Shortened eutectic mixture of lidocaine and prilocaine plus skin cooling for pediatric vaccination pain: A randomized non-inferiority trial

Abstract

BACKGROUND

Vaccination is a cornerstone of pediatric primary care; however, injection-site pain remains a barrier to acceptance and on-time uptake. While applying a eutectic mixture of lidocaine and prilocaine (EMLA) can reduce pain, its 30-60 minutes onset is impractical in high-volume primary-care settings. Brief skin cooling, which reduces peripheral nerve conduction, is effective within seconds and may complement a shortened EMLA application time without compromising analgesia.

AIM

To determine whether 20-minute EMLA plus 30-second ice-pack cooling is non-inferior to the standard 40-minute EMLA for pediatric vaccination pain.

METHODS

A single-center, parallel-group, open-label, randomized, controlled, non-inferiority trial was conducted with 150 children aged 4-15 years who received a quadrivalent inactivated influenza vaccine (Vaxigrip Tetra, southern-hemisphere formulation; Sanofi Pasteur, Lyon, France). The primary endpoint was the self-reported Wong-Baker FACES Pain Rating Scale score immediately after injection. The non-inferiority margin was +1.4 points (one-sided α = 0.025). An intention-to-treat analysis was performed, with a per-protocol sensitivity check.

RESULTS

All 150 children completed the follow-up (74 in the standard group and 76 in the intervention group). The adjusted mean difference in the pain score immediately after injection (intervention group minus standard group) was -0.30 points (95% confidence interval: -1.00 to 0.50). The upper limit of the 95% confidence interval was below the prespecified non-inferiority margin of +1.4 points. The median preparation time fell from 47 minutes to 27 minutes. All adverse events were grade 1, according to the Common Terminology Criteria for Adverse Events, and self-resolving. Exploratory analyses suggested that there were fewer mild events at 15 minutes in the intervention group (25.0% vs 45.9%, P = 0.010). Caregiver satisfaction was high in both groups.

CONCLUSION

The 20-minute EMLA plus brief skin-cooling regimen was non-inferior to the standard 40-minute regimen for managing pediatric vaccination pain and reduced the preparation time by a median of 20 minutes.

Key Words: Pediatric vaccination; Procedural pain; Lidocaine-prilocaine; Skin cooling; Wong-Baker FACES Pain Rating Scale; Non-inferiority trial

Core Tip: In this single-center, open-label, randomized non-inferiority trial conducted with 150 children aged 4-15 years who received a quadrivalent influenza vaccine, a 20-minute topical application of a eutectic mixture of lidocaine and prilocaine combined with 30 seconds of ice-pack skin cooling met the prespecified non-inferiority criterion for post-injection pain when compared with the standard 40-minute eutectic mixture of lidocaine and prilocaine regimen. The intervention reduced the preparation time by a median of 20 minutes. Exploratory analyses suggested fewer mild adverse events at 15 minutes, and caregiver satisfaction was high in both groups. This pragmatic, low-cost protocol is suitable for high-volume primary-care vaccination services.

INTRODUCTION

Vaccination is one of the most cost-effective public health interventions, preventing millions of deaths each year[1]. However, injection-related pain and fear remain important barriers to vaccination acceptance and on-time uptake and adherence to national immunization schedules in childhood[2,3]. Needle phobia is highly prevalent in children and is associated with vaccine hesitancy, future avoidance of injections, and a poorer healthcare experience for both the child and the caregiver[3-5]. Thus, reducing procedural pain during vaccination is a clinically and operationally important objective for pediatric primary-care services[4,6].

A eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA) is the most widely used topical anesthetic for pediatric needle procedures, and there is extensive evidence of its efficacy in infants, children, and adolescents[2,7-9]. However, the recommended 30-60-minute application time is operationally difficult to achieve in vaccination clinics with high patient volumes, and this contributes to the limited adoption and inconsistent use of the EMLA in real-world settings[7,10,11]. Therefore, there is considerable interest in developing strategies that preserve an EMLA’s analgesic efficacy while shortening the application time.

Skin cooling is a potentially complementary technique. Based on the gate-control theory of pain[12], brief cooling can reduce the peripheral nerve conduction velocity and raise the pain threshold within seconds[13]. Several trials and a systematic review have shown that ice-pack or vapocoolant skin cooling reduces injection-related pain in children and is well tolerated, although the effect sizes are variable, and cooling alone may be insufficient in younger or more anxious children[14-16].

Hence, given that both the application of an EMLA and brief skin cooling have shown efficacy in reducing injection-related pain, we aimed to determine whether combining a shorter EMLA application time with brief skin cooling is non-inferior to the standard application of an EMLA. The tested regimen, which has the potential to deliver dermal analgesia while inducing immediate sensory modulation, was designed as a practical workflow-oriented procedure that can be integrated into typical vaccination clinic scheduling. To our knowledge, such a regimen has not been evaluated in a non-inferiority trial in a real-world primary-care pediatric vaccination setting. Therefore, we conducted a randomized, controlled, non-inferiority trial to determine whether a 20-minute application of an EMLA combined with 30 seconds of ice-pack skin cooling is non-inferior to the standard 40-minute application of an EMLA for reducing pain immediately after intramuscular influenza vaccination in children aged 4-15 years.

MATERIALS AND METHODS

Reporting standards

This trial was designed and is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement for parallel-group randomized trials[17] and the CONSORT extension for non-inferiority and equivalence trials[18].

Study design and setting

We conducted a single-center, parallel-group, open-label, two-arm, randomized, controlled, non-inferiority trial with a 1:1 allocation in the pediatric outpatient vaccination clinic of Chulabhorn Hospital at Chulabhorn Royal Academy (Bangkok, Thailand). The trial was prospectively registered with the Thai Clinical Trials Registry (TCTR) on February 2, 2025 (TCTR20250202006), prior to participant enrollment, which took place from May 26, 2025 to May 31, 2025.

Participants and eligibility

We enrolled children aged 4-15 years who were scheduled to receive a single intramuscular dose of a quadrivalent inactivated influenza vaccine. The exclusion criteria were as follows: Glucose-6-phosphate dehydrogenase deficiency; allergy to lidocaine, prilocaine, or any vaccine component; a rash, eczema, or an open wound at the intended injection site; and severe cardiac arrhythmia. Written informed consent was obtained from the parent or legal guardian of each participant. In addition, age-appropriate consent was obtained from the children who understood the study procedure. Consent was obtained in accordance with the approved protocol and institutional ethics requirements.

Randomization, allocation concealment, and blinding

A computer-generated randomization sequence was prepared in advance using block randomization with a block size of four. Allocations were placed in sequentially numbered opaque sealed envelopes that were opened only after the participant had been enrolled. Because the interventions differed in application time and ice pack use, this was an open-label trial; the participants, their caregivers, and the clinical staff were aware of the group assignment. However, the data analyst was blinded to the group identity until the database was locked.

Intervention

All participants received a single 0.5-mL intramuscular dose of a quadrivalent inactivated influenza vaccine (Vaxigrip Tetra, 2025 southern-hemisphere formulation; Sanofi Pasteur, Lyon, France). Each dose was administered to the deltoid muscle by a trained study nurse using a 27-gauge, 25-mm (1-inch) needle and a standardized injection technique.

The participants assigned to group A (the standard group) were treated with 1 g of 5% EMLA cream (2.5% lidocaine and 2.5% prilocaine). This was applied to a 3 cm × 3 cm area over the deltoid and covered with a transparent occlusive dressing for 40 minutes. The cream was wiped off immediately before vaccination.

The participants assigned to group B (the intervention group) received the same dose of 5% EMLA cream; however, the cream was applied for 20-30 minutes only. The cream was then wiped off, and a single-use, pre-frozen ice pack was applied directly over the intended injection site for 30 seconds immediately before vaccination.

Outcomes

The primary endpoint for the non-inferiority analysis was the self-reported pain score recorded 10-30 seconds after needle withdrawal using the Wong-Baker FACES Pain Rating Scale[19,20]. This scale comprises six faces that are scored in two-point increments from 0 to 10. Higher scores indicate greater pain intensity. It is validated for children aged ≥ 3 years and is widely used in Thai pediatric practice. Each participant rated their pain after the assessor showed them the scale and provided standardized verbal instructions in Thai.

In addition, pain scores were recorded immediately before injection and 5 minutes after injection to allow for the characterization of the pain trajectory and to provide context for the primary endpoint. More specifically, pain at 5 minutes after injection was prespecified in the trial registration (TCTR20250202006) and was analyzed as a supportive time-point assessment. The primary endpoint for the sample size determination and primary statistical inference was the pain score recorded 10-30 seconds after injection.

The secondary outcomes were as follows: Injection-site and systemic adverse events at 5 minutes and 15 minutes post-vaccination; caregiver satisfaction; and total preparation time, defined as the interval (in minutes) from the EMLA application to the vaccine administration. All secondary outcomes were prospectively designated as exploratory and were not adjusted for multiplicity. Adverse events were assessed at 5 minutes and 15 minutes after vaccination by a trained study nurse using a standardized checklist of events (i.e., pain, swelling, bruising/ecchymosis, erythema, pruritus, and anaphylaxis). All events were graded using the Common Terminology Criteria for Adverse Events version 5.0[21]. Caregiver satisfaction was assessed using an investigator-developed questionnaire adapted from the protocol-specified satisfaction assessment. The final instrument comprised eight items scored on a four-point Likert scale (1 = strongly disagree to 4 = strongly agree), covering perceived pain control, perceived quality of the method, alignment with expectations, willingness to recommend, willingness to use again, child cooperation, and global satisfaction. Items were adapted from previously published pediatric procedural-satisfaction instruments, and face- and content-validity reviews were conducted by a panel of three pediatricians and two pediatric nurses. The instrument was pilot-tested by 15 caregivers prior to trial enrollment to refine the wording. The questionnaire has not undergone formal psychometric validation (factor analysis, criterion validity); therefore, the satisfaction findings should be considered exploratory.

Sample size calculation

The sample size was calculated for the primary non-inferiority analysis of the mean Wong-Baker FACES Pain Rating Scale scores immediately after injection. The non-inferiority margin (Δ) was prespecified as +1.4 points, derived from published estimates of the minimum clinically important difference (MCID) on pediatric self-reporting pain scales[22,23]. With a common SD of 2.0, a one-sided α of 0.025, and 80% power, 64 children per group (n = 128) were required to demonstrate non-inferiority[24,25]. The minimum sample size was increased to 136 participants to allow for approximately 10% attrition. To improve the precision and maintain the robustness of the results against protocol deviations, 150 children were enrolled within the planned recruitment window. The database was then locked, without interim outcome review. Data from all 150 participants were analyzed.

Statistical analysis

An intention-to-treat (ITT) analysis was performed, with a per-protocol sensitivity analysis conducted as a robustness check. Continuous variables are presented as mean ± SD or median [interquartile range (IQR)] values according to distribution, and categorical variables are presented as n (%).

The primary analysis utilized a linear mixed-effects model featuring random participant intercepts and fixed effects for group, time point, and their interaction. Adjusted mean differences are presented as group B scores minus group A scores. Given that lower Wong-Baker FACES Pain Rating Scale scores indicate less pain, a negative adjusted mean difference value implied that the participants in group B experienced less pain than those in group A. The group B protocol was deemed non-inferior to the group A protocol if the upper boundary of the two-sided 95% confidence interval (CI) for the adjusted mean difference (group B minus group A) immediately after injection was below the prespecified margin of +1.4 points (equivalent to a one-sided α of 0.025).

For the secondary endpoints, the proportions of adverse events at 5 minutes and 15 minutes were compared between groups using Fisher’s exact test. The relative risk (RR) estimates with 95%CIs are presented. Caregiver satisfaction scores were compared using the Mann-Whitney U test. Exploratory logistic regression was used to identify characteristics associated with any pain (Wong-Baker Pain Rating Scale score ≥ 1) immediately and 5 minutes after injection. Variables with a univariable P < 0.20 were entered into a multivariable model.

P-values are reported to three decimal places. Analyses were performed using R version 4.3 (R Foundation for Statistical Computing, Vienna, Austria). The statistical analysis plan was reviewed by an independent biostatistician prior to the database being locked.

RESULTS

Participant recruitment and flow

From May 26, 2025 to May 31, 2025, 150 children were recruited and randomized into two groups: 74 into group A (the standard group) and 76 into group B (the intervention group). All 150 participants completed the follow-up and were included in the ITT analysis. Three participants in group A had minor protocol deviations (EMLA application < 35 minutes) and were excluded from the per-protocol sensitivity analysis. The participant flow is shown in Figure 1.

Figure 1 Consolidated Standards of Reporting Trials flow diagram showing participant enrollment, allocation, follow-up, and analysis. A total of 150 children were recruited and randomized into two groups: 74 were allocated to group A and received a eutectic mixture of lidocaine and prilocaine (EMLA) for 40 minutes, and 76 were allocated to group B and received the EMLA for 20 minutes plus skin cooling for 30 seconds. All participants completed the follow-up and were included in the intention-to-treat analysis. Three participants in group A were excluded from the per-protocol analysis due to minor protocol deviations (EMLA application duration shorter than the predefined per-protocol threshold). EMLA: Eutectic mixture of lidocaine and prilocaine; ITT: Intention-to-treat. Claude (Anthropic, San Francisco, CA, United States) was used to generate the foundational digital layouts and structural frameworks for this figure.

Baseline characteristics

The participants’ demographic and clinical characteristics were balanced between the groups at baseline (Table 1). The median age was approximately 8.5 years in both groups, and the prevalence of a pre-existing fear of needles was similar between the groups (group A: 35.1% vs group B: 40.8%).

Table 1 Baseline demographic and clinical characteristics of participants (intention-to-treat population, n = 150), n (%)/median (interquartile range).

Characteristic	Group A: EMLA 40 minutes (n = 74)	Group B: EMLA 20 minutes + cooling (n = 76)	P value
Child characteristics
Age (year)	8.50 (6.33-10.67)	8.46 (6.25-10.46)	0.870
Male sex	27 (36.5)	30 (39.5)	0.830
Weight (kg)	26.00 (20.62-42.75)	25.35 (20.00-39.25)	0.680
Height (cm)	127.50 (116.00-149.25)	128.25 (117.75-138.12)	0.970
BMI (kg/m2)	16.59 (14.49-19.62)	15.48 (14.18-18.26)	0.270
Overweight or obese	21 (28.4)	17 (22.4)	0.510
Obese	12 (16.2)	10 (13.2)	0.770
Allergy1	4 (5.4)	5 (6.6)	> 0.999
Underlying condition2	18 (24.3)	21 (27.6)	0.780
Fear of needles	26 (35.1)	31 (40.8)	0.590
Family characteristics
Parental report of fear of needles	8 (10.8)	11 (14.5)	0.670
Parent’s education ≥ Bachelor’s degree	67 (90.5)	63 (82.9)	0.260
Number of siblings	2.0 (2.0-2.0)	2.0 (1.0-2.0)	0.520
Caregiver present at injection	62 (83.8)	66 (86.8)	0.770

¹Allergy includes parental report of allergy to drug (e.g., cefaclor, amoxicillin), seafood, cow’s milk, egg, or mixed allergens.

²Underlying conditions include asthma, atopic dermatitis, chronic eczema, allergic rhinitis, congenital heart disease, attention-deficit/hyperactivity disorder, obstructive sleep apnoea, thalassaemia or single kidney.

P values are from Mann-Whitney U tests for continuous variables and Fisher’s exact tests for categorical variables. EMLA: Eutectic mixture of lidocaine and prilocaine; BMI: Body mass index.

Primary outcome: Pain immediately after injection

The mean pain scores at the three assessed time points are shown in Figure 2. In the linear mixed-effects model, the adjusted mean difference (group B minus group A) in the pain score immediately after injection was -0.30 points (95%CI: -1.00 to 0.50). Given that the upper limit of the 95%CI was below the prespecified non-inferiority margin of +1.4 points, the criterion for non-inferiority was satisfied. The per-protocol analysis (n = 147) results were consistent with those of the ITT analysis (adjusted mean difference of -0.27 points, 95%CI: -1.07 to 0.53). The results for all three time points are shown in Table 2 and Figure 3.

Figure 2 Mean Wong-Baker FACES Pain Rating Scale scores over time by treatment group. Pain scores were recorded before injection, immediately after injection, and 5 minutes after injection. The solid lines represent the mean pain scores for each group, and the shaded bands represent the 95% confidence intervals. The participants in group A received a eutectic mixture of lidocaine and prilocaine for 40 minutes, and those in group B received the eutectic mixture of lidocaine and prilocaine for 20 minutes plus skin cooling for 30 seconds. EMLA: Eutectic mixture of lidocaine and prilocaine. Claude (Anthropic, San Francisco, CA, United States) was used to generate the foundational digital layouts and structural frameworks for this figure.

Figure 3 Non-inferiority forest plot of adjusted mean differences in Wong-Baker FACES Pain Rating Scale scores between the groups. Estimates are presented as adjusted mean differences (group B minus group A), with corresponding 95% confidence intervals. Negative values indicate that the participants who received the eutectic mixture of lidocaine and prilocaine for 20 minutes plus skin cooling experienced less pain than those who received the eutectic mixture of lidocaine and prilocaine for 40 minutes. The dashed vertical line represents the prespecified non-inferiority margin of +1.4. Non-inferiority was confirmed when the upper boundary of the 95% confidence interval was below the prespecified margin. CI: Confidence interval. Claude (Anthropic, San Francisco, CA, United States) was used to generate the foundational digital layouts and structural frameworks for this figure.

Table 2 Wong-Baker FACES Pain Rating Scale scores and non-inferiority analysis at each assessment time point (linear mixed-effects model, intention-to-treat population, n = 150), mean ± SD.

Time point	Group A	Group B	Adjusted difference (B-A)	95%CI	Non-inferiority
Before injection	0.89 ± 1.37	0.95 ± 2.08	+0.07	-0.70 to +0.80	Met
Immediately after injection (primary)	2.73 ± 2.66	2.42 ± 3.03	-0.30	-1.00 to +0.50	Met
5 minutes after injection	2.00 ± 2.20	1.76 ± 2.29	-0.22	-1.00 to +0.50	Met

Adjusted mean differences are presented as group B minus group A; because lower Wong-Baker FACES scores indicate less pain, negative values favour group B. Non-inferiority was concluded if the upper bound of the two-sided 95% confidence interval lay below the prespecified margin of Δ = +1.4 points (equivalent to a one-sided α of 0.025). The model included a random intercept per participant and fixed effects for group, time point and their interaction. CI: Confidence interval.

Secondary outcomes

The median total preparation time (from EMLA application to vaccine administration) was 47 minutes (IQR: 42-53) in group A and 27 minutes (IQR: 25-30) in group B. This indicated that there was a median saving of 20 minutes (approximately 43%). The observed adverse events were uniformly mild (Common Terminology Criteria for Adverse Events grade 1) and self-limiting in both groups (Table 3). At 5 minutes, the overall incidence of any adverse event was 70.3% in group A and 56.6% in group B (RR: 0.81, 95%CI: 0.63-1.03; P = 0.092, Fisher’s exact test). At 15 minutes, the overall incidence was lower in group B than in group A (25.0% vs 45.9%; RR: 0.54, 95%CI: 0.34-0.86; P = 0.010), and less residual pain was reported in group B at 15 minutes (17.1% vs 31.1%; RR: 0.55, 95%CI: 0.30-1.00; P = 0.056). No anaphylaxis or serious adverse events were observed.

Table 3 Adverse events at 5 minutes and 15 minutes after vaccination (intention-to-treat population), n (%).

Adverse event (CTCAE v5.0, grade 1 unless noted)	Group A	Group B	Risk ratio (B/A), 95%CI	P value
At 5 minutes after injection
Pain	42 (56.8)	39 (51.3)	0.90 (0.67-1.22)	0.517
Swelling	0 (0.0)	1 (1.3)	Not estimable	> 0.999
Bruising/ecchymosis	0 (0.0)	0 (0.0)	Not estimable	> 0.999
Erythema	9 (12.2)	4 (5.3)	0.43 (0.14-1.34)	0.156
Pruritus	13 (17.6)	6 (7.9)	0.45 (0.18-1.12)	0.089
Anaphylaxis	0 (0.0)	0 (0.0)	Not estimable	> 0.999
Any event	52 (70.3)	43 (56.6)	0.81 (0.63-1.03)	0.092
At 15 minutes after injection
Pain	23 (31.1)	13 (17.1)	0.55 (0.30-1.00)	0.056
Swelling	1 (1.4)	2 (2.6)	1.95 (0.18-21.02)	> 0.999
Bruising/ecchymosis	1 (1.4)	1 (1.3)	0.97 (0.06-15.28)	> 0.999
Erythema	12 (16.2)	7 (9.2)	0.57 (0.24-1.36)	0.227
Pruritus	7 (9.5)	3 (3.9)	0.42 (0.11-1.55)	0.206
Anaphylaxis	0 (0.0)	0 (0.0)	Not estimable	> 0.999
Swelling and erythema combined	1 (1.4)	2 (2.6)	1.95 (0.18-21.02)	> 0.999
Any event	34 (45.9)	19 (25.0)	0.54 (0.34-0.86)	0.010

P values from Fisher’s exact tests. Risk ratios are presented as group B/group A with 95% confidence intervals calculated by the log-normal approximation; values below 1.00 indicate a lower risk in group B. Risk ratios are not estimable when one or both cells contain zero events. All adverse events were Common Terminology Criteria for Adverse Events grade 1 (mild) and self-resolving. CTCAE: Common Terminology Criteria for Adverse Events; CI: Confidence interval.

The level of caregiver satisfaction was high in both groups: The median total satisfaction score (maximum: 32) was 31 (IQR: 29-32) in group A and 32 (IQR: 30-32) in group B (P = 0.180). Two items - perceived quality of pain reduction and alignment with expectations - showed higher scores in group B (item-level P < 0.05); all other items were scored similarly between the groups.

Exploratory analysis of factors associated with pain

In a prespecified exploratory analysis (Table 4), the binary outcome was “any pain” (Wong-Baker Pain Rating Scale score ≥ 1) vs “no pain” (score = 0). A pre-existing fear of needles was independently associated with any pain immediately after injection (adjusted odds ratio of 0.39 for “not afraid” vs “afraid”; 95%CI: 0.19-0.82; P = 0.012). Younger age showed an association in the univariable analysis (P = 0.020) but not after adjustment. No factor was independently associated with “any pain” at 5 minutes after injection. A detailed description of the pain scores by category at each time point is provided in Supplementary Table 1. It is important to note that this analysis was descriptive in nature and was not used to support the primary non-inferiority conclusion.

Table 4 Univariable and multivariable analyses of factors associated with any pain (Wong-Baker score ≥ 1) immediately after injection and at 5 minutes after injection.

Time point	Variable	Univariable P value	Multivariable OR (95%CI)	Multivariable P value
Immediately after injection	Younger age (per 1-year decrease)	0.020	1.10 (0.96-1.26)	0.180
	Fear of needles (not afraid vs afraid)	0.010	0.39 (0.19-0.82)	0.012
5 minutes after injection	BMI z-score -1.5 to -3 (underweight)	0.050	0.38 (0.12-1.19)	0.100
	Parental education = high school (vs Bachelor)	0.040	0.37 (0.09-1.48)	0.160
	Number of siblings (greater)	0.030	0.61 (0.32-1.16)	0.130

Logistic regression of any pain (Wong-Baker score ≥ 1) vs no pain (score 0). Variables with univariable P < 0.20 were entered into the multivariable model. OR: Odds ratio; CI: Confidence interval; BMI: Body mass index.

DISCUSSION

In this single-center, parallel-group, randomized, non-inferiority trial conducted with 150 children aged 4-15 years who received a quadrivalent influenza vaccine, a shortened EMLA application time combined with brief skin cooling met the prespecified non-inferiority criterion for the primary endpoint (i.e., pain immediately after injection), with supportive findings at the pre-injection and 5-minute post-injection time points. The upper boundary of the two-sided 95%CI for the adjusted mean difference (group B minus group A) was below the prespecified non-inferiority margin of +1.4 points on the Wong-Baker FACES Pain Rating Scale. Caregiver satisfaction was high in both groups, adverse events were uniformly mild, and the shortened protocol reduced the total preparation time by a median of 20 minutes (43%).

Biological plausibility of the pain outcomes

Injection-related pain is brief and predominantly superficial, and it is biologically plausible that the participants in group B experienced less pain than those in group A. Brief skin cooling lowers peripheral nociceptor activity and slows nerve conduction within seconds[12,13]. For example, Algafly and George[13] showed that the dermal temperature affects nerve conduction in a musculoskeletal cryotherapy context (in the ankle). As such, skin cooling would have complemented the dermal analgesia delivered by the EMLA, which takes effect after 20 minutes and deepens with longer application[26]. The 20-minute application period used in group B is within the EMLA’s effective onset window, while the ice-pack cooling provided fast-onset sensory modulation at the moment of injection. The 30-second cooling duration used in group B was chosen to minimize discomfort and to avoid extending the pre-injection workflow rather than to achieve a specific dermal temperature threshold. The trial was not designed to evaluate the analgesic contribution of the cooling component, which may be increased through a longer cooling time (e.g., 3-5 minutes). Generating mechanistic proof of an additive or synergistic effect was also beyond the scope of this trial.

Our findings are consistent with those of other pediatric trials and meta-analyses showing that an EMLA and cooling each reduce injection pain[7-9,15,16]. They also extend prior work by demonstrating that the two modalities can be combined in a real-world primary-care setting to induce effective analgesia.

Operational implications for primary-care vaccination services

The findings of this trial have clinically important operational implications. The total preparation time was reduced by approximately 20 minutes in the intervention group [group B median preparation time: 27 minutes (IQR: 25-30)]. Thus, we met our operational target of reducing the time from EMLA application to vaccine administration to approximately 25-30 minutes, aligning the interval with the scheduling windows often used in high-volume pediatric vaccination clinics. In a typical pediatric vaccination clinic, this translates into substantial gains in throughput, reduced waiting, and a lower opportunity cost for caregivers. In addition, the intervention is easy to implement and uses inexpensive, widely available consumables (5% EMLA cream and single-use ice packs), supporting its scalability in resource-limited settings.

Clinical acceptability of the non-inferiority margin

On the six-face Wong-Baker FACES Pain Rating Scale, a non-inferiority margin of +1.4 points corresponds to approximately one face (each face represents a two-point increment) and is within published estimates of the MCID for pediatric self-reported pain scales[22,23]. Because the primary aim of the trial was to demonstrate that a shortened regimen is not meaningfully worse than the standard regimen, a margin was chosen that reflects a between-group difference that a pediatrician or caregiver would be unlikely to consider clinically important when weighed against a 20-minute reduction in preparation time and the operational gains described above. Therefore, a difference equal to or below this margin was deemed clinically acceptable a priori and unlikely to change routine clinical decisions or caregiver acceptance of the shortened regimen in high-volume primary-care vaccination services.

Adverse events and safety

All adverse events recorded in both arms were mild and transient. The lower incidence of any adverse event at 15 minutes in group B was driven mainly by lower rates of residual pain and pruritus, consistent with the shorter dermal exposure to lidocaine-prilocaine[27].

This trial was not designed to assign causality to individual adverse events, and adverse-event attribution in a combined-intervention trial is inherently uncertain. Local pain immediately after injection was considered most plausibly procedure-related, whereas erythema, pruritus, and other local skin changes may have reflected EMLA exposure, cooling-induced vasoreactivity, mechanical trauma from the injection, or a combination of these factors.

The combined regimen may be a safer alternative to cooling or EMLA application alone. Including the EMLA provides dermal analgesia that lasts beyond that induced by the brief cooling, while the transient counter stimulation provided by the cooling at the moment of injection helps to reduce dermal exposure to lidocaine-prilocaine. As multiplicity was not adjusted for secondary outcomes, the between-group differences should be interpreted as exploratory and hypothesis-generating data, and not as proving causality or superiority over ice-only treatment, which was not evaluated in this trial.

Caregiver satisfaction

Although overall satisfaction did not differ significantly between the groups, two items - perceived quality of pain reduction and alignment with expectations - were rated higher in group B. This may reflect that the caregivers perceived the protocol to be more modern and efficient. Caregiver experience is itself a determinant of future vaccination adherence[5], and protocols that combine pain reduction with operational efficiency may meaningfully improve uptake.

Factors associated with pain perception

A pre-existing fear of needles was the only factor independently associated with any pain immediately after injection in our cohort, consistent with the well-described contributions of anticipatory anxiety, prior procedural memory, and individual behavioral factors to pediatric procedural pain[4,28,29]. Targeted non-pharmacological co-interventions (e.g., distraction, parental coaching, age-appropriate preparation) may further reduce pain in this subgroup[4,6,28].

Future perspectives

Our findings warrant further investigation. First, future studies should triangulate self-reported pain with objective and/or behavioral indicators, such as heart rate, crying duration, facial coding, and skin conductance response, to reduce reliance on self-reporting and to strengthen inferences in pediatric procedural-pain trials. This could include using wearable devices that monitor physiological parameters and digitally measuring objective pain indicators. Second, the safety and efficacy of the intervention should be evaluated in other routine pediatric vaccinations (e.g., diphtheria, tetanus, and acellular pertussis, human papillomavirus, and coronavirus disease 2019 vaccination), particularly those in which the injection volume, administration route, and reactogenicity profile may differ, and across broader age ranges to establish external validity. Third, factorial or multi-arm dose-response trials comparing the standard 40-minute EMLA application, a 20-minute EMLA application alone, cooling alone, and the combined regimen are needed to determine the independent and incremental analgesic contribution of each component and the optimal cooling duration. Finally, a stratified approach should be used when children with a fear of needles are included in future studies.

Strengths and limitations

The strengths of this trial include its prospective registration, prespecified non-inferiority margin grounded in published estimates of the MCID[22,23], complete follow-up of all 150 randomized participants, prespecified ITT and per-protocol analyses, blinded statistical analysis, use of a validated pediatric self-reporting pain scale[19,20], and direct relevance to high-volume primary-care vaccination services. The prospective registration, prespecified non-inferiority margin, ITT analysis with a per-protocol sensitivity check, blinded outcome analysis, and reporting according to the CONSORT 2010 statement[17] and its extension for non-inferiority and equivalence trials[18] together provide a methodological framework consistent with contemporary standards for pragmatic pediatric non-inferiority trials.

Several limitations should be noted. First, the trial was conducted in a single urban Thai tertiary pediatric vaccination clinic, which may limit the generalizability of the findings to other settings. Second, because the primary outcome was child self-reported pain and the interventions were visibly different, the open-label design may have introduced expectation or contextual-cue bias. During the consent process, parents/legal guardians and children able to provide assent were informed that the trial compared two topical pain-reduction approaches for vaccination; however, they were not informed that either regimen was expected to be superior. After allocation, participants, caregivers, and clinical staff were aware of the assigned regimen because the interventions differed in application time and ice-pack use. Although allocation was concealed until enrolment, standardized neutral instructions were used for pain-score assessment, and the statistical analysis was performed blinded to group identity, prior beliefs about cooling or topical anesthesia, visible ice-pack use, and different waiting times may have influenced self-reported pain scores in either direction. The open-label design also carries an inherent risk of performance and detection bias, although the use of a validated self-reporting scale mitigate this risk. Additionally, randomization using a fixed block size of four in an open-label trial could, in principle, have allowed staff to anticipate the final allocation within a block; however, sequentially numbered opaque sealed envelopes were opened only after consent and enrollment to preserve allocation concealment. Third, the primary outcome relied solely on self-reported pain. Objective physiological or behavioral pain indicators should be included in future studies. Fourth, the caregiver satisfaction instrument has not undergone formal psychometric validation; therefore, the satisfaction findings are exploratory. Fifth, follow-up was restricted to the 15-minute in-clinic observation window. Hence, local and systemic adverse events that occurred after this time were not evaluated, nor was the longer-term tolerability of repeat exposure. Sixth, the trial did not include a 20-minute EMLA-only arm or a cooling-only arm. Therefore, the independent contributions of these components cannot be determined, and factorial or multi-arm dose-response studies are required. Seventh, only intramuscular delivery of an influenza vaccine to children aged 4-15 years was assessed; hence, the applicability of our findings to other vaccines, age groups, and routes of administration is uncertain. Although anxiety-related measures were considered during early protocol development, the evaluation of anxiety-related data was not included in the prespecified analysis plan, such data were not collected consistently, and anxiety-related outcomes are not reported. Finally, secondary outcomes were not adjusted for multiplicity, and any between-group differences should be interpreted as hypothesis-generating data.

CONCLUSION

A shortened EMLA application (20 minutes) combined with brief skin cooling (30 seconds) was non-inferior to the standard 40-minute EMLA regimen for pain management during pediatric intramuscular influenza vaccination. The intervention also reduced the total preparation time by a median of 20 minutes and was associated with uniformly mild adverse events and high caregiver satisfaction. This practical, low-cost regimen may be suitable for high-volume primary-care pediatric vaccination services.

ACKNOWLEDGEMENTS

We thank all participants and their caregivers, the research nurses, and the support staff in the Chulabhorn Hospital pediatric vaccination clinic for their dedication to the trial.