1 y
0-48 mo; single inability to tolerate 2 wk, 1 and 6 mo, procedure [n = 77] or NIPS; infants and
center (hospital oral fluids; allergy to or measles- control [n = 85]) children 13-48 mo
based) any component of mumps-rubella Infants and children CHEOPS
6-48 mo: sucrose12%
the anesthetic 12 mo Except for sign ificance
2 mL 2 min before the
evaluated; infants Multiple injections: level, pain scores NR
procedure (n = 34) or
with cerebral palsy BCG 2 mo, lidocaine-prilocaine for infants and
OPTaP-IPVand cream 1 g 1 h before children 13-48 mo
Hib 2, 4, 6, and the procedure; applied
16-24 mo; 1M or on right thigh ordeltoid
~ SC, 16- or (n = 24) or no
i: 25-mm needle intervention (n = 30)
3I'D
.....
(JJ (continued)
Vl
l:
"'0
"'0
1D
3I'D
...
:::l

C:l
N
o
o
10
Table I (continued).

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Combinations of:2:2 Analgesic Interventions

Berberich and Yes N = 41; children Significant DTaP and IPV, Multimodal distraction Pain: Child FPS-R,
Landman,26 4-6 y; single concurrent illness; 1M; 2S-gauge, strategy grou p: parent FPS-R,
2009, US center inability to follow SIS-in needle; application of observer FLACC
intervention measles-mumps- vapocoolant (ethyl
directions or answer rubella, SC; chloride) to the
pain scale question; 26-gauge, SIS-in injection site followed
recent (within 1 y) needle by placement of
venipuncture or horseshoe-shaped,
hospitalization; plastic, multipronged
. . .
prevIous Invasive gripper (Bionix,
procedures other Toledo, Ohio) below
than perinatal and around the spray
. . .
circumcIsion site and then child
asked to follow the
descent of a vibrating
instrument (Wahl,
Shelton, Connecticut)
on the opposite arm,
timed to reach the
elbow just as each of
2 injections
administered (n = 20)
or control group (no
intervention) (n = 21);
intervention was
repeated for both 1M
and SC injections :<
Vl
::r
~
(continued) ::r
.....
Vl
...
I'D

.....
N
~
 .....
Vl
Q
N :::l
N ;:;.
Table I (continued). ~
-l
::r
Included I'D

Author, Year, in Meta- Population P:l

"'0
I'D
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes ...;:;.
l:

III
Boivin et al,27 Yes N = 239; children Contraindication to Measles-mumps- Multimodal strategy Pain: Child VAS, FPS;
2008, France 4-12 y; multicenter vaccination or rubella or OPT or group: education and observer VAS,
(general practice lidocaine-prilocaine OPTP or hepatitis preparation of the CHEOPS (only in
clinic/hospital patch; concomitant B or other vacci nes parents, child education 4-6 y); parent VAS
clinic) painful disease; mental in the arm in the by parents, Priorix used
delay; parental refusal multi modal preferentially in case of
strategy group or combined measles-
in various sites mumps-rubella vaccine,
(NR) in the application of lidocaine-
control grou p prilocaine patch 1 h
before vaccination, prior
education of the child
by doctor about
potential painful aspects
of vaccination, presence
of 1 parent during the
procedure, and
distraction by blowing
bubbles during the
procedure (n = 107); or
control group: usual
clinical practice of the
participating physician,
~ including variety of
i: injection sites, with or
3I'D
without an anesthetic
.....
(JJ
patch or freezing spray
Vl
l: and distraction methods
"'0
"'0 (n = 132)
1D
3I'D
(continued)
...
:::l

C:l
N
o
o
10

Table I (continued).

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Cohen Reis Yes N = 62; children Sensitivity to amide OPTaP 0.5 mL, 1M; Lidocaine-prilocaine Pain: Child FPS; parent
and 4-6 y; single center anesthetics; glucose- 26-gauge, 1/2-in cream 2.5 g x 1 h plus VAS, FPS; nurse VAS,
Holubkov,28 (hospital clinic) 6-phosphate needle in the arm distraction (blowing FPS; blinded observer
1997, US deficiency; congenital on a pinwheel) (n = 21) OSBO, VAS (linear
or idiopathic or distraction plus and faces), GMS, cry
methemoglobinemia; vapocoolant spray duration
severe hepatic or renal (fluori-methane) Anxiety and distress:
disease; use of class I applied immediately Child VAS, parent VAS
antiarrhythmic drugs; before the injection
sensitivity to dichloro- and held firmly on the
difluoromethane injection site x 15 sec
and/or trich loro- (n = 20) or distraction
monofluoromethane alone (n = 21)
Cohen Reis et Yes N = 120; infants NR OPT, IPV, Hib, Oral sucrose 25% 10 mL Pain: Observer, first cry
al,29 6-16 wk; single hepatitis B, and followed by sucking and total cry duration
2003, US center (hospital heptavalent (pacifier or bottle) and
clinic) pneumococcal parental holding
conjugate vaccine; (n = 60) or control
0.5 mL each, 1M; (n = 60)
26-gauge, 1.59-cm
needle in the thigh

(continued)
:<
Vl
::r
~
::r
.....
Vl
N
...
I'D

(JJ ~
 .....
Vl
Q
N :::l
.j::o. ;:;.
~
-l
::r
I'D

Table I (continued). P:l

"'0
I'D

Included
...;:;.
l:

III
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Eland,24*t Yes N = 40; children NR OPT 0.5 mL, 1M; Refrigerant topical Pain: Child CAS
1981,US 4.7-5.7 y; single 25-gauge, 5/8-in anesthetic spray Anxiety: Parent VAS,
center (pediatric needle in the thigh (Frigiderm) plus nurse VAS
clinic) cognitive information
or refrigerant topical
anesthetic spray
(Frigiderm) plus no
cognitive information
or aerosol air spray
plus cognitive
information or aerosol
air spray plus no
cognitive information;
spray applied 3-5 sec
on the leg before
vaccination
Lindh et al;10 Yes N = 90; infants Infants with medical OPT 0.5 mL, 1M; Lidocaine-prilocaine Pain: Parent VAS;
2003, Sweden 3 mo; single center illnesses 23-gauge, 25-mm 1 g x 1 h plus glucose observer VAS, MBPS,
(pediatric clinic) needle in the thigh 1 mL (300 mg/mL) x latency to cry, and
2 min before total crying time
~ vaccination (n = 45) or
i:
3I'D placebo cream and
sterile water (n = 45)
.....
(JJ

Vl
l:
(continued)
"'0
"'0
1D
3I'D
...
:::l

C:l
N
0
0
10 I Table I (continued).

Included
Author, Year, in Meta- Population
Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Breastfeeding
Abdel Razek Yes N = 120; infants Concurrent illness; Type of vaccine Breastfeeding during Pain: Cry duration,
and Az 1-12 mo; preterm; diagnosis of and site NR and after the procedure neo natalji nfant pai n
EI-Oein;11 mu Iticenter cerebral palsy or (n = 60) or control rating scale, FPRS
2009, Jordan (health clinics) intrauterine growth (n = 60)
retardation; not
breastfeeding
Oilli et al,llt Yes N = 250; infants Intercurrent illness; 1 Injection: Infants <6 mo: breast- Pain: Observer, cry
2009, Turkey and children preterm infants; hepatitis B 0-2 wk, feeding (30-60 sec duration; infants <1 y
0-48 mo; single inability to tolerate 1 and 6 mo or before and during the NIPS; infants and
center (hospital oral fluids; allergy to measles-mumps- procedure [n = 77] or children 13-48 mo
based) any component of the rubella 12 mo control [n = 85]) CHEOPS
Infants and children
anesthetic evaluated; Multiple injections: Except for sign ificance
6-48 mo: sucrose 12%
infants with cerebral BCG 2 mo, OPTaP- level, pain scores NR
2 mL 2 min before
palsy IPVand Hib 2, 4, the procedure (n = 34) for infants and
6, and 16-24 mo; or lidocaine-prilocaine children 13-48 mo
injectio ns were cream 1 g 1 h before
1M orSC, 16- or the procedure; applied
25-mm needle on right th igh or
deltoid (n = 24) or no
intervention (n = 30)
Efe and Ozer;12 Yes N = 66; infants Concurrent illness; OPT 0.5 mL; 1M Breastfeeding before, Pain: Observer, first
2007, Turkey 2-4 mo; single preterm infants; in the thigh; during, and after the and total cry duration,
center (ambulatory infants not breast- 26-gauge, procedure (n = 33) or total cry in the first
clinic) feeding; diagnosis of 1.59-cm needle control (n = 33); 3 min
cerebral palsy immunization was Physiologic: heart rate
performed at the end
and oxygen saturation
of the third min of
breastfeeding while the :<
Vl
infant was still sucking ::r
~
::r
.....
Vl
N
(continued) ...
I'D

til ~
 .....
Vl
Q
N :::l
0\ ;:;.
~
-l
::r
I'D
Table I (continued). P:l
"'0
I'D
Included ...;:;.
l:

Author, Year, in Meta- Population III

Country Analysis Enrolled (Setting) Exclusion Criteria Type of Vaccine Intervention* Outcomes

Moddares et Yes N = 130; infants Infants receivi ng Hepatitis B, 1M; Breastfeeding during Pain: Observer DAN scale
al;13 born >37 wk oxygen therapy or dose and and after the procedure
2006, Iran gestation and age ventilated; Apgar technique NR (n = 65) or control
<24 h; single center score <7 at 5 min; (n = 65); breastfeeding
(hospital based) born by Cesarean 2 min before and
section; maternal use
continued for 45 sec
of narcotics during
after the injection
delivery and labor;
received feeds <30 min
before the procedure;
maternal inability to
breastfeed

DPTP ~ dlphthena, pertussIS, tetanus, and poliO; FPS ~ Faces Pain Scale (0 ~ no pain and 6 ~ worst pain); VAS ~ visual analog scale (0 ~ no pain, 100 mm ~
maximal pain); CH EOPS ~ Children's Hospital of Eastern Ontano Pain Scale; CFCS ~ Child Facial Coding System (10 facial actions scored for intensity [0 ~ no
action, 1 ~ slight action, 2 ~ distinct to maximal action] and summed for each second for vanous phases of the procedure); NR ~ not reported; CAMPIS-R ~
Child-Adult Medical Procedure Interaction Scale-Revised (proportion of the procedure engaged In the child COping, child distress, and nurse coping promoting
behaVior); Hlb ~ Haemophtlus tnfluenzae type b; MBPS ~ Modified BehaVioral Pain Scale (range, 0-10); DPTaP-IPV-Hlb ~ dlphthena, tetanus tOXOid, acellular per-
tuSSIS, Inactivated poliO vaCCine, and H tnfluenzae type b tetanus tOXOid conjugate vaccine; VRS ~ verbal rating scale (1 ~ no pain, 4 ~ very painful); DPT ~
dlphthena-pertussls-tetanus; BCG ~ bacille Calmette-Guenn; NIPS ~ Neonatal Infant Pain Scale; NNS ~ nonnutntlve sucking; UWCH ~ University of WisconSin
Children's Hospital (5 domains: cry, facial expression, behaVioral, body movements, and sleep; each scored from 0-5); CAS ~ colored analog scale (shade of red
to indicate Intensity of pain; range, 0-10); FPS-R ~ Faces Pain Scale-Revised; MAX ~ Maximally Dlscnmlnatlve Facial Movement Coding System; FLACC ~ Face,
Leg, Activity, CrYing, Consolabillty Scale; OSBD ~ Observational Scale of BehaVioral Distress; GMS ~ Global Mood Scale (range, 1-7); FPRS ~ Facial Pain Rating
Scale (0 ~ no hurt and 5 ~ hurts worst); DAN ~ Douleur Algue du Nouveau-ne (range, 0-10).
~ *Trademarks: Vanvax (Merck Frosst Canada & Co., Montreal, Quebec, Canada); M-M-R 11 (Merck Frosst Canada & Co.); Pentacel (Sanofl Pasteur Ltd., Toronto,
i:
3I'D Ontano, Canada); Recomblvax (Merck Frosst Canada & Co.; Pnonx (Smith Kline Beecham Pharma, Oakville, Ontano, Canada); Prevnar (Wyeth Pharmaceuticals,
Inc., Montreal, Quebec, Canada); Infannx (GlaxoSmlthKllne Biologicals, Rlxensart, Belgium); Fnglderm (Fnglderm Corporation, Huntington Beach,
.....
(JJ
California).
Vl
l: tStudy Included In >1 category.
"'0
"'0
1D
3I'D
...
:::l

C:l
N
0
0
10

I
Table II. Assessment of risk of bias of included studies on various pharmacologic and combined interventions for immunization pain.

Blinding of Incomplete
Adequate Outcome Outcome Free of Free of
Sequence Allocation Assessors Data Selective Other Overall
Author, Year, Country Generation Concealment and Patients Addressed Reporting Bias Risk

Local Anesthetic Agents

Cassidy et al,2 2001, Canada Unclear Unclear Yes Yes Yes Yes Unclear
Cohen et al,3* 1999, US Unclear Unclear Unclear Yes Yes Yes Unclear
Cohen et al,4* 2006, US Yes Unclear Unclear Yes No Unclear High
Halperin et ai,S 2000, Canada Yes Yes Yes Yes Yes Yes Low
Halperin et al,6 2002, Canada Yes Unclear Yes Yes Yes Yes Unclear
Hansen and Sorensen,? 1993, Denmark Unclear Unclear Yes Yes Unclear Unclear Unclear
O'Brien et ai,S 2004, Canada Yes Yes Yes Yes Yes Yes Low
Taddio et al,9 1994, Canada Yes Yes Yes Yes Yes Yes Low
Uhari,lO 1993, Finland Unclear Unclear Yes Yes Yes Yes Unclear
Dilli et al,lh 2009, Turkey Unclear Yes No Yes Yes Yes High
Sweet-Tasting Solutions
Allen et al,12 1996, US Unclear Yes Yes Unclear Yes Yes Unclear
Barr et al,13 1995, Canada Unclear Unclear Yes Yes Yes Yes Unclear
Hatfield et al,14 2008, US Yes Unclear Yes Yes Yes Yes Unclear
Hatfield,ls 2008, US Yes Unclear Yes Yes Yes Yes Unclear
Lewindon et al,16 1998, Australia Unclear Yes Yes Yes Yes Yes Unclear
Lewkowski et al,17 2003, Canada Unclear Unclear Unclear Yes Yes Yes Unclear
Mowrey,lS 2007, US Yes Unclear Yes Yes Yes Yes Unclear
Ramenghi et al,19* 2002, UK Yes Unclear Yes Yes Yes Yes Unclear
Soriano Faura and Gomez Gil,20 2003, Spain Unclear Unclear Yes Yes Yes Yes Unclear
Thyr et al,21 2007, Sweden Unclear Yes Yes Yes Yes Yes Unclear
Dilli et al,lh 2009, Turkey Unclear Yes No Yes Yes Yes High

(continued) I :<
Vl
::r
~
::r
.....
Vl
N
...
I'D

'I ~
 .....
Vl
Q
N :::l
00 ;:;.
~
Table II (continued). I -l
::r
I'D
P:l
"'0
Blinding of Incomplete I'D

Adequate Outcome Outcome Free of Free of

...;:;.
l:

Sequence Allocation Assessors Data Selective Other Overall

I III

Author, Year, Country Generation Concealment and Patients Addressed Reporting Bias Risk

Vapocoolants
Abbott and Fowler-Kerry,22 1995, Canada Unclear Unclear Yes Yes Yes Yes Unclear
Cohen et al,23 2009, US Yes No No Yes Yes Yes High
Eland,24* 1981, US Unclear Unclear Unclear Yes Yes Yes Unclear
Maikler,25 1991, US Yes Yes Yes Yes Yes Yes Low
Comparison of 2 Analgesic Interventions
Cohen et al,3* 1999, US Unclear Unclear Unclear Yes Yes Yes Unclear
Cohen et al,4* 2006, US Yes Unclear Unclear Yes No Unclear High
Ramenghi et al,19* 2002, UK Yes Unclear Yes Yes Yes Yes Unclear
Dilli et al,lh 2009, Turkey Unclear Yes No Yes Yes Yes High
Combinations of:2:2 Analgesic Interventions
Berberich and Landman,26 2009, US Yes No No Yes Yes Unclear High
Boivin et al,27 2008, France No No No Yes Yes Unclear High
Cohen Reis and Holubkov,28 1997, US Unclear Unclear No Yes Yes Yes High
Cohen Reis et al,29 2003, US Yes Yes Yes Yes Yes Yes Low
Eland,24* 1981, US Unclear Unclear Unclear Yes Yes Yes Unclear
Lindh et al;10 2003, Sweden Yes Yes Yes Yes Yes Yes Low
Breastfeeding
Abdel Razek and Az EI-Dein;11 2009, Jordan Unclear No Unclear Yes Yes Yes High
Dilli et al,lh 2009, Turkey Yes Yes No Yes Yes Yes High
~ Efe and Ozer;12 2007, Turkey Unclear Yes Unclear Yes Yes Unclear Unclear
i:
3I'D I Moddares et al;13 2006, Iran Unclear Unclear No Yes Yes Unclear High

.....
(JJ

Vl
l: *Study appears In >1 category.
"'0
"'0
10
I Yes ~ low risk of bias; No ~ high risk of bias; Unclear ~ lack of information or uncertainty about the potential for bias.
3I'D
...
:::l

C:l
 V. Shah et al.

Topical Local
Anesthetics Placebo
Weight, SM 0, SMD
Study or Subgroup Mean SO Total Mean SO Total % IV, Random, 95% CI IV, Random, 95% CI

Halperin et ai,s 2000 3.10 1.78 80 3.80 2.03 78 30.2 -0.37 (-0.68 to -0.05) •
Halperin et al,6 2002 3.99 1.88 73 4.74 1.43 80 28.9 -0.45 (-0.77 to -0.13) •
O'Brien et ai,s 2004 1.50 1.60 61 2.30 2.20 59 22.8 -0.41 (-0.78 to -0.05) -_--I
Taddio et al,9 1994 5.00 1.75 49 6.00 2.00 47 18.0 -0.53 (-0.94 to -0.12)
Total (95% CI) 263 264 100.0 -0.43 (-0.60 to -0.26) ~
Heterogeneity: t" - 0.00; X" - 0.41; df- 3 (P - 0.94); I" - 0% .---...----+-----r-----,
Test for overall effect: z - 4.88 (P - 0.001) -1 -0.5 0 0.5
Favors Favors
Topical Local Placebo
Anesthetics

Figure 2. Effectiveness oftopicallocal anesthetics for immunization pain, as assessed using the Modified Behavioral Pain Scale (differ-
ence between the scores before and after vaccination). SMD ~ standardized mean difference; df~ degrees offreedom.

(95% CI, -1.00 to -0.49; P < 0.001); heterogeneity
was not significant.
Two studies 9 ,11 (110 infants and children; data
missing for 4) that reported on cry duration were in-
cluded in a meta-analysis. Cry duration was signifi-
cantly lower in the lidocaine-prilocaine group than in
the placebo (no intervention) group (WMD, -28.88 sec;
95% CI, -40.23 to -17.54; P < 0.001). Considerable
heterogeneity was reported for this outcome ('/.,2 = 45;
P < 0.001; J2 = 98%), and a qualitative approach was
used for data analysis. In the study by Dilli et aI, 11
infants in the lidocaine-prilocaine group cried for a
shorter duration than did infants in the control group
(MD, -90 sec; 95% CI,-111.16 to -68.84; P < 0.001).
The SMD was -4.17 sec (95% CI, -6.27 to -2.07;
P = 0.001). In contrast, the study by Taddio et a1 9
found no difference in cry duration between the
lidocaine-prilocaine and placebo groups (MD, -4.20 sec;
95% CI, -17.65 to 9.25); the SMD was -0.12 (95%
CI, -0.52 to 0.28).
Qualitative Analysis for Pain and Distress
In the study by Cassidy et al,2 fewer children re-
ported clinically significant pain (FPS score, ::::3) in the
lidocaine-prilocaine group than in the placebo group
(RR, 0.39; 95% CI, 0.23 to 0.67; P < 0.001). The RD
was -0.27 (95% CI, -0.40 to -0.13; P < 0.001), and
the NNT to prevent 1 child from having pain was 3.7
(95% CI, 2.5 to 7.7). Observer CFCS pain scores
(range, 0-20) and parent VAS scores (range, 0-100 mm)
were also lower in the lidocaine-prilocaine group
than in the placebo group; MDs were -2.20 (95% CI,
-4.05 to -0.35; P = 0.02) and -15.10 (95% CI, -23.03
to -7.17; P < 0.001), respectively. The pain score from
an observer-rated, modified version of the CHEOPS
(range, 3-9) appeared to be lower in the lidocaine-
prilocaine group (MD,-0.30; 95% CI,-0.64 to 0.04),
but the difference was not statistically significant.
In a crossover study, Cohen et a13 reported no sig-
nificant differences between lidocaine-prilocaine and
typical care (nurse interaction with the children ac-
cording to the nurse's routine) in mean (SD) child self-
reported VAS pain (32.25 [35.67] vs 31.19 [39.36] mm)
and child self-reported VAS distress scores (24.39 [35.52]
vs 22.86 [34.22] mm). Similarly, no significant differ-
ences were observed in nurse-reported VAS pain scores
(12.61 [11.44] vs 11.11 [8.87] mm) or distress scores
(19.32 [15.89] vs 12.65 [10.12] mm). Nurse-coping
behaviors, however, were significantly higher with
typical care than with lidocaine-prilocaine (P = 0.012;
data not reported [NR]).
Cohen et a1 4 reported no significant difference
in the mean (SD) child distress score between the
lidocaine-prilocaine group and the typical-care group
using the MBPS (21.20 [6.50] vs 20.20 [5.80]);
the MBPS scores were reported as the sum across
4 procedure phases (range, 0-40). Mean (SD) parent-
and nurse-reported VAS distress scores did not differ
significantly between the groups (78.60 [28.90] vs
91.10 [8.10] mm and 53.10 [22.70] vs 61.30 [27.10] mm,
respectively). Investigators did not report on the
number of infants who participated in each interven-
tion category, preventing calculation of MDs and
95% CIs.

2009 S129
 Clinical Therapeutics
In a comparison of lidocaine-prilocaine and no
intervention, Dilli et alII reported a significant re-
duction in the NIPS score (range, 3-7) (MD, -4.00;
95% CI, -4.83 to -3.17; P < 0.001) in infants 6 to
12 months of age, and in the CHEOPS score (range,
4-13) (P = 0.001; data = NR) in infants and children
13 to 48 months of age. The RR of having clinically
significant pain (NIPS score, >3) in 6- to 12-month-
old infants was 0.20 (95% CI, 0.05 to 0.86; P = 0.03).
The RD was -0.86 (95% CI, -1.18 to -0.54; P <
0.001). The NNT to prevent 1 child from having pain
was 1.2 (95% CI, 0.8 to 1.8).
Taddio et a1 9 reported a significant increase in the
latency to first cry (MD, 0.90 sec; 95% CI, 0.46 to
1.34; P < 0.001) and decrease in the duration of first
cry (MD,-1.30 sec; 95% CI,-2.55 to -0.05; P = 0.04)
for infants who received lidocaine-prilocaine versus a
placebo.
In the study by Uhari,1O nurses reported a lower
mean VAS pain score (range, 0-10 cm) (2.5 vs 3.8;
P < 0.003) and VAS crying score (range, 0-10 cm) (2.8
vs 4.0; P < 0.003) for infants who received lidocaine-
prilocaine than for those who received a placebo
(SDs = NR). Similarly, parents reported lower mean
VAS pain and crying scores in the lidocaine-prilocaine
group than in the placebo group (2.9 vs 4.8; P < 0.001,
and 3.6 vs 5.3; P < 0.003, respectively) (SDs = NR).
Effectiveness ofTopical Local Anesthetics
Based on Route ofInjection
Four studies2,6,9,10 evaluated topical local anesthetics
for intramuscular vaccine injection pain, and 2 studies 5,8
evaluated these agents for subcutaneous vaccine in-
jection pain. In the excluded trials, the route of admin-
istration was NR in 3 trials,3,4,7 and injections were
administered intramuscularly or subcutaneously in
1 trial. ll In 1 triaF (149 children; data missing for 2)
in which vaccine was administered intramuscularly,
child self-reported pain using the FPS was lower in
the lidocaine-prilocaine group (MD, -0.98; 95% CI,
-1.65 to -0.31; P = 0.004). In the other 2 trials
(249 infants; data missing for 16),6,9 in which vaccine
was administered intramuscularly, lidocaine-prilocaine
reduced pain as assessed by the difference in the MBPS
scores before and after vaccination. The SMD was
-0.47 (95% CI, -0.72 to -0.22; P < 0.001). There was
no significant heterogeneity for this outcome. In the
study by Uhari 10 in which vaccine was administered
intramuscularly, VAS pain scores were lower in the
S130
lidocaine-prilocaine group (P < 0.003; data not in-
cluded in the meta-analysis because SDs were NR).
In 2 trials (278 infants; data missing for 2) in which
vaccine was administered subcutaneously,5,8 pain scores
were lower in the topical anesthetic group; the SMD
was -0.38 (95% CI, -0.62 to -0.14; P = 0.002). No
significant heterogeneity was noted for this outcome.
Local Skin Reactions
Five trials 2,5,6,9,10 reported on transient local skin re-
actions associated with the use of lidocaine-prilocaine;
data from 3 of those trials (485 participants; data
missing for 1)2,5,6 were pooled in a meta-analysis. In
1 study6 in which multiple doses were administered,
data from the last dose with the most participants and
highest reported incidence were used in the analysis.
The incidence of pallor was higher with lidocaine-
prilocaine than with placebo (RR, 2.01; 95% CI, 1.53
to 2.63; P < 0.001; RD, 0.22; 95% CI, 0.14 to 0.29;
P < 0.001; NNH, 4.54; 95% CI, 3.44 to 7.14). No
significant difference in the incidence of erythema was
observed between the groups (RR, 1.30; 95% CI,0.97
to 1.74). Edema was not reported in any of the chil-
dren in these 3 trials.2.5,6
In a study of amethocaine gel,8 increased incidences
of the following adverse events were reported: ery-
thema (RR, 1.93; 95% CI, 1.42 to 2.63; P < 0.001;
RD, 0.41; 95% CI, 0.26 to 0.57; P < 0.002; NNH,
2.40; 95% CI, 1.75 to 3.80); pallor (RR, 1.75; 95%
CI, 1.07 to 2.87; P < 0.003; RD, 0.20; 95% CI,0.04
to 0.37; P < 0.02; NNH, 5.0; 95% CI, 2.7 to 25.0);
and edema (RR, 6.53; 95% CI, 2.43 to 17.52; P <
0.001; RD, 0.37; 95% CI, 0.23 to 0.52; P < 0.001;
NNH, 2.70; 95% CI, 1.90 to 4.34).
One study2 examined alterations in skin sensation
in children. The incidence of itchiness was signifi-
cantly higher in the lidocaine-prilocaine group than in
the placebo group (RR, 3.29; 95% CI, 1.40 to 7.72;
P < 0.006; RD, 0.18; 95% CI, 0.07 to 0.29; P < 0.002;
NNH, 5.55; 95% CI, 3.44 to 14.28). No significant
differences were observed in cold sensation (RR, 0.80;
95% CI, 0.45 to 1.40), tenderness (RR, 1.32; 95% CI,
0.62 to 2.80), or burning (RR, 1.10; 95% CI,0.41
to 2.82).
Antibody Responses
Three trials (445 infants and children)5,6,8 com-
pared the effects of topical local anesthetics with those
of placebo on the antibody response following vacci-
Volume 31 Supplement B
 V. Shah et a!.

nation (Table III). The RR (95% CI) of achieving pro-
tective antibody titers to each component of the vaccine
was calculated from 2 studies 5,6 of lidocaine-prilocaine.
In the first trial by Halperin et aI,s no significant differ-
ence in the RR of vaccination success rate was found
for measles (0.99; 95% CI, 0.89 to 1.09), mumps (0.93;
95% CI, 0.85 to 1.02), or rubella (0.99; 95% CI,
0.90 to 1.07) between infants who received lidocaine-
prilocaine and those who received placebo. In the sec-
ond trial by Halperin et al,6 no significant differences in
vaccination success rates were observed for hepatitis B
(1.01; 95% CI, 0.93 to 1.10) or Haemophilus influ-
enzae type b (Hib) conjugate vaccine (1.13; 95% CI,
0.93 to 1.38) between infants who received lidocaine-
prilocaine and those who received placebo. O'Brien et
a1 8 evaluated the antibody responses of 60 infants ran-
domized to amethocaine or placebo for measles-
mumps-rubella vaccination. No significant difference
in the overall rate of vaccination success (antibody ti-
ters positive for measles, mumps, or rubella) was ob-
served between the amethocaine and placebo groups
(RR, 1.01; 95% CI, 0.91 to 1.13).
Sweet-Tasting Solutions
Eleven studies (1452 infants and children)II-21 in-
vestigated the effects of sweet-tasting solutions (Table I).
Nine of the studies evaluated sucrose,11-16,18-20 1 study
evaluated chewing gum,17 and 1 study evaluated glu-
cose. 21 In 3 studies,13,15,21 the efficacy of sweet-tasting
solutions was evaluated longitudinally. In the studies
by Barr et al 13 and Hatfield,15 infants received sucrose
or sterile water for immunizations at 2 and 4 months
of age, whereas in the study by Thyr et al,21 infants
received glucose or sterile water for immunizations at
3,5, and 12 months of age. The risk of bias was unclear
in 10 studies l2 - 21 and high in 1 study ll (Table II). In the
included trials, pain and distress were measured using
various tools, including cry duration, 12,13,16,18,19,20 Uni-
versity of Wisconsin Children's Hospital (UWCH) Pain
Scale,14,15 VAS,16,21 FPS,17 MBPS,18 colored analog scale
(CAS),17 CHEOPS,l1 and NIPS. 11
Quantitative (Meta-Analytic) Analysis for
Effects on Pain and Distress
Data on infant pain responses from vaccine injection
were pooled for 6 trials (665 infants) in which sucrose
with or without nonnutritive sucking (NNS; use of a
pacifier) was compared with no intervention or sterile
water with and without NNS.l 1,14,16,18-20 In the study
by Ramenghi et al,1 9 infants were evaluated once at 2,
3, or 4 months (2 injections at each sitting). Therefore,
data on pain scores for the first injection (diphtheria-

Table III. Percentage of participants achieving protective antibody titers.*

Lidocaine- Relative Risk

Study, Year, Country Prilocaine Placebo (95% CI) P

Halperin et ai,S 2000, Canada N = 78 N = 79

Measles 89.7% 91.1% 0.99 (0.89-1.09) 0.79
Mumps 88.3% 94.9% 0.93 (0.85-1.02) 0.14
Rubella 92.3% 93.7% 0.99 (0.90-1.07) 0.74

Halperin et al,6 2002, Canada N = 81 N = 81

Hepatitis B 94.4% 92.1% 1.01 (0.93-1.10) 0.75
Hib 75.3% 66.3% 1.13 (0.93-1.38) 0.23

O'Brien et al,8 2004, Canada N = 30 N = 30

Combined measles, mumps, and
rubella response 88.0% 87.0% 1.01 (0.91-1.13) 0.82

*Tlters: >120 reciprocal dilution for measles, >231 unlts/mL for mumps (enzyme-linked Immunosorbent assay), >8 IU/mL for
rubella, >10 miU/mL for hepatitis B, and >1 I-Ig/mL for Haemophtlus tnfluenzae type b (Hlb) polynbosylnbltol phosphate
were considered to be protective.

2009 S131
 Clinical Therapeutics

pertussis-tetanus [DPT]) were available from these
infants at each age category and are included in the
meta-analysis. The study by Ramenghi et aP9 has been
referenced for each of the 3 categories in Figure 3. In
the study by Hatfield et al,14 pain scores after the third
(last) injection were included in the meta-analysis. The
SMD was -0.56 (95% CI, -0.72 to -0.40; P < 0.001)
(Figure 3). Heterogeneity was significant for this out-
come (Z2 = 41.80; P < 0.001; Jl = 83 %); thus, data
from the individual studies were analyzed qualitatively.
Dilli et alII reported a significant reduction in NIPS
scores (range, 3-7) (MD, -3.00; 95% CI, -4.02 to
-1.98; P < 0.001) in infants 6 to 12 months of age
who received sucrose compared with a control group
(no intervention). The SMD for this outcome was
-1.97 (95% CI, -3.12 to -0.83; P < 0.001). Hatfield
et al 14 reported less pain in infants who received su-
crose and NNS than in those who received water and
NNS before sequential injection of 3 vaccines (7 min-
utes after the first injection and 2 minutes after the
third injection). The MD, using the UWCH Pain Scale
(range, 0-5), was lower for infants who received su-
crose and NNS (-2.16; 95% CI, -2.69 to -1.63; P <
0.001). The SMD was -1.85 (95% CI, -2.41 to -1.30;
P < 0.001). In the study by Lewindon et al,16 cry dura-
tion was significantly reduced in infants who received
sucrose (MD, -23.0 sec; 95% CI, -32.83 to -13.17;
P < 0.001); the SMD was -0.88 (95% CI, -1.28 to
-0.49; P < 0.001). In the study by Mowrey,18 no sig-
nificant difference in MBPS scores (range, 0-10) was
observed at 120 seconds after the last of 3 injections
for infants who received sucrose compared with those
who received sterile water. Similarly, the study by Ra-
menghi et al 19 found no significant difference in the
percent time crying between infants who received su-
crose and those who received sterile water (MD, -4.59;
95% CI, -12.38 to 3.20; P = 0.25). Soriano Faura and
Gomez GiFo reported a shorter duration of cry-
ing in infants who received sucrose (MD, -5.10 sec;
95% CI, -9.31 to -0.89; P = 0.02); the SMD was
-0.27 (95% CI, -0.48 to -0.05; P = 0.02).
Data on total cry duration were pooled for 4 trials
(499 infants). 11,16,18,20 The total cry duration was sig-
nificantly shorter for infants who received sucrose
than for those who received sterile water or no treat-
ment (WMD, -9.41 sec; 95% CI, -13.18 to -5.64;
P < 0.001); heterogeneity was significant for this out-
come (Z2 = 39.10; P = 0.001; Jl = 92%). The SMD was
-0.43 (95% CI, -0.61 to -0.25; P < 0.001). Again,
heterogeneity was significant (Z2 = 17.99; P < 0.004;
Jl = 83 %), and data from the individual studies were
analyzed qualitatively.
Two studies 16 ,20 reported reduced total cry dura-
tion in infants who received sucrose compared with
those who received sterile water during immunization.
In the study by Lewindon et al,16 cry duration was sig-
nificantly reduced in infants who received sucrose
(MD, -23.00 sec; 95% CI, -32.83 to -13.17; P < 0.001).

Sucrose Control
Weight, SMO SMO
Study or Subgroup Mean SO Total Mean SO Total % IV, Fixed, 95% CI IV, Fixed, 95% CI

Oill, et al,l1 2009 3.00 1.75 13 6.00 0.5 7 1.9 -1.97 (-3.12 to -0.83) ~
Hatfield et al,14 2008 0.59 1.20 38 2.75 1.1 35 8.2 -1.85 (-2.41 to -1.30)
Lewlndon et al,16 1998
Mowrey,18 2007
36.00 21.00
2.81 1.66
54
25
59.00
4.04
30.0
2.8
53
24
15.8
7.7
-0.88
-0.53
(-1.28 to -0.49)
(-1.10 to 0.04)
-------
Ramenghl et al,19 2002* 35.00 30.10 15 42.50 31.2 16 5.0 -0.24 (-0.95 to 0.47)
Ramenghl et al,19 2002t 29.20 18.20 16 28.30 2.4 15 5.0 0.07 (-0.64 to 0.77)
Ramenghl et al,19 2002t 17.2014.80 15 52.80 43.2 16 4.3 -1.06 (-1.82 to -0.30)
SOriano Faura and
Gomez GiI,"o 2003 25.50 16.00 165 30.60 22.0 158 52.1 -0.27 (-0.48 to -0.05]
Total (95% CI)
,
341
,
324 100.0 -0.56 (-0.72 to -0.40] ~---
Heterogeneity. Z 41.80, df - 7 (P < 0.001), I 83%
0 I I I I

Test for overall effect: z - 6.96 (P < 0.001)

-3 -2 -1 o
Favors Favors
Sucrose Control

Figure 3. Effectiveness of sucrose with or without non nutritive sucking compared with placebo for immunization pain, as assessed using
validated pain tools. SMD ~ standardized mean difference; df~ degrees offreedom. *2-Month evaluation; t3-month evalua-
tion; t4-month evaluation.

S132 Volume 31 Supplement B


The SMD was -0.88 (95% CI, -1.28 to -0.49; P <
0.001). Similarly, in the study by Soriano Faura and
Gomez Gil,20 the duration of crying was significant-
ly reduced in infants who received sucrose (MD,
-5.10 sec; 95% CI, -9.31 to -0.89; P = 0.02); the
SMD was -0.27 (95% CI, -0.48 to -0.05; P = 0.02).
Dilli et alII also reported a significantly shorter cry
duration (MD, -80.00 sec; 95% CI, -106.27 to
-53.73; P < 0.001) in infants 6 to 12 months of age
who received sucrose than in those who received no
intervention; the SMD was -2.51 (95% CI, -3.77 to
-1.24; P = 0.001). Likewise, for children 13 to 48 months
of age, the crying time was shorter for those who re-
ceived sucrose than for those who received no sucrose
(P = 0.002; data = NR). In contrast, the study by
Mowrey18 reported no significant difference in cry
duration between infants 2 to 6 months of age who
received sucrose and those who received sterile water
(MD, -9.52 sec; 95% CI, -31.58 to 12.54; and SMD,
-0.24; 95% CI, -0.80 to 0.32). In that study,18 infants
received 3 injections during 1 visit compared with a
single injection in the study by Soriano Faura and
Gomez GiFo and 2 injections in the study by Lewin-
don et a1. 16
Qualitative Analysis for Pain and Distress
Lewkowski et al 17 reported no significant differ-
ence in child self-reported pain using a CAS (range,
0-10) between the group that received sweetened
chewing gum (sweet taste) and the group that received
unsweetened chewing gum before immunization. To
assess the effect of sweet taste, the gum was chewed
for 1 minute and stopped 1 minute before the proce-
dure. Furthermore, no significant difference in child
self-reported pain using the CAS was observed be-
tween the group that received sweetened chewing gum
(chewing the gum for 2 minutes up to and during the
time of pain stimulus [injection]) and the group that
received unsweetened chewing gum. The mean CAS
rating was 3.6 for the sweet taste group (SD = NR),
3.8 for the sweet taste plus chew group, 2.7 for the
chew plus no sweet taste group, and 3.4 for the con-
trol group. In addition, no significant between-group
differences were observed in mean child self-reported
FPS scores (sweet taste group, 2.3; sweet taste plus
chew group, 2.2; chew plus no sweet taste group, 2.1;
and control group, 2.0).
Allen et al 12 reported that in 2-week-old infants,
the percentage of time spent crying (averaged across
2009
v. Shah et al.
30-second intervals after injection for a maximum of
3 minutes) was higher for infants in the no-intervention
group than for those in the sucrose or sterile water
groups (P < 0.005; data = NR). For older infants, ad-
ministration of sucrose or sterile water resulted in
significantly shorter crying time compared with no
intervention when they received 1 injection (P < 0.05),
but not with 2 injections.
In the study by Dilli et al,l1 the RR of having clini-
cally significant pain (NIPS score, >3) was 0.34 (95%
CI, 0.16 to 0.75; P = 0.007), and the RD was -0.69
(95% CI, -0.99 to -0.40; P < 0.001) in the sucrose
group compared with the group that received no in-
tervention. The NNT to prevent pain in 1 child was
1.4 (95% CI, 1.0 to 2.5). For children 13 to 48 months
of age, the CHEOPS score (range, 4-13) was lower for
those who received sucrose than for those who re-
ceived no sucrose (P = 0.001; data NR).
Lewindon et al 16 reported that sucrose was more
effective than water in reducing attributes of crying
associated with immunization: duration of first cry
(MD,-13.00 sec; 95% CI,-20.42 to -5.58; P < 0.001),
mean total duration of crying time during the first
3 minutes (MD,-23.00 sec; 95% CI,-32.80 to -13.20;
P < 0.001), and mean duration of crying from start to
finish (MD, -26.00 sec; 95% CI, -37.20 to -14.80;
P < 0.001). Nurse VAS distress ratings (range, 0-
100 mm) were lower for sucrose than for sterile water
(MD, -8.00; 95% CI, -15.02 to -0.98; P = 0.03).
However, parent VAS distress ratings (range, 0-
100 mm) did not differ significantly (MD, -7.00; 95%
CI, -15.91 to 1.91).
Ramenghi et aP9 compared 50% sucrose, hydroge-
nated glucose, and sterile water in 3 groups of infants
receiving 2 vaccines (their first, second, or third DPT
vaccine, followed by Hib vaccine) during 1 sitting.
Pain was assessed after each injection. The percent
crying time was shorter for infants who received 50%
sucrose than for those who received sterile water for
the first (-23.10; 95% CI, -41.50 to -4.74; P = 0.01),
second (-12.70; 95% CI,-21.30 to -4.10; P = 0.004),
and third DPT immunizations (-38.90; 95% CI,
-61.90 to -16.00; P < 0.001). For Hib vaccination,
the percent time crying was shorter for infants who
received 50% sucrose than for those who received
sterile water for the second (-21.10; 95% CI, -40.60
to -1.56; P = 0.03) and third Hib immunizations
(-40.60; 95% CI, -62.80 to -18.40; P < 0.001), but
not for the first Hib immunization (-16.20; 95% CI,
S133
 Clinical Therapeutics
-47.00 to 14.62). When hydrogenated glucose was
compared with sterile water, the percent time crying
was shorter for infants who received glucose only for
the third DPT (-29.50; 95% CI, -52.73 to -6.27; P =
0.01) and Hib immunization (-39.40; 95% CI,-66.48
to -12.32; P = 0.004).
Three trials (216 infants)13,15.21 evaluated sweet-
tasting solutions longitudinally. In the study by Barr et
al,13 a significant reduction in the percentage of time
the infants cried during the first minute after vaccine
injection was observed between infants who received
sucrose and those who received water at 2 and 4 months
of age (MD, -13.80; 95% CI, -15.83 to -11.77; P <
0.001), but no significant difference was observed
during the 10 seconds in which the vaccine was being
injected (MD, 0.10; 95% CI, -1.93 to 2.13).
In the longitudinal study by Hatfield,15 in which
infants were given either sucrose and NNS with a
pacifier or sterile water and NNS, no significant dif-
ference was noted in observer-rated UWCH Pain Scale
scores (range, 0-5) immediately after 3 sequential im-
munizations (2 minutes after administration of su-
crose or water) (MD, 0.15; 95% CI, -0.45 to 0.75).
Less pain was observed at 3 minutes after the last in-
jection (5 minutes after administration of sucrose or
water) in infants treated with sucrose and NNS than
in those who received water and NNS using observer-
rated UWCH Pain Scale scores (MD, -2.75; 95% CI,
-3.42 to -2.08; P < 0.001). The SMD for this outcome
was -2.51 (95% CI, -3.35 to -1.66; P < 0.001). No
significant difference in response was noted between
2- and 4-month-old infants (data NR).
The longitudinal study by Thyr et all 1 reported that
the mean crying time during the first 2 minutes after
vaccination was significantly shorter in infants who
received 30% glucose than in those who received ster-
ile water at 5 and 12 months of age (6 vs 16 sec; P =
0.017, and 14 vs 29 sec; P = 0.03, respectively), but
not at 3 months (18 vs 23 sec) (SDs = NR).
Adverse Reactions
Two studies (89 infants)15,18 reported on the inci-
dences of adverse events after administration of
sweet-tasting solutions. In the study by Hatfield, 15
which compared sucrose and sterile water, adverse
events (coughing or gagging) occurred on 5 occasions.
In the group that received sucrose, coughing occurred
in 2 infants each at 2 and 4 months of age; in the
group that received sterile water, gagging occurred in
S134
1 infant at 2 months of age. The incidences of cough-
ing (5.0%) and gagging (2.5%) were not significantly
different between the sucrose and sterile water groups.
All infants recovered within 10 seconds, and none of
the adverse events were considered to be clinically
significant. No episodes of choking were reported in
the trial by Mowrey. 18
Vapocoolants
Four studies (247 infants and children)22-25 investi-
gated vapocoolants (skin refrigerants). The overall risk
of bias was low for 1 study,25 unclear for 2 studies,22.24
and high for 1 study23 (Table II). Pain and distress were
measured using YAS,22·24,25 cry attributes (eg, cry dura-
tion),25 FPS-R,22 and the Maximally Discriminative
Facial Movement Coding System (MAX).25
Quantitative (Meta-Analytic) Analysis for
Effects on Pain and Distress
Data were pooled for 2 studies including 100 chil-
dren treated with a vapocoolant or placebo spray.22.24
Child self-rated pain using a 4-point scale was lower
in the group treated with the vapocoolant (WMD,
-0.46; 95% CI, -0.83 to -0.09; P = 0.02); significant
heterogeneity was reported for this outcome (Z2 =
6.01; P = 0.01; Jl = 83%). The SMD was -0.43 (95%
CI, -0.83 to -0.02; P = 0.04), and heterogeneity was
significant (Z2 = 5.51; P = 0.02; Jl = 82%). Data from
the individual studies were analyzed qualitatively. In
the study by Abbott and Fowler-Kerry,22 no signifi-
cant difference was observed between the vapocoolant
and placebo groups (MD, -0.06; 95% CI, -0.55 to
0.43). In the study by Eland,24 use of a vapocoolant
was associated with a significant reduction in pain
compared with placebo (MD, -1.00; 95% CI, -1.57
to -0.43; P < 0.001).
Two studies 22 .23 in 117 children who self-reported
pain found no significant difference between vapo-
coolants and typical care (no treatment). The SMD was
-0.10 (95% CI, -0.47 to 0.27). Significant heteroge-
neity was reported for this outcome (Z2 = 9.89; P =
0.02; Jl = 90%); thus, data from the individual stud-
ies were analyzed qualitatively. In the study by Abbott
and Fowler-Kerry,22 the vapocoolant was associated
with a significant reduction in pain (MD, -0.66; 95%
CI,-1.14 to -0.18; P = 0.007), whereas Cohen et all 3
found no significant difference between the vapo-
coolant and control groups (MD,-1.86; 95% CI,-0.05
to 3.77).
Volume 31 Supplement B

Qualitative Analysis for Pain and Distress
In a study by Maikler 25 that compared a vapocool-
ant and a placebo spray (compressed air), observer-
rated pain did not differ significantly based on the
MAX (MD, -0.40 sec; 95% CI, -0.91 to 0.11) or cry
duration (MD, -0.29 sec; 95% CI, -0.80 to 0.22). No
significant differences were noted between the 2 groups
in the latency to onset of facial expression, cry (in-
tense or protest cry duration), or movement character-
istics (latency, symmetry, or total number of move-
ments). Latency to cry was longer in infants who
received vapocoolant spray than in those who re-
ceived placebo spray (P = 0.02; data NR).
Cohen et aIl3 reported that, compared with
typical care (described as routine care given by
nurses to deal with children's inj ection-related dis-
tress), the vapocoolant was not more effective in
reducing pain based on caregiver VAS (range,
0-100 mm) (MD, 6.38; 95% CI, -6.60 to 19.36)
or nurse VAS (range, 0-100 mm) (MD, 6.09; 95%
CI, -13.63 to 25.81).
Oral Analgesics
None of the studies in the systematic review evalu-
ated the effectiveness of oral analgesics (acetamino-
phen or ibuprofen) for vaccine injection pain.
Comparison of 2 Analgesic Interventions
Four studies (318 infants and children)3,4,11,1 9 com-
pared 2 analgesic interventions (Table I). The overall
risk of bias was unclear for 2 studies 3. 19 and high for
2 studies 4,11 (Table II). Pain and distress were measured
using CAMPIS-R,3 VAS,3,4 MBPS,4 cry duration,11,19
NIPS,l1 and CHEOPS.11
Qualitative Analysis for Pain and Distress
Topical Local Anesthetics Versus Sucrose
In the study by Dilli et aPl in infants 6 to 12 months
of age, cry duration (seconds) and NIPS scores (range,
3-7) did not differ significantly between infants who
received lidocaine-prilocaine and those who received
sucrose; MDs were -10.00 (95% CI, -35.50 to 15.50)
and -1.00 (95% CI, -2.21 to 0.21), respectively.
The RR of having clinically significant pain (NIPS
score, >3) did not differ significantly between the
groups (0.38; 95% CI, 0.03 to 4.23). Among infants
13 to 48 months of age, no significant differences in
cry duration or CHEOPS scores were observed be-
tween the groups (data NR).
2009
V. Shah et a!.
Topical Local Anesthetics Versus Distraction
Two studies compared lidocaine-prilocaine and
distraction: nurse coaching plus movie distraction 3 or
nurse-directed movie distraction. 4 In the crossover
study by Cohen et al,3 no significant difference was
observed between the lidocaine-prilocaine and dis-
traction groups for mean (SD) child self-reported VAS
pain scores (range, 0-100 mm) (32.52 [35.67] vs
33.89 [38.74] mm) or child self-reported VAS distress
scores (24.39 [35.52] vs 25.83 [37.62] mm). Like-
wise, no significant differences were observed between
nurse-reported VAS child pain scores (12.61 [11.44]
vs 11.73 [9.03] mm) or VAS child distress scores
(19.32 [15.89] vs 14.94 [14.00] mm). Observer
CAMPIS-R child-coping behaviors were higher (P <
0.001) and child-distress scores were lower (P < 0.001) for
the distraction group than for the lidocaine-prilocaine
group (data NR). Distraction was associated with more
nurse-initiated coping-promoting behaviors than was
use of lidocaine-prilocaine (P < 0.001).
The study by Cohen et a1 4 similarly reported no
significant difference in mean (SD) child distress
scores using observer-rated MBPS scores (range, 0-40)
(21.2 [6.5] vs 19.0 [4.8]) or nurse-reported VAS child
distress scores (53.1 [22.7] vs 55.0 [26.4] mm). The
mean (SD) parent-reported VAS child distress score
(range, 0-100 mm) was lower in the distraction group
than in the lidocaine-prilocaine group (84.8 [15.7] vs
91.1 [8.1] mm), but the difference was not statistically
significant.
Sucrose: 50% Versus 25%
In the study by Ramenghi et al,1 9 the percent crying
time was lower for infants who were given 50% su-
crose than for those given 25% sucrose during the
second DPT (-13.60; 95% CI, -25.96 to -1.24; P =
0.03) and second Hib (-15.80; 95% CI, -25.25 to
-6.35; P = 0.001) injections. No significant differences
in the percent time crying were observed between
the 2 groups for the first and third DPT and Hib
injections.
Sucrose (50% and 25%) Versus Hydrogenated Glucose
In the study by Ramenghi et al,1 9 the percent time
crying was lower for infants who received 50% su-
crose than for those who received hydrogenated glu-
cose during the first DPT (-21.00; 95% CI, -37.60 to
-4.25; P = 0.01), second DPT (-15.00; 95% CI,
-28.50 to -1.52; P = 0.03), and second Hib (-16.60;
S135
 Clinical Therapeutics

95% CI, -28.35 to -4.85; P = 0.006) injections. No
significant differences were observed between the
3 DPT and Hib injections when 25% sucrose was
compared with hydrogenated glucose.
Combinations of;:::2 Analgesic Interventions
Six studies (592 infants and children)24,26-30 evalu-
ated combinations of pharmacologic and other types
of analgesic interventions for immunization pain
(Table I). The overall risk of bias was high for
3 studies,26-28 low for 2 studies,2 9 ,30 and unclear for
1 study24 (Table II). Pain was assessed using various
tools, including the FPS,27,28 Observational Scale of
Behavioral Distress (OSBD),28 modified MBPS,30
VAS,24,27,28,30 cry characteristics,28-30 CHEO PS, 27
FPS-R,26 and the Face, Legs, Activity, Crying, Consol-
ability (FLACC) Scale. 26
Quantitative (Meta-Analytic) Analysis for
Effects on Pain and Distress
Meta-analyses were performed for the following
outcomes: child self-reported pain, cry duration, parent-
rated child pain using VAS, and nurse- or physician-
rated child pain using VAS. For these analyses, we in-
cluded data for outcomes that contained the most
subjects. If >2 treatment groups were included in
a study, data were abstracted from only 2 groups:
1 active treatment group (the analgesic intervention
with proven efficacy, as per previous results) and the
control group.
Child self-reported pain ratings were combined for
4 studies (350 children; data missing for 12) (Figure
4).24,26-28 The SMD was -0.52 (95% CI, -0.73 to
-0.30; P = 0.001). Heterogeneity was not significant
for this outcome.
Data on cry duration were pooled for 3 studies
(229 infants and children; data missing for 23).28-30
The WMD was -18.87 seconds (95% CI, -32.05 to
-5.69; P = 0.005); no significant heterogeneity was
reported for this outcome. The SMD was -0.36 (95%
CI, -0.62 to -0.10; P = 0.007); again, heterogeneity
was not significant.
Parent-rated child pain using VAS was combined
for 3 studies (365 infants and children; data missing
for 6).27,28,30 The WMD was -15.66 mm (95% CI,
-19.74 to -11.57; P < 0.001); no significant heteroge-
neity was reported for this outcome. The SMD was
-0.76 (95% CI,-0.98 to -0.55; P < 0.001); heteroge-
neity was not significant.
Nurse- or physician-rated child pain using a VAS
was combined for 3 studies (368 infants and children;
data missing for 3).27,28,30 The WMD was -17.85 mm
(95% CI,-21.43 to -14.28; P < 0.001); heterogeneity
was significant for this outcome (Z2 = 14.47; P =
0.007; J2 = 86%). The SMD was -0.99 (95% CI,
-1.20 to -0.77; P < 0.001); heterogeneity was signifi-
cant (Z2 = 8.65; P = 0.01; J2 = 77%). Data from the
individual studies were analyzed qualitatively. When
analyzed separately, the results of all 3 studies were
significant (all, P < 0.05; data = NR).
Qualitative Analysis for Pain and Distress
Boivin et aIl7 reported that, compared with a con-
trol group consisting of usual practices (ie, individual

Combined
Interventions Control
Weight, SMO SMO
Study or Subgroup Mean SO Total Mean SO Total % IV, Fixed, 95% CI IV, Fixed, 95% CI

-
Berberich and
Landman,"6 2009 2.00 1.48 20 6.75 5.90 21 10.6 -1.07 (-1.73 to -0.41)
BOIvin et aV 7 2008 17.50 19.90 100 27.90 24.30 127 65.4 -0.46 (-0.73 to -0.20)
Cohen Rels and
Holubkov,"81997 3.00 2.40 21 4.10 2.30 21 12.2 -0.46 (-1.07 to 0.15)
Eland,"" 1981 1.90 1.20 20 2.30 0.80 20 11.8 -0.38 (-1.01 to 0.24)
Total (95% CI) 161 189 100.0 -0.52 (-0.73 to -0.30)
Heterogeneity: X" - 3.10; df - 3 (P - 0.38); I" - 3%
Test for overall effect: z - 4.71 (P < 0.001) -2 -1.5 -1 -0.5 0 0.5
Favors Combined Favors
Interventions Control

Figure 4. Effectiveness of combined analgesic interventions as assessed using child self-reported pain scores. SMD ~ standardized mean
difference; df~ degrees offreedom.

S136 Volume 31 Supplement B


physician practices that mayor may not have included
some pain-relieving interventions such as different
vaccination injection sites [data NR], topical local
anesthetics, vapocoolants, and distraction), a multi-
modal strategy involving multiple interventions (Table I)
was associated with a significant reduction in vaccine
injection pain, as assessed by child self-reported
FPS-R scores (range, 0-10) (MD, -1.10; 95% CI,
-1.81 to -0.39; P = 0.002). The SMD was -0.43 (95%
CI, -0.71 to -0.14; P = 0.003). The multimodal strate-
gy was also effective when assessed using observer
CHEOPS scores (range, 4-13) (MD, -1.80; 95% CI,
-2.93 to -0.67; P = 0.002).
Berberich and Landman 26 reported lower parent-
rated FPS-R scores (range, 0-10) (MD, -4.28; 95%
CI, -5.99 to -2.57; P < 0.001) for children in the mul-
tifaceted distraction strategy group (including a com-
bination of vapocoolant spray, use of a plastic multi-
pronged gripper at the injection site, and use of a
vibrating instrument that descends slowly on the con-
tralateral arm [visual distraction]) than for those in
the control group (no intervention). Similarly, the
observer-rated FLACC score (range, 0-10) was lower
in the multifaceted distraction strategy group than in
the control group (MD, -4.06; 95% CI, -5.61 to
-2.51; P < 0.001).
Cohen Reis and Holubkov 28 reported lower
observer-rated VAS scores (range, 0-100 mm) (MD,
-24.00; 95% CI, -42.26 to -5.74; P = 0.01) for chil-
dren in the lidocaine-prilocaine plus distraction group
than for children in the distraction group. The observer-
rated child distress score using the OSBD (range,
0-11) was lower for children who received lidocaine-
prilocaine plus distraction than for those who received
distraction alone (MD, -1.80; 95% CI, -3.29 to -0.31;
P = 0.02). Similarly, Global Mood Scale (GMS) scores
(range, 1-7) at 1 minute were lower in the group that
received the combined interventions (MD, -1.60; 95%
CI, -2.78 to -0.42; P = 0.008). At 5 minutes, no signifi-
cant difference was observed for this outcome.
Cohen Reis and Holubkov 28 reported that, com-
pared with distraction alone, vapocoolant spray
(cotton ball saturated with Huori-methane applied for
15 seconds at the injection site) plus distraction was
associated with a significant reduction in vaccine in-
jection pain, as assessed using child self-reported FPS
scores (range, 0-6) (MD, -2.10; 95% CI, -3.54 to
-0.66; P = 0.004). The SMD was -0.88 (95% CI,
-1.52 to -0.23; P = 0.008). The parent-rated VAS
2009
v. Shah et a!.
(range, 0-100 mm) (MD, -22.80; 95% CI, -38.22
to -7.38; P = 0.004), nurse-rated VAS (range, 0-
100 mm) (MD, -23.60; 95% CI, -36.37 to -10.83;
P < 0.001), and observer-rated VAS scores (range,
0-100 mm) (MD, -23.50; 95% CI, -44.31 to -2.69;
P = 0.03) were lower in the vapocoolant spray plus
distraction group than in the group that received dis-
traction alone. Similarly, scores were lower for parent
FPS (range, 0-6) (MD,-1.40; 95% CI,-2.41 to -0.39;
P = 0.007), nurse FPS (range, 0-6) (MD, -1.50; 95%
CI, -2.30 to -0.70; P < 0.001), and observer FPS
scores (range, 0-6) (MD, -1.40; 95% CI, -2.56 to
-0.24; P = 0.02). Observer-rated distress, using OSBD
scores (range, 0-11), was lower for children who re-
ceived vapocoolant spray plus distraction than for
those who received distraction alone (MD, -1.90;
95% CI, -3.50 to -0.30; P = 0.02). Similarly, GMS
scores (range, 1-7) at 1 minute were lower (MD,
-1.50; 95% CI, -2.75 to -0.25; P = 0.02). At 5 min-
utes, no significant difference was observed for this
outcome. No significant difference in cry duration
was observed between the groups when vapocoolant
spray plus distraction was compared with distraction
alone (MD, -30.1; 95% CI, -61.04 to 0.84).
In the same study by Cohen Reis and Holubkov,28
no significant difference in vaccine injection pain was
observed using child self-reported FPS scores (range,
0-6) (MD, 1.00; 95% CI, -0.47 to 2.47) between
children who received lidocaine-prilocaine plus dis-
traction and those who received vapocoolant spray
plus distraction. In addition, pain scores did not differ
significantly between the groups for parent-rated VAS
(range, 0-100 mm) (MD, 3.00; 95% CI, -11.40 to
17.40), nurse-rated VAS (range, 0-100 mm) (MD, -2.00;
95% CI, -14.07 to 10.07), or observer-rated VAS
scores (range, 0-100 mm) (MD,-0.50; 95% CI,-19.30
to 18.30). Likewise, scores did not differ significantly
for parent-rated pain using FPS (range, 0-6) (MD,
0.30; 95% CI, -0.68 to 1.28), nurse-rated FPS (range,
0-6) (MD, 0.20; 95% CI, -0.66 to 1.06), or observer-
rated FPS scores (range, 0-6) (MD, 0.10; 95% CI,
0.99 to 1.19). No significant difference in observer-
rated OSBD distress scores (range, 0-11) (MD, 0.10;
95% CI, -1.31 to 1.51), cry duration (MD, 1.80 sec;
95% CI, -13.31 to 16.91), or GMS scores at 1 or
5 minutes (data NR) were observed between the
groups.
In a study by Cohen Reis et al,2 9 the combination
of sucrose, tactile stimulation (use of NNS with a
S137
 Clinical Therapeutics
pacifier or sucking a formula bottle), and parental
holding led to shorter first cry duration (ie, the inter-
val from the initiation of cry to the first pause in cry-
ing) (-38.50 sec; 95% CI, -52.94 to -24.06; P <
0.001) compared with the control group (lying supine
on the table with no analgesic intervention). The SMD
was -0.97 (95% CI, -1.35 to -0.58; P < 0.001).
Eland 24 compared the effectiveness of a vapocool-
ant and placebo spray in combination with or without
provision of cognitive information for reducing injec-
tion pain in children 4.7 to 5.7 years of age. Cognitive
information consisted of telling the children that the
spray would make their shot hurt less than other shots
they have had in the past. Child self-reports of pain
using CAS (range, 0-3) did not differ significantly
between the children who received vapocoolant spray
plus cognitive information and those who received
vapocoolant spray with no cognitive information
(MD, -0.4; 95% CI, -1.04 to 0.24).
Lindh et a130 reported a reduction in MBPS scores
(range, 0-10) obtained 0 to 10 seconds after the injec-
tion (-2.30; 95% CI, -3.09 to -1.51; P < 0.001) and
11 to 20 seconds after the injection (-1.50; 95% CI,
-2.45 to -0.55; P = 0.002) for infants who received
lidocaine-prilocaine and glucose compared with those
who received placebo cream and water. In addition,
fewer infants cried in the group that received lidocaine-
prilocaine plus glucose (RR, 0.74; 95% CI, 0.62 to
0.90; P = 0.002; RD, -0.25; 95% CI, -0.39 to -0.11;
P < 0.001; NNT, 4.0; 95% CI, 3.0 to 9.0). The laten-
cy to cry was longer for infants who received
lidocaine-prilocaine and glucose (MD, 2.60 sec; 95%
CI, 1.45 to 3.75; P < 0.001).
Breastfeeding
Four trials (478 infants)IUI-33 examined the anal-
gesic effects of breastfeeding (Table I). The overall
risk of bias was unclear in 1 study32 and high in
3 studies 11,31,33 (Table II). In all 4 studies, infants who
were breastfed before, during, and after the procedure
were compared with infants who were not breastfed.
Pain and distress were measured using cry dura-
tion, 11,3 1,32 NIPS,11,31 Douleur Aigue du Nouveau-ne
(DAN) scale,33 and FPS scores. 31
Quantitative (Meta-Analytic) Analysis for
Effects on Pain and Distress
Infant pain responses (cry duration 11,31,32 and the
DAN scale [range, 0-10]33) were combined for 4 stud-
S138
ies (474 infants; data missing for 4) that compared
breastfeeding before, during, and after immunization
and no treatment. 11 ,31-33 The SMD was -2.03 (95%
CI, -2.26 to -1.80; P < 0.001) (Figure 5). Significant
heterogeneity was reported for this outcome (Z2 =
48.80; P < 0.001; J2 = 94%); thus, data from the indi-
vidual studies were analyzed qualitatively. In the
3 studies 11,3U2 that reported cry duration, individual
analyses found a consistent pattern of results for each
trial (all, P < 0.001; data NR). In the study by
Moddares et al,33 observer-rated DAN scores (range,
0-10) were lower for breastfed infants than for those
in the control group (MD, -3.26; 95% CI, -3.79 to
-2.73; P < 0.001). The SMD was -2.11 (95% CI,
-2.54 to -1.68; P < 0.001).
Data from 3 studies (344 infants; data missing
for 4)11,31,32 were pooled in a meta-analysis for cry
duration. Infants who were breastfed before, during,
and after immunization cried for a shorter duration
than did control infants (WMD, -38.00 sec; 95% CI,
-42.27 to -33.73; P < 0.001). Considerable heteroge-
neity was reported for this outcome (Z2 = 271. 79; P <
0.001; J2 = 99%); data from the individual studies
were analyzed qualitatively, and a consistent pattern
of results was found for each trial (all, P < 0.001;
data NR). The SMD was -2.00 (95% CI, -2.27 to
-1.73; P < 0.001).
Qualitative Analysis for Pain and Distress
Abdel Razek and Az El-Dein31 assessed infant pain
using the Facial Pain Rating Scale (0 = no hurt and
5 = hurts worst). Fewer infants were reported to have
pain (score, 0 vs ::::1; categorized as no pain vs pain)
when breastfed before, during, and after immuniza-
tion than when not breastfed (RR, 0.87; 95% CI, 0.78
to 0.96; P = 0.007). The RD was -0.13 (95% CI,
-0.22 to -0.04; P = 0.004) and the NNT to prevent
1 infant from having pain was 7.7 (95% CI, 4.5
to 25.0).
Adverse Reactions
None of the 93 breastfed infants in the 2 studies
that reported adverse events 3U2 experienced aspira-
tion, vomiting, cyanosis, or respiratory change during
or after immunization.
DISCUSSION
In this systematic review and the meta-analyses, we
examined the effectiveness of pharmacologic interven-
Volume 31 Supplement B
 V. Shah et al.

Breastfeedlng Control
Weight, SMO SMO
Study or Subgroup Mean SO Total Mean SO Total % IV, Fixed, 95% CI IV, Fixed, 95% CI

Abdel Razek and

Az EI-Oeln,31 2009 125.33 12.18 60 148.66 13.96 60 29.2 -1.77 (-2.19 to -US)
Oill, et al,l1 2009 20.00 30.00 73 150.00 45.00 85 22.2 -3.33 (-3.82 to -2.85)
Efe and Ozer,3" 2007 35.85 40.11 33 76.24 49.61 33 20.4 -0.88 (-1.39 to -0.38)
Moddares et al,33

•
2006 3.52 1.37 65 6.78 1.69 65 28.2 -2.11 (-2.54 to -1.68)
Total (95% CI) 231 243 100.0 -2.03 (-2.26 to -1.80)
Heterogeneity: X" - 48.80; df - 3 (P < 0.001); I" - 94%
I I I I I
Test for overall effect: z - 17.38 (P < 0.001) -4 -3 -2 -1 0 1
Favors Favors
Breastfeedlng Control

Figure 5. Effectiveness of breastfeeding for immun ization pain, as assessed using validated pain tools. SM D ~ standardized mean dif-
ference; df ~ degrees of freedom.

tions for vaccine injection pain (ie, topical local anes-
thetics, sweet-tasting solutions, vapocoolants, oral anal-
gesics), comparisons of 2 different analgesic interven-
tions, and combinations of ::::2 analgesic interventions,
including breastfeeding (Table IV). Topical local anes-
thetics exert their pharmacologic effects by reversibly
inhibiting the generation and transmission of pain im-
pulses by blocking the transmission of action potential
across nerve endings located in the dermis. 46 By produc-
ing dermal analgesia (topical local anesthetics penetrate
to a depth of ~5 mm below the skin surface), they ef-
fectively reduce the pain from needle puncture. 47 Topi-
cal local anesthetics (lidocaine-prilocaine and ametho-
caine) have been well studied for vaccine injection
pain in infants and children. l -!! The effectiveness of
topical local anesthetics was assessed using reductions
in child self-reported pain and observer assessments us-
ing the MBPS, VAS, and cry duration. l ,5-9,1! SMDs
ranged from -0.43 to -0.75, suggesting a moderate ef-
fect size. The NNT to prevent 1 child from having pain
ranged from 1.2 in infants!! to 3.7 in children. l Further-
more, topical local anesthetics were found to be effec-
tive for both intramuscular and subcutaneous vaccine
injections, with SMDs ranging from -0.38 to -0.47.
Of the 8 included trials l ,5-!! that compared a topi-
cal local anesthetic with a placebo or no intervention,
all but 1 study 7 reported a beneficial effect of the an-
algesic intervention on immunization pain. These find-
ings are consistent with the effectiveness of topical
local anesthetics for other procedures such as circum-
cision, venipuncture, and venous cannulation in neo-
nates, children, and adults. 48 - 5!

Table IV. Effectiveness of pharmacologic and combined interventions assessed in the systematic review.

Interventio n Reduced Pain

Topical local anesthetics (Iidocaine-prilocaine, amethocaine) Yes

Sweet-tasting solutions (sucrose, glucose) Yes
Vapocoolants ?
Oral analgesics (acetaminophen or ibuprofen) NA*
Comparison of 2 different analgesic interventions ?
Combinations of::::2 analgesic interventions, including breastfeeding Yes

Yes ~ there IS eVidence to recommended use of stated intervention; ? ~ there IS insufficient eVidence to recommend the use
of stated intervention at this time; NA ~ not applicable.
*No studies were Identified In the literature search.

2009 S139
 Clinical Therapeutics
Compared with the positive studies, which included
infants and children up to 6 years of age, the trial with
negative results 7 included older children (11-15 years).
It is unclear why the results were negative for this
trial. 7 It is unlikely that topical local anesthetics lose
their effectiveness with increasing patient age, because
a previous study reported effectiveness of lidocaine-
prilocaine cream for immunization pain in adults. 52
There may have been differences in the methodology
in this study7 that would explain the discrepant find-
ings. For example, it is unclear how the older children
were prepared for the procedure. If the children were
experiencing anxiety before the procedure, the anxiety
may have contributed to anesthetic failure. Pain was
assessed using a YRS of 1 to 4, which may be too in-
sensitive, and scoring was described as "done in con-
sultation with the investigators," which may have in-
fluenced the results. Despite the negative results from
this trial/ 59% of parents stated that they would use
topical local anesthetics for future vaccinations.
It is important to note that topical local anesthetics
may be more effective in some children than in others.
Factors that may affect the child's ability to reduce
pain include the child's state of anxiety, age, tempera-
ment, and genetic variability. 53-55 The more anxious
the child is before the procedure, the more likely he or
she will be to report pain, irrespective of the pain-
relieving medication used. 54 Children with a high pain
phenotype (ie, child self-reported pain score of 4-
10 on the Oucher Scale) are more likely to be younger,
have increased general activity (temperament), and
score higher for anxiety. The presence of endothelin
receptor A genotype polymorphism56 may also affect
pain response. In 1 study,56 endothelin receptor A
genotype was present in 67.4% of children with high
pain scores compared with 39.5% of children with
low pain scores (P = 0.026). As a consequence of these
issues, age, temperament, and anxiety should be con-
sidered when selecting procedural pain-relieving strate-
gies. For those with genetic predisposition to topical
local anesthetic failure, a longer application time or an
alternative analgesic strategy may be required.
Topical local anesthetics were found to cause tran-
sient local skin reactions. The most common local re-
actions caused by lidocaine-prilocaine were pallor
and itchiness. Pallor occurs due to the vasoactive
properties of the drugs. Lidocaine-prilocaine typically
causes a biphasic vascular response; vasoconstriction
(maximal after 90-minute application) is followed by
S140
erythema secondary to vasodilatation (usually after
;::: 120 minutes of application).57-60 Amethocaine pro-
duces erythema secondary to its vasodilatory proper-
ties. These data are consistent with previous studies in
children. 61 - 63 It should be noted that even though the
use of topical local anesthetics was associated with
pallor or erythema, it is unlikely that these changes in
color influenced investigators during pain assessments.
The findings regarding the effectiveness of topical 10-
cal anesthetics are consistent in most of the studies.
Among these studies, both infants and children were
enrolled and pain was assessed by children, investiga-
tors, nurses, and parents using validated tools, there-
fore making the results generalizable.
The potential exists for repeated use of topical lo-
cal anesthetics to lead to allergic reactions. No clear
pattern of sensitization has been reported for adults
undergoing repeated vascular access for hemodialysis
with lidocaine-prilocaine. 64 ,65 Several cases of sensiti-
zation have been reported for amethocaine,50 and re-
peated use has been associated with increased inci-
dences of pruritus and rash. 66 These reactions were
transient and resolved spontaneously after discontinu-
ation of therapy. Sensitization has not been reported
for pediatric patients who received repeated doses of
amethocaine for venipuncture. 63 The issue of risk of
hypersensitivity following repeated use of local anes-
thetics warrants additional study.
Because topical local anesthetics are applied at the
same site as vaccines are administered and have anti-
microbial activity, it has been hypothesized that their
concomitant use during vaccination may lead to inac-
tivation of vaccines or impaired absorption. 67- 7o This
systematic review found that topical local anesthetics
did not interfere with vaccine response. No inter-
actions between topical local anesthetics and the
DPTaP-IPY-Hib (diphtheria, tetanus toxoid, acellular
pertussis, inactivated polio vaccine, and H influenzae
type b tetanus toxoid conjugate vaccine), hepatitis B,
or measles-mumps-rubella vaccines were reported in
any of the trials that were included in this review
(Table III).5,6,8 The data are consistent with studies
performed in adults undergoing bacille Calmette-
Guerin vaccine administration. 71 It is not clear wheth-
er topical local anesthetics interact differentially with
various antigens. To date, published studies have not
found an increased risk of vaccine failure with differ-
ent antigens, and there is no a priori reason to suspect
this to be the case. We recommend that testing for
Volume 31 Supplement B

interactions between topical local anesthetics be in-
corporated as part of Phase III trials for new vaccines.
Despite their proven effectiveness and tolerability,
topical local anesthetics have not been incorporated
into clinical practice. We have previously reported
that lidocaine-prilocaine was used in only 1 % of vac-
cinations. 34 The most commonly identified barriers
regarding their use, as identified by physicians,34 in-
clude: (1) long application time needed for effective-
ness (eg, 60 minutes for lidocaine-prilocaine), which
leads to potentially longer clinic visits; (2) concerns
regarding parental ability to apply topical local anes-
thetics properly; and (3) cost. These concerns have not
been substantiated by parents. When mothers were
asked about barriers to the use of these anesthetics,
they identified lack of knowledge about their avail-
ability as the main barrier. They did not identify feasi-
bility or cost as barriers to their use. 34 Other studies 7,9,10
support the notion that parents are able to apply topi-
cal local anesthetics correctly when trained to do so
and would pay the additional cost of the agents to
reduce their child's pain.
Sufficient evidence suggested that sweet-tasting so-
lutions reduced pain response during immunization.
The quality scores of the included studies indicated a
high risk of bias for 1 studyll and an unclear risk of
bias for 10 studies. 12- 21 In 10 trials,1l-20 the dose of
sucrose ranged from 750 flL to 2 mL, with concentra-
tions varying from 12% to 75%, whereas in 1 trial,21
the dose of glucose was 2 mL, for a concentration of
30%. A meta-analysis of 6 studies 11,14,16,18-20 that
compared sucrose with or without NNS (pacifier) to
no intervention or sterile water with and without NNS
indicated a standardized effect size of 0.56, suggesting
a moderate effect. For cry duration, the mean reduc-
tion was 9 seconds, with an SMD of -0.43. The NNT
to prevent 1 infant from having clinically significant
pain (NIPS score, >3) was 1.4 (95% CI, 1.0 to 2.5).
Our finding of a beneficial effect of sucrose for vac-
cine injection pain is consistent with results of studies
involving other invasive skin-breaking procedures per-
formed in neonates and young infants such as heel lance
and venipuncture. 72- 74 The mechanism of action of su-
crose is believed to include release of endogenous opi-
oids and distraction. 75 Furthermore, the beneficial effect
of sucrose may be enhanced with the use of a pacifier
(NNS). Of the 9 trials that compared sucrose 11,12-16,18-20
and 1 study that compared chewing gum with a pla-
cebo or no intervention,17 all except 2 studies l7,18 re-
2009
V. Shah et al.
ported a beneficial effect of the analgesic intervention
on immunization pain. Mixed results were noted in
2 trials. 12,19 The studies with positive results included
infants 1 to 48 months of age, whereas 1 of the trials
with negative results 17 evaluated children 9 to 11 years
of age. Possible reasons for the failure of sweetened
chewing gum to reduce pain are that sucrose is inef-
fective after early childhood or the administration
method was inappropriate. In the second study with
negative results,18 the reason for failure of sucrose was
unclear. The investigators used usual doses of sucrose
(2 mL of 50% solution) and validated measures of
pain (cry duration and MBPS). However, infants re-
ceived 3 injections in 1 sitting, which may have resulted
in an intensity of pain that was too great for sucrose
to relieve. The total duration of the procedure was not
reported, and it is not clear whether repeated admin-
istration of sucrose would have been beneficial. How-
ever, in another study14 in which infants received
3 injections sequentially, the analgesic effect of sucrose
persisted for >9 minutes. Further studies are needed to
confirm or refute the effectiveness of sucrose for re-
ducing pain from multiple injections.
Three trials 13,15,21 that evaluated the effects of
sweet-tasting solutions longitudinally (age-related chang-
es in effectiveness) reported that both sucrose and glu-
cose were effective in reducing vaccination pain over
time, as assessed using cry duration and UWCH Pain
Scale scores. In the study by Thyr et al,21 statistically
significant reductions in mean crying time during the
first 2 minutes after vaccination were found at 5 and
12 months of age (P = 0.017 and P = 0.03, respec-
tively), but not at 3 months of age. The mean crying
time appeared to be lower in the glucose group at
3 months, but the difference was not statistically
significant.
Adverse events such as coughing and gagging from
sweet-tasting solutions were reported in only 1 trial. 15
None of these adverse events were clinically signifi-
cant. Adverse events such as choking and desaturation
have been reported in neonatal trials of sucrose, but
none of these events required medical intervention. 72
This review did not determine the optimal dose of
sucrose or other sweeteners. In a meta-analysis of
sucrose in the neonatal population, the effective dose
was reported to range from 0.012 to 0.12 g.72 In a
separate review/ 6 a dose of 0.2 to 0.5 g was consid-
ered to be optimal for full-term infants. Additional
benefit was observed with higher doses (0.5-1.5 g), 16,19,20
S141
 Clinical Therapeutics
but not all of these differences were statistically signifi-
cant. Future studies are needed to compare different
doses of sucrose for vaccine injection pain.
There was insufficient evidence for or against va-
pocoolants for vaccine injection pain management.
Yapocoolants were evaluated in 4 studies ll- 25 with
inconsistent results. The SMDs ranged from -0.10
(not significant) to -0.43 (moderate effect size). In
some studies,77,78 the positive results may be ex-
plained by a placebo effect. Children in the study by
Abbott and Fowler-Kerryll were informed that
"something was going to be put on their arm that will
feel cool but may really make the needle hurt less."
This positive suggestion may have accounted for the
beneficial effect of vapocoolants in this study. The
overall risk of bias was high in 1 study,23 low in
1 study,25 and unclear in 2 studies.22,24 In all 4 of
these studies, the types of vapocoolants that were
evaluated varied, and it is not known whether they
were equivalent in terms of effectiveness. Both fluoro-
ethyl and dichlorotetrafluoroethane contain chloro-
fluorocarbons that have been shown to be damaging
to the ultraviolet light-protective ozone layer and
therefore have been banned since 1997. Currently, the
only commercially available vapocoolant that has
been tested for immunization pain is ethyl chloride
refrigerant. 23 In the only study that evaluated its use,
the results were negative. 23
Our results are comparable to those of studies that
examined vapocoolants in children and adults under-
going painful procedures such as venous cannula-
tion79-86 and intradermal skin testing,87 in which the
effectiveness of vapocoolants has not been consistent.
In the only study performed in adults for vaccine in-
jection pain,88 vapocoolant spray was found to be ef-
fective in reducing pain compared with application of
a cold (4°C) saline placebo.
Differences in the apparent effectiveness of vapo-
coolants may be due to differences in administration
techniques. The application time for effectiveness is
generally between 4 and 10 seconds (until blanching
of the skin occurs). Due to the speed of evaporation,
the painful procedure should be performed 0:;60 sec-
onds after application. Yapocoolant sprays provide
transient anesthesia secondary to evaporation-induced
skin cooling, which reduces pain. 89 In the 2 studies in
our review with positive results, the application time
was lOll and 15 28 seconds. The vapocoolant was not
applied directly to the skin in either study. Rather, a
S142
cotton ball was saturated with vapocoolant, and the
cotton ball was applied to the skin; the vaccine was
injected within a few seconds after removal of the cot-
ton ball. In the 3 negative studies included in our
review,23-25 vapocoolant was sprayed directly on the
skin immediately before the injection 24 for 2 to 3 sec-
onds 25 or applied to the skin via a cotton ball held in
place for 20 seconds. 23 In summary, variability in ad-
ministration techniques may have contributed to the
inconsistent effects of vapocoolants. 34
It is important to note that vapocoolants cause
cooling and/or burning sensations on the skin that can
be uncomfortable for some people, including young
children, who may perceive it as a noxious stimulus.
No adverse events were reported in any of the studies
in this review, but it is not clear whether such events
were recorded in a systematic manner. Considering
the published data and the issues described, vapocool-
ants cannot be routinely recommended as a strategy
for reducing vaccine injection pain at this time. More-
over, they are not recommended for use in combina-
tion with topical local anesthetics, due to the presence
of diminished skin sensation from the local anesthet-
ics and, consequently, a potential for more serious
adverse skin reactions.
None of the studies that were identified in the lit-
erature search evaluated the effectiveness of oral anal-
gesics (acetaminophen or ibuprofen) for immuniza-
tion pain. Pediatricians may recommend oral anal-
gesics to parents as a pain-relieving intervention for
vaccine injection pain. 34 However, no evidence was
found to recommend the use of either agent as a meth-
od of pain relief for vaccine injections. It is astonishing
that, despite such widespread use of these agents in
children, no study of their effects on vaccine injection
pain was identified. A study that addresses this issue
may be warranted.
In the 4 studies 3,4,1 1,1 9 in which 2 analgesic inter-
ventions were compared (eg, lidocaine-prilocaine vs
sucrose), there was insufficient evidence to suggest
superiority of one intervention over another. Further-
more, the risk of bias was either unclear or high in all
of these studies. Hence, no conclusions could be drawn.
We found evidence to support the effectiveness
of combinations of analgesic interventions, including
topical local anesthetics and sweetening agents. This is
not surprising, because each of the interventions was
reported to be effective when used alone. The SMDs
for combinations of interventions ranged from -0.36
Volume 31 Supplement B

to -0.99, suggesting a small to large effect size. The
specific interventions used in the included studies l4 ,l7-3o
were varied and warrant some discussion.
In the study by Boivin et al,27 a comprehensive pain
management strategy (combination of pharmacologic
and nonpharmacologic interventions, each with prov-
en efficacy) was compared with a control group con-
sisting of usual practices (ie, individual physician
practices that may or may not have included some
pain-relieving interventions such as different vaccina-
tion injection sites [data NR], topical local anesthet-
ics, vapocoolants, and distraction). In the study by
Berberich and Landman,l6 use of a multifaceted dis-
traction strategy (combination of vapocoolant spray,
use of a plastic multipronged gripper at the injection
site, and use of a vibrating instrument that descends
slowly on the contralateral arm [visual distraction])
reduced the pain of vaccine injection. Another studyl8
compared 3 strategies: lidocaine-prilocaine plus dis-
traction, vapocoolant plus distraction, and distraction
alone. In our review, we found inconclusive evidence
of the effectiveness of vapocoolants as a single inter-
vention. It is possible that the combination of a vapo-
coolant and distraction may reduce vaccine injection
pain due to either an additive or synergistic effect of
the 2 interventions or a placebo effect of the vapo-
coolant (as previously described). Cognitive-behavioral
interventions such as distraction have been reported
to be effective in reducing the pain and distress associ-
ated with needle-related procedures. 90 Cohen Reis et
a12 9 reported that the group that received a combina-
tion of sucrose, tactile stimulation (use of a pacifier or
formula bottle after administration of sucrose), and
parental holding experienced less injection pain than
did the control group, which received no treatment.
The combination of lidocaine-prilocaine and glucose
also was associated with reduced injection pain com-
pared with placebo cream and sterile water. 30 The
NNT to prevent 1 infant from having clinically signif-
icant pain was 4.0 (95% CI, 3.0 to 9.0).
This review found that breastfeeding before, dur-
ing, and after immunization reduced pain, as assessed
using cry duration 1Uul and the DAN scale. 33 The
SMD was -2.03, indicating a large effect size. The
NNT to prevent 1 infant from having clinically
significant pain was 7.7. 31 The proposed mechanisms
by which breastfeeding provides analgesia include:
(1) presence of a comforting person (mother)91;
(2) diversion of attention (sucking and distraction)91,9l;
2009
v. Shah et al.
(3) physical sensation (skin-to-skin contact with com-
forting person)91; and (4) sweet-tasting substances
and other chemicals (presence of lactose or other in-
gredients in breast milk).93 Breast milk contains a
higher concentration of tryptophan, a precursor of
melatonin, which has been reported to increase the
concentration of ~-endorphins.94,95
The findings from this systematic review are consis-
tent with the effectiveness of breastfeeding in alleviat-
ing pain for procedural pain management in neonates,
such as heel lances and venipunctures. 96 Compared
with other analgesics used in the neonatal period,
such as sucrose, glucose, or topical local anesthetics,
breastfeeding/breast milk is a natural, cost-neutral,
time-efficient, and convenient intervention that could
be easily adopted from the perspectives of health care
providers and parents. Apart from the nutritional and
psychological value of breastfeeding, the analgesic
properties may encourage more mothers to breast-
feed. One theoretical concern with use of breastfeed-
ing as an analgesic intervention is the association of
breastfeeding with pain and whether that would affect
the maternal-infant bond and success of breastfeed-
ing. This is unlikely given that vaccine injections are
uncommon; hence, breastfeeding would not be a reli-
able cue of an upcoming painful procedure for the
infant.
It is important to recognize that for breastfeeding to
be effective as an analgesic, an adequate latch needs to
be established, which may not be achieved in all in-
fants. Therefore, alternative pain-relieving strategies
such as the use of sweet-tasting solutions should be
considered. The use of supplemental breast milk may
be considered; however, it has not been shown to con-
sistently reduce procedure-related pain in neonates and
has not been evaluated for vaccine injection pain. 96
Methodologic challenges and limitations of this
review include the small number of studies for various
interventions (eg, vapocoolants, breastfeeding), small
sample size, limited age range of the participants, lim-
ited number of vaccines evaluated, low study quality
ratings, variability in pain assessments, marked het-
erogeneity between studies in terms of control inter-
ventions, and missing summary statistics (for a few
trials). The risk of bias was high or unclear for 84%
(27/32) of included trials, leading to uncertainty re-
garding the internal validity of the findings. Further-
more, many of these trials were published before the
CONSORT (Consolidated Standards of Reporting
S143
 Clinical Therapeutics
Trials) guidelines 97 were adopted. The included trials
used various methods of assessing pain in children,
which made it difficult to combine and contrast the
results. To address this issue, data were analyzed using
SMDs in addition to WMDs. Authors were not con-
tacted for missing data.
Based on our review, areas for future research were
identified. For topical local anesthetics, these included
addressing the effects of topical local anesthetics on
vaccination success rates as part of Phase III trials
evaluating new vaccines and hypersensitivity follow-
ing repeated doses. Future studies evaluating sweeten-
ers, particularly sucrose, should determine the optimal
method of use, including dose and frequency of ad-
ministration (when multiple vaccines are given), and
the upper age limit of effectiveness. The role of ex-
pressed breast milk has not been studied, and further
research is needed. Additional well-designed trials with
appropriate administration techniques are needed to
confirm or refute the effectiveness of vapocoolants.
The added benefits of combination strategies require
investigation, with the goal of eliminating, rather than
reducing, vaccine injection pain. Finally, studies ad-
dressing whether the gap between research findings
and clinical practice can be narrowed by communica-
tion and dissemination strategies aimed at practition-
ers, professional groups, and families will be important
in establishing the common goal of pain-free, tolera-
ble, and effective immunization for children.
CONCLUSION
Topical local anesthetics, sweet-tasting solutions, and
combined interventions, including breastfeeding, were
associated with reductions in immunization pain in
children and should be recommended for routine use
in clinical practice.
ACKNOWLEDGM ENTS
We wish to thank the chief librarian at The Hospital
for Sick Children (Elizabeth Uleryk) for conducting
the literature searches. This research was funded by a
Canadian Institutes of Health Research (CIHR) Know-
ledge Synthesis grant awarded to Dr. Taddio and col-
leagues (KRS - 91783). Dr. Taddio is supported by a
CIHR New Investigator Award. The authors have in-
dicated that they have no conflicts of interest regard-
ing the content of this article and that there was no
industry involvement in the design, conduct, analysis,
or publication of this systematic review.
S144
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(continued on next page)
S147
Clinical Therapeutics

Appendix. Search strategies for MEDLIN E, EM BASE, CI NAHL, and the Cochrane Central Register of Controlled
Trials.

Set History Results Comments

MEDLINE (1950-October, Week 3,2008)

Pain measurement/ or exp pain/ or Antibody Formation/ or Crying/ or 602,516 Pain terms
anxiety/ or fear/ or panic/ or (adverse adj2 effect:).ti,ab. or (side adj2
effect:).ti,ab. or (skin adj2 reaction:).ti,ab. or (distress* or discomfort*
or fright* or anxious).ti,ab.

2 Immunization/ or immunization, passive/ or adoptive transfer/ or 376,085 Immunization

immunotherapy, adoptive/ or immunization schedule/ or immunization, or vaccine terms
secondary/ or immunotherapy, active/ or vaccination/ or mass
immunization/ or (simultaneous or sequential).ti,ab. or exp vaccines/

3 Analgesics/ or lidocaine/ or prilocaine/ or tetracaine/ or sweetening agents/ 1,060,605 Analgesics/

or aspartame/ or cyclamates/ or dietary sucrose/ or fructose/ or glucose/ sweetener terms
or lactose/ or maltose/ or mannitolj or molasses/ or saccharin/ or sorbitolj
or stevia/ or sucrose/ or xylitolj or Ice/ or ethyl chloride/ or (anesthetics,
localj and refrigeration/) or Acetaminophen/ or ibuprofen/ or (freezing
or freeze or freezes or ice or ices or icing or iced or coolant: or cool or
cooling or vapocoolant: or "vapo-coolant" or "vapo-coolants" or (skin
adj2 refrigerant:) or dichlorotetrafluoroethane or fluro-ethyl or fluorimethane
or "fluori-methane" or pentafluoropropane or tetrafluoroethane).mp.
or Breast Feeding/ or Milk, Human/ or massage:.mp. or (pressure or
cuddling or cuddle: or hold:).ti,ab.

4 Guidelines as topic/ or practice guidelines as topic/ or evaluation studies 1,447,055 Study design/
as topic/ or exp clinical trials as topic/ or validation studies as topic/ or methodology
((clinical: adj5 trial:) or random: or ((singl: or doubl: or tripl: or trebl:) terms
adj5 (mask: or blind:)) or (control: adj5 group:) or (quasi adj5 randomiz:)
or (quasi adj5 randomis:)).ti,ab. or (clinical trial, all or clinical trial,
phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial,
phase iv or clinical trial or controlled clinical trial or evaluation studies
or guideline or meta analysis or multicenter study or practice guideline
or randomized controlled trial or validation studies).pt.

5 1 and 2 and 3 and 4 364 Base clinical set

6 Limit 5 to humans 340 Human limit

7 Limit 6 to "all child (0 to 18 years)" 100 Age group limit

8 5 and (neonat: or newborn: or infan: or child: or adolescen: or teen:).mp. 103 Age group
textwords

9 7 or 8 103 Final results

(continued)

S148 Volume 31 Supplement B

 v. Shah et al.

Appendix (continued).

Set History Results Comments

EMBASE (1980-Week 43,2008)

1 Pain assessment/ or pain/ or injection pain/ or vaccination reaction/ or 409,491 Pain terms
exp application site reaction/ or exp injection site reaction/ or antibody
production/ or crying/ or facial expression/ or gesture/ or fear/ or
anticipatory anxiety/ or anxiety/ or (adverse adj2 effect:).ti,ab. or (side
adj2 effect:).ti,ab. or (skin adj2 reaction:).ti,ab. or (distress* or discomfort*
or fright* or anxious).ti,ab.

2 Immunization/ or mass immunization/ or passive immunization/ or active 317,636 Immunization

immunization/ or immunotherapy/ or adoptive immunotherapy/ or or vaccine terms
adoptive transfer/ or vaccination/ or bcg vaccination/ or influenza
vaccination/ or measles vaccination/ or revaccination/ or (simultaneous
or sequential).ti,ab. or exp vaccine/

3 Analgesic agent/ or exp antipyretic analgesic agent/ or exp Local Anesthetic 1,033,539 Analgesics/
Agent/ or exp Sweetening Agent/ or mannitolj or Molasses/ or ice/ or sweetener terms
Chloroethane/ or freezing/ or (ethyl adj2 chloride).mp. or (freezing or
freeze or freezes or ice or ices or icing or iced or coolant: or cool or
cooling or vapocoolant: or "vapo-coolant" or "vapo-coolants" or (skin
adj2 refrigerant:) or dichlorotetrafluoroethane or fluro-ethyl or fluorimethane
or "fluori-methane" or pentafluoropropane or tetrafluoroethane).mp. or
breast feeding/ or Breast Milk/ or (breastfed: or breastfeeding).mp. or
(breast adj2 fed).mp. or (breast adj2 feeding).mp. or (breast adj2 milk).
mp. or massage:.mp. or (pressure or cuddling or cuddle: or hold: or ices
or ice or iced or cold or hot or temperature).ti,ab. or (freezing or freeze
or freezes).ti,ab. or refrigeration/ or (shot adj2 blocker).ti,ab.

4 Exp clinical trial/ or double blind procedure/ or single blind procedure/ Study design/
or triple blind procedure/ or validation study/ or (evaluation studies or methodology
evaluation study).ti,ab. or exp practice guideline/ or ((clinical: adj5 trial:) terms
or random: or ((singl: or doubl: or tripl: or trebl:) adj5 (mask: or blind:))
or (control: adj5 group:) or (quasi adj5 randomiz:) or (quasi adj5
random is:)).ti,ab.

5 1 and 2 and 3 and 4 818 Base clinical set

6 Limit 5 to human 780 Human limit

7 Limit 6 to (infant <to one year> or child <unspecified age> or preschool 136 Age group limit
child <1 to 6 years> or school child <7 to 12 years> or adolescent <13 to
17 years»

8 6 and (neonat: or newborn: or infan: or child: or adolescen: or teen:). 235 Age group
mp. textwords

9 7 or 8 235 Final results

(continued)

2009 S149
Clinical Therapeutics

Appendix (continued).

Set History Results Comments

CINAHL (1982-0ctober, Week 3,2008)

1 Treatment related pain/ or Pain Measurement/ or exp pain/ or Antibody 93,714 Pain terms
Formation/ or Crying/ or anxiety/ or fear/ or (adverse adj2 effect:).ti,ab.
or (side adj2 effect:).ti,ab. or (skin adj2 reaction:).ti,ab. or (distress* or
discomfort* or fright* or anxious).ti,ab.
2 Immunization/ or immunization schedule/ or Immunization Programs/ 23,657 Immunization
or Immunotherapy/ or (immunization: or immunisation:).mp. or or vaccine terms
(simultaneous or sequential).ti,ab. or exp vaccines/
3 exp Analgesics/ or Lidocaine/ or anesthetics, localj or benzocaine/ or 28,705 Analgesics/
bupivacaine/ or emLa cream/ or lidocaine/ or prilocaine/ or procaine/ sweetener terms
or tetracaine/ or sweetening agents/ or aspartame/ or cyclamates/ or
saccharin/ or sorbitolj or xylitol/ or Dietary Sucrose/ or fructose/ or
glucose/ or lactose/ or sucrose/ or mannitol/ or sorbitolj or xylitol/ or
ethyl chloride/ or Cryotherapy/ or Refrigeration/ or freezing/ or
acetaminophen/ or ibuprofen/ or (molasses or stevia or maltose or freezing
or freeze or freezes or ice or ices or icing or iced or coolant: or cool or
cooling or vapocoolant: or "vapo-coolant" or "vapo-coolants" or (skin
adj2 refrigerant:) or dichlorotetrafluoroethane or fluro-ethyl or fluorimethane
or "fluori-methane" or pentafluoropropane or tetrafluoroethane).mp. or
exp Breast Feeding/ or Milk, Human/ or pressure or cuddling or cuddle:
or hold: or ices or ice or iced or cold or hot or temperature).ti,ab. or
(freezing or freeze or freezes).ti,ab. or refrigeration/ or (shot adj2
blocker).ti,ab.
4 exp evaluation research/ or clinical trials/ or double-blind studies/ or 123,052 Study design/
intervention trials/ or preventive trials/ or single-blind studies/ or therapeutic methodology
trials/ or triple-blind studies/ or ((random: adj2 control: adj2 trial:) or terms
(random: adj2 clinic: adj2 trial:)).ti,ab. or ((clinical: adj5 trial:) or random:
or ((singl: or doubl: or tripl: or trebl:) adj5 (mask: or blind:)) or (control:
adj5 group:) or (quasi adj5 randomiz:) or (quasi adj5 randomis:)).ti,ab.
5 1 and 2 and 3 and 4 60 Base clinical set
6 Limit 5 to (newborn infant <birth to 1 month> or infant <1 to 23 months> 31 Age group limit
or preschool child <2 to 5 years> or child <6 to 12 years> or adolescence
<13 to 18 years»
7 5 and (neonat: or newborn: or infan: or child: or adolescen: or teen:).mp. 33 Age group
textwords
8 6 or 7 33 Final set
Cochrane Central Register of Controlled Trials (4th Quarter, 2008)
Pain measurement/ or exp pain/ or Antibody Formation/ or Crying/ or 69,518 Pain terms
anxiety/ or fear/ or panic/ or (adverse adj2 effect:).ti,ab. or (side adj2
effect:).ti,ab. or (skin adj2 reaction:).ti,ab. or (distress* or discomfort*
or fright* or anxious).ti,ab.

(continued)

S150 Volume 31 Supplement B

 v. Shah et al.

Appendix (continued).

Set History Results Comments

2 exp vaccines/ or immunization/ or immunization, passive/ or adoptive 13,050 Immunization

transfer/ or immunotherapy, adoptive/ or immunization schedule/ or or vaccine terms
immunization, secondary/ or immunotherapy, active/ or vaccination/ or
mass immunization/ or (immunization: or immunisation:).mp. or
(simultaneous or sequential).ti,ab.
3 Analgesics/ or Acetaminophen/ or ibuprofen/ or anesthetics, local/ or 65,838 Relaxation
lidocaine/ or prilocaine/ or tetracaine/ or sweetening agents/ or aspartame/ techniques or
or cyclamates/ or dietary sucrose/ or fructose/ or glucose/ or lactose/ psychology
or maltose/ or mannitolj or molasses/ or saccharin/ or sorbitolj or terms
stevia/ or sucrose/ or xylitolj or Ice/ or ethyl chloride/ or refrigeration/
or (freezing or freeze or freezes or ice or ices or icing or iced or coolant:
or cool or cooling or vapocoolant: or "vapo-coolant" or "vapo-coolants"
or (skin adj2 refrigerant:) or dichlorotetrafluoroethane or fluro-ethyl or
fluorimethane or "fluori-methane" or pentafluoropropane or
tetrafluoroethane).mp. or breast feeding/ or milk, human.mp. or (breastfed:
or breastfeeding).mp. or (breast adj2 fed).mp. or (breast adj2 feeding).
mp. or (breast adj2 milk).mp. or massage:.mp. or (pressure or cuddling
or cuddle: or hold: or ices or ice or iced or cold or hot or temperature).
ti,ab. or (shot adj2 blocker).ti,ab.
4 1 and 2 and 3 280 Base clinical set
5 4 and (infan: or newborn: or neonat: or child: or teen: or adolescen: or 109 Age group
pediatric: or paediatric:).mp. textwords

2009 S151
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