Trial of a topically administered local anesthetic (EMLA cream) for pain relief during central venous port accesses in children with cancer

Trial of a topically administered local anesthetic (EMLA cream) for pain relief during central venous port accesses in children with cancer

Vol. 91Vo. 4 May 1994 Jounzat of Pain and Synptom Management 259 Angela IV. .Miser, MB, T. Suan Goh, MB, Ann Marie Dose, RN, Judith R O’Fallon, PhD...

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Vol. 91Vo. 4 May 1994

Jounzat of Pain and Synptom Management

259

Angela IV. .Miser, MB, T. Suan Goh, MB, Ann Marie Dose, RN, Judith R O’Fallon, PhD, Robert D. Niedringhaus, MD, Donna L. Betcher, RN, Patricia Simmons, RN, Darlene J. MacRellar, RN, Marilyn Arnold, RN, and Charles L. Loprinzi, MD Division of Medical Oncolo~ (A.WM., A.M.D., D.L.B., C.L.L.) and Cancer Statistics (JRO.), Muyo Clinic and Mqo Foundation, Rochester, Minnesota; Saskatchewan Cancer Foundation (T.S. G.}, Allan Blair Memorial Clinic, Regina, Saskatchezoan, Canada; Dd~th Community Clinical Oncotogy Program (RD.N.), Duluth, Minnesota; Sioux Comzuni~ Cancer Consortium (P.S.), Sioux Falls, South Dako?a; St. Luke’s Hospitals CCOP (D.fM.), Fargo, North Dakota; and Iowa Oncology Research Association CCOP (M.A.), Des Moines, Iowa

Abstract Procedure-re&ed pain is a signi/cant problem for many children receiving qtotaxic chemothera~. In an effort to lessen this toxici& we studied the eficaq and saf@ty of administering topical local anesthesia using EMLA cream in 4 7 eualuable chiidren with cancer undergoing implanted central venous port injections. Children (c 21 years old) scheduled to undergo repeated venous access procedures were selected f&r study. A placebo-controlled, ramiomized, double-blind, crossover stud] design was utilized. Statistically signifiiant &creases in pain intensity scores (P e 0.002) were recorded by both children and investigators dun’ng the use of EMLA cream as compared with placebo. There was a good correlation between pain scores recorded by both puttits and health care provzders using both visual analog scab and catego&d pain measurement tools. The topical application of EMLA cream 5 % promdes high& effective supe@ial anesthesia, and promises to be extremes usefulforpain relief dun’ngpercutaneous access procedures in cancer patients. J Pain

Symptom Manage 1994;9:259-264.

Procedure-related pain, children, cq’totoxic chemotherapy, EMU

cream

Address Tqbn’nt request-s to: Charles L. Loprinzi, MD, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA.

related pain is one of the most unpleasant and

Acceptedfor publication: September 23, 1993.

feared

0 U.S. Cancer Pain Relief Committee, 1994 Published by Ekevier, New krk, New York

For many children with cancer, aspects

of the

entire

procedure-

management

08853924/91/Si.W

260

Miser et id.

program. J These procedures, which include bone marrow aspirations, lumbar punctures, and v&punctures, are peArformed with sufficient frequency during most cancer treatment programs to make them an ever-present threat during the entire course of therapy. Even procedures such as venous port accesses and finger pricks which, for an adult, usually cause only minor pain and anxiety, can be terrifying for a child for whom an “attack” by a needle engenders such fear that any resulting pain may be enormously magnified. We elected to study, using a double-blind, placeb~on~olled, crossover design, the ability of topically applied EMLA cream 5% (Astra Pharmaceutical Products) to produce local anesthesia of sufftcient depth to render a minor procedure, specifically a central venous port injection, almost or completely painless. This product, a eutectic mixture of lidocaine and prilocaine, has been extensively used in clinical practice for many years in Europe and more recently in Canada, and has an established record for producing excellent super& cial anesthesia. While a previous report has indicated efficacy of this product during central venous port injections, only eight patients were discussed? and, because this procedure is one of the commonest now performed in pediatric oncology practice, it was deemed appropriate to gather more experience using this procedure. Finally, the literature on toxicity following repeated exposure to EMLA cream is extremely sparse, and we felt it important to investigate this aspect of EML,A use because multiple exposures can be anticipated during use of this product for ongoing patient management.

MuteGals and Mdwds Children with cancer, age 3-21 years, who were scheduled to uudergo two central venous port injections within a l-month period, were eligible for study. Becanse from previously reported studies the effective dose and application time for patients with heavily pigmented skin were not clear, only children with skin types I, II, or III,S based on sunburning history, were included. Patients with a history of an allergic reaction to local anesthetics, sun

screens, or suntan lotions, or with skin disease or excoriation at the proposed application site were not eligible for study. Patients receiving systemic analgesic, sedative, hypnotic or other end-altering drugs, which coufd inff uence the validity of the study pain-intensity assessments, were also excluded. Finally, because methemo globinemia is a potential side effect of EMU cream (although this toxicity has been reported only in infants), patients receiving drugs such as sulfonamides, nitrites, nitrates, and aniline dyes, which could exacerbate this condition, were also excluded from the study.

After written informed consent for study participation was obtained, each child was randomly assigned to one of two treatment groups specifying the order in which the study creams were to be administered: one group received EML.A cream for the first procedure and placebo cream for the second, while the other received the study creams in reverse order. A stratified randomization procedure was used with two stratification factors: age in years (3-7 vs 8-l 1 vs 12-15 vs 16-21) and prior experience with the venous port access procedure (yes vs no). The health-care professional performing the venous port access procedure was then supplied with a tube of cream identified by code number.

Treatmmt and Evaluation Methodology EMLA cream 5% (containing 25 mg lidsCaine base and 25 mg prilocaine base per 5 g) or an ide~tic~-appea~ng placebo was applied topically over the implanted port site 66 min prior to the scheduled needle insertion. To ensure correct application, a qualified healthcare professional, generally a study nurse, applied the cream and placed an occlusive dressing (Tegaderm) over it. A dose of 2.5 g EMLA was used for children aged 3-12 years, and 5 g for older children; identical volumes of cream were used during the placebo treatment. After the 66-min application time, the cream was wiped off with a gauze pad and the skin prepared in the usual fashion, e.g., with alcohol and/or iodine-bled solution. The needle was then inserted into the port in the usual fmhion. The health-care professional performing the procedure noted any acute skin changes or

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Procedure-RelatedPain in Children

abnormal sensations reported by the patient; local skin examination was also performed by the parent and/or child 24 hr after each procedure. independent pain assessments were performed 5-15 min following each procedure, first by an observing health-care professional who did not perform the access procedure and then by the chifd. An independent observer was used for pain assessment to exclude the possibility that observed local blanching or erythema, reported to be more frequent following EMLA cream than placebo application, might bias pain-intensity assessments. Both the child and the observer completed a cartoon face scale+-” (CFS) and a visual analogue scale (VAS).’ The CFS used was the five-face scale, picturing facial cartoons from happy to sad and crying, which was used by the North Central Cancer Treatment Group in a previous study.” Tbe visual analogue scale was presented vertically as a “pain thermometer.“4 Children too young to comprehend the pain assessment tool(s) or refusing to use them returned blank forms; a parent or other adult was not permitted to complete the scales on behalf of the child, The second, crossover, procedure was generally performed by the same health-care professional who performed the first procedure (if logisticaily possible) using an identical technique. Pain-intensi~ assessments and toxicity observations were performed in a similar manner. Time intervals of 24 hr to 1 month between procedures were permiued. Following completion of both study prcpcedures, the child was asked which cream he or she preferred. Patients were then eligible to enter an open label continuation phase receiving EMMA cream as needed for future percutaneous access procedures. This continuation study was designed to investigate the development of toxicity, which might occur only following repeated exposure to the drug, pa~c~~~y topical sensitization. The study was designed to detect a clinically meaningful EMLA benefit defined as follows: because the placebo effect can be substantial in analgesic studies, EMLA would be considered effective if it could reduce the pain score by an average of 30% in this population, i.e., if the mean pain score for EML4 was less than 70% of that for placebo. Based on preliminary information from pilot studies, a sample size of 30

261

Table E

Treatment sequence EMILA, then Patient characteristics

Gender Male Female Age group (years,) 3-7 8-11 12-15 16-21

placebo (N= 25)

Placebo, then EMLA fN= 22)

TOtal (N= 4’7)

12 10

28 19

7 8 9 1

8 5 7 2

15 13 16 3

2 7

2 7 12

4 14 28

16 9

Skin type

Burn, never tan Burn. sometimes tan Tan, sometimes burn

16

patients completing both study procedures within a l-month period would provide 90% power for detecting a 30% reduction in the children’s VAS scores using a one-sided 0.025level t test.

A total of 52 children were entered into the study; of these, 47 completed both study procedures, i.e., received both EML.A cream and placebo in random, double-blind order within a l-month period. The two treatment sequence groups were well balanced with respect to the on-study patient characteristics (Table 1). For anaIyzing treatment effectiveness, 47 children had at least one set of pain scores for both study procedures. Pain scores recorded by the patients themselves were available for 46 children, while pain scores recorded by the obsening healthcare professional for both procedures were available for 42 children. Figures 1 and 2 summarize the pain-intensity scores independently recorded by the children and the observing health-care professionais. To assess effectiveness, the recommended crossover analysis was performed for each of the four types of pain scores (VAS and CFS for patients and health-care professionals). That is, the score recorded for the second procedure

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Miser et al.

262

10 0 Child VAS !l=46

Child CFS n-46

HCP VAS n-42

HCP CFS n=42

Fig. 1. Median values of all pain scores recorded for each study cream (EMLA vs. placebo) regardless of the procedure (first vs second) on which the cream was administered, as measured by the child or the health-care professional (HCP) using the visual analogue scale (VAS) or the categorical face scale (CFS).

was subtracted from the score recorded for the first procedure, and the t test was applied to compare the values of these differences be-

tween the two treatment-sequence groups. All of these t tests had P values less than 0.002, indicating significantly less pain after EMMAcream administration than after placebo administration. This analysis provides estimates of the expected drop in children’s pain scores for EMLA compared with placebo in the pediatric cancer population of 26.5 units (U) for VAS and 33.2 (U) for CFS. The corresponding expected decreases in health-care professionals’ pain scores are 17.7 (U) for VAS and 20.1 (U) for CFS. This analysis provides unbiased estimates of the true population values four

provided there is no difference in the canyover e&cts of the two treclmnts. To test the equality of the

carryover effects of EMLA and placebo for each of the four types of pain scores, a two-sample Wilcoxon test was done to compare the sum of the scores recorded for the two procedures between the two treatment-sequence groups. Because all four of these Wiicoxon tests produced P values of > 0.3, we concluded that there was no evidence of differential carryover effects between the two study creams as measured by any of the four pain scores. After completing both procedures, the children were asked to respond to the following question: “Thinking about the pain relief YOLI received from each cream and any side effects that you felt with them, did you like one of the creams better than the other?” In response, 40

(85%) preferred EML.A. 3 (6%) preferred placebo, and 4 (9%) “didn’t like either cream” or “liked both creams the same.” It was of interest to assess \he strength of association between the four -pairs of pain scores that “should” be correlared with each other if they were measuring thrl same reality. The Spearman rank-correlation cioefficients for the pain scores recorded for the first procedure were 0.659 for the association between the VAS scores recorded by patients vs health-care professionals, 0.794 for the association between the CFS scored recorded by patients vs healthcare professionals, 0.883 for the association between the VAS vs CFS scores recorded by the health-care professionals, and 0.831 for the association between the VAS vs CFS recorded by the patients. All pairs showed strong evidence (P < 0.0001) of a positive linear association, i.e., if one pain score increased (decreased), the other tended to increase (decrease). Within 30 min following the venous port access procedure, the health-care professional who performed the procedure assessed and recorded any immediate local or systemic toxicity. There were 45 patients with toxicity information recorded by the attending healthcare professional. Of these, five (11%) exhibited some degree of skin toxicity-four while on EMLA and the other while on placebo. No patient had recorded toxicity for both study patches. The recorded toxicities consisted of redness in four patients (three on EMLA, one Fig. 2. Frequency of the visual analogue scale (VAS) pain scores recorded by children for each study cream regardless of the procedure (first vs second) on which the cream was administered. Similar data were seen with the other three pain measurement methodologies. 70 60 2

50

ln I3

40

2

30

z

20 10 0 o-12.5

12.6-37.5

37.6-62.5

62 6 87.5

Pain intensity (VAS)

87.6-100

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Procedure-RelatedPain in Children

B 2

40

4 5

20 0

Pmcedllre 1

Procadure 2

Child score

Prowdure 1

procedure2

HCP score

Fig. 3. Median values of pain scores using the visual analogue scale (VAS). following EML4 fblaekcircles) vs placebo ~~hjt~ circles) administ~tion, by procedure, as measured by children and health-care professionals (HCP).

on placebo) and itchiness in two patients (both on EMLA). Approximately 24 hr after the procedure, the patient or a family member examined the skin at the application site and recorded any observed abnormalities_ A total of 46 patients provided this toxicity information. Of these, one exhibited mild itchiness at the site of EMU ap@ication. This was a patient for whom toxicity assessment info~a~on by the attending health-care professional was not recorded. No toxicity was recorded by the patient/family for the five patients with toxicity recorded by the health-care professional on the previous day_ Thus, toxicity was not a significant problem following first time cream application. All patients completing the two blinded study procedures and choosing to use EML.A cream for future percutaneous access procedures were followed for local and systemic toxicity during each subsequent EMLA cream application. A total of 411 procedures were documented in 42 patients, but one patient had no toxicity data recorded by either the patient or the health-care professional. Of these, the following toxicities were noted immediately following the needle access procedure: seven patients had 11 incidents of “barely noticeable” redness, and ten patients had I6 incidents of “definite” redness. Of these 16 reports, ten patients had had EMLA applied for 65-120 min, and six had an application time of longer than 120 min. All redness resolved within 24 hr. Additionally, there was one report of moderate itching following EMMA use. These 18 patients, who had received 2-30 previous EMLA applica-

243

tions, continued to use EMLA subsequently without severe side effects. The numerous additional reports of transient skin blanching under the EMLA application site and redness under the area of adhesion of the covering transparent dressing were not recorded as cases of true EMI toxicity. In addition to the above, there were two reports of “beet redness” and “blisters” with EMLA use, with redness and blistering continuing for a number of days aftenvards, but eventually resolving. Both patients had used EMLA IQ-12 times previously without incident, and were hospitalized, receiving continuous intravenous therapjr through the implanted port, and receiving EML.A applications at approximately 3-day intervals, when the toxicit)l occurred.

Because the frequent performance of percutaneous needle access procedures is universal among children undergoing cancer therapy, and as needle punctures are abhorred by the vast majority of youn~ters, a method of painlessly delivering effecthtie local anesthesia would be a major boon in the practice of pediatric oncology. In the past, available local anesthetic creams have had insufficient penetration of intact skin to provide adequate anesthesia, and local cooling, for instance using ethyl chloride, has provided partial pain relief at best.8 Far greater anesthetic penetration of the skin is now possible with the development of a eutectic mixture of lidocaine base and prilocaine base in which 80% of each droplet consists of lidocaine and prilocaine (in contrast to only 20% active substance in the singl~om~onent fo~ulations). Systemic al3 sorption can occur, however, but results in very low circulating plasma concentrations of drug_!‘.‘0 This placeb~on~olled study of EMLA cream demonstrated excellent analgesic efficacy and little toxicity when used for pRin relief during central venous port accesses. Although adult patients were not included, it is logical to assume that EMU cream would also provide effective analgesia for older patients undergoingvenous access procedures. This finding is in concert with findings from other studies that addressed the analgesic efficacy of this drug

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during such procedures as venipunctures,“*” lumbar punctures,” central venous port injections,? dermatologic procedures,14 and split the ability of skin grafting,‘” and confirms EMLA cream to provide adequate superficial analgesia following application times of 60 min or longer. Although the long application time is inconvenient in some clinical situations, the child with cancer receiving scheduled painful percutaneous access procedures would rarely find the time element to be problematic. Finally, the successful performance of a pediatric analgesic intervention study in a cooperative group setting is an exciting advance, opening the possibility of further group analgesic studies which, because of small patient numbers in single institutions, could not otherwise be accomplished. In addition, it offers the hope of incorporating state-of-the-art pain relief methodologies into clinical practice by familiarizing pediatricians with the use of currently available analgesic strategies.

Aclzmwledgments This study was conducted as a collaborative trial of North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-35103, CA-37417, and CA-35101.

3. Fitzpatrick TD, Eisen AZ, Wolff K, Friedberg Austen AF. Dermatology and general medicine, ed. New York: McGraw-Hill, 1987:1.538.

IM, 3rd

4. Elliott SC, Miser AW, Dose AM, et al. Epidemiologic features of pain in pediatric cancer patients: a cooperative community-based study. Clin J Pain 1991;7:263-268. 5. Pothmann J, Goepel R. Comparison of the visual analog scale (VAS) and the Smiley analog scale (SAS) for the evaluation of pain in children. Pain 1984;(suppl2):525. 6. Szyfelbein SK, Osgood PF, Carr DB. The assessment of pain and plasma beta-endorphin immunoreactivity in burned children. Pain 1985; 22:173-182. 7. Gracely RH. Psychophysical assessment of human pain. In: Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy, vol. 3. New York: Raven, 1979:805-824. 8. Hagerdorn M. Does a topical skin cooling agent alter a child’s pain perception during a DPT injection? J Pain Symptom Manage 1991;6:169. 9. Evers H, Von Dardel 0, Juhlin L, Ohlsen L, Vinnars E. Dermal effects of compositions based on the eutectic mixture of lignocaine and prilocaine (EMLA). Br J Anaesth 1985;57:997. 10. Ehrenstrom-Reinz GME, Reiz SLA. EMMA: a eutectic mixture of local anesthetics for apical anesthesia. Acta Anesth Stand 1982;26:596-598. 11. Hallen B, Uppfeldt A. Does lidocaine-prilocaine cream permit pain-free insertion of IV catheters in children? Anesthesiology 1982;57:340-342. 12. Hallen B, Carlsson P, Uppfeldt A. Clinical study of a lignocaine prilocaine cream to relieve the pain of venipuncture. Br J Anaesth 1985;57:326-328.

Rf erences

13. Hallen B, Olsson GL, Uppfeldt A. Pain-free venipuncture. Anesthesia 1984;39:969-972.

1. Mcgrath PJ. Hsu E, Cappelli M, Luke B, Goodman JT, Dunn-Geier J. Pain from pediatric cancer: a survey of an outpatient oncology clinic. J Psychosr+ cial Oncol 1990;8: 109-l 24.

14. Juhlin L, Evers H, Broberg F. A lidocaineprilocaine cream for superficial skin surgery and painful lesions. Acta Derm Venereol (Stockh) 1980;60:544-546.

2. Halperin DL. Koren G, Attias D, Pellegrini E, Greenberg ML, Wyss M. Topical skin anesthesia for venous, subcutaneous drug reservoir and lumbar punctures in children. Pediatrics 1989;84:281-284.

15. Ohlsen L, Englesson S, Evers H. An anesthetic lidocaine/prilocaine cream (EMMA) for epicutaneous application tested for cutting split skin grafts. Stand J Plast Reconstr Hand Surg 1985;19:201-209.