The availability of vaccines has been a major breakthrough in the field of medicine, and vaccination programs have been the most cost-effective way of reducing the burden of communicable diseases. Despite the proven benefits of vaccination, many individuals globally have not reaped its benefits. Therefore, as part of an on-going effort to improve vaccination rates, the World Health Organization and their partners have developed the “Global Vaccination Action Plan” with the goal to improve vaccination compliance and reduce mortality from communicable diseases throughout an individual’s lifespan.1 As more vaccines become available and incorporated into vaccination schedules, individuals are subjected to an increasing number of injections. Vaccine injections are the most common source of iatrogenic pain in children and adults and an important contributing factor to noncompliance with vaccination.2–4 Pain associated with vaccination is now recognized as an important adverse event following immunization, and managing pain should therefore be part of every vaccination.5
Over the last several decades, numerous strategies including pharmacological, physical, procedural, process, and psychological interventions have been evaluated to mitigate the pain from vaccine injections.6 Despite the effectiveness of many of these interventions, they are not routinely used by health care providers in clinical practice.7 Pharmacological and combined interventions in particular, are rarely used due to barriers to implementation such as uncertainty about their effectiveness, concerns regarding adverse consequences, time commitment, and potential cost.
In a previous systematic review published on this topic in 2009,8 evidence was found to support several interventions that were then incorporated into a clinical practice guideline for vaccination pain management in children.6 Since that analysis, new literature has been published, including evaluation of combined interventions. Hence, there was a need to update the review. In addition, the previous synthesis was limited to children and it was deemed necessary to expand the synthesis to adults. Therefore, the HelpELiminatePain in KIDS (HELPinKIDS) team made a decision to expand the scope of the synthesis to include the literature on adult populations (HELPinKids&Adults).
The objective of this systematic review was to assess the effectiveness and safety of combined interventions and pharmacotherapy in reducing the pain associated with vaccine injections in children and adults. The interventions evaluated included: (1) breastfeeding (which combines sweet-tasting solution, sucking, and holding [physical comfort]), either before or during vaccine injections; (2) topical anesthetics; (3) sweet-tasting solutions (sucrose and glucose); (4) vapocoolants; (5) oral analgesics (acetaminophen and ibuprofen); and (6) 2 interventions versus 1 intervention (ie, topical anesthetic and breastfeeding vs. topical anesthetics alone; sweet-tasting solutions and non-nutritive sucking vs. sweet-tasting solutions or non-nutritive sucking alone; or sweet-tasting solutions and breastfeeding vs. breast feeding or sweet-tasting solutions alone).
The methodological details used to perform this systematic review are described elsewhere.9 In short, both the Grading of Assessments, Recommendations, Development, and Evaluation (GRADE)10 and Cochrane11 methodologies guided the review.
A comprehensive literature search was performed using the search strategy developed by the authors based on their content expertise and in consultation with an academic librarian for the following databases: EMBASE, Medline, PsycINFO, CINAHL, and ProQuest Dissertations & Theses Global (inception—February 26, 2015). No language restrictions were applied. The titles and abstracts of the articles were screened and retrieved articles were assessed for eligibility by 2 reviewers (V.S., A.T.). In addition, reference lists from eligible articles were reviewed to identify additional studies.
This review included: (1) children and adults undergoing vaccine injections in any setting (eg, hospital, community) or if not undergoing vaccine injections, the closest related needle procedure or context (eg, venipuncture, venous cannulation, needle puncture into a subcutaneous [SC] port); and (2) randomized controlled trials (RCTs) or studies with a quasi-randomized study design. We included studies published as full or short reports, as well as published academic theses. We excluded studies in which the analgesic intervention or the outcome of interest was not clearly defined, published abstracts, letters, commentaries, and editorials.
The included clinical questions and outcomes of interest (Table 1) were prioritized by the HELPinKids&Adults team.
Outcomes of Interest
As per the GRADE methodology, outcomes of interest were categorized as critical and important outcomes for inclusion in the review and data for these outcomes were extracted from the eligible studies. The critically important and important outcomes for included clinical questions are shown in Table 1. Self-report of pain was prioritized as the critically important outcome when self-report of pain was possible (eg, child over 3 y of age). For children under 3 years, distress was the critically important outcome. Fear was prioritized as a critical outcome only for topical anesthetics and required the ability to self-report.
For health care professionals, safety (adverse consequences), fidelity, feasibility, and preference are major issues that need to be addressed before implementing evidence-based interventions in practice. Therefore, the above-listed outcomes were prioritized as important outcomes and are included in the presentation of outcomes. For topical local anesthetics, we examined transient changes in skin color (pallor or erythema), edema and effects on the immune response. Episodes of aspiration, vomiting, cyanosis, and respiratory change during and after the procedure were assessed for breastfeeding; episodes of choking, coughing, gagging, nausea, vomiting, and physiological instability were assessed for sweet-tasting solutions (eg, sucrose, glucose), and oral analgesics. For vapocoolants, pain during application and skin reactions were evaluated. Data on immunogenicity was examined for oral analgesics. We also reported on the fidelity (use or compliance with the intervention), feasibility (ease of adoption in clinical practice), and preferences (choosing one intervention over the other) for each of the intervention as available.
The methodologic quality of the studies was assessed by 2 reviewers using the Cochrane Collaboration’s Risk of Bias tool, and the overall summary assessment of the Risk of Bias was designated for individual studies.11
Data Abstraction and Synthesis
Data were abstracted on a predesigned form by 2 reviewers (V.S., A.T.) and checked for accuracy. The trials had to include the data necessary for pooling in a meta-analysis, such as means and standard deviations (SDs), and the prioritized outcomes had to be assessed by the child or adult (self-report) or by others using validated tools.12,13
Modification of the original data was done as needed on a predefined, restricted basis according to established methods.14 For example, means (and SDs) were calculated from medians, ranges, and 95% confidence intervals (CIs), or estimated from graphs.14 As pain, distress, or both were assessed at multiple timepoints in the included studies, the data were standardized and analyzed as follows (according to the procedure phase): (1) the preprocedure phase, which occurred postintervention but before vaccine injection(s); (2) the acute procedure phase (within the first minute of needle puncture and vaccine injection); and (3) the recovery procedure phase (1 to 5 min after vaccine injection(s)) to determine the effectiveness of an intervention.
Established methods were used to pool data before inclusion in the meta-analysis if data were available from multiple observers evaluating the same outcome (eg, parent-rated or clinician/researcher-rated child distress) or if available at multiple timepoints within the same procedure phase (eg, acute distress measured every 15 s within the first minute of vaccine injection).15 The scores were first standard on a scale of 0 to 10, using an estimated correlation of 0.25.16 This process allowed all the data pertaining to an outcome to contribute to the summary statistic included in the meta-analysis and reduce bias from either “selecting/picking the data” from individual studies included in the meta-analysis.9 Authors of trials were contacted for further details or provision of original data if the published report contained insufficient information. Missing data were not imputed.
All statistical analyses were conducted using Review Manager (RevMan) version 5.2, the statistical software provided by the Cochrane Collaboration (Copenhagen, Denmark).11 Results are presented as standardized mean difference (SMD) and 95% CI or relative risk (RR) and 95% CI as appropriate. All meta-analyses were conducted using a random-effects model. Statistical heterogeneity was assessed using I 2 and χ2 tests.11 If appropriate, a sensitivity analysis was performed by including and excluding studies with a high likelihood of bias, as assessed by the Risk of Bias tool.11 Funnel plots were performed to assess for the possibility of publication bias if there were sufficient trials (>10).11
Separate analyses were planned for the following interventions based on the age of the participants and/or attributes of the interventions: (1) breastfeeding (0 to 2 y); (2) topical anesthetics (children 0-12 y, adolescents > 12 y and adults); (3) sweet tasting solutions (0-2 y); and (4) vapocoolants (children 0 to 3 y, children older than 3 to 17 y, and adults). In addition, separate analyses were conducted to account for differences in the timing of administration of interventions (ie, breastfeeding immediately before, during, and after the procedure vs. breastfeeding prevaccine injection). Finally, subgroup analyses were planned to examine the impact of sucrose concentration according to 3 dose intervals: low concentration (<20%), moderate concentration (20% to <50%), and high concentration (≥50%). Analyses are presented according to these decisions. Post-hoc additional analyses were carried out to examine the effects of study methodology, heterogeneity, or both.
Evidence Profiles and Summary of Findings
The GRADE profiler software (version 3.6.1) was used to create evidence profiles and summary of findings tables in which all judgments and information pertaining to the evaluation of the quality of evidence were recorded. The quality of evidence could be rated as high, moderate, low, and very low. If a benefit was noted across all the critical outcomes, the intervention was said to be beneficial; if the results were inconsistent, the intervention was said to have mixed benefit. Interventions without statistical evidence of benefit were said to have no evidence of benefit.
The database searches yielded 114,251 references and an additional 138 references were identified separately from manual searches. All references were stored in an EndNote library that identified 32,155 duplicates. The remaining 82,234 references were reviewed by 2 of the authors (V.S., A.T.) against the inclusion criteria.9 Five studies were excluded after reviewing the full manuscript as it included: (1) combined interventions versus control (n=1)17; (2) a no comparator group (n=2),18,19; (3) did not include intervention according to the clinical question (n=1)20; and (4) the procedure was SC injection of normal saline (n=1).21
Sixty-one studies investigating pharmacological and combined interventions were included in the review.22–82 In 6 cases, multiple citations were identified for the same study; 2 of these included a dissertation47,59 and published manuscript with the same data,46,58 whereas the other 4 included multiple citations for the same study.28,31,32,63 A total of 55 studies were included in this review. The study selection log is shown in Figure 1.
Characteristics of included studies are described in Table 2. Except for 2 studies39,82 that used cross-over designs, the trials used between-groups (parallel) designs. All studies provided data for ≥2 treatment arms. The majority of the studies included children, adolescents, or both (n=52) and only 3 studies included adults.51,80,82
Quality of Included Studies and Risk of Bias
The methodologic quality (Risk of Bias) assessments for the critical outcomes of the included studies are presented in Table 3. Depending on the intervention evaluated, the overall Risk of Bias varied from high (eg, for breastfeeding and vapocoolants because of lack of blinding) to unclear (eg, for topical anesthetics and sweet-tasting solutions as there was insufficient information to make judgments) to low Risk of Bias (for acetaminophen based on a single study).
Overall Quality of Evidence and Treatment Effects
A quantitative summary of the treatment effects for available critical outcomes are described below. For several clinical questions, multiple indicators of the same critical outcome were included (eg, distress measured in the preprocedure phase of the procedure, the acute phase, or the recovery phase, or various combinations of these). For the purposes of presentation, the critical outcome indicators with the most number of participants are included. If the critical outcome was distress, the acute and the acute and recovery phases were also prioritized over other indicators of distress for presentation. Further, a qualitative summary across all critical outcomes is presented in Table 4. Information on immunogenicity (important outcome) is summarized in Table 5 while information on other important outcomes (adverse events, fidelity, feasibility, and preference) is presented in Table 6. Supporting GRADE Evidence Profiles and Summary of Findings tables (Tables, Supplemental Digital Content 1 to 14) and accompanying Forest plots (Figures, Supplemental Digital Content 1 to 14) for critically important and important outcomes are included as Supplemental Digital Content.
Should Breastfeeding be Used During Vaccine Injections in Children 0 to 2 Years?
The analgesic effect of breastfeeding was examined in 9 trials22–27,29,30,33 including data on 858 infants (0 to 12 mo). In all studies, breastfeeding was commenced immediately before vaccination and continued during and afterward. In the included trials, the comparator arm varied from the infant being swaddled in the bassinet/placed on the table24,26 held in the mother’s arms,27,29 restrained by the mother,22 given distilled water25 to a no intervention roup.23,30,33
Benefit of breastfeeding was observed for all the critical outcomes analyzed, including acute and acute plus recovery distress (Table and Figure, Supplemental Digital Content 1, http://links.lww.com/CJP/A249). The SMD was −1.78 (CI, −2.35, −1.22) for acute distress (n=792; data from 8 studies).22,23,25–27,29,30,33 For distress during the acute plus recovery phase (n=424) the SMD was −1.89 (CI, −3.19, −0.59). Considerable heterogeneity was reported for this outcome, which can be explained by the potential differences in the implementation of the intervention (breastfeeding and the control group) and age of the infant (studies included infants less than 24 h of age to up to 12 mo). There was low to very low quality of evidence due to methodologic limitations of the included studies (Table, Supplemental Digital Content 2, http://links.lww.com/CJP/A250).
If Breastfeeding is Not Used During Vaccine Injections, Should Breastfeeding be Used Before Vaccine Injections in Children 0 to 2 Years?
Two trials34,35 including 100 infants (6 wk to less than 3 mo of age) evaluated the effect of breastfeeding before vaccination. Breastfeeding ceased 2 to 60 minutes before injection.34,35 The control group included holding34 or no intervention.35 The results were mixed (Table and Figure, Supplemental Digital Content 3, http://links.lww.com/CJP/A251). Breastfeeding prevaccine injection was associated with lower acute distress: SMD −1.43 (CI, −2.14, −0.72) as well as acute plus recovery distress combined: SMD −1.47 (CI, −2.05, −0.90) (Figure, Supplemental Digital Content 4, http://links.lww.com/CJP/A252). No benefit was noted for distress recovery. The quality of evidence ranged from moderate to low quality (Table, Supplemental Digital Content 5, http://links.lww.com/CJP/A253).
Should Topical Anesthetics be Applied Before Vaccine Injections in Children 0 to 12 Years?
Fifteen studies23,34,36–46,48,49 including infants and children investigated the effect of topical anesthetics. In 10 included studies, vaccines were administered intramuscularly34,37–39,41,42,44,45,48,49; in 2 studies,43,46 they were administered subcutaneously; and in 3 studies,23,36,40 both intramuscular (IM) and SC vaccines were given. Lidocaine-prilocaine cream 5% was applied in 11 studies,23,34,36,37,39–42,44,47,48 lidocaine-prilocaine patch 5% was applied in 3 studies,38,43,44 whereas amethocaine gel 4% was applied in 1 study.46 The majority of studies (n=8) included a placebo.36,38,41–43,45,47,48 A meta-analysis of 13 studies23,34,36–39,42–46,48,49 including 1424 infants demonstrated lower levels of acute distress in the topical anesthetics group: SMD −0.91 (CI, −1.36, −0.47). Observer-rated acute distress for child was lower in the topical anesthetics group: SMD −1.13 (CI, −1.78, −0.47) in 1 study including 42 children.41 For distress during the acute plus recovery phase (n=546) the SMD was −0.68 (CI, −1.24, −0.13). The results were mixed for other indicators of distress. A meta-analysis of 3 studies38,39,41 including 269 children between 4 and 11 years showed no benefit of topical anesthetics on self-report of pain: SMD −0.29 (CI, −0.64, 0.05). However, removal of the data from 1 study with a high Risk of Bias39 altered the result in favor of topical anesthetics: SMD −0.47 (CI, −0.73, −0.21). The SMD (CI) for fear was 0.04 (CI, −0.29, 0.37; n=68) (Table and Figure, Supplemental Digital Content 6, http://links.lww.com/CJP/A254). The quality of evidence ranged from moderate to very low (Table, Supplemental Digital Content 7, http://links.lww.com/CJP/A255).
Should Topical Anesthetics be Applied Before Vaccine Injections in Adolescents Older than 12 Years and Adults?
Two studies50,51 evaluated the analgesic effects of topical anesthetics in adolescents older than 12 years and adults. Pain was lower in the topical anesthetic group: SMD −0.85 (CI, −1.38, −0.32) in the study by Taddio et al,51 whereas acute distress was not lower: SMD 0.05 (CI, −0.31, 0.41) in the study by Hansen et al50 (Table and Figure, Supplemental Digital Content 8, http://links.lww.com/CJP/A256). The quality of evidence was moderate (Table, Supplemental Digital Content 9, http://links.lww.com/CJP/A257).
Three trials,43,44,46 including 445 infants and children assessed antibody response following vaccination. Results are presented in Table 5. There was no difference in the immune response to vaccine in topical anesthetics compared with placebo group for Measles-Mumps-Rubella, diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b, and hepatitis B. In a separate study, Dohlwitz et al83 reported no effect of topical anesthetics on Bacillus-Calmette-Guérin vaccine response in 388 children.
Should Topical Anesthetics be Used Before Vaccine Injections in Combination With Breastfeeding During Vaccine Injections (Rather than Topical Anesthetics or Breastfeeding Alone) in Children 0 to 2 Years?
In one study42 including 60 infants less than 3 months of age, topical anesthetics combined with breastfeeding were compared with topical anesthetics alone during vaccine injections. Distress was the critical outcome. The results were mixed (Table and Figure, Supplemental Digital Content 10, http://links.lww.com/CJP/A258). The combination of topical anesthetics preinjection and breastfeeding during injection did not reduce distress in the acute phase of the procedure (SMD: −0.35 [CI, −0.86, 0.16]); however, distress during the acute plus recovery phase of the procedure was reduced (SMD: −0.83 [CI, −1.36, −0.30]) (Figure, Supplemental Digital Content 11, http://links.lww.com/CJP/A259). The quality of evidence was low (Table, Supplemental Digital Content 12, http://links.lww.com/CJP/A260).
Should Sucrose Solution be Given Before Vaccine Injections in Children 0 to 2 Years?
Eighteen studies including infants and young children aged 2 weeks to 48 months investigated the effects of sucrose.23,35,52–58,60–62,64–69 The concentration of sucrose ranged from 12% to 75% except for the study by Chattopadhyay et al54 where the concentration of sucrose was described as a “saturated solution.” The majority of studies (n=9) used sucrose in the concentration of 20% to 33%.35,55–58,61,62,67,69 Except for 3 studies,52,57,58 all used a volume of 2 mL. The majority of studies (n=15) administered sucrose 2 minutes before the procedure.23,35,52,53,55–58,61,62,64–67,69
In a meta-analysis including 881 infants, sucrose was associated with lower acute distress: SMD −0.37 (CI, −0.67, −0.06). Similarly, acute plus recovery distress score was lower in the sucrose group: SMD −0.76 (CI, −1.19, −0.34); n=2071 (Table and Figure, Supplemental Digital Content 13, http://links.lww.com/CJP/A261). The RR (CI) for dichotomous outcome of acute distress was 0.37 (CI, 0.2-0.69) (Figure, Supplemental Digital Content 14, http://links.lww.com/CJP/A262). The quality of evidence of included studies was high to moderate (Table, Supplemental Digital Content 15, http://links.lww.com/CJP/A263).
Benefit of sucrose in the concentration of 50% or 70% was observed for all the critical outcomes analyzed, including acute distress and acute plus recovery distress. The SMD (CI) were −0.31 (−0.61, −0.02; n=259 infants) for acute distress; and −1.43 (−2.34, −0.52; n=1006 infants) for acute plus recovery distress. Mixed results were found for sucrose in the concentration of 20% to 33%. Benefit was observed for the acute plus recovery (SMD −0.85 [CI, −1.6, −0.11]) and recovery phases (SMD −1.13 [CI: −1.89, −0.37]). There was no evidence of a benefit of sucrose in the concentration of 12% across all indicators of distress analyzed (Table and Figure, Supplemental Digital Content 13, http://links.lww.com/CJP/A261).
Should Glucose Solution be Given Before Vaccine Injections in Children 0 to 2 Years?
Six trials25,70–74 investigated the effect of glucose on vaccine injection pain in infants 12 hours to 12 months. The concentration of glucose was 25% in 3 studies,25,70,72 30% in 2 studies,73,74 and 50% in 1 study.71 The volume administered ranged from 1 to 2 mL and timing varied from 2 minutes before to immediately prior the procedure. The results were mixed (Table and Figure, Supplemental Digital Content 16, http://links.lww.com/CJP/A264). In a meta-analysis including all trials (n=818 infants), acute plus recovery distress was lower in the glucose group: SMD −0.69 (CI, −1.03, −0.35). There was no evidence of a benefit of glucose on acute distress (n=520): SMD −0.59 (CI, −1.38, 0.20) (Table and Figure, Supplemental Digital Content 16, http://links.lww.com/CJP/A264). The quality of evidence ranged from high to moderate (Table, Supplemental Digital Content 17, http://links.lww.com/CJP/A265).
Should Sweet-tasting Solutions (Sucrose, Glucose) be Used Before Vaccine Injections in Combination With Non-Nutritive Sucking (Finger/Thumb, Pacifier) During Vaccine Injections (Rather than Sweet-tasting Solutions or Non-Nutritive Sucking Alone) in Children 0 to 2 Years?
One study73 including 74 infants 3 months of age compared the effect of sweet-tasting solutions (glucose) before vaccine injection and non-nutritive sucking during vaccine injection to sweet-tasting solution or non-nutritive sucking alone. There was no evidence of benefit of the combination of glucose and non-nutritive sucking (pacifier) compared with glucose or non-nutritive sucking (pacifier) alone across all indicators of distress evaluated. For acute plus recovery, the SMD was −0.32 (CI, −0.79, 0.15) and the RR was 0.99 (CI, 0.78, 1.26) (Table and Figure, Supplemental Digital Content 18, http://links.lww.com/CJP/A266). The included study did not assess treatment fidelity with non-nutritive sucking. The quality of evidence was very low (Table, Supplemental Digital Content 19, http://links.lww.com/CJP/A267).
Should Breastfeeding and Sweet-tasting Solutions (Sucrose, Glucose) be Combined Together Before Vaccine Injections (Rather than Breastfeeding or Sweet-tasting Solutions Alone) in Children 0 to 2 Years?
One study35 including 90 infants aged less than 3 months evaluated the effect of a combination of breastfeeding and sweet-tasting solutions (sucrose) versus breastfeeding or sucrose alone. There was no evidence of a benefit of breastfeeding and sucrose versus either alone across all indicators of distress, The SMD for acute distress was 0.28 (CI, −0.34, 0.90) and for acute recovery it was 0.06 (CI, −0.37, 0.5) (Table and Figure, Supplemental Digital Content 20, http://links.lww.com/CJP/A268). The quality of evidence was low (Table, Supplemental Digital Content 21, http://links.lww.com/CJP/A269).
Should Vapocoolants be Applied Before Vaccine Injections in Children 0 to 3 Years?
One study75 including 60 infants between 6 weeks and 3 months investigated the effect of vapocoolant versus control (compressed air spray). In this study, the vapocoolant and placebo were both sprayed on the injection site for 2 to 3 seconds right before injection. Vapocoolant spray did not reduce acute distress (the only indicator of distress included in the study): SMD −0.44 (CI, −0.96, 0.07) (Table and Figure, Supplemental Digital Content 22, http://links.lww.com/CJP/A270). The quality of evidence was low (Table, Supplemental Digital Content 23, http://links.lww.com/CJP/A271).
Should Vapocoolants be Applied Before Vaccine Injections in Children Older than 3 to 17 Years?
Five trials were included in the systematic review.41,76–79 In 3 trials,41,76,77 the vapocoolant was applied to the injection site using sterile cotton ball for 10 to 20 seconds, whereas in the other 2 trials, the vapocoolant was sprayed directly on the site with application time of 3 to 7 seconds.78,79 The control group consisted of placebo spray, distraction, or a no intervention group. In a meta-analysis of 4 trials including 228 children, there was no evidence of a benefit on pain: SMD −0.38 (CI, −0.89, 0.13) (Table and Figure, Supplemental Digital Content 24, http://links.lww.com/CJP/A272). The quality of evidence was low (Table, Supplemental Digital Content 25, http://links.lww.com/CJP/A273).
Should Vapocoolants be Applied Before Vaccine Injections in Adults?
One trial80 including 185 adults was identified for inclusion in the review. A cotton ball saturated with vapocoolant or cold saline (4°C) was applied for 15 seconds in the arm. Acute pain was lower in the vapocoolant group: SMD −0.78 (CI, −1.08, −0.48) (Table and Figure, Supplemental Digital Content 26, http://links.lww.com/CJP/A274). The quality of evidence was low (Table, Supplemental Digital Content 27, http://links.lww.com/CJP/A275).
Should (Oral) Acetaminophen be Given Before Vaccine Injections in Individuals of all Ages?
No trial evaluating the effectiveness of orally administered acetaminophen for vaccine injection pain was identified, and indirect evidence was obtained from the closest related needle procedure (SC injection into an implanted intravenous port).81 The study population included 51 infants and children (1 to 18 y of age) with cancer randomized to acetaminophen or placebo 60 minutes before the procedure. All children in both the groups also received lidocaine-prilocaine patch/cream. There was no difference in pain between groups: SMD −0.64 (CI, −1.43, 0.15) (Table and Figure, Supplemental Digital Content 28, http://links.lww.com/CJP/A276). The quality of evidence was low (Table, Supplemental Digital Content 29, http://links.lww.com/CJP/A277).
Five studies84–88 evaluated the effect of prophylactic acetaminophen/paracetamol (administered at the time or just after the vaccine) on immune response to vaccination. Results from these studies are presented in Table 5. In 3 trials including 442 adults, the use of prophylactic acetaminophen did not affect the immune response to influenza vaccine as measured using the hemagglutination inhibition antibody assay.84,85,87
In the study by Doedée et al,86 use of prophylactic paracetamol was associated with a 26% reduction in antihepatitis B surface antigen antibody levels in 178 adults even though all participants achieved levels of >10.0 IU/L (considered to be seroprotective). Prophylactic paracetamol was associated with reduction in immune response to DTPa+HBV+IPV/Hib (hexavalent diphtheria-tetanus-3 component acellular pertussis-hepatitis B-inactivated poliovirus type 1, 2, and 3-Haemophilus influenzae type b); and PHiD-CV (10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate vaccine) in 459 children.88
Should (Oral) Ibuprofen be Given Before Vaccine Injections in Individuals of all Ages?
No trial was identified that evaluated orally administered ibuprofen for vaccine injection pain, and evidence was obtained from a cross-over trial that compared the effectiveness of ibuprofen 5% cream to lidocaine-prilocaine 5% cream in 20 adults undergoing venipuncture.82 Lidocaine-prilocaine 5% cream was superior to ibuprofen cream in preventing the pain associated with venipuncture: SMD 0.77 (CI, 0.06, 1.48) (Table and Figure, Supplemental Digital Content 30, http://links.lww.com/CJP/A278). The quality of evidence was very low (Table, Supplemental Digital Content 31, http://links.lww.com/CJP/A279).
No studies have evaluated the effect of oral ibuprofen on immune response to vaccines.
In this systematic review and meta-analysis, we examined the effectiveness of various pharmacological interventions and combined interventions for vaccine injection pain in individuals across the lifespan. These interventions included breastfeeding during and before vaccine injection, topical anesthetics, sweet-tasting solutions (sucrose and glucose), vapocoolants, oral analgesics (acetaminophen and ibuprofen), and the combination of 2 interventions versus 1 intervention. We found evidence for a benefit of breastfeeding, topical anesthetics, sweet-tasting solutions, and combinations of topical anesthetics and breastfeeding for reducing vaccine injection pain in infants and children. In adults, limited data demonstrate some benefit of topical anesthetics and vapocoolants.
This review found evidence of a benefit of breastfeeding. These findings are consistent with those reported in our previous review and clinical practice guideline6,8 and a Cochrane review including neonates undergoing needle procedures.89 Breastfeeding is a simple and cost-neutral intervention that can be easily adopted across vaccination settings by caregivers and health care professionals. It provides analgesia through several mechanisms including comfort (close proximity to the mother), distraction, and stimulation of the orotactile and mechnoreceptors (sucking on the breast),90 and presence of sweet-tasting substances in the mother’s milk.91–93 Exclusive breastfeeding until 6 months is recommended by the World Health Organization due to the nutritional and psychological benefits of breastfeeding; and supports breastfeeding for 2 years or beyond.94 The analgesic effects of breastfeeding further promote breastfeeding as the method of choice for infant feeding.
For the intervention to be effective, an adequate latch should be established before and continued during and after the procedure. This may not be always possible to achieve as the infant may be sleepy or not interested in feeding or not hungry and an alternative pain management strategy should be considered.
Breastfeeding Prevaccine Injection
If breastfeeding cannot be achieved during the procedure, breastfeeding prevaccine injection should be encouraged as it has some benefits on distress secondary to satiation of the infant.34,35 There are no data regarding breastfeeding before and during vaccine injections. It is possible that breastfeeding before may cause less infants to latch during the vaccine injections.
Topical anesthetics were effective in reducing pain associated with vaccine injections administered by various routes including intramuscular and subcutaneous in children and adults. This conclusion was based on 17 studies which predominantly used a comparator of placebo. In terms of mechanism, topical anesthetics temporarily inhibit the generation and transmission of pain impulses by blocking the action potentials across nerve endings located in the dermis.95 By producing dermal analgesia (topical local anesthetics penetrate to a depth of ~5 mm below the skin surface), they effectively reduce the pain from needle puncture.
Despite their proven effectiveness, topical anesthetics are not used in clinical practice as part of standard care. Topical anesthetics require an application time of 20 to 60 minutes depending on the commercial preparation that is used. This is an obstacle to clinical use. However, if there is insufficient waiting time at the clinic, they can be applied ahead of time. In 2 studies included in this review,38,48 instructions were provided to parents on how to apply the cream at home on the day of vaccination. In the study by Cassidy et al,38 54/161 (86%) of the parents applied the topical anesthetic correctly and in the study by Taddio et al,48 96/100 (96%) of the parents applied it correctly. Further, 84/96 (88%) parents reported that they could fit the application of the cream in their schedules and 87 (91%) reported that the cream was not difficult to apply.48 Our findings regarding the feasibility of home application is consistent with other studies in which topical anesthetics have been applied at home by parents before venipuncture required for minor day care surgeries (eg, endoscopy) provided optimal education was given.96,97 Two studies reported on the mean waiting time before vaccine injection in the clinics demonstrating feasibility of application of topical anesthetics onsite. In the study by Abuelkheir et al36 (Saudi Arabia), the mean waiting time before the vaccine injection was 57 minutes (SD=16.7), whereas in the study by Taddio et al98 (Canada), the mean waiting time reported was 41.6 minutes (SD=28.6). Application of the topical anesthetics while awaiting the appointment is possible if there is sufficient time. This also allows clinicians to assist in their administration (eg, ensuring they are placed in the correct anatomic location).
The cost of topical anesthetics requires some discussion. The cost of EMLA patch is ∼Canadian $12, while the cost of a 60 g tube is ∼$50 which can be used for multiple applications. At present, individuals are usually asked to absorb their cost. It is generally assumed that individuals would not pay, however, there are some data suggesting they would. In 1 included study, parents were willing to pay $11.90 for topical anesthetics for future injections.41 In another study by Ughasoro et al99 caregivers were willing to pay $8.31 for topical anesthetics which is more that the cost of the cream itself.
Several practical issues should be addressed before its adoption in clinical practice including: (1) ease of availability over the counter depending on geographic location (eg, in USA topical anesthetics are available only if prescribed); (2) time to apply the topical anesthetics while waiting for injection to be administered (wait times vary between clinics); and (3) feasibility of parental education. Therefore, helping parents plan for and advocate for proper pain management ahead of time (eg, prescriptions for topical anesthetics when availability in some geographical regions is limited and educating parents), is critical for its implementation in practice.
There is concern that concomitant use of topical anesthetics during vaccination may lead to inactivation of the vaccines or impair absorption due to its antimicrobial activity.100–103 No interference by topical local anesthetics were detected with the DPTaP-IPV-Hib, hepatitis B, or Measles-Mumps-Rubella vaccines in any of the trials that were included in this review (Table 5).43,44,46 The data are consistent with studies performed in adults undergoing Bacille-Calmette-Guérin vaccine administration.83 It is not clear whether these results with topical anesthetics can be generalized to other vaccine antigens; we suggest that testing for interactions between topical local anesthetics should be incorporated in trials evaluating new vaccine antigens.
The use of topical anesthetics was associated with transient local skin reactions such as pallor and erythema.
We found sufficient evidence of benefit from sucrose to reduce pain response during vaccination.23,35,52–58,60–62,64–69 The majority of studies used sucrose in the concentration of 20% to 33% with a typical volume of 2 mL.35,55–58,61,62,67,69 The sucrose concentrations used ranged from 12% to 75%. Also sucrose was administered 2 minutes before the procedure in majority of the studies.23,35,52,53,55–58,61,62,64–67,69
Our finding of a beneficial effect of sucrose for vaccine injection pain is consistent with results of studies involving other invasive skin-breaking procedures performed in neonates and young infants such as heel lance and venipuncture.104 The mechanism of action of sucrose is believed to include release of endogenous opioids and distraction.105
A subgroup analysis based on the concentration of sucrose demonstrated a consistent benefit of concentrations of 50% or 75% across all indicators of infant distress, whereas the results were mixed with concentrations between 20% and 33%. Sucrose in the concentration of 12% was not effective in reducing any of the distress indicators. On the basis of this analysis, sucrose in the dose of 2 mL with concentrations >20% should be used for vaccine injection pain.
Adverse events from sweet-tasting solutions such as coughing and gagging were reported in only 1 trial,58 whereas no episodes of choking or any other adverse events were reported in 2 other trials.60,64 None of these adverse events were clinically significant, as all infants recovered spontaneously within 10 seconds. More consistent documentation of the presence or absence of adverse events is recommended in future research.
The effectiveness of glucose was mixed and not as robust as sucrose. Sucrose should be the preferred sweet-tasting solution, however, if not available glucose should be considered as an alternative. Glucose solution for intravenous administration is easily available in clinical practice in resource-limited countries and is a practical alternative to sucrose for pain management. In settings where sweet-tasting solutions are not available, they can be prepared by using 1 packet of table sugar mixed with 2 teaspoonfuls of clean/sterile water; however, attention needs to be paid to the use of clean/sterile water.
Vapocoolants are volatile liquids that when applied on the skin provides transient anesthesia secondary to evaporation-induced skin cooling.106 The cold sensation may reduce pain by gating pain signals so that cold is experienced rather than pain. The other proposed mechanism is that they decrease the velocity of nerve impulse transmission across nerve fibers.107 As vapocoolants cause cooling and/or burning sensations on the skin, it can be uncomfortable for some individuals including children who may perceive it as a noxious stimulus.8
On the basis of the lack of evidence of benefit, vapocoolants cannot be recommended for use in infants and children. In a single study in adult population, vapocoolants were effective in reducing pain associated with vaccine injection.80 Vapocoolants are an attractive alternative to topical anesthetics due to the short application time (s). However, their application may be associated with discomfort because of the cold sensation that may be perceived as painful. In the included study, there was no report of discomfort from vapocoolant application. In a recent systematic review on venipuncture pain, the pain relief provided by vapocoolants was offset by the pain of their application.108 As the cold sensation may be perceived differently among individuals, their preferences should be taken into consideration when offering vapocoolants.
No trials that evaluated oral analgesics (acetaminophen or ibuprofen) for vaccination pain were identified. Evidence from other needle procedures showed no benefit of either acetaminophen or ibuprofen.81,82 More concerning is the recent data on the effect of prophylactic acetaminophen on immune response study to vaccination.86,88 The use of prophylactic paracetamol was associated with reduction in antibody levels for several vaccines evaluated including hepatitis B, DTPa+HBV+IPV/Hib, and PHiD-CV.86,88 No data on the effect of prophylactic ibuprofen on immune response was identified. Oral analgesics contain sweet-tasting solutions as flavoring agents and individuals may wish to offer them for use before vaccinations; however, sweet-tasting solutions such as sucrose and glucose should be offered instead because of the potential to interfere with the vaccine response.
Two Versus One Intervention
There was evidence of a benefit of the combination of topical anesthetics and breastfeeding.42 There were no additive benefits of combining glucose and pacifier73 or breastfeeding and sucrose.35 These data are limited to single studies with small sample sizes. In previous studies in neonates, the combination of sucrose and pacifiers has been shown to work better than either alone.109
Strengths, Limitations, and Future Research
The major strength of this review is the availability of large evidence base for some of the included interventions (eg, breastfeeding, topical anesthetics in children, and sweet-tasting solutions) and methodological rigor in terms of blinding and quality of included studies. This results in more confidence in our conclusions. In addition, a meticulous approach that included both the GRADE and Cochrane methodologies was used to conduct this systematic review and meta-analysis.
Methodologic challenges and limitations of this review include the small sample sizes for some of the included interventions (eg, vapocoolants across lifespan, topical anesthetics in adults, and oral analgesics) and limited age range of the participants. Furthermore, many of these trials were published before the Consolidated Standards of Reporting Trials (CONSORT) guidelines110 were adopted. On the basis of our review, areas for future research include: (1) evaluation of the effectiveness of expressed breast milk and bottle feeding (in babies whose parents choose to offer bottle to provide expressed breast milk or formula); (2) evaluation of the effects of topical anesthetics on immune response to newer vaccines across lifespan; (3) studies to identify the optimal dose, concentration, and timing of administration of sweet-tasting solutions; (4) additional studies on vapocoolants to confirm or refute its use in children and adults; and (5) combined interventions compared with single active intervention with the goal to reduce pain experienced to zero.
In summary, breastfeeding, topical anesthetics, and sweet-tasting solutions are effective interventions that can be used in infants, children, and adults to reduce vaccine injection pain. Despite the evidence regarding the effectiveness of these interventions for >20 years, children and adults around the world have not reaped the benefits. Rather than conducting effectiveness/efficacy studies for well-studied, effective interventions, it is time to conduct implementation science research so that the use of these interventions becomes the standard of care in clinical practice globally. Educating our consumers (children, parents, and adults undergoing vaccination) and health care providers is crucial to make these changes. There is some evidence that education of individuals can lead to increased use.111
1. World Health Organization. Global Vaccine Action Plan 2011-2020. Geneva: 2012.
2. Schechter NL, Zempsky WT, Cohen LL, et al.. Pain reduction during pediatric immunizations: evidence-based review and recommendations. Pediatrics. 2007;119:e1184–e1198.
3. Nir Y, Paz A, Sabo E, et al.. Fear of injections in young adults: prevalence and associations. Am J Trop Med Hyg. 2003;68:341–344.
4. Taddio A, Ilersich AF, Ilersich AN, et al.. From the mouth of babes: getting vaccinated doesn’t have to hurt. Can J Infect Dis Med Microbiol. 2014;25:196–200.
5. Gidudu JF, Walco GA, Taddio A, et al.. Immunization site pain: case definition and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2012;30:4558–4577.
6. Taddio A, Appleton M, Bortolussi B, et al.. Reducing the pain of childhood vaccination—an evidence-based clinical practice guideline. CMAJ. 2010;182:E843–E855.
7. Taddio A, Manley J, Potash L, et al.. Routine immunization practices: use of topical anesthetics and oral analgesics. Pediatrics. 2007;120:e637–e643.
8. Shah V, Taddio A, Reider MJ. HELPinKIDS Team. Effectiveness and tolerability of pharmacologic and combined interventions for reducing injection pain during routine childhood immunizations: systematic review and meta-analyses. Clin Ther. 2009;31:S104–S151.
9. Taddio A, McMurtry CM, Shah V, et al.. Methodology for knowledge synthesis of the management of vaccination pain and needle fear. Clin J Pain. 2015;31(10S):S12–S19.
10. Guyatt GH, Oxman AD, Schunemann HJ, et al.. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64:380–382.
11. Higgins JPT, Green S. eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration, 2011. Available at: http://www.cochrane-handbook.org
. Accessed June 14, 2015.
12. Stinson JN, Kavanagh T, Yamada J, et al.. Systematic review of the psychometric properties, interpretability and feasibility of self-report pain intensity measures for use in clinical trials in children and adolescents. Pain. 2006;125:143–157.
13. Von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children and adolescents aged 3 to 18 years. Pain. 2007;127:140–150.
14. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance form the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13.
15. Borenstein M, Hedges LV, Higgins JPT, et al.. Introduction to Meta-Analysis. West Sussex, UK: John Wiley & Sons; 2009.
16. Achenbach TM, McConaughy SH, Howell CT. Child/adolescent behavioral and emotional problems: implications of cross-informant correlations for situational specificity. Psych Bull. 1987;101:213–232.
17. Lindh V, Wiklund U, Blomquist HK, et al.. EMLA cream and oral glucose for immunization pain in 3-month-old infants. Pain. 2003;104:381–388.
18. Taddio A, Lord A, Hogan ME, et al.. A randomized controlled trial of analgesia during vaccination in adults. Vaccine. 2010;28:5365–5369.
19. Gray L, Garza E, Zageris D, et al.. Sucrose and warmth for analgesia in healthy newborns: an RCT. Pediatrics. 2015;35:e607–e614.
20. Lewkowski MD, Barr RG, Sherrad A, et al.. Effects of chewing gum on responses to routine painful procedures in children. Physiol Behav. 2003;79:257–265.
21. Taddio A, Robieux I, Koren G. Effect of lidocaine-prilocaine cream on pain from subcutaneous injection. Clin Pharm. 1992;11:347–349.
22. Abdel Razek A, El-Dein NA. Effect of breast-feeding on pain relief during infant immunization injections. Int J Nurs Pract. 2009;15:99–104.
23. Dilli D, Göker Küçük I, Dallar Y. Interventions to reduce pain during vaccination in infancy. J Pediatr. 2009;154:385–390.
24. Efe E, Ozer ZC. The use of breast-feeding for pain relief during neonatal immunization injections. Appl Nurs Res. 2007;20:10–16.
25. Goswami G, Upadhyay A, Gupta NK, et al.. Comparison of analgesic effect of direct breastfeeding, oral 25% dextrose solution and placebo during 1st DPT vaccination in healthy term infants: a randomized, placebo controlled trial. Indian Pediatr. 2013;50:649–653.
26. Iqbal A, Malik R, Siddique M, et al.. Breastfeeding for pain relief during Bacillus Calmette-Guerin (BCG) vaccination in term neonates. Pak J Med Health Sci. 2014;8:403–406.
27. Modarres M, Jazayeri A, Rahnama P, et al.. Breastfeeding and pain relief in full-term neonates during immunization injections: a clinical randomized trial. BMC Anesthesiol. 2013;13:22.
28. Moddares M, Vasegh Rahimparvar SF, Mehran A, et al.. Effects of breast feeding on pain of injection in newborns. Hayat. 2007;12:31–37.
29. Shah Ali S, Taavoni S, Haghani H, et al.. Comparison of the effect of breast sucking with being in the mothers hug on pain relieving during immunization injection. JBUMS. 2009;11:32–37.
30. Taavoni S, ShahAli S, Haghani H, et al.. Comparison the effect of breastfeeding with routine clinical procedure on pain relieving during immunization injection. J Arak Univ Med Sci. 2009;11:33–40.
31. Taavoni S, Shah-Ali S, Haghani H, et al.. Comparative study of the effect of being in mother’s hug and routine clinical procedure on neonates’ pain during immunization injection in health centers of West Tehran. Iran J Nurs. 2010;22:48–55.
33. Thomas T, Shetty AP, Bagali PV. Role of breastfeeding in pain response during injectable immunisation among infants. Nurs J India. 2011;102:184–186.
34. Achema G, Oyeleye BA, Olaogun AE. Pain relief strategies for infants taking DPT immunization in health centres. Afr J Midwifery Womens Health. 2011;5:123–127.
35. Sahebihagh MH, Hosseinzadeh M, Mohammadpourasl A, et al.. The effect of breastfeeding, oral sucrose and combination of oral sucrose and breastfeeding in infant’s pain relief during the vaccination. Iran J Nurs Midwifery Res. 2011;16:9–15.
36. Abuelkheir M, Alsourani D, Al-Eyadhy A, et al.. EMLA™ cream: a pain-relieving strategy for childhood vaccination. J Int Med Res. 2014;42:329–336.
37. Basiri-Moghadam M, Kianmehr M, Pasban-Noghabi S, et al.. Comparison of EMLA cream with rattles on reducing immunization pain in four months infants. JPMA. 2014;64:874–878.
38. Cassidy KL, Reid GJ, McGrath PJ, et al.. A randomized double-blind, placebo-controlled trial of the EMLA patch for the reduction of pain associated with intramuscular injection in four to six-year-old children. Acta Paediatr. 2001;90:1329–1336.
39. Cohen LL, Blount RL, Cohen RJ, et al.. Comparative study of distraction versus topical anesthesia for pediatric pain management during immunizations. Health Psychol. 1999;18:591–598.
40. Cohen LL, Bernard RS, McClellan CB, et al.. Topical anesthesia versus distraction for infants’ immunization distress: evaluation with 6-month follow-up. Child Health Care. 2006;35:103–121.
41. Cohen Reis E, Holubkov R. Vapocoolant spray is equally effective as EMLA cream in reducing immunization pain in school-aged children. Pediatrics. 1997;100:E5.
42. Gupta NK, Upadhyay A, Agarwal A, et al.. Randomized controlled trial of topical EMLA and breastfeeding for reducing pain during wDPT vaccination. Eur J Pediatr. 2013;172:1527–1533.
43. Halperin SA, McGrath P, Smith B, et al.. Lidocaine-prilocaine patch decreases the pain associated with the subcutaneous administration of measles-mumps-rubella vaccine but does not adversely affect the antibody response. J Pediatr. 2000;136:789–794.
44. Halperin BA, Halperin SA, McGrath P, et al.. Use of lidocaine-prilocaine patch to decrease intramuscular injection pain does not adversely affect the antibody response to diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae
type b conjugate and hepatitis B vaccines in infants from birth to six months of age. Pediatr Infect Dis J. 2002;21:399–405.
45. Kumar M. A Study of Effect of Topical Anaesthetics on Injection Pain During Immunization in Infants
[dissertation]. Bangalore, Karnataka: 2014.
46. O’Brien L, Taddio A, Ipp M, et al.. Topical 4% amethocaine gel reduces the pain of subcutaneous measles-mumps-rubella vaccination. Pediatrics. 2004;114:e720–e724.
47. O’Brien L. Relief of Measles-Mumps-Rubella Vaccination Pain Using Topical 4% Amethocaine
[dissertation]. Toronto, ON, Canada: 2004.
48. Taddio A, Nulman I, Goldbach M, et al.. Use of lidocaine-prilocaine cream for vaccination pain in infants. J Pediatr. 1994;124:643–648.
49. Uhari M. A eutectic mixture of lidocaine and prilocaine for alleviating vaccination pain in infants. Pediatrics. 1993;92:719–721.
50. Hansen BW, Sorensen PV. The EMLA cream versus placebo in MMR vaccination of older children in general practice. Ugeskr Laeger. 1993;155:2263–2265.
51. Taddio A, Nulman I, Reid E, et al.. Effect of lidocaine-prilocaine cream (EMLA™) on pain of intramuscular Fluzone™ injection. Can J Hosp Pharm. 1992;45:227–230.
52. Allen KD, White DD, Walburn JN. Sucrose as an analgesic agent for infants during immunization injections. Arch Pediatr Adolesc Med. 1996;150:270–274.
53. Barr RG, Young SN, Wright JH, et al.. “Sucrose analgesia” and diphtheria-tetanus-pertussis immunizations at 2 and 4 months. J Dev Behav Pediatr. 1995;16:220–225.
54. Chattopadhyay D, Kundu P, Gunri S, et al.. Effect of oral sucrose on pain during DPT immunization in older infants. Indian J Public Health. 2011;55:136–138.
55. Harrington JW, Logan S, Harwell C, et al.. Effective analgesia using physical interventions for infant immunizations. Pediatrics. 2012;129:815–822.
56. Harrison D, Elia S, Manias E, et al.. Sucrose and lollypops to reduce immunization pain in toddlers and young children: Two pilot randomized controlled trials. Neonat Paediatr Child Health Nurs. 2014;17:19–26.
57. Hatfield LA, Gusic ME, Dyer A-M, et al.. Analgesic properties of oral sucrose during routine immunizations at 2 and 4 months of age. Pediatrics. 2008;121:e327–e334.
58. Hatfield LA. Sucrose decreases infant biobehavioral pain response to immunizations: a randomized controlled trial. J Nurs Scholarsh. 2008a;40:219–225.
59. Hatfield LA. A Randomized Double Blind Placebo Controlled Trial Examining the Analgesic Properties of Oral Sucrose During Routine Immunizations at Two and Four Months of Age
[dissertation]. Hershey, PA: 2006.
60. Lewindon PJ, Harkness L, Lewindon N. Randomised controlled trial of sucrose by mouth for the relief of infant crying after immunisation. Arch Dis Child. 1998;78:453–456.
61. Liaw J-J, Zeng W-P, Yang L, et al.. Nonnutritive sucking and oral sucrose relieve neonatal pain during intramuscular injection of hepatitis vaccine. J Pain Symptom Manage. 2011;42:918–930.
62. Moradi F, Imani A, Keyghobadi S, et al.. Effects of intra-oral intake of different concentrations of sucrose on biobehavioral pain response to immunizations in infants. Koomesh. 2012;13:414–419.
63. Moradi F, Imani A, Keyghobadi S, et al.. Assessment of the effect of 20% oral sucrose and pain relief from hepatitis B vaccine injection in full term infants. J Zanjan Univ Med Sci Health Serv. 2012a;20:61–68.
64. Mowery BD. Effects of sucrose on immunization injection pain in Hispanic infants. Diss Abstr Int. 2008;68(11-B):7252.
65. Poulsen M. Cane sugar unsuitable for use as analgesic in paediatric vaccination [Danish]. Sygeplejersken. 2009;109:54–57.
66. Priambodo A, Julia M, Ismail D. Effect of oral sugar solution for reducing pain in infants underwent diphtheria, pertussis, tetanus (DPT) immunization: a randomized, double-blind controlled trial. Paediatr Indones. 2008;48:23–27.
67. Ramenghi LA, Webb AV, Shevlin PM, et al.. Intra-oral administration of sweet-tasting substances and infants’ crying response to immunization: a randomized, placebo-controlled trial. Biol Neonate. 2002;81:163–169.
68. Soriano Faura J, Gomez Gil A. Controlled clinical study of sucrose administration to reduce the duration of crying in infants undergoing vaccination [Spanish]. Acta Pediatr Esp. 2003;61:234–238.
69. Yilmaz G, Caylan N, Oguz M, et al.. Oral sucrose administration to reduce pain response during immunization in 16–19-month infants: a randomized, placebo-controlled trial. Eur J Pediatr. 2014;173:1527–1532.
70. Chermont AG, Falcao LFM, De Souza Silva EHL, et al.. Skin-to-skin contact and/or oral 25% dextrose for procedural pain relief for term newborn infants. Pediatrics. 2009;124:e1101–e1107.
71. Golestan M, Akhavan Karbasi S, Modares-Mosadegh M, et al.. Analgesic effects of glucose and water in neonates. Acta Med Iran. 2007;45:461–464.
72. Kassab M, Sheehy A, King M, et al.. A double-blind randomised controlled trial of 25% oral glucose for pain relief in 2-month old infants undergoing immunisation. Int J Nurs Stud. 2012;49:249–256.
73. Mörelius E, Theodorsson E, Nelson N. Stress at three-month immunization: parents’ and infants’ salivary cortisol response in relation to the use of pacifier and oral glucose. Eur J Pain. 2009;13:202–208.
74. Thyr M, Sundholm A, Teeland L, et al.. Oral glucose as an analgesic to reduce infant distress following immunization at the age of 3, 5 and 12 months. Acta Paediatr. 2007;96:233–236.
75. Maikler VE. Effects of a skin refrigerant/anesthetic and age on the pain responses of infants receiving immunizations. Res Nurs Health. 1991;14:397–403.
76. Abbott K, Fowler-Kerry S. The use of a topical refrigerant anesthetic to reduce injection pain in children. J Pain Symptom Manage. 1995;10:584–590.
77. Cohen LL, MacLaren JE, DeMore M, et al.. A randomized controlled trial of vapocoolant for pediatric immunization distress relief. Clin J Pain. 2009;25:490–494.
78. Eland JM. Minimizing pain associated with prekindergarten intramuscular injections. Issues Compr Pediatr Nurs. 1981;5:361–372.
79. Luthy KE, Beckstrand RL, Pulsipher A. Evaluation of methods to relieve parental perceptions of vaccine-associated pain and anxiety in children: a pilot study. J Pediatr Health Care. 2013;27:351–358.
80. Mawhorter S, Daugherty L, Ford A, et al.. Topical vapocoolant quickly and effectively reduces vaccine-associated pain: results of a randomized, single-blinded, placebo controlled study. J Travel Med. 2004;11:267–272.
81. Hedén L, von Essen L, Ljungman G. Effect of high-dose paracetamol on needle procedures in children with cancer—a RCT. Acta Paediatr. 2014;103:314–319.
82. Smith AJ, Eggers KA, Stacey MR. Topical ibuprofen for skin analgesia prior to venepuncture. Anaesthesia. 1996;51:495–497.
83. Dohlwitz A, Hellenberg L, Svedmyr J, et al.. No negative influence of EMLA application prior to BCG vaccination. Acta Paediatr. 1998;87:480–481.
84. Aoki FY, Yassi A, Cheang M, et al.. Effects of acetaminophen on adverse effects of influenza vaccination in health care workers. CMAJ. 1993;149:1425–1430.
85. Chernesky M, O’Neill D, Pickard L, et al.. Immunogenicity and adverse reactions on influenza vaccination in elderly patients given acetaminophen or placebo. Clin Diagn Virol. 1993;1:129–136.
86. Doedée AM, Boland GJ, Pennings JL, et al.. Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials. PLoS One. 2014;9:e98175.
87. Gross PA, Levandowski RA, Russo C, et al.. Vaccine immune response and side effects with the use of acetaminophen with influenza vaccine. Clin Diagn Lab Immunol. 1994;1:134–138.
88. Prymula R, Siegrist CA, Chlibek R, et al.. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009;374:1339–1350.
89. Shah PS, Herbozo C, Aliwas LL, et al.. Breastfeeding or breast milk for procedural pain in neonates. Cochrane Database Syst Rev. 2012;12:CD004950.
90. Gibbins S, Stevens B. Mechanisms of sucrose and non-nutritive sucking in procedural pain management in infants. Pain Res Manag. 2001;6:21–28.
91. Blass EM, Shide DJ, Zaw-Mon C, et al.. Mother as shield: differential effects of contact and nursing on pain responsivity in infant rats—evidence for nonopioid mediation. Behav Neurosci. 1995;109:342–353.
92. Gunnar MR, Fisch RO, Malone S. The effects of a pacifying stimulus on behavioral and adrenocortical responses to circumcision in the newborn. J Am Acad Child Psychiatry. 1984;23:34–38.
93. Blass EM. Milk-induced hypoalgesia in human newborns. Pediatrics. 1997;99:825–829.
94. Critch JN. Canadian Paediatric Society; Nutrition and Gastroenterology Committee. Nutrition for healthy term infants, six to 24 months: an overview. Paediatr Child Health. 2014;19:547–552.
95. Denson DD, Mazoit JXSinatra RS, Hord H, Ginsberg B, Preble LM. Physiology and pharmacology of local anesthetics. Acute Pain: Mechanisms & Management. St Louis, MO: Mosby-Year Book; 1992:124–139.
96. Guttormsen AB, Nordahl SHG, Olofsson J. Home application of EMLA cream prior to venipuncture. Is it feasible in paediatric ENT day care surgery? Int J Pediatr Otorhinolaryngol. 1995;31:47–52.
97. Koh JL, Fanurik D, Stoner J, et al.. Efficacy of parental application of eutectic mixture of local anesthetics for intravenous insertion. Pediatrics. 1999;103:e79.
98. Taddio A, Hogan ME, Gerges S, et al.. Addressing parental concerns about pain management during childhood vaccination. Is there enough time to include pain management in the ambulatory setting? Clin J Pain. 2012;28:238–242.
99. Ughasoro MD, Udem ND, Chukwudi NK, et al.. Caregivers’ willingness-to-pay for a topical anesthetic cream for minor medical procedures in children. Niger J Clin Pract. 2014;17:506–510.
100. Wimberly N, Willey S, Sullivan N, et al.. Antibacterial properties of lidocaine. Chest. 1979;76:37–40.
101. Zaidi S, Healy TE. A comparison of the antibacterial properties of six local analgesic agents. Anaesthesia. 1977;32:69–70.
102. Schmidt RM, Rosenkaranz HS. Antimicrobial activity of local anesthetics: lidocaine and procaine. J Infect Dis. 1970;121:597–607.
103. Fazly Bazaz BS, Salt WG. Local anesthetics as antimicrobial agents: structure-action considerations. Microbios. 1983;37:45–64.
104. Stevens B, Yamada J, Lee GY, et al.. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev. 2013;1:CD001069.
105. Blass EM, Watt LB. Suckling- and sucrose-induced analgesia in human newborns. Pain. 1999;83:611–623.
106. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150();917–919.
107. Ernst E, Fialka V. Ice freezes pain? A review of the clinical effectiveness of analgesic cold therapy. J Pain Symptom Manage. 1994;9:56–59.
108. Hogan ME, Smart S, Shah V, et al.. A systematic review of vapocoolants for reducing pain from venipuncture and venous cannulation in children and adults. J Emerg Med. 2014;47:736–749.
109. Elserafy FA, Alsaedi SA, Louwrens J, et al.. Oral sucrose and a pacifier for pain relief during simple procedures in preterm infants: a randomized controlled trial. Ann Saudi Med. 2009;29:184–188.
110. Schulz KF, Altman DG, Moher D. for the CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. BMC Med. 2010;8:18.
111. Pillai Riddell R, Taddio A, McMurtry CM, et al.. Process interventions for vaccine injections: systematic review of randomized Controlled trials and quasi-randomized controlled trials. Clin J Pain. 2015;31(10S):S99–S108.