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

doi:10.5409/wjcp.123652

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World Journal of Clinical Pediatrics

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2219-2808

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Clin Pediatr. Dec 9, 2026; 15(4): 123652
Published online Dec 9, 2026. doi: 10.5409/wjcp.123652

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

Paveewan Jiravisitkul, Manunya Tandhansakul, Chanikarn Thongkam, Saraiorn Thonginnetra

Paveewan Jiravisitkul, Manunya Tandhansakul, Department of Pediatrics, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok 10210, Thailand

Chanikarn Thongkam, Division of Outpatient Department, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok 10210, Thailand

Saraiorn Thonginnetra, Princess Srisavanggavadhana Faculty of Medicine, Chulabhorn Royal Academy, Bangkok 10210, Thailand

Author contributions: Jiravisitkul P and Thonginnetra S designed the research and wrote the manuscript; Jiravisitkul P, Tandhansakul M, Thongkam C, and Thonginnetra S performed the research and collected the data; Jiravisitkul P and Thonginnetra S analyzed the data; Thonginnetra S verified the underlying data and supervised the statistical analysis. All authors reviewed and approved the final manuscript.

AI contribution statement: AI tools were used solely for linguistic refinement and assistance with figure layout. ChatGPT (GPT-4 model; OpenAI, San Francisco, CA, United States) was used for English language editing to improve clarity and fluency. Claude (Anthropic, San Francisco, CA, United States) was used to generate the foundational digital layouts and structural frameworks for Figures 1, 2, and 3. No AI tool was used in the study design, data generation, statistical analysis, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors, in accordance with the guidelines of the International Committee of Medical Journal Editors and the Committee on Publication Ethics.

Supported by Chulabhorn Royal Academy through the Research Excellence Group Funding Programmed of Chulabhorn Hospital, Chulabhorn Royal Academy, No. 544/2568.

Institutional review board statement: The study protocol was approved by the Ethics Committee of Chulabhorn Royal Academy on April 11, 2025 (approval No. EC 016/2568).

Clinical trial registration statement: This study was prospectively registered with the Thai Clinical Trials Registry (https://www.thaiclinicaltrials.org) on February 2, 2025 (TCTR20250202006).

Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.

Data sharing statement: De-identified individual participant data and the study protocol are available from the corresponding author upon reasonable request, subject to institutional approval.

Corresponding author: Paveewan Jiravisitkul, MD, Principal Investigator, Department of Pediatrics, Chulabhorn Hospital, Chulabhorn Royal Academy, 906 Kamphaeng Phet 6 Road, Talat Bang Khen Subdistrict, Lak Si, Bangkok 10210, Thailand. paveewan.jir@cra.ac.th

Received: May 25, 2026
Revised: July 10, 2026
Accepted: July 28, 2026
Published online: December 9, 2026
Processing time: 114 Days and 16.6 Hours

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.

Keywords: 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.