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. 2026 Mar 12;185(4):176. doi: 10.1007/s00431-026-06826-5

The use of the S-Caine patch is safe and feasible in children younger than three: a nonrandomised clinical trial

Britt Anciaux 1,✉, Katrien Lanckmans 2, Ronald Buyl 3, Tom De Potter 4, Gerlant van Berlaer 5,6,7
PMCID: PMC12982313  PMID: 41817881

Abstract

Effective pain control in infants and toddlers is challenging, with limited data on topical anaesthetic safety. This study evaluates the safety and feasibility of a single S-Caine patch, a eutectic 70 mg lidocaine/70 mg tetracaine mixture with heat-assisted delivery, in children under 3 years. In this nonrandomised clinical trial (2019–2024) at a single tertiary paediatric centre, 67 of 106 eligible children under 3 years (median 0.55 years [IQR, 0.13–1.09]; range 3 days–3 years; 58% male) with arterial or central venous catheters received a single S-Caine patch applied for 30 min. Primary outcomes were safety, measured by plasma lidocaine concentrations (Cmax) versus a 0.100 mg/L safety threshold, adverse events monitoring, and feasibility assessed by Likert scales. Secondary outcomes included subgroup analyses by demographic and procedural factors. Median plasma lidocaine concentrations at − 15, 15, 30, 60, 120, and 240 min were < 0.010, < 0.010, 0.018, 0.020, 0.016, and 0.013 mg/L, respectively. Median Cmax was 0.025 [0.014–0.038] mg/L, remaining well below the predefined safety threshold across all subgroups (p < 0.001). Two patients exceeded the threshold (0.270 and 0.110 mg/L) without clinical effects. Minor adverse events occurred in 49 patients (73%): exclusively transient local erythema; resolving or decreasing within 30 min. Feasibility was excellent (≥ 4/5) in 87% at application and 82% at removal. Conclusion: In this clinical trial including 67 children, the S-Caine patch was safe and feasible for use in patients under three, with plasma lidocaine concentrations well below strict clinically relevant thresholds and adverse events only occurring locally, supporting its role as a non-invasive analgesic for procedural pain. Future studies are needed to confirm safety in larger paediatric populations. Clinical Trial Registration: EU Clinical Trials Register, EudraCT Number 2019–002094-55, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-002094-55/BE.

What is Known:

• Procedural pain management in young children is challenging, as current options are often invasive, distressing, or carry systemic side effects. Safe, effective, and non-invasive analgesic strategies are limited, particularly for infants and toddlers undergoing common procedures.

What is New:

• The S-Caine patch provides a safe, non-invasive analgesic option for children under three, with plasma lidocaine levels well below strict safety thresholds and only minor transient local reactions, improving procedural comfort and reducing reliance on systemic pain interventions.

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Supplementary Information

The online version contains supplementary material available at 10.1007/s00431-026-06826-5.

Keywords: Pain management; Anaesthetics, Local; Lidocaine; Pharmacokinetics; Safety; Feasibility

Introduction

When children become patients, they frequently undergo painful procedures such as cannulation, blood sampling, and other punctures through sensitive skin [1, 2]. These are particularly distressing in young children, especially in the emergency department (ED) or paediatric intensive care unit (PICU), where mechanically ventilated patients experience frequent painful interventions [3]. Despite the importance of adequate pain management, clinicians still underestimate pain [1, 4, 5]. Ignoring pain perception leads to negative short- and long-term effects on the child’s outcomes, development, and behaviour (e.g. heightened pain sensitivity, poorer recovery, increased anxiety with future procedures) [6, 7]. Over the past decades, improved recognition has encouraged the use of both pharmacologic and nonpharmacologic strategies [8].

Topical anaesthetics such as liposomal lidocaine, tetracaine, or lidocaine/prilocaine eutectic mixtures (with melting points lower than individual components) provide non-invasive alternatives to injectable anaesthesia [9]. However, their use is limited by delayed onset, restricted absorption, and local side effects [10–12]. These challenges are particularly relevant in infants and toddlers, where pharmacokinetic data remain scarce, making effective pain management a persistent challenge. In this group, lidocaine/prilocaine cream (EMLA® 5%) and tetracaine gel (amethocaine 4%, Ametop®) are most used, yet trials and meta-analyses show inconsistent results regarding efficacy, onset, and cost [4, 9, 13–15]. The ideal topical anaesthetic would combine safety, rapid onset, prolonged duration, and ease of use [1].

The lidocaine/tetracaine patch (Synera®/Rapydan®) contains 70 mg of each agent and employs Controlled Heat-Assisted Drug Delivery (CHADD) technology, warming the skin to 39–41 °C to enhance absorption and vasodilation [9, 10, 16–20]. Compared with EMLA®, it provides faster onset (≤ 30 min), longer duration (120 min), and deeper anaesthesia (6.8 mm) [9, 11, 21–23]. It also reduces pain more effectively than placebo (59% vs. 20%) [24] and outperforms EMLA® in pain incidence (12% vs. 46%) [25] and first-attempt cannulation success (92.4% vs. 85%) [26].

Safety depends on pharmacokinetics and toxicity. Absorption varies with dose, skin integrity, and application time; in older children, up to two 30-min applications per 24 h are recommended [27]. Lidocaine peaks within 2 h, higher with heated than unheated patches, though prolonged use beyond 4 h does not increase systemic exposure [17]. Lidocaine is hepatically metabolised to monoethylglycinexylidide (MEGX), with renal clearance reduced in infants [11, 27, 28]. Half-life averages 1.8 h but may reach 12 h with hepatic impairment [29]. Toxicity—such as central nervous system symptoms, cardiac depression, and arrhythmias—usually occurs above 5 mg/L in adults, but in infants, CNS effects may develop—according to one author—at 1 mg/L, due to immature metabolism, reduced protein binding, and higher surface-to-weight ratio, although no case was reported [28–30]. A single S-Caine patch is unlikely to cause systemic toxicity, but multiple patches increase risk [31]. As analgesic efficacy is a pharmacodynamic effect mediated by sodium channel blockade, efficacy can be extrapolated from adults and older children to younger paediatric populations, whereas safety requires direct pharmacokinetic evaluation [32].

Tetracaine data are limited, because of rapid hydrolysis and instability [26, 33]. Systemic toxicity is rare, with isolated cases reported [34] but has not been consistently observed in children older than three [18, 28, 35, 36].

Due to the lack of data, the use of the S-Caine patch in children under 3 years is currently not recommended [31]. This study aims to evaluate its safety and feasibility in this age group.

Methods

Participants

This prospective, open-label, nonrandomised, single-arm, interventional pharmacokinetic study was conducted from October 2019 to November 2024 at the Department of Paediatrics and PICU of UZ Brussel, Belgium. Hospitalised children under 3 years of age, with stable vital signs, and in whom a central catheter was placed as part of standard clinical care, were eligible for inclusion. The list of inclusion/exclusion criteria can be found in Table S1.

Data collection and measurements

After confirming eligibility and obtaining written informed consent, a single S-Caine patch was applied for 30 min to intact skin. Localisations of the patch application corresponded to the places where punctures would normally be performed, excluding the nappy area due to concerns of excessive parabens penetration in immature skin [37]. Patient and outcome data were recorded using registration forms and securely stored in REDCap version 13.3.5 (Vanderbilt University, Nashville, TN, USA).

Lidocaine plasma concentrations were measured at six predefined time points via central catheters: 15 min before application of the patch (t−15), 15 min after application (t15), at patch removal after 30 min (t30), and at 60 (t60), 120 (t120), and 240 (t240) min (Table S2). Blood samples (Li-heparin) were centrifuged at 3000 rpm for 10 min, and plasma stored at − 20 °C until analysis. Lidocaine was stable for 48 h at room temperature [38]. Quantification was conducted at the BELAC-accredited UZ Brussel laboratory using a validated liquid chromatography (LC) method with photodiode array detection (PDA), with a lower limit of quantification (LLOQ) of 0.010 mg/L [38]. Lidocaine identity was confirmed by UV spectrum matching. Precision of this technique, expressed as coefficient of variation, was 6.3% at 0.286 mg/L and 4.1% at 0.072 mg/L, with lower percentages indicating higher measurement reproducibility.

Safety monitoring included predefined thresholds: if concentrations exceeded 0.100 mg/L, the treating physician was notified; participation was discontinued at 0.500 mg/L. Enrolment of new participants would be halted if ≥ 1.000 mg/L was reached in any subject. Lidocaine concentrations were disclosed to investigators only after inclusion and were accessible solely within restricted medical patient records.

Outcomes

Primary outcomes were safety and feasibility. Safety was assessed by plotting lidocaine plasma concentrations (y-axis) over time (x-axis) to visualise the pharmacokinetic profile and identify potential outliers, i.e. values exceeding the predefined safety threshold of 0.100 mg/L—corresponding to one-tenth of the lowest concentration associated with presumed toxicity in young children [1, 39].

Local adverse events—erythema, oedema, and blanching, based on commonly reported side effects in the literature [2, 19, 40]—were evaluated at each blood sampling time point (Table S2) and scored from 0 to 4 using a primary skin irritation system (Table S3) [41]. Possible systemic adverse events were monitored at the same time intervals, defined as abnormal vital signs (oxygen saturation, respiratory rate, heart rate/rhythm, blood pressure, temperature, diuresis, and level of consciousness). All patients remained under supervision for at least 8 h after application of the patch [28].

Feasibility was measured by caregiver ratings of patch usability on a five-point Likert scale (1 = very poor; to 5 = excellent), addressing ease of application, patch size, adhesion, ease of removal, and perceived pain during removal [42].

Secondary outcomes included subgroup analyses of safety and feasibility according to demographic and procedural factors. Based on physiological and pharmacokinetic considerations, subgroups were defined based on (0–6 months, 6–12 months, 12–36 months), sex (male, female), ethnicity (Caucasian, Middle East and North African (MENA), Black African), weight-for-height ratio (WFH; Z-scores based on standardized growth curves from birth to maturity in Flanders, Belgium [43]: Z < −1, − 1 < Z < + 1, Z > 1), vascular access type (central venous, arterial), and patch application site (elbow fold, upper leg, lower back, back of the hand, suprapubic, foot), with primary outcome differences tested accordingly.

Statistical analysis

Statistical analysis was performed using RStudio version 2023.9.1.494 (RStudio, Boston, MA, USA). A priori power analysis for a one-sample, two-sided t-test (α = 0.05, power = 80%), indicated that a sample size of 100 patients could detect a 0.03 mg/L difference between the observed mean peak plasma concentration and the predefined safety threshold of 0.100 mg/L, assuming a standard deviation of 0.107 mg/L (Cohen’s d = 0.28). The chosen margin of 0.03 mg/L (≈30% of the threshold) was considered clinically meaningful while balancing analytical precision (LLOQ 0.010 mg/L, CV ≈4–6%) and single-centre recruitment feasibility. As plasma concentration variables were non-normally distributed, results are presented as medians with interquartile ranges [Q1–Q3]. Likert scores are reported as mean ± standard deviation (SD), and categorical variables as frequencies and percentages. A two-sided p-value < 0.05 was considered statistically significant. For statistical analysis, plasma concentrations below the LLOQ were set at 0.005 mg/L. Maximum plasma concentrations (Cmax) were compared to the safety threshold using the Wilcoxon signed-rank test. Differences in Cmax between subgroups were assessed using the Mann–Whitney U test (two groups) and the Kruskal–Wallis test (three or more groups). Associations between demographic and procedural variables and Cmax were further explored using univariable and multivariable linear regression, adjusted for weight-for-height ratio, with β coefficients and Type III ANOVA p-values reported. Subgroup differences in adverse event occurrence were evaluated using Fisher’s exact test, and Likert scores were analysed using the Student’s t-test or the Kruskal–Wallis test as appropriate.

Ethical considerations

The study was performed according to the ethical guidelines of the 1975 Declaration of Helsinki and approved by the local Ethics Review Committee of Universitair Ziekenhuis Brussel and the Belgian Federal Agency for Medicines and Health Products (EUDRACT:2019–002094-55). Written informed consent was obtained from legal guardians of the patients. This study was conducted under the supervision of the Clinical Trials Office at UZ Brussel, ensuring compliance with medical and ethical standards for interventions in young patients. This manuscript was prepared in accordance with the TREND (Transparent Reporting of Evaluations with Non-randomized Designs) guidelines. The corresponding checklist is included as Table S4.

Results

Study population

Of 106 eligible patients meeting all inclusion criteria, 72 initiated the study while 34 legal guardians declined informed consent for personal reasons beforehand. Five patients were excluded afterwards because of incomplete data: two due to unprocessed samples, two because of insufficient sample collection, and one after catheter dislocation during the time of sampling. A detailed participant flow is presented in Fig. 1. This resulted in 67 included patients (median age, 0.55 [0.13–1.09] years; age range, 3 days to 3 years; 58% male). Baseline characteristics are shown in Table 1.

Fig. 1.

Fig. 1

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Flow diagram of participant enrolment

Table 1.

Baseline demographic and procedural characteristics of the overall study population

Patient characteristics Total (n = 67)
Demographic

Age

Age groups (n)

Median 0.55 [IQR 0.96] years

 < 6 months = 32 (48%)

6–12 months = 16 (24%)

 > 12 months = 19 (28%)
Sex (n) 39 (58%) male
Weight 7.1 [5.8] kg
Height 66.0 [24.0] cm
Weight for height ratio

Median − 0.25 [− 1.5 to 0.5]

Low (z < − 1) = 25 (37%)

Mid (− 1 < z < 1) = 31 (46%)

High (z > 1) = 11 (16%)
Ethnicity (n)

Caucasian = 40 (57%)

MENA = 23 (34%)

Black African = 4 (6%)
Procedural
Patch application site (n)

Elbow fold = 21 (30%)

Upper leg = 20 (30%)

Lower back = 10 (15%)

Back of the hand = 7 (10%)

Suprapubic = 6 (9%)

Foot = 4 (6%)
Vascular access type (n)

Central venous catheter = 52 (78%)

Arterial catheter = 15 (22%)
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MENA Middle East and North African

Safety study

Distribution of lidocaine plasma concentrations at multiple time points is illustrated in Fig. 2. Median plasma lidocaine concentrations at time points t−15, t15, t30, t60, t120, and t240 were < 0.010 [< 0.010– < 0.010] mg/L, < 0.010 [< 0.010– < 0.010] mg/L, 0.018 [< 0.010–0.036] mg/L, 0.020 [< 0.010–0.031] mg/L, 0.016 [< 0.010–0.029] mg/L, and 0.013 [< 0.010–0.026] mg/L, respectively. Cmax was 0.025 mg/L [0.014–0.038]. Cmax occurred in 2 patients (3%) at t15, in 33 (49%) at t30, in 9 (13%) at t60, in 8 (12%) at t120, and in 15 (22%) at t240. Cmax, as well as concentrations at all measured time points, was significantly lower than the safety threshold (p < 0.001). This finding was consistent across all demographic and procedural subgroups (p < 0.001). Only 2 patients exceeded the safety threshold (Cmax 0.270 mg/L at t15 and 0.110 mg/L at t30) without any clinical repercussions. In both cases, the concentrations dropped significantly to 0.049 mg/L by t30 and 0.030 mg/L by t60, respectively.

Fig. 2.

Fig. 2

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Distribution of lidocaine plasma concentrations at multiple time points following S-Caine patch application in children under 3 years of age. For clarity of presentation, the outlier value of 0.270 mg/L at t15 is not displayed. P-values represent results of Wilcoxon signed-rank tests comparing concentrations at each time point with the 0.1 mg/L safety threshold

Safety analysis across subgroups is illustrated in Table 2. No differences in Cmax were observed after stratifying for age, sex, WFH, ethnicity, vascular access type, or patch application site. Although slightly higher median Cmax values were observed in the youngest group (0–6 months, 0.030 [0.017–0.038] mg/L) compared to the 6–12 months (0.024 [0.0211–0.03] mg/L) and 12–36 months group (0.019 [0.014–0.04] mg/L), this difference was not statistically significant (p = 0.512). Additionally, univariable regression and multivariable regression adjusted for WFH showed no associations between age, sex, WFH, ethnicity, vascular access type, or patch application site with Cmax.

Table 2.

Safety analysis across subgroups. Cmax differences across subgroups were evaluated using the Wilcoxon rank-sum test for two-level variables and the Kruskal–Wallis test for variables with three or more levels. Univariable linear regression models were used to estimate subgroup effects relative to the reference category, and the overall significance of each stratifying variable was determined using Type III sum-of-squares analysis of variance (ANOVA). Multivariable models repeated this analysis with adjustment for the scaled weight-for-height ratio

Cmax Univariable regression Multivariable regression
Median [Q1–Q3], mg/L p β (95% CI) p β (95% CI) p
Age 0.512 0.344 0.380
< 6 months (n = 32) 0.030 [0.017–0.038] (Reference category) (Reference category)
6–12 months (n = 16) 0.024 [0.011–0.035]  − 0.015 (− 0.038 to 0.008) 0.187  − 0.016 (− 0.039 to 0.008) 0.018
> 12 months (n = 19) 0.019 [0.014–0.041]  − 0.011 (− 0.033 to 0.010) 0.294  − 0.012 (− 0.035 to 0.011) 0.292
Sex 0.863 0.428 0.444
Male (n = 39) 0.028 [0.013–0.042] (Reference category) (Reference category)
Female (n = 28) 0.024 [0.018–0.034]  − 0.007 (− 0.026 to 0.011) 0.428  − 0.007 (− 0.027 to 0.012) 0.444
WFH 0.619 0.938 0.938
Low (z < − 1) (n = 25) 0.030 [0.014–0.042] (Reference category) (Reference category)
Mid (− 1 < z < 1) (n = 31) 0.022 [0.012–0.038] 0.003 (− 0.018 to 0.024) 0.804 0.003 (− 0.018 to 0.024) 0.804
High (z > 1) (n = 11) 0.024 [0.020–0.035]  − 0.002 (− 0.030 to 0.026) 0.895  − 0.002 (− 0.030 to 0.026) 0.895
Ethnicity 0.890 0.746 0.687
Caucasian (n = 40) 0.024 [0.015–0.036] (Reference category) (Reference category)
MENA (n = 23) 0.025 [0.010–0.040] 0.007 (− 0.012 to 0.027) 0.451 0.008 (− 0.013 to 0.028) 0.456
Black African (n = 4) 0.035 [0.021–0.046] 0.001 (− 0.039 to 0.040) 0.984 0.001 (− 0.040 to 0.041) 0.990
Vascular access type 0.874 0.556 0.539
Arterial catheter (n = 15) 0.028 [0.014–0.037] (Reference category) (Reference category)
Central venous catheter (n = 52) 0.023 [0.014–0.038] 0.006 (− 0.015 to 0.028) 0.556 0.007 (− 0.16 to 0.030) 0.539
Patch application site 0.069 0.443 0.982
Elbow fold (n = 21) 0.030 [0.025–0.044] (Reference category) (Reference category)
Back of the hand (n = 7) 0.013 [0.009–0.017]  − 0.030 (− 0.062 to 0.003) 0.073  − 0.031 (− 0.065 to 0.003) 0.071
Upper leg (n = 20) 0.022 [0.014–0.046]  − 0.011 (− 0.034 to 0.013) 0.368  − 0.010 (− 0.035 to 0.014) 0.408
Lower back (n = 10) 0.022 [0.016–0.035]  − 0.016 (0.045–0.012) 0.256  − 0.017 (− 0.047 to 0.013) 0.255
Suprapubic (n = 5) 0.032 [0.014–0.036]  − 0.016 (− 0.053 to 0.021) 0.383  − 0.017 (− 0.055 to 0.021) 0.373
Foot (n = 4) 0.012 [0.005–0.022]  − 0.029 (− 0.070 to 0.011) 0.154  − 0.031 (− 0.072 to 0.011) 0.149
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MENA Middle East and North African

Adverse events

No serious patch-related adverse events were observed. Five patients did show systemic effects (notably fever, desaturation, and vomiting), but all solely in the context of their illness leading to their hospitalisation at the time of inclusion, as confirmed by the supervising physician. Local adverse events occurred in 49 patients (73%) at the time of patch removal, manifesting as local erythema, and further classified as very slight in 17 patients, mild in 22 patients, moderate in 8 patients, and severe in 2 patients. Very slight oedema was noted in two patients with mild erythema, and very slight blanching in one patient with moderate erythema; no erythema or blanching occurred in other patients. Among the 49 patients with erythema, resolution occurred within 30 min in 45% and within 90 min in 86%; erythema persisted at 240 min in five patients (10%), with decreasing intensity over time. Table 3 presents the occurrence of local adverse events across subgroups stratified by age, sex, weight-for-height category, ethnicity, vascular access type, and patch application site. Local erythema occurred significantly more frequently in Caucasian (33/40 (83%)) and MENA patients (17/23 (74%)) as compared to Black African patients (0/4 (0%)) (p = 0.003). No significant differences were observed in the other subgroup comparisons.

Table 3.

Local Adverse Events: exclusively manifesting as local erythema, across subgroups. Differences are tested using Fisher’s exact test

Adverse events, n (%) p
Age 0.544
< 6 months (n = 32) 22 (69%)
6–12 months (n = 16) 12 (75%)
> 12 months (n = 19) 16 (84%)
Sex 1.000
Male (n = 39) 29 (74%)
Female (n = 28) 21 (75%)
WFH 0.608
Low (z < − 1) (n = 25) 17 (68%)
Mid (− 1 < z < 1) (n = 31) 23 (79%)
High (z > 1) (n = 11) 8 (73%)
Ethnicity 0.003
Caucasian (n = 40) 33 (83%)
MENA (n = 23) 17 (74%)
Black African (n = 4) 0 (0%)
Vascular access type 0.743
Arterial catheter (n = 15) 12 (80%)
Central venous catheter (n = 52) 38 (73%)
Patch application site 1.000
Elbow fold (n = 21) 16 (76%)
Back of the hand (n = 7) 5 (71%)
Upper leg (n = 20) 15 (75%)
Lower back (n = 10) 7 (70%)
Suprapubic (n = 5) 4 (80%)
Foot (n = 4) 3 (75%)
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Feasibility

Overall satisfaction of patch application ease, adherence, and ease of removal were rated by caregivers as “at least 4 out of 5” in 58 patients (87%) at patch application and in 55 patients (82%) at patch removal, with mean Likert scores of 4.48 ± 0.84 and 4.37 ± 0.92, respectively. The mean Likert scores at 0 and 30 min for the first age group (0–6 months) were 4.25 ± 0.95 and 4.22 ± 1.01. The second (6–12 months) and third (12–36 months) age group scored 4.62 ± 0.81 and 4.31 ± 1.01; and 4.74 ± 0.56 and 4.68 ± 0.58, respectively. There was no significant difference between the Likert scores compared among age groups, using a one-way ANOVA test and at 0 min (p = 0.097) and 30 min (p = 0.210). Although in six patients (four in age group 1, one in age group 2, and one in age group 3), the patch was oversized and failed to adhere properly, loosening prematurely. Table 4 presents feasibility study across subgroups stratified by age, sex, weight-for-height category, ethnicity, vascular access type, and patch application site. None of these were statistically significant.

Table 4.

Feasibility across subgroups. Caregiver satisfaction at patch application and removal was rated using a 5-point Likert scale (1 = lowest, 5 = highest). Differences in scores between subgroups were assessed using one-way ANOVA

Patch application Patch removal
Likert score, mean (SD) p Likert score, mean (SD) p
Overall 4.48 ± 0.84 / 4.37 ± 0.92 /
Age 0.097 0.210
 < 6 months (n = 32) 4.25 ± 0.95 4.22 ± 1.01
6–12 months (n = 16) 4.62 ± 0.81 4.31 ± 1.01
> 12 months (n = 19) 4.74 ± 0.56 4.68 ± 0.58
Sex 0.636 0.679
Male (n = 39) 4.44 ± 0.82 4.33 ± 0.90
Female (n = 28) 4.54 ± 0.88 4.43 ± 0.96
WFH 0.214 0.798
Low (z < − 1) (n = 25) 4.24 ± 0.93 4.40 ± 0.82
Mid (− 1 < z < 1) (n = 31) 4.55 ± 0.83 4.38 ± 0.90
High (z > 1) (n = 11) 4.73 ± 0.65 4.18 ± 1.25
Ethnicity 0.197 0.272
Caucasian (n = 40) 4.50 ± 0.82 4.28 ± 1.04
MENA (n = 23) 4.57 ± 0.79 4.61 ± 0.66
Black African (n = 4) 3.75 ± 1.26 4.00 ± 0.82
Vascular access type 0.955 0.411
Arterial catheter (n = 15) 4.47 ± 0.74 4.20 ± 1.01
Central venous catheter (n = 52) 4.48 ± 0.87 4.42 ± 0.89
Patch application site 0.688 0.974
Elbow fold (n = 21) 4.43 ± 0.81 4.24 ± 1.14
Back of the hand (n = 7) 4.29 ± 0.95 4.43 ± 1.13
Upper leg (n = 20) 4.50 ± 0.89 4.45 ± 0.69
Lower back (n = 10) 4.70 ± 0.68 4.50 ± 0.85
Suprapubic (n = 5) 4.80 ± 0.45 4.40 ± 0.89
Foot (n = 4) 4.00 ± 1.41 4.52 ± 0.96
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Discussion

Safety

In 49% of cases, maximum lidocaine concentrations were observed at 30 min, and in 78% within the expected 2 h [17]. In 22% of patients, however, the peak occurred at 240 min, reflecting a slow accumulation of lidocaine despite a very gradual rise. Plasma concentrations did not decline to baseline (LLOQ 0.010 mg/L), with 62% of patients (n = 42) remaining above this level at 4 h, consistent with prior reports of detectable baseline levels up to 24 h post-application [17]. Due to ethical constraints, no more than six blood samples per patient were collected. The steady decline in plasma concentrations without secondary peaks supports the patch’s reassuring safety profile regarding Cmax.

Maximum lidocaine plasma concentrations in this study remained well below toxic levels reported in the literature [44, 45]. Only two patients exceeded the predefined safety threshold of 0.100 mg/L, with Cmax 0.270 mg/L at t15 and 0.110 mg/L at t30. Both remained asymptomatic with no clinical repercussions, and levels quickly fell below the threshold. This safety threshold should be viewed as a very conservative guideline rather than an absolute toxicological cut-off, next to the need for careful clinical monitoring in paediatric patients [46]. Transient, isolated elevations within expected pharmacokinetic variability and analytical uncertainty are not necessarily indicative of safety concerns. Notably, the 0.110 mg/L concentration may be affected by measurement variability, since the precision of the LC-PDA method ranges from 1.4% to 7.9%, with accuracy between 91.7% and 106.5% [47]. With ~ 5% precision, 0.110 mg/L corresponds to 0.105–0.116 mg/L, marginally exceeding the threshold. Both cases occurred in patients from the youngest age group; nonetheless, no statistically significant differences in Cmax were detected between age groups. These findings contrast with previous data suggesting an inverse correlation between age and lidocaine exposure, although that study included merely four children under the age of three [27].

Adverse events

Erythema occurred in three-quarters of patients, most likely due to the vasodilatory effect due to local warming by the patch [9, 18, 20]. This aligns with previous studies but shows a higher prevalence than reported in older children (~ 30%) [2] and adults (3–10%) [40]. The increased sensitivity in younger children may be attributed to differences in skin pharmacokinetics, including a higher surface area-to-body weight ratio [1, 48], although in this study no significant difference in erythema occurrence was observed between age groups (p = 0.544). Other known application site reactions [31]—such as rash, pruritus, or blisters—were not observed. In patients with dark skin, erythema was not observed likely because pigmentation hindered accurate detection, which may result in cases going unnoticed [49]. No serious patch-related adverse events were observed, consistent with previous studies [11, 18, 21, 22].

Feasibility

The 0–6 months age group had lower mean Likert scores at both application and removal, reflecting possible dissatisfaction related to patch size for smaller body surfaces, although these issues—noted in six patients—did not affect the overall positive satisfaction rate. Future studies are warranted to directly compare the feasibility, clinical effectiveness, and cost of the S-Caine patch with conventional topical anaesthetic creams in young children.

Limitations

First, this study’s nonrandomised single-centre design limits external validity and may introduce selection bias. However, strict inclusion criteria, standardised monitoring, and objective outcome definitions mitigated these risks. Second, although a target sample size of 100 participants was defined a priori, recruitment was constrained by the single-centre ICU setting and the requirement for informed consent. Patient inclusion was performed by the two principal investigators and was only consecutive during periods when they were present in the ICU. An interim post hoc power analysis conducted after two-thirds of the target enrolment showed that the achieved sample was sufficient. Based on the observed effect size (d = 0.89, μ = 0.033, SD = 0.037; α = 0.05), the analysis yielded a power > 0.999, confirming adequate statistical strength with 67 participants. One protocol deviation involved a patient weighing 2.88 kg, who remained clinically stable and gained 9.9% body weight within 2 weeks, minimizing any potential impact on study validity. Third, no significant associations were found between mean Cmax and independent variables (sex, ethnicity, vascular access, or application site) when adjusted for weight-for-height ratio. While percutaneous absorption is known to inversely correlate with stratum corneum thickness and may vary with skin pigmentation [10, 11, 48, 50], subgroup sizes—particularly among dark-pigmented patients (n = 4) and less common application sites (foot [n = 4], suprapubic [n = 6])—were too small for definitive conclusions. These analyses should be considered exploratory. Fixed sampling intervals may have missed intermediate peaks, meaning Cmax and erythema might not have occurred simultaneously. Finally, concentrations of MEGX, lidocaine’s main metabolite, and tetracaine were not measured. Although MEGX levels could have provided additional safety insight, prior research suggests transdermal lidocaine absorption from heated patches remains below toxic thresholds [17, 28, 51]. Tetracaine’s rapid enzymatic degradation in plasma precluded reliable detection under routine clinical conditions [1, 18, 33, 47, 52].

Conclusion

In this nonrandomised clinical trial including 67 children younger than 3 years, the use of the S-Caine patch was safe, with plasma lidocaine concentrations remaining well below predefined clinically relevant thresholds. Only transient local skin reactions were observed, and no systemic adverse events occurred. Feasibility was rated positively, though improvements in patch size and adhesion may enhance usability. Future studies are needed to compare its clinical effectiveness, feasibility, and cost with conventional methods, and to confirm safety in larger paediatric populations.

Supplementary Information

Below is the link to the electronic supplementary material.

ESM 1 (113.7KB, docx)

Supplementary Material 1 (DOCX 113 KB)

Acknowledgements

We would like to express our sincere gratitude to the young patients who participated in this study, and to their parents for providing informed consent during a complex, difficult and uncertain time. Furthermore, we wish to acknowledge the valuable support and collaboration of the nursing and medical staff of the Paediatric and PICU departments.

Abbreviations

BELAC

Belgian Laboratory Accreditation Corporation

CHADD

Controlled heat-assisted drug delivery

Cmax

The maximum concentration (mg/L)

IQR

Interquartile ranges

LC

Liquid chromatography

LLOQ

Lower limit of quantification

MEGX

Monoethylglycinexylidide

MENA

Middle East and North Africa

PDA

Phosphodiode array

PICU

Paediatric intensive care unit

SD

Standard deviation

WFH

Weight-for-height ratio

Authors’ Contributions

Dr Britt Anciaux contributed to the methodology, formal analysis, investigation, patient inclusion, data curation, project administration, original manuscript writing and visualisation. Katrien Lanckmans contributed to lab analysis and provided resources. Ronald Buyl contributed to the power and formal analysis and supervision. Dr Tom De Potter contributed to data analysis, statistics, and review. Prof Dr Gerlant van Berlaer contributed to conceptualisation, methodology, patient inclusion, project administration, supervision, and review. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding

None.

Data availability

Deidentified individual participant data (stored in REDCap registry), including data dictionaries, study protocols, the statistical analysis plan, and the informed consent form, will be available upon publication to researchers with a methodologically sound proposal. Proposals should be submitted to [britt.kristien.anciaux@vub.be](mailto:britt.kristien.anciaux@vub.be).

Declarations

Ethics approval

The study was performed according to the ethical guidelines of the 1975 Declaration of Helsinki and approved by the local Ethics Review Committee of Universitair Ziekenhuis Brussel and the Belgian Federal Agency for Medicines and Health Products (EUDRACT:2019–002094-55).

Consent to participate

Written informed consent was obtained from legal guardians of the patients.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.O’Brien L, Taddio A, Lyszkiewicz DA, Koren G (2005) A critical review of the topical local anesthetic amethocaine (Ametop) for pediatric pain. Pediatr Drugs 7:41–54. 10.2165/00148581-200507010-00004 [DOI] [PubMed]
  • 2.Singer AJ, Taira BR, Chisena EN, Gupta N, Chipley J (2008) Warm lidocaine/tetracaine patch versus placebo before pediatric intravenous cannulation: a randomized controlled trial. Ann Emerg Med 52:41–47. 10.1016/j.annemergmed.2008.01.336 [DOI] [PubMed] [Google Scholar]
  • 3.Baarslag MA, Jhingoer S, Ista E, Allegaert K, Tibboel D, Van Dijk M (2019) How often do we perform painful and stressful procedures in the paediatric intensive care unit? A prospective observational study. Aust Crit Care 32:4–10. 10.1016/j.aucc.2018.04.003 [DOI] [PubMed] [Google Scholar]
  • 4.Pywell A, Xyrichis A (2015) Does topical amethocaine cream increase first-time successful cannulation in children compared with a eutectic mixture of local anaesthetics (EMLA) cream? A systematic review and meta-analysis of randomised controlled trials. Emerg Med J 32:733–737. 10.1136/emermed-2014-204066 [DOI] [PubMed] [Google Scholar]
  • 5.Mondardini MC, Vasile B, Amigoni A, Baroncini S, Conio A, Mantovani A et al (2014) Update of recommendations for Analgosedation in pediatric intensive care unit. Minerva Anestesiol 80:1018–1029 [PubMed] [Google Scholar]
  • 6.Leroy PL, Costa LR, Emmanouil D, van Beukering A, Franck LS (2016) Beyond the drugs: nonpharmacologic strategies to optimize procedural care in children. Curr Opin Anaesthesiol 29(1):S1-13. 10.1097/ACO.0000000000000312 [DOI] [PubMed] [Google Scholar]
  • 7.Martin SR, Heyming T, Kain AS, Krauss BS, Campos B (2023) Eliminating pain disparities for children in the emergency department. Acad Emerg Med 30:1075–1077. 10.1111/acem.14723 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Zempsky WT, Cravero JP; Committee on Pediatric Emergency Medicine, and Section on Anesthesiology and Pain Medicine (2004) Relief of pain and anxiety in pediatric patients in emergency medical systems. Pediatrics 114:1348–56. 10.1542/peds.2004-1752 [DOI] [PubMed]
  • 9.Sethna NF, Verghese ST, Hannallah RS, Solodiuk JC, Zurakowski D, Berde CB (2005) A randomized controlled trial to evaluate S-Caine patch for reducing pain associated with vascular access in children. Anesthesiology 102:403–408. 10.1097/00000542-200502000-00025 [DOI] [PubMed] [Google Scholar]
  • 10.Tadicherla S, Berman B (2006) Percutaneous dermal drug delivery for local pain control. Ther Clin Risk Manag 2:99–113 [PMC free article] [PubMed] [Google Scholar]
  • 11.Croxtall JD (2010) Lidocaine/tetracaine medicated plaster: in minor dermatological and needle puncture procedures. Drugs 70:2113–2120. 10.2165/11206390-000000000-00000 [DOI] [PubMed] [Google Scholar]
  • 12.Caltagirone R, Raghavan VR, Adelgais K, Roosevelt GE (2018) A randomized double blind trial of needle‐free injected lidocaine versus topical anesthesia for infant lumbar puncture. In Macy ML (ed) Acad Emerg Med 25:310–6. 10.1111/acem.13351 [DOI] [PubMed]
  • 13.Arendts G, Stevens M, Fry M (2008) Topical anaesthesia and intravenous cannulation success in paediatric patients: a randomized double-blind trial. Br J Anaesth 100:521–524. 10.1093/bja/aen003 [DOI] [PubMed] [Google Scholar]
  • 14.Van Kan HJM, Egberts ACG, Rijnvos WPM, Ter Pelkwijk NJ, Lenderink AW (1997) Tetracaine versus lidocaine-prilocaine for preventing venipuncture-induced pain in children. Am J Health Syst Pharm 54:388–392. 10.1093/ajhp/54.4.388 [DOI] [PubMed] [Google Scholar]
  • 15.Newbury C, Herd DW (2009) Amethocaine versus EMLA for successful intravenous cannulation in a children’s emergency department: a randomised controlled study. Emerg Med J 26:487–491. 10.1136/emj.2008.065110 [DOI] [PubMed] [Google Scholar]
  • 16.Friedman PM, Fogelman JP, Nouri K, Levine VJ, Ashinoff R (1999) Comparative study of the efficacy of four topical anesthetics. Dermatol Surg 25:950–954. 10.1046/j.1524-4725.1999.99138.x [DOI] [PubMed] [Google Scholar]
  • 17.Marriott TB, Charney MR, Stanworth S (2012) Effects of application durations and heat on the pharmacokinetic properties of drug delivered by a lidocaine/tetracaine patch: a randomized, open-label, controlled study in healthy volunteers. Clin Ther 34:2174–2183. 10.1016/j.clinthera.2012.08.008 [DOI] [PubMed] [Google Scholar]
  • 18.Ruetzler K, Sima B, Mayer L, Golescu A, Dunkler D, Jaeger W et al (2012) Lidocaine/tetracaine patch (Rapydan) for topical anaesthesia before arterial access: a double-blind, randomized trial. Br J Anaesth 109:790–796. 10.1093/bja/aes254 [DOI] [PubMed] [Google Scholar]
  • 19.Sawyer J, Febbraro S, Masud S, Ashburn MA, Campbell JC (2009) Heated lidocaine/tetracaine patch (Synera™, Rapydan™) compared with lidocaine/prilocaine cream (EMLA®) for topical anaesthesia before vascular access. Br J Anaesth 102:210–215. 10.1093/bja/aen364 [DOI] [PubMed] [Google Scholar]
  • 20.Hull Wade M (2002) Heat-enhanced transdermal drug delivery: a survey paper. J Appl Res 2:7 [Google Scholar]
  • 21.Wallace MS, Kopecky EA, Ma T, Brophy F, Campbell JC (2010) Evaluation of the depth and duration of anesthesia from heated lidocaine/tetracaine (Synera) patches compared with placebo patches applied to healthy adult volunteers. Reg Anesth Pain Med 35:507–513. 10.1097/AAP.0b013e3181fa69b8 [DOI] [PubMed]
  • 22.Shomaker TS, Zhang J, Love G, Basta S, Ashburn MA (2000) Evaluating skin anesthesia after administration of a local anesthetic system consisting of an S-Caine patch and a controlled heat-aided drug delivery (CHADD) patch in volunteers. Clin J Pain 16:200–204. 10.1097/00002508-200009000-00004 [DOI] [PubMed] [Google Scholar]
  • 23.Curry SE, Finkel JC (2007) Use of the Synera™ patch for local anesthesia before vascular access procedures: a randomized, double-blind, placebo-controlled study. Pain Med 8:497–502. 10.1111/j.1526-4637.2006.00204.x [DOI] [PubMed] [Google Scholar]
  • 24.Kramers C. BF. Lidocaine (2022) CHDR Leiden; https://toxicologie.org/wp-content/uploads/Monografie-lidocaine.pdf
  • 25.Soltesz S, Dittrich K, Teschendorf P, Fuss I, Molter G (2010) Topical anesthesia before vascular access in children. Comparison of a warmth-producing lidocaine-tetracaine patch with a lidocaine-prilocaine patch. Anaesthesist 59:519–23. 10.1007/s00101-010-1727-5 [DOI] [PubMed]
  • 26.Cozzi G, Borrometi F, Benini F, Neri E, Rusalen F, Celentano L et al (2017) First‐time success with needle procedures was higher with a warm lidocaine and tetracaine patch than an eutectic mixture of lidocaine and prilocaine cream. Acta Paediatr 106:773–778. 10.1111/apa.13764 [DOI] [PubMed] [Google Scholar]
  • 27.Eurocept. SmPC Rapydan medicated patch (2011) [cited 2019 Apr]. Available from: https://db.cbg-meb.nl/smpc/h100315_smpc.pdf
  • 28.Curtis LA, Dolan TS, Seibert HE (2009) Are one or two dangerous? Lidocaine and topical anesthetic exposures in children. J Emerg Med 37:32–39. 10.1016/j.jemermed.2007.11.005 [DOI] [PubMed] [Google Scholar]
  • 29.Zorginstituut Nederland. Lidocaine/tetracaine. Farmacotherapeutisch Kompas [Internet]. [cited 2019 Jun]. Available from: https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/l/lidocaine_tetracaine
  • 30.Spray A, Siegfried E (2001) Dermatologic toxicology in children. Pediatr Ann 30:197–202. 10.3928/0090-4481-20010401-07 [DOI] [PubMed] [Google Scholar]
  • 31.FDA (2014) SYNERA® (lidocaine and tetracaine) Topical Patch [Internet]. Galen US Inc; p. 13. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021623s015s017lbl.pdf
  • 32.Conklin LS, Hoffman EP, van den Anker J (2019) Developmental pharmacodynamics and modeling in pediatric drug development. J Clin Pharmacol 59:S87–94. 10.1002/jcph.1482 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Wilder RT (2000) Local anesthetics for the pediatric patient. Pediatr Clin North Am 47:545–558. 10.1016/s0031-3955(05)70225-x [DOI] [PubMed] [Google Scholar]
  • 34.Maulidi H, McNair C, Seller N, Kirsh J, Bradley TJ, Greenway SC et al (2012) Arrhythmia associated with tetracaine in an extremely low birth weight premature infant. Pediatrics 130:e1704. 10.1542/peds.2011-1743 [DOI] [PubMed] [Google Scholar]
  • 35.Jain A, Rutter N (2000) Local anaesthetic effect of topical amethocaine gel in neonates: randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 82:F42-45. 10.1136/fn.82.1.f42 [DOI] [PMC free article] [PubMed]
  • 36.Willatts DG, Reynolds F (1985) Comparison of the vasoactivity of amide and ester local anaesthetics. An intradermal study. Br J Anaesth 57:1006–1011. 10.1093/bja/57.10.1006 [DOI] [PubMed] [Google Scholar]
  • 37.European Medicines Agency (EMA), Committee for Medicinal Products for Human Use (CHMP) (2015) Reflection paper on the use of methyl- and propylparaben as excipients in human medicinal products for oral use [Internet]. [cited 2019 Jun]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-use-methyl-and-propylparaben-excipients-human-medicinal-products-oral-use_en.pdf
  • 38.Chik Z, Lee TD, Holt DW, Johnston A, Tucker AT (2006) Validation of high-performance liquid chromatographic--mass spectrometric method for the analysis of lidocaine in human plasma. J Chromatogr Sci 44:262–265. 10.1093/chromsci/44.5.262 [DOI] [PubMed] [Google Scholar]
  • 39.Clinical pharmacology of antiarrhythmic drugs. In: Pharmacologic Bases of Antiarrhythmic Therapy [Internet]. 2019 [cited 2019 Apr]. Available from: https://thoracickey.com/clinical-pharmacology-of-antiarrhythmic-drugs/
  • 40.Masud S, Wasnich RD, Ruckle JL, Garland WT, Halpern SW, Mee-Lee D et al (2010) Contribution of a heating element to topical anesthesia patch efficacy prior to vascular access: results from two randomized, double-blind studies. J Pain Symptom Manag 40:510–519. 10.1016/j.jpainsymman.2010.01.022 [DOI] [PubMed] [Google Scholar]
  • 41.Sreejayan N, Marone PA, Lau FC, Yasmin T, Bagchi M, Bagchi D (2010) Safety and toxicological evaluation of a novel chromium(III) dinicocysteinate complex. Toxicol Mech Methods 20:321–333. 10.3109/15376516.2010.487880 [DOI] [PubMed] [Google Scholar]
  • 42.Sullivan RW, Ryzewski M, Holland MG, Marraffa JM (2013) Compounded ointment results in severe toxicity in a pediatric patient. Pediatr Emerg Care 29:1220–2. 10.1097/PEC.0b013e3182aa4748 [DOI] [PubMed]
  • 43.Roelants MDSJ (2024) Vlaamse Groeicurven 2024
  • 44.Leopold A, Wilson S, Weaver JS, Moursi AM (2002) Pharmacokinetics of lidocaine delivered from a transmucosal patch in children. Anesth Prog 49:82–7 [PMC free article] [PubMed]
  • 45.Parker JF, Vats A, Bauer G (2004) EMLA toxicity after application for allergy skin testing. Pediatrics 113:410–411. 10.1542/peds.113.2.410 [DOI] [PubMed] [Google Scholar]
  • 46.Oda Y (2016) Pharmacokinetics and systemic toxicity of local anesthetics in children. J Anesth 30:547–550. 10.1007/s00540-016-2201-6 [DOI] [PubMed] [Google Scholar]
  • 47.Qin W-W, Jiao Z, Zhong M-K, Shi X-J, Zhang J, Li Z-D et al (2010) Simultaneous determination of procaine, lidocaine, ropivacaine, tetracaine and bupivacaine in human plasma by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 878:1185–1189. 10.1016/j.jchromb.2010.03.003 [DOI] [PubMed] [Google Scholar]
  • 48.Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M, Ramos JT (2011) Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics 3:53–72. 10.3390/pharmaceutics3010053 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Ben-Gashir MA, Hay RJ (2002) Reliance on erythema scores may mask severe atopic dermatitis in black children compared with their white counterparts. Br J Dermatol 147:920–925. 10.1046/j.1365-2133.2002.04965.x [DOI] [PubMed] [Google Scholar]
  • 50.Sandby-Møller J, Poulsen T, Wulf HC (2003) Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits. Acta Derm Venereol 83:410–413. 10.1080/00015550310015419 [DOI] [PubMed] [Google Scholar]
  • 51.Campbell TJ, Williams KM (1998) Therapeutic drug monitoring: antiarrhythmic drugs. Br J Clin Pharmacol 46:307–319. 10.1046/j.1365-2125.1998.t01-1-00768.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Hino Y, Ikeda N, Kudo K, Tsuji A (2000) Sensitive and selective determination of tetracaine and its metabolite in human samples by gas chromatography-mass spectrometry. J Anal Toxicol 24:165–169. 10.1093/jat/24.3.165 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ESM 1 (113.7KB, docx)

Supplementary Material 1 (DOCX 113 KB)

Data Availability Statement

Deidentified individual participant data (stored in REDCap registry), including data dictionaries, study protocols, the statistical analysis plan, and the informed consent form, will be available upon publication to researchers with a methodologically sound proposal. Proposals should be submitted to [britt.kristien.anciaux@vub.be](mailto:britt.kristien.anciaux@vub.be).

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