- Email: [email protected]
Depth of cutaneous analgesia after application of a eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA cream)
Depth of cutaneous analgesia after application of a eutectic mixture of the local anesthetics lidocaine and prilocaine (EMLA cream) Carl-Fredrik Wahlgren, MD, PhD,a,b and Hans Quiding, PhDb Stockholm and Södertälje, Sweden Background: EMLA cream, a eutectic mixture of lidocaine and prilocaine, is a topical anesthetic, frequently used to avoid pain during venipuncture and superficial surgery. However, the depth of analgesia needs further exploration. Objective: Our purpose was to investigate the depth of cutaneous analgesia after application of EMLA cream. Methods: In a single-blind crossover study, EMLA cream was applied under occlusion to the left thighs of 16 subjects. Eleven had application times of 60 and 120 minutes. Five subjects had application times of 3 to 4 hours. Approximately 10 minutes after removal of the EMLA cream, a skin biopsy punch (diameter 4 mm) was inserted to a depth of 1 mm into the skin and the subject rated the pain intensity on a visual analogue scale. If there was no pain or if pain was assessed as acceptable, a new biopsy punch was inserted at a new site to the depth of 2 mm. In this manner, the insertion depth was gradually increased in steps of 1 mm down to a maximum of 6 mm. No skin specimens were removed. Results: After 60 and 120 minutes of EMLA application the mean insertion depths with acceptable pain were 2.9 and 4.5 mm (P < .01), respectively. After 3 to 4 hours of application, 6-mm deep insertions were made with acceptable pain in all 5 subjects. Conclusion: Skin biopsy punch insertions in steps of 1 mm appear adequate for assessing the depth of cutaneous analgesia. Biopsy punch insertions with acceptable pain can be made to depths of 1 to 2 mm after 60 minutes, to 2 to 3 mm after 120 minutes, and to 6 mm after 3 to 4 hours of EMLA cream application. (J Am Acad Dermatol 2000;42:584-8.)
C
utaneous application of EMLA cream, a eutectic mixture of the two local anesthetics lidocaine and prilocaine, reduces the perception of pain1 and temperature.2 After 60 minutes of cutaneous application under occlusion, the local effect of EMLA is sufficient for needle insertion and minor superficial skin surgery.1 The analgesic efficacy increases with longer application time1 and after 120 minutes of application, EMLA cream induces sufFrom the Department of Dermatology and Venereology, Karolinska Hospital and Institute, Stockholma; and Clinical Research and Development, AstraZeneca, Södertälje.b Supported by Astra Pain Control AB, Södertälje, Sweden. Accepted for publication Nov 4, 1999. Reprint requests: Carl-Fredrik Wahlgren, MD, PhD, Department of Dermatology and Venereology, Karolinska Hospital, Box 120, SE171 76 Stockholm, Sweden. E-mail: [email protected]. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/104303 doi:10.1067/mjd.2000.104303
584
ficient analgesia for the cutting of split-skin grafts with a dermatome.3 Although EMLA cream has been clinically used for a long period (eg, approved since 1984 in Sweden and since 1992 in the United States), few data exist on the depth of skin analgesia. The question has previously been approached by using an intravenous needle, which was inserted slowly and perpendicularly into the skin on the dorsal side of the forearm until pain was perceived.4 For cutting skin stimuli, such as punch biopsies or scalpel incisions, no systematic data on the depth of analgesia appear to exist. The aim of the present study was to explore to which depth a skin biopsy punch could be inserted with acceptable pain after 60 and 120 minutes of EMLA cream application.
MATERIAL AND METHODS Subjects Sixteen healthy volunteers, 8 male and 8 female, all
J AM ACAD DERMATOL VOLUME 42, NUMBER 4
Caucasians, were included in the study, which was performed in the Astra Human Pharmacology Unit at the Huddinge Hospital, Stockholm, Sweden. The median age of the subjects was 31 years (range, 19-45 years). Inclusion criteria were as follows: age between 18 and 46 years, healthy according to a physical examination, clinical chemistry and hematology investigations, intact skin on the left thigh, and written consent to participate. Exclusion criteria were pregnancy, breastfeeding, history of allergy to lidocaine or prilocaine, history of keloids, skin sensitivity to tape, or suspicion of noncompliance with the study procedure. The investigation was performed in accordance with the principles stated in the Declaration of Helsinki and was approved by the local Ethics Committee. Study design and EMLA cream treatment EMLA Cream 5% (AstraZeneca, Södertälje, Sweden), a eutectic mixture of 25 mg lidocaine and 25 mg prilocaine per gram of cream, was used for topical anesthesia. Two application times, a short and a long, were used in each subject and randomized to the first and second visits. In 11 subjects (group A), the two EMLA cream application times were within ±10% from 60 and 120 minutes; the ranges were 55 to 65 minutes and 119 to 131 minutes, respectively. In 5 subjects (group B), one or both application times deviated more than 10% from 60 and 120 minutes, and the ranges were 78 to 130 minutes and 121 to 232 minutes, respectively. The investigator who performed the biopsy punch insertions was blinded with regard to application times. Two application areas (each 40 cm2), a proximal and a distal, were used on the ventral aspect of the left thigh. At the first visit, EMLA cream was applied to the proximal area and at the second visit 1 week later to the distal area. The dosage was 1.0 to 1.5 g/10 cm2. Plastic film (Tegaderm, 3M Svenska AB, Sollentuna, Sweden) was used for occlusion. All subjects had 2 follow-up visits after 2 and 7 months to check the healing of the scars after the skin biopsy punch insertions. In group A, subjects who perceived unacceptable pain at an insertion depth of 4 mm or less after 120 minutes of EMLA application (total of 5 subjects) were asked to participate in an additional test with 200 minutes of application. Three of the 5 subjects could participate and this part of the study was performed at a third visit 10 to 12 weeks after the second visit and with the application time known to the investigator. Skin biopsy punch insertions and assessment of pain Approximately 10 minutes after removal of the
Wahlgren and Quiding 585
Fig 1. Disposable skin biopsy punch placed into the plastic device, which controls insertion depth of punch. In this figure, the edge of the biopsy punch is 5 mm below the bottom plate of the device, that is, the punch cannot be inserted deeper than 5 mm into the skin.
EMLA cream, a sterile disposable skin biopsy punch (Miltex Instrument Company, Inc, Lake Success, NY) with a diameter of 4 mm was inserted by rotation into the skin. The aim of this procedure was to provoke a clinically relevant cutting pain stimulus to a defined skin depth. The punched skin specimens were not removed but kept in position in the skin with Steri-Strip skin closure tape (3M, St Paul, Minn) to minimize the tissue scarring. A plastic device was specifically constructed to control the insertion depth of the biopsy punch (Fig 1). The bottom plate (50 × 30 mm) of the device was gently pressed onto the skin and the biopsy punch inserted through a 10-mm wide hole in the plate. The shaft of the biopsy punch has a flange approximately 48 mm from the cutting edge. No further insertion of the punch is possible when the flange meets a shelf on the plastic device. The shelf level can be adjusted mechanically with a screw. Depths can be selected in steps of 0.25 mm between 0.0 and 7.0 mm. In the present study, the first depth was 1 mm. Thirty seconds after the insertion of the biopsy punch to this depth, the subject rated the pain intensity on a 100-mm visual analogue scale.5-7 If pain was perceived, the subject also rated whether or not it was acceptable. If the pain intensity was below 50 mm and was judged acceptable, and the subject was willing to continue, a new disposable biopsy punch was inserted at another site to a depth of 2 mm. Then pain was rated again. In this way, the skin insertion depth was increased in steps of 1 mm to a maximum of 6 mm. The time between insertions was approximately 1 minute.
586 Wahlgren and Quiding
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Table I. Frequency of subjects with skin biopsy punch insertions with acceptable pain in relation to 60 and 120 minutes (±10%) of EMLA cream application and insertion depths Skin biopsy punch insertion depth (mm) EMLA application time
60 min 120 min
1
2
3
4
5
6
100% 100%
91% 100%
64% 91%
18% 73%
9% 45%
9% 36%
All subjects (n = 11) had both application times.
Table II. Frequency of 6-mm deep skin biopsy punch insertions with acceptable pain in relation to EMLA application times EMLA application time (min) Interval
55-119 (n = 15) 120-179 (n = 15) 180-232 (n = 5)
Mean
Frequency of 6-mm deep insertions with acceptable pain
70 125 201
20% 47% 100%
Thirteen subjects had two application times and 3 had 3.
Two potential sources of error in the assessment of the biopsy punch insertion depths were identified: (1) variations in length of the disposable skin biopsy punches, and (2) elevation of the skin through the hole in the bottom plate of the plastic device. After insertion the variation in length from the cutting edge to the flange was measured in 153 of the total 156 disposable skin biopsy punches used in the study. The variation ranged between –0.3 and +0.1 mm, with a mean of 0.0 mm. Because these variations were small in comparison with the 1-mm steps of the biopsy punch insertions, they were not adjusted for. When the plastic device for standardized skin biopsy punch insertions (Fig 1) was placed on the thigh, an elevation of the skin could occur in the central hole of the bottom plate through which the insertion was made. The elevation was measured with a measure rod (resolution 0.1 mm) for all 156 insertions and ranged between 0.0 and 0.4 mm, with a mean of 0.1 mm. These elevations were considered to have no significant importance and thus no adjustments were conducted. Statistical analyses The SAS system version 6.12 (SAS Institute Inc, Cary, NC) was used for the statistical analysis. Treatment differences between 60 and 120 minutes
of EMLA application were tested for treatment and period effects using the Wilcoxon rank sum test for a 2 × 2 crossover design.8 When testing the treatment effect, such a test adjusts for possible period effects. A two-tailed value of P less than .05 was considered statistically significant.
RESULTS Group A The proportion of subjects undergoing biopsy punch insertions with acceptable pain gradually decreased with increasing depths as summarized in Table I. The 1- and 2-mm deep punch insertions were performed in all 11 subjects at both application times and were rated as acceptable on all but one insertion. Approximately 10 minutes after 60 and 120 minutes of application, approximately 50% of the subjects had biopsy punch insertions 3 and 5 mm deep, respectively, with acceptable pain. Punch insertion to the maximum depth of 6 mm was performed with acceptable pain in 9% and 36% of the subjects after 60 and 120 minutes of application, respectively. The mean maximum biopsy punch insertion depth with acceptable pain was 2.9 mm (median, 3 mm; range, 1-6 mm) after 60 minutes of application and 4.5 mm (median, 4 mm; range, 2-6 mm) after 120 minutes of application (P < .01). Group A and B After the longer of the two application times the maximum acceptable punch insertion depth was increased in 11 subjects and unchanged in 5 (Fig 2). However, in 4 of these 5 subjects the maximum depth of 6 mm had already been reached after the shorter application time. In the subjects with approximately 200 minutes of application time at a third visit, pain was perceived as acceptable at the maximum insertion depth of 6 mm for all 3 subjects (Fig 2, thicker lines). Table II shows the frequency of 6-mm deep punch insertions with acceptable pain in relation to the application times of EMLA. Six millimeter deep inser-
J AM ACAD DERMATOL VOLUME 42, NUMBER 4
Wahlgren and Quiding 587
tions with acceptable pain were performed on all 5 occasions with 3 to 4 hours of application and on approximately half of the 15 occasions with 2 to 3 hours’ application time. No adverse events related to EMLA were reported. At the follow-up visit after 2 months, one of the 156 biopsy punch insertions had healed with a cosmetically unsatisfactory result because the scar tissue was elevated about 2 mm above the skin level. This was treated with razor blade surgery. An inspection at 7 months after the biopsy insertions revealed healing with no or minimal scarring in all subjects.
DISCUSSION In the present study, disposable skin biopsy punches with a diameter of 4 mm were used together with a specially constructed mechanical device to explore the depth of cutaneous analgesia after topical application of EMLA cream. Biopsy punches were chosen to produce a cutting painful skin stimulus relevant to the everyday clinical practice of most dermatologists. The variations in length of the disposable punches (–0.3 to +0.1 mm) and the elevation of skin through the hole in the bottom plate of the device (0.0 to +0.4 mm) were potential sources of error in the measurement of the insertion depth. Taken together, these effects give at worst a theoretical error in the insertion depth of –0.3 or +0.5 mm. The worst measured error was –0.1 or +0.3 mm. The sources of error were consequently minor and no adjustments were made. Furthermore, any skin elevation was probably due to individual factors and would therefore not affect comparisons between the two application times. The biopsy punches were taken from unbroken packages and variations in the length of the punches would thus be at random. With the present technique, the measurement of the depth of cutaneous analgesia in steps of 1 mm seems justified and adequate. Another methodological aspect is the technique used for pain assessment. Pain was rated by the subjects using a VAS.5-7 In addition, if pain was perceived (VAS > 0 mm) it was assessed as acceptable or not acceptable. In this way, the investigators did not have to interpret which pain intensities were unacceptable for the procedure. Not acceptable pain corresponded to a median VAS score of 75 mm (range, 40100 mm). In a study of pain measurement in healthy volunteers, words describing pain intensity were matched to VAS values.9 The words “moderate pain” and “severe pain” corresponded to a median VAS score of 49 and 91 mm, respectively. Furthermore, in studies of postoperative pain, analgesics have been needed subjectively at pain intensities (medians) between approximately 50 and 70 mm on a 100-mm
Fig 2. Maximum skin biopsy punch insertion depth with acceptable pain as function of application time of EMLA cream. For each of the 16 subjects, the two application times (a shorter and a longer) are connected with a line (n = 16). Thicker lines represent the 3 subjects receiving EMLA cream for 180 to 200 minutes in a third additional test.
VAS.10,11 If these data are applied to the findings of our study, unacceptable pain would correspond to a need for analgesics and a verbal intensity rating between “moderate pain” and “severe pain.” Few studies have focused on the depth of skin analgesia induced by topical anesthetics. EMLA cream applied for 2 to 5 hours under occlusion has been shown to provide sufficient analgesia for the cutting of split-skin grafts with a dermatome depth of 0.25 to 0.58 mm.3 In another study, the depth of skin analgesia after EMLA cream application was investigated with the use of an 18-gauge intravenous needle.4 The maximal depth of skin analgesia was approximately 5 mm, observed 30 minutes after a 90minute application and during the 60-minute period after a 120-minute application of EMLA cream. However, the depth of 5 mm represented a combination of the needle’s indentation of the skin surface due to mechanical pressure and the actual depth of needle penetration into the skin. The exact extent of the indentation was not presented, but the needle could be introduced approximately 1.8 mm perpendicularly to the skin without pain in areas without active treatment. Therefore the stated maximal depth of 5 mm of skin analgesia4 might in fact have been somewhat less. In the present investigation, the analgesic efficacy of EMLA increased with longer application time, which is in agreement with previous studies.1-4 Approximately 10 minutes after removal of EMLA cream, the mean maximum biopsy punch insertion depth with acceptable pain was 2.9 mm after 60 min-
588 Wahlgren and Quiding
utes of application and 4.5 mm after 120 minutes of application. Insertions, 6 mm deep, were made with acceptable pain on all occasions after 3 to 4 hours of EMLA application. However, the analgesic effect decreases with extensive application times1,3; for surgical procedures on intact skin in adults, the manufacturer recommends a maximum application time of 5 hours. We acknowledge the excellent work of Kia Eriksson, research nurse, and Marie Nilsson, statistician, AstraZeneca. We thank Sune Mårtensson, instrument maker at the Department of Clinical Engineering, Karolinska Hospital, Stockholm, for supreme technical construction skill. REFERENCES 1. Juhlin L, Evers H. EMLA: a new topical anaesthetic. Adv Dermatol 1990;5:75-92. 2. Arendt-Nielsen L, Bjerring P. The effect of topically applied anaesthetics (EMLA® cream) on thresholds to thermode and argon laser stimulation. Acta Anaesthesiol Scand 1989;33:46973.
J AM ACAD DERMATOL APRIL 2000
3. Lähteenmäki T, Lillieborg S, Ohlsén L, Olenius M, Strömbeck JO. Topical analgesia for the cutting of split-skin grafts: a multicenter comparison of two doses of a lidocaine/prilocaine cream. Plast Reconstr Surg 1988;82:458-62. 4. Bjerring P, Arendt-Nielsen L. Depth and duration of skin analgesia to needle insertion after topical application of Emla cream. Br J Anaesth 1990;64:173-7. 5. Huskisson EC. Visual analogue scales. In: Melzack R, editor. Pain measurement and assessment. New York: Raven Press; 1983. p. 33-7. 6. Price DD, McGrath PA, Rafii A, Buckingham B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 1983;17:45-56. 7. Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain measurement: an overview. Pain 1985;22:1-31. 8. Senn S. Statistical issues in drug development. Chichester: John Wiley & Sons; 1997. p. 237-48. 9. Sriwatanakul K, Kelvie W, Lasagna L. The quantification of pain: an analysis of words used to describe pain and analgesia in clinical trials. Clin Pharmacol Ther 1982;32:143-8. 10. Quiding H, Oksala E, Happonen R-P, Lehtimäki K, Ojala T. The visual analog scale in multiple-dose evaluations of analgesics. J Clin Pharmacol 1981;21:424-9. 11. Quiding H, Häggquist S-O. Visual analogue scale and the analysis of analgesic action. Eur J Clin Pharmacol 1983;24:475-8.
C
utaneous application of EMLA cream, a eutectic mixture of the two local anesthetics lidocaine and prilocaine, reduces the perception of pain1 and temperature.2 After 60 minutes of cutaneous application under occlusion, the local effect of EMLA is sufficient for needle insertion and minor superficial skin surgery.1 The analgesic efficacy increases with longer application time1 and after 120 minutes of application, EMLA cream induces sufFrom the Department of Dermatology and Venereology, Karolinska Hospital and Institute, Stockholma; and Clinical Research and Development, AstraZeneca, Södertälje.b Supported by Astra Pain Control AB, Södertälje, Sweden. Accepted for publication Nov 4, 1999. Reprint requests: Carl-Fredrik Wahlgren, MD, PhD, Department of Dermatology and Venereology, Karolinska Hospital, Box 120, SE171 76 Stockholm, Sweden. E-mail: [email protected]. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/104303 doi:10.1067/mjd.2000.104303
584
ficient analgesia for the cutting of split-skin grafts with a dermatome.3 Although EMLA cream has been clinically used for a long period (eg, approved since 1984 in Sweden and since 1992 in the United States), few data exist on the depth of skin analgesia. The question has previously been approached by using an intravenous needle, which was inserted slowly and perpendicularly into the skin on the dorsal side of the forearm until pain was perceived.4 For cutting skin stimuli, such as punch biopsies or scalpel incisions, no systematic data on the depth of analgesia appear to exist. The aim of the present study was to explore to which depth a skin biopsy punch could be inserted with acceptable pain after 60 and 120 minutes of EMLA cream application.
MATERIAL AND METHODS Subjects Sixteen healthy volunteers, 8 male and 8 female, all
J AM ACAD DERMATOL VOLUME 42, NUMBER 4
Caucasians, were included in the study, which was performed in the Astra Human Pharmacology Unit at the Huddinge Hospital, Stockholm, Sweden. The median age of the subjects was 31 years (range, 19-45 years). Inclusion criteria were as follows: age between 18 and 46 years, healthy according to a physical examination, clinical chemistry and hematology investigations, intact skin on the left thigh, and written consent to participate. Exclusion criteria were pregnancy, breastfeeding, history of allergy to lidocaine or prilocaine, history of keloids, skin sensitivity to tape, or suspicion of noncompliance with the study procedure. The investigation was performed in accordance with the principles stated in the Declaration of Helsinki and was approved by the local Ethics Committee. Study design and EMLA cream treatment EMLA Cream 5% (AstraZeneca, Södertälje, Sweden), a eutectic mixture of 25 mg lidocaine and 25 mg prilocaine per gram of cream, was used for topical anesthesia. Two application times, a short and a long, were used in each subject and randomized to the first and second visits. In 11 subjects (group A), the two EMLA cream application times were within ±10% from 60 and 120 minutes; the ranges were 55 to 65 minutes and 119 to 131 minutes, respectively. In 5 subjects (group B), one or both application times deviated more than 10% from 60 and 120 minutes, and the ranges were 78 to 130 minutes and 121 to 232 minutes, respectively. The investigator who performed the biopsy punch insertions was blinded with regard to application times. Two application areas (each 40 cm2), a proximal and a distal, were used on the ventral aspect of the left thigh. At the first visit, EMLA cream was applied to the proximal area and at the second visit 1 week later to the distal area. The dosage was 1.0 to 1.5 g/10 cm2. Plastic film (Tegaderm, 3M Svenska AB, Sollentuna, Sweden) was used for occlusion. All subjects had 2 follow-up visits after 2 and 7 months to check the healing of the scars after the skin biopsy punch insertions. In group A, subjects who perceived unacceptable pain at an insertion depth of 4 mm or less after 120 minutes of EMLA application (total of 5 subjects) were asked to participate in an additional test with 200 minutes of application. Three of the 5 subjects could participate and this part of the study was performed at a third visit 10 to 12 weeks after the second visit and with the application time known to the investigator. Skin biopsy punch insertions and assessment of pain Approximately 10 minutes after removal of the
Wahlgren and Quiding 585
Fig 1. Disposable skin biopsy punch placed into the plastic device, which controls insertion depth of punch. In this figure, the edge of the biopsy punch is 5 mm below the bottom plate of the device, that is, the punch cannot be inserted deeper than 5 mm into the skin.
EMLA cream, a sterile disposable skin biopsy punch (Miltex Instrument Company, Inc, Lake Success, NY) with a diameter of 4 mm was inserted by rotation into the skin. The aim of this procedure was to provoke a clinically relevant cutting pain stimulus to a defined skin depth. The punched skin specimens were not removed but kept in position in the skin with Steri-Strip skin closure tape (3M, St Paul, Minn) to minimize the tissue scarring. A plastic device was specifically constructed to control the insertion depth of the biopsy punch (Fig 1). The bottom plate (50 × 30 mm) of the device was gently pressed onto the skin and the biopsy punch inserted through a 10-mm wide hole in the plate. The shaft of the biopsy punch has a flange approximately 48 mm from the cutting edge. No further insertion of the punch is possible when the flange meets a shelf on the plastic device. The shelf level can be adjusted mechanically with a screw. Depths can be selected in steps of 0.25 mm between 0.0 and 7.0 mm. In the present study, the first depth was 1 mm. Thirty seconds after the insertion of the biopsy punch to this depth, the subject rated the pain intensity on a 100-mm visual analogue scale.5-7 If pain was perceived, the subject also rated whether or not it was acceptable. If the pain intensity was below 50 mm and was judged acceptable, and the subject was willing to continue, a new disposable biopsy punch was inserted at another site to a depth of 2 mm. Then pain was rated again. In this way, the skin insertion depth was increased in steps of 1 mm to a maximum of 6 mm. The time between insertions was approximately 1 minute.
586 Wahlgren and Quiding
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Table I. Frequency of subjects with skin biopsy punch insertions with acceptable pain in relation to 60 and 120 minutes (±10%) of EMLA cream application and insertion depths Skin biopsy punch insertion depth (mm) EMLA application time
60 min 120 min
1
2
3
4
5
6
100% 100%
91% 100%
64% 91%
18% 73%
9% 45%
9% 36%
All subjects (n = 11) had both application times.
Table II. Frequency of 6-mm deep skin biopsy punch insertions with acceptable pain in relation to EMLA application times EMLA application time (min) Interval
55-119 (n = 15) 120-179 (n = 15) 180-232 (n = 5)
Mean
Frequency of 6-mm deep insertions with acceptable pain
70 125 201
20% 47% 100%
Thirteen subjects had two application times and 3 had 3.
Two potential sources of error in the assessment of the biopsy punch insertion depths were identified: (1) variations in length of the disposable skin biopsy punches, and (2) elevation of the skin through the hole in the bottom plate of the plastic device. After insertion the variation in length from the cutting edge to the flange was measured in 153 of the total 156 disposable skin biopsy punches used in the study. The variation ranged between –0.3 and +0.1 mm, with a mean of 0.0 mm. Because these variations were small in comparison with the 1-mm steps of the biopsy punch insertions, they were not adjusted for. When the plastic device for standardized skin biopsy punch insertions (Fig 1) was placed on the thigh, an elevation of the skin could occur in the central hole of the bottom plate through which the insertion was made. The elevation was measured with a measure rod (resolution 0.1 mm) for all 156 insertions and ranged between 0.0 and 0.4 mm, with a mean of 0.1 mm. These elevations were considered to have no significant importance and thus no adjustments were conducted. Statistical analyses The SAS system version 6.12 (SAS Institute Inc, Cary, NC) was used for the statistical analysis. Treatment differences between 60 and 120 minutes
of EMLA application were tested for treatment and period effects using the Wilcoxon rank sum test for a 2 × 2 crossover design.8 When testing the treatment effect, such a test adjusts for possible period effects. A two-tailed value of P less than .05 was considered statistically significant.
RESULTS Group A The proportion of subjects undergoing biopsy punch insertions with acceptable pain gradually decreased with increasing depths as summarized in Table I. The 1- and 2-mm deep punch insertions were performed in all 11 subjects at both application times and were rated as acceptable on all but one insertion. Approximately 10 minutes after 60 and 120 minutes of application, approximately 50% of the subjects had biopsy punch insertions 3 and 5 mm deep, respectively, with acceptable pain. Punch insertion to the maximum depth of 6 mm was performed with acceptable pain in 9% and 36% of the subjects after 60 and 120 minutes of application, respectively. The mean maximum biopsy punch insertion depth with acceptable pain was 2.9 mm (median, 3 mm; range, 1-6 mm) after 60 minutes of application and 4.5 mm (median, 4 mm; range, 2-6 mm) after 120 minutes of application (P < .01). Group A and B After the longer of the two application times the maximum acceptable punch insertion depth was increased in 11 subjects and unchanged in 5 (Fig 2). However, in 4 of these 5 subjects the maximum depth of 6 mm had already been reached after the shorter application time. In the subjects with approximately 200 minutes of application time at a third visit, pain was perceived as acceptable at the maximum insertion depth of 6 mm for all 3 subjects (Fig 2, thicker lines). Table II shows the frequency of 6-mm deep punch insertions with acceptable pain in relation to the application times of EMLA. Six millimeter deep inser-
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tions with acceptable pain were performed on all 5 occasions with 3 to 4 hours of application and on approximately half of the 15 occasions with 2 to 3 hours’ application time. No adverse events related to EMLA were reported. At the follow-up visit after 2 months, one of the 156 biopsy punch insertions had healed with a cosmetically unsatisfactory result because the scar tissue was elevated about 2 mm above the skin level. This was treated with razor blade surgery. An inspection at 7 months after the biopsy insertions revealed healing with no or minimal scarring in all subjects.
DISCUSSION In the present study, disposable skin biopsy punches with a diameter of 4 mm were used together with a specially constructed mechanical device to explore the depth of cutaneous analgesia after topical application of EMLA cream. Biopsy punches were chosen to produce a cutting painful skin stimulus relevant to the everyday clinical practice of most dermatologists. The variations in length of the disposable punches (–0.3 to +0.1 mm) and the elevation of skin through the hole in the bottom plate of the device (0.0 to +0.4 mm) were potential sources of error in the measurement of the insertion depth. Taken together, these effects give at worst a theoretical error in the insertion depth of –0.3 or +0.5 mm. The worst measured error was –0.1 or +0.3 mm. The sources of error were consequently minor and no adjustments were made. Furthermore, any skin elevation was probably due to individual factors and would therefore not affect comparisons between the two application times. The biopsy punches were taken from unbroken packages and variations in the length of the punches would thus be at random. With the present technique, the measurement of the depth of cutaneous analgesia in steps of 1 mm seems justified and adequate. Another methodological aspect is the technique used for pain assessment. Pain was rated by the subjects using a VAS.5-7 In addition, if pain was perceived (VAS > 0 mm) it was assessed as acceptable or not acceptable. In this way, the investigators did not have to interpret which pain intensities were unacceptable for the procedure. Not acceptable pain corresponded to a median VAS score of 75 mm (range, 40100 mm). In a study of pain measurement in healthy volunteers, words describing pain intensity were matched to VAS values.9 The words “moderate pain” and “severe pain” corresponded to a median VAS score of 49 and 91 mm, respectively. Furthermore, in studies of postoperative pain, analgesics have been needed subjectively at pain intensities (medians) between approximately 50 and 70 mm on a 100-mm
Fig 2. Maximum skin biopsy punch insertion depth with acceptable pain as function of application time of EMLA cream. For each of the 16 subjects, the two application times (a shorter and a longer) are connected with a line (n = 16). Thicker lines represent the 3 subjects receiving EMLA cream for 180 to 200 minutes in a third additional test.
VAS.10,11 If these data are applied to the findings of our study, unacceptable pain would correspond to a need for analgesics and a verbal intensity rating between “moderate pain” and “severe pain.” Few studies have focused on the depth of skin analgesia induced by topical anesthetics. EMLA cream applied for 2 to 5 hours under occlusion has been shown to provide sufficient analgesia for the cutting of split-skin grafts with a dermatome depth of 0.25 to 0.58 mm.3 In another study, the depth of skin analgesia after EMLA cream application was investigated with the use of an 18-gauge intravenous needle.4 The maximal depth of skin analgesia was approximately 5 mm, observed 30 minutes after a 90minute application and during the 60-minute period after a 120-minute application of EMLA cream. However, the depth of 5 mm represented a combination of the needle’s indentation of the skin surface due to mechanical pressure and the actual depth of needle penetration into the skin. The exact extent of the indentation was not presented, but the needle could be introduced approximately 1.8 mm perpendicularly to the skin without pain in areas without active treatment. Therefore the stated maximal depth of 5 mm of skin analgesia4 might in fact have been somewhat less. In the present investigation, the analgesic efficacy of EMLA increased with longer application time, which is in agreement with previous studies.1-4 Approximately 10 minutes after removal of EMLA cream, the mean maximum biopsy punch insertion depth with acceptable pain was 2.9 mm after 60 min-
588 Wahlgren and Quiding
utes of application and 4.5 mm after 120 minutes of application. Insertions, 6 mm deep, were made with acceptable pain on all occasions after 3 to 4 hours of EMLA application. However, the analgesic effect decreases with extensive application times1,3; for surgical procedures on intact skin in adults, the manufacturer recommends a maximum application time of 5 hours. We acknowledge the excellent work of Kia Eriksson, research nurse, and Marie Nilsson, statistician, AstraZeneca. We thank Sune Mårtensson, instrument maker at the Department of Clinical Engineering, Karolinska Hospital, Stockholm, for supreme technical construction skill. REFERENCES 1. Juhlin L, Evers H. EMLA: a new topical anaesthetic. Adv Dermatol 1990;5:75-92. 2. Arendt-Nielsen L, Bjerring P. The effect of topically applied anaesthetics (EMLA® cream) on thresholds to thermode and argon laser stimulation. Acta Anaesthesiol Scand 1989;33:46973.
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