2019 年 1 巻 3 号 p. 95-101
BACKGROUND
Preparations of 2.5% lidocaine plus 2.5% prilocaine cream (trade name EMLA® cream) or 5% lidocaine cream (trade name LMX5® cream) are used for local anesthesia. To our knowledge, no study has directly compared the analgesic effects for venipuncture between EMLA® cream and LMX5® cream. We conducted a double-blinded randomized crossover trial to evaluate the analgesic effects of these two creams in healthy adults using a visual analogue scale (VAS).
METHODS
This crossover trial enrolled 24 healthy adult participants randomly assigned to 4 groups by combining 2 formulations of anesthetics and different left-right arm-treatment protocols. The primary outcome was each subject’s VAS score (range 0 to 100) for pain during blood sampling. The secondary outcomes were blood sampling site, blood sampling volume, blood sampling frequency, and occurrence of side effects. We conducted a multivariate regression analysis for the VAS score after adjusting for participants’ background characteristics while also adjusting for clustering of arm-treatment protocols within individuals using a generalized estimating equation.
RESULTS
There were no significant differences between EMLA® and LMX5® cream after adjusting for participants’ background characteristics, including age and sex (difference: 2.83; 95% confidence interval: −11.25 to 16.92; P value: 0.693). There were also no marked differences in secondary outcomes between EMLA® cream and LMX5® cream. No adverse reactions that could be clinically problematic were observed with either cream.
CONCLUSION
This randomized crossover trial showed that there was no significant analgesic difference between EMLA® cream and LMX5® cream. Both creams were effective without clinically serious side effects.
The registration number is UMIN000011463.
The registry website is UMIN (http://www.umin.ac.jp/ctr/index.htm).
Blood sampling is an essential procedure in medical practice. However, the pain of puncturing the skin with a needle may make it difficult to perform the procedure itself, particularly in children. Previous studies have shown that using a topical anesthetic cream [1] or distracting patients using cards with pictures [2] had analgesic effects. Preparations of 2.5% lidocaine plus 2.5% prilocaine cream (trade name EMLA® cream) [1, 3, 4] or 5% lidocaine cream (trade name LMX5® cream) [5, 6] have been used as local anesthesia for blood collection or vaccination. In a previous study comparing EMLA® and 4% lidocaine cream in meatotomy of patients with meatal stenosis, there were no marked differences in the analgesic effects after application ≥45 minutes; however, 4% lidocaine cream showed a greater analgesic effect after application <30 minutes [7]. To our knowledge, no previous study has directly compared the analgesic effects of EMLA® cream and LMX5® cream for blood sampling or vaccination. It is clinically important to select drugs that reduce pain more when collecting blood in children.
We therefore conducted a double-blinded randomized crossover trial to evaluate the analgesic effects of EMLA® cream and LMX5® cream in healthy adults using a visual analog scale (VAS).
This prospective, randomized, double-blind, crossover trial was conducted at the National Center for Child Health and Development (NCCHD) on August 13, 2013. The research participants did not need to pay any money to join this research, and we provided a ¥1000 book card as a reward for each participant. We recruited participants from among NCCHD staff using an electronic employee bulletin board. We only recruited staff members who voluntarily responded in kind to our e-mailed participation request. We fully explained the trial procedures to participants and obtained their written consent. The participants were informed that they could refuse to participate at any time even if they had initially agreed to participate. The protocol was approved by the Ethics Committee at NCCHD.
STUDY POPULATIONEligible participants for this trial had to satisfy all of the following criteria: (i) be 20 to 60 years of age at the time of the blood sampling, (ii) voluntarily participate by themselves as staff of the NCCHD, and (iii) give their consent specifically for this research. The following participants were excluded: (i) those with any history of allergies to the anesthetic agents; (ii) those with severe skin diseases, such as eczema, accompanied by erosion at the site of blood sampling; (iii) those who previously underwent blood sampling following application of EMLA® cream or LMX5® cream; (iv) those who had difficulty providing informed consent in Japanese; (v) those judged by the attending physician(s) to have difficulty participating in this research (including based on the patient’s health condition).
RANDOMIZATION AND INTERVENTIONFor randomization, an allocation table (allocation key) created using a computer was used. The allocation table was managed by an administrator who was not involved in applying the anesthetic cream or in performing blood sampling during this trial. Neither the blood sampler, blood collection assistant, nor the subject was informed as to which arm the topical anesthetic cream would be applied. To ensure such anonymity, each cream was prepared in advance by transferring it to another container without a trade-name label. Subjects were assigned to one of four groups. Group 1 received EMLA® cream on the right arm and LMX5® cream on the left arm. The order of blood sampling was the right arm first, then the left arm. Group 2 received EMLA® cream on the right arm and LMX5® cream on the left arm. The order of blood sampling was the left arm first, then the right arm. Group 3 received LMX5® cream on the right arm and EMLA® cream on the left arm. The order of blood sampling was the right arm first, then the left arm. Group 4 received LMX5® cream on the right arm and EMLA® cream on the left arm. The order of blood sampling was the left arm first, then the right arm.
Within 60 to 90 minutes before blood collection, the subjects in each group had the designated cream applied to the predetermined blood sampling sites on both arms in the same order as the blood collection would be performed. Each application amount was 0.25 g of cream over an area of about 10 cm2. Subjects had blood drawn in the specified order after one hour by any of four medical doctors who each had at least three years of clinical experience. In principle, the blood-sampling site was the antecubital vein of the elbow, but in difficult cases, sampling from the cephalic or basilic vein was also permitted. The volume of blood to be collected was planned to be 2 mL from each arm using only 23-G metal needles (Terumo Corporation, Tokyo, Japan). If the subject requested to stop participating in the blood sampling tests due to pain during blood collection or when taking blood samples was difficult, we then carefully confirmed that the venipuncture had been successfully carried out and that the needle had only punctured the skin during the blood sample procedures. As a result, all participants were therefore able to continue to participate in this study.
The specimen of collected blood was handed over to the patient as a specimen for medical examination at the participant’s request.
DATA COLLECTIONDemographic data of subjects were collected at the time of blood sampling, including age, sex, allergic disease complications (food allergy, pollinosis, allergic rhinitis, or atopic dermatitis), dominant arm, blood-sampling site (antecubital, cephalic, or basilic vein), and actual amount of blood sampled. We also recorded who the blood sampler was, the time taken for blood sampling, how many times the needle punctured the skin, and the coating time of the local anesthetic.
OUTCOMESThe primary outcome was the VAS score (range 0 to 100) [8–10] for pain during blood sampling scored by each subject. On this VAS scale, 0 indicates no pain, and 100 indicates the worst pain imaginable [8]. Secondary outcomes for each arm included time required to collect blood, blood-sampling site, blood-sampling volume, blood-sampling frequency, and the occurrence of side effects, including skin erythema.
STATISTICAL ANALYSESWe assumed a median VAS score without anesthetic cream of 44 and a normalized interquartile range of 23.7 from a previous study [9].
Since no clinically significant difference in the VAS score has yet been established, we referred to the findings of previous clinical trials [11–13] and set the cutoff level for a significant difference in the VAS score at ≥20. When calculating with α = 0.05 and power = 80%, 23 participants in each group were determined to be necessary.
According to the crossover design which stipulated that blood would be collected twice per person, the subjects were divided into four groups as described above, the sample size was ultimately set at 24 subjects consisting of 6 individuals per group.
Data were analyzed within the Division of Japan Environment and Children’s Study, National Center for Child Health and Development.
Categorical variables were compared using Fisher’s exact test, and continuous variables were compared using Wilcoxon’s rank sum test or the Kruskal-Wallis equality-of-populations rank test. First, we conducted univariate analyses for the primary and secondary outcomes of EMLA® cream and LMX5® cream. We conducted a repeated measure analysis of variance to confirm whether or not there was a period effect. As a post-hoc analysis, we also conducted a multivariate regression analysis for the VAS score after adjusting for age, sex, and coating time of the local anesthetic while also adjusting for clustering of arm-treatment protocols within individuals using a generalized estimating equation. Participants were divided into halves according to the coating time of the local anesthetic so that the number of participants in each half was almost equal. Values of P < 0.05 in a 2-sided test were considered statistically significant. All statistical analyses were conducted using the software program Stata, version 15 (StataCorp, College Station, TX, USA).
A total of 24 participants joined this study and were randomly assigned to 4 groups. There were no participants who met the exclusion criteria. One participant was initially assigned to group 4, but the cream was mistakenly applied to the incorrect arm. Due to the nature of this trial, the as-treated analysis was deemed to be more appropriate than the intention-to-treat analysis, and the participant was reassigned to group 1 (Fig. 1). The mean age was 36.7 years old (range 25 to 29 years old), and 33% of participants were men.
EMLA®, 2.5% lidocaine plus 2.5% prilocaine cream (trade name EMLA® cream); LMX5®, 5% lidocaine cream (trade name LMX5® cream); VAS, visual analogue scale.
Table 1 shows the background characteristics and details of blood sampling for participants in the four groups. There were no statistically significant differences in the background characteristics among the groups. Table 2 shows the results of univariate analyses comparing the primary and secondary outcomes between EMLA® cream and LMX5® cream. There were no significant differences in the primary or secondary outcomes between EMLA® cream and LMX5® cream. Regarding side effects, only one participant complained of mild itching at the application area of EMLA® cream. No others showed skin erythema or any serious side effects.
| Total | Group 1 | Group 2 | Group 3 | Group 4 | P value | |
|---|---|---|---|---|---|---|
| N | 24 | 7 | 6 | 6 | 5 | |
| Age (years), mean (SD) | 36.7 (8.0) | 32.3 (5.2) | 42.5 (11.3) | 36.5 (5.9) | 36.0 (6.3) | 0.24 |
| Male | 8 (33%) | 3 (43%) | 0 (0%) | 3 (50%) | 2 (40%) | 0.25 |
| Complication of allergic diseases | 12 (50%) | 3 (43%) | 4 (67%) | 2 (33%) | 3 (60%) | 0.64 |
| Right-handed | 23 (96%) | 7 (100%) | 6 (100%) | 5 (83%) | 5 (100%) | 0.37 |
| Blood sampling site | 0.34 | |||||
| Both antecubital veins | 21 (88%) | 5 (71%) | 5 (83%) | 6 (100%) | 5 (100%) | |
| Antecubital vein and other sites (cephalic or basilic vein) | 3 (12%) | 2 (29%) | 1 (17%) | 0 (0%) | 0 (0%) | |
| Mean amount of blood sampling (mL), mean (SD) | 1.8 (0.4) | 1.6 (0.5) | 1.8 (0.4) | 2.0 (0.0) | 1.8 (0.4) | 0.27 |
| Mean time taken for blood sampling (minutes), mean (SD) | 0.6 (0.5) | 1.0 (0.6) | 0.7 (0.6) | 0.3 (0.3) | 0.5 (0.4) | 0.17 |
| Total number of times the skin was punctured | ||||||
| twice | 20 (83%) | 5 (71%) | 4 (67%) | 6 (100%) | 5 (100%) | 0.25 |
| more than twice | 4 (17%) | 2 (29%) | 2 (33%) | 0 (0%) | 0 (0%) | |
| Coating time of local anesthetic (minutes), mean (SD) | 70.8 (12.7) | 68.0 (6.6) | 68.8 (10.5) | 77.2 (20.9) | 69.2 (10.0) | 0.89 |
SD, standard deviation
| Outcome | EMLA® cream (N = 24) | LMX5® cream (N = 24) | P value |
|---|---|---|---|
| Visual analogue scale, mean (SD) | 29.0 (28.5) | 31.8 (27.4) | 0.529 |
| Blood sampling site (antecubital veins) | 23 (95.8%) | 22 (91.7%) | 1.000 |
| Blood sampling volume, mean (SD) | 1.75 (0.665) | 1.83 (0.565) | 0.669 |
| Blood sampling frequency, mean (SD) | 1.08 (0.282) | 1.13 (0448) | 0.966 |
| Any side effect | 1 (4.2%) | 0 (0%) | 1.000 |
EMLA®, 2.5% lidocaine plus 2.5% prilocaine cream (trade name EMLA® cream);
LMX5®, 5% lidocaine cream (trade name LMX5® cream); SD, standard deviation
Table 3 shows the results of a post-hoc multivariate regression analysis for the VAS score. Depending on whether or not the coating time of the local anesthetic exceeded 65 minutes, the participants were divided into 2 groups of roughly equal size. There were no significant differences between EMLA® cream and LMX5® cream after adjusting for participants’ background characteristics (difference: 2.83; 95% confidence interval: −11.25 to 16.92; P value: 0.693). Coating for >65 minutes significantly reduced the VAS scores compared with coating for ≤65 minutes (difference: −22.4, 95% confidence interval: −39.5 to −5.34, P value: 0.010) (Fig. 2).
| Coefficient | 95% confidence interval | P value | |
|---|---|---|---|
| Topical anesthetic | 0.693 | ||
| EMLA® cream | Ref. | ||
| LMX5® cream | 2.83 | −11.3–16.9 | |
| Age (years) | 0.59 | −0.38–1.56 | 0.231 |
| Male | 16.4 | −1.80–34.5 | 0.077 |
| Coating time of local anesthetic | 0.010 | ||
| 60–65 (minutes) | Ref. | ||
| 66–110 (minutes) | −22.2 | −39.0–−5.29 |
Ref, reference; EMLA®, 2.5% lidocaine plus 2.5% prilocaine cream (trade name EMLA® cream); LMX5®, 5% lidocaine cream (trade name LMX5® cream)
EMLA®, 2.5% lidocaine plus 2.5% prilocaine cream (trade name EMLA® cream); LMX5®, 5% lidocaine cream (trade name LMX5® cream). The dashed line indicates 66 minutes of coating time of the local anesthetic.
We conducted a randomized crossover trial to evaluate the analgesic effect at the time of blood collection of two kinds of topical anesthetic creams: EMLA® cream and LMX5® cream. The results showed that the VAS scores after applying each cream was around 30, and there was no significant difference in the analgesic effect between EMLA® cream and LMX5® cream.
Previous studies have shown that both EMLA® [1, 3, 4, 7, 10] and LMX5® [5–7, 14] have analgesic effects. We assumed a median VAS score without anesthetic cream of 44 from a previous study [9] and confirmed an analgesic effect for both creams, similar to previous studies. As in a previous study comparing EMLA® and 4% lidocaine cream in meatotomy of patients with meatal stenosis [7], there was no marked difference in the analgesic effect between EMLA® cream and LMX5® cream in venipuncture at the time of blood sampling. Although the present study did not evaluate the equivalence of the effects of both creams, the results may indicate that both creams have similar analgesic effects not only in mucosal analgesia but also in percutaneous venipuncture.
There were no marked differences in the blood-sampling site, volume, or frequency between EMLA® cream and LMX5® cream. If the ease of blood collection differed between the creams, the blood-sampling site, volume, and frequency would also be different. We demonstrated that there were no marked differences in the difficulty of collecting blood by applying either cream.
Side effects were found only with EMLA® cream (mild pruritus), but no adverse reactions that could be clinically problematic were observed. This is consistent with previous reports showing that EMLA® cream induced mild side effects such as blanching and erythema but no serious side effects [3, 10].
After the application of EMLA® cream, it is usually recommended to cover the area with occlusive dressing. In the present study, however, due to concerns about ensuring convenience and avoiding side effects, we did not wrap the application area with occlusive dressing and instead applied the cream somewhat thickly. Had we wrapped the area, the analgesic effect may have been improved, although the side effects might also have increased.
Our post-hoc multivariate regression analysis showed that coating with local anesthetic for >65 minutes significantly reduced the VAS score compared to coating for less time. It was found that the application of both topical anesthetics for >65 minutes prior to blood sampling may be more effective than shorter time intervals.
Previous studies showed that both EMLA® and LMX5® cream had an analgesic effect that increased with coating time [1, 3–7, 10, 14]. Our data confirmed that both drugs had a sufficient effect (≥20 reduction in the VAS score) on suppressing pain at the time of venipuncture.
Several limitations associated with the present study warrant mention. First, the estimated sample size may have been too small. However, our findings suggested that there was little difference in the analgesic effect of either cream, so it is highly likely that the results would not change even if the sample size were increased. Second, due to the small sample size, we were unable to create a model that included many variables at the same time for a multivariate analysis. However, we believed that the clinically important items were included in the model used. Third, our finding of a significant analgesic effect when the creams were applied >65 minutes before blood collection was obtained from a post-hoc analysis rather than the planned protocol. If a cream must be applied more than one hour before blood collection in order to obtain a stronger effect, it may not be feasible to use in an actual clinical setting. Such a long waiting time may confuse the clinic and place stress on patients, especially children. Finally, the participants of this study were all adults, so how these results will translate to children is unclear. As children are the subjects who most require pain relief during venipuncture, further studies in children are needed.
Our first randomized crossover study showed that there was no significant difference in the analgesic effect for adults between EMLA® cream and LMX5® cream. Both creams showed an analgesic effect without marked differences in usability or clinically serious side effects. In the future, evaluation trials of the analgesic effectiveness of these creams in children should be conducted.
The trial was funded by the Japanese Ministry for the Environment.
The authors declare no conflicts of interest associated with this manuscript.
