P&T News: November 1994, Vol. 15, No. 5
Mark K. Sorenson, R.Ph.
Peer Review Status: Internally Peer Reviewed by Michael E.
Trigg, M.D., Professor, Department of Pediatrics
The need to reduce procedure-related pain, and the subsequent anxiety in children, has led to the development of a topical formulation that can effectively anesthetize the skin, EMLA (eutectic mixture of local anesthetics) cream. EMLA cream (lidocaine 2.5% and prilocaine 2.5%) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1:1 by weight. A eutectic mixture has a melting point below room temperature; therefore, both local anesthetics exist as a liquid oil rather than as crystals. The incorporation of this liquid into the emulsion base results in a concentration of 80% lidocaine-prilocaine to be present within the emulsion droplets of a cream that has only a 5% total concentration of anesthetic agents.(1) The high concentration of the local anesthetics in a high water content vehicle promotes the transdermal spread of the anesthetic ingredients.
EMLA cream has FDA-approved labeling for use as a topical anesthetic on normal intact skin for local analgesia in patients one month of age or older. It is not recommended for use in patients with broken skin or on mucous membranes because there is much greater absorption of lidocaine and prilocaine through non-intact skin.(2) Table 1 provides guidelines for EMLA cream use.
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Table 1. GUIDELINES FOR EMLA CREAM USE Administration 1. Prior to the procedure, apply 2.5 gram of cream (1/2 of a 5 gram tube) per 20 to 25 cm-squared (approximately 2 inch by 2 inch) of skin directly in a thick layer at the site of the procedure. Apply EMLA cream at least 60 minutes prior to minor procedures and at least 120 minutes prior to major procedures. 2. Cover the cream with the supplied Tegaderm® occlusive dressing. Be sure to allow the EMLA cream to remain in a thick layer. Seal the dressing edges carefully, assuring that there is no leakage. 3. Remove the thin paper frame from the occlusive dressing and recheck the dressing edges for product leakage. Note the time of cream application. 4. Immediately before the procedure remove the dressing and cream. Clean the area as usual and begin the procedure. The duration of effective skin anesthesia will be at least 1 hour after removal of the occlusive dressing. Contraindications
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Pharmacology
When EMLA cream is applied to intact skin under an occlusive
dressing, anesthesia will develop within the underlying skin. This
anesthesia develops due to the release of lidocaine and prilocaine
from the cream into the epidermal and dermal skin layers and
subsequent accumulation of local anesthetics at the site of dermal
pain receptors and nerve endings. The onset, depth, and duration of
local anesthesia by EMLA cream are affected by regional blood flow,
epidermal and dermal skin thickness, and the duration of application
of the product. Onset of anesthesia is the most rapid (within 5 to 30
minutes) in body areas with low blood flow and thin skin barriers,
but the duration is short and analgesic efficacy starts to decline
immediately after removal of the cream. Onset may be delayed and
efficacy reduced in locations with high blood flow due to increased
vascular uptake and reduced drug concentrations around nerve endings.
Duration of anesthesia is greatest in body regions with thick
epidermis and low blood flow (e.g., arms and hands).(3)
To provide sufficient analgesia for procedures such as venipuncture, EMLA cream should be applied under an occlusive dressing for at least 60 minutes prior to the procedure. For procedures such as bone marrow aspirations or lumbar puncture, EMLA cream should be applied under occlusive dressing for at least 90 to 120 minutes prior to the procedure. After removal of EMLA cream, the depth of anesthesia penetration increases for an additional 30 minutes, at which time maximal penetration occurs.(4) This effect is though to be due to a continued diffusion of lidocaine and prilocaine along a concentration gradient from superficial skin layers. Maximal penetration of analgesia is achieved by 2 to 3 hours. After removal of the cream from the skin, analgesia continues in the underlying tissues for several hours.
Application of EMLA cream causes a transient, biphasic vascular response.(1) Initially, there is blanching of the skin, which is likely due to a concentration dependent vasoconstrictive effect of the local anesthetics at the capillary bed level. After longer application times (2 hours or greater) erythema develops after the cream is removed. The erythema is thought to be due to vasodilatation of vessels of the upper dermis, probably because of the direct effects of the local anesthetics on vascular smooth muscle.
Comparative Clinical Trials - Venipuncture
The analgesic effects of EMLA were compared to infiltrated
lidocaine in 40 children ages 7 to 12 years undergoing venipuncture
prior to minor ambulatory surgical procedures.(7) Children were
randomly assigned to receive either 2.5 grams of EMLA cream applied
over the anticipated venipuncture site (dorsum of the hand) covered
with an occlusive dressing for 60 minutes or 0.2 ml of 1% lidocaine
infiltrated at the same site using a 30-gauge needle. The patient's
response to analgesia was assessed first during the performance of a
skin "nick" using the bevel of a 19-gauge needle, and again during
the actual venipuncture with a 20-gauge needle. The child's pain
response to venipuncture was scored by the anesthesiologist
performing the venipuncture, an independent observer, and the child
using a 0 to 10 visual analogue pain scale. Additionally, the degree
of cooperation exhibited by the child during the procedure was noted
by the observer. Thirty-nine of the 40 children had satisfactory
analgesia for venipuncture. One patient in the EMLA group had
inadequate analgesia by all three pain assessments. No differences in
pain were seen between the two groups as scored by the
anesthesiologist, the observer, and the children. The authors stated
that the recorded degree of cooperation with the procedure showed a
poor correlation with the child's pain scores; however, further
analysis of cooperation was not provided.
No published studies have compared the analgesic effects of EMLA to topical refrigerants (e.g., ethyl chloride spray) in children.(6)
Placebo-Controlled Clinical Trials-Venipuncture
The efficacy of EMLA cream in reducing pain in infants, toddlers,
and older children undergoing venipuncture has been evaluated in
several double-blind, placebo-controlled studies.(7-9)
Robieux et al(7) evaluated the efficacy of EMLA in 41 chronically ill infants and toddlers between 3 and 36 months of age undergoing venipuncture. Two grams of cream (either EMLA or placebo) were applied to the venipuncture site at least 45 minutes prior to the procedure and covered by an occlusive dressing. Methemoglobin levels were measured in patients when sufficient blood (obtained for routine tests) were available. Levels were measured since infants are particularly vulnerable to the effects of methemoglobin-inducing drugs (see Precautions) because of their incomplete maturation of the methemoglobin reductase system and increased susceptibility of fetal hemoglobin to oxidation. Pain during venipuncture was scored according to a behavioral pain scale and a visual analogue scale by the investigator, the nurse performing the venipuncture, and the patient's mother (when present). Difficulty of the venipuncture was also recorded. Changes in the behavioral pain scale from pre-venipuncture to post-venipuncture were small in the EMLA group than in the placebo group (p less than 0.01). The mean visual analogue pain scale scores were significantly lower with EMLA cream than with placebo (p = 0.01) as rated by all observers. Difficulty of puncture was similar in the EMLA and placebo groups; however, the efficacy of EMLA was not as apparent in patients determined to have difficult venipunctures. Serum methemoglobin levels were similar in the EMLA cream and placebo groups and did not increase above normal levels.
Cooper et al(8) assessed pain response and ease of venipuncture in 40 patients from 3 to 13 years of age randomly selected to receive EMLA cream or placebo. Patients received two grams of either EMLA or placebo cream covered by an occlusive dressing at the venipuncture site at least 60 minutes prior to the procedure. Patients were evaluated by a verbal and a linear scale used by both the child and an observer. Of the 20 EMLA patients, 19 reported pain as "did not hurt" (15 patients) or "hurt a little" (4 patients). Patients receiving EMLA cream had lower pain scores on the verbal and visual scales as reported by the child (p less than 0.001; p less than 0.01) and the observer (p less than 0.01; p less than 0.01). The anesthetist reported a significant improvement in the ease of venipuncture in the EMLA group (p less than 0.05).
Ehrenstrom Reiz and Reiz(9) randomly selected 60 children from 6 to 15 years of age undergoing venipuncture to receive two grams of EMLA cream or placebo covered by an occlusive dressing. Application of the cream occurred at least 60 minutes prior to venipuncture. Each child and a nurse evaluated pain on a 3-point verbal scale. Of the EMLA patients, 19 reported no pain, 10 reported slight to moderate pain, and one patient reported severe pain. In the placebo group, three patients (one of whom was heavily sedated) had no pain. Eighteen placebo-treated patients had slight to moderate pain and nine had severe pain. The authors concluded that EMLA cream provided significantly better pain control than placebo when evaluated by the nurse's and child's verbal score (P less than 0.001 for each).
Additional blinded, randomized, placebo-controlled studies in children from 4 to 15 years of age undergoing venipuncture have shown similar results.(10-13)
Additional Uses
Most recently, several studies have evaluated the use of EMLA
cream for procedures other than venipuncture in children. In a
double-blind, crossover trial, the efficacy of EMLA cream was studied
in children greater than 5 years of age with leukemia who were
required to undergo repeated subcutaneous drug reservoir and lumbar
punctures.(14) Patients (n = 8) received two grams of EMLA or placebo
cream covered by an occlusive dressing one hour prior to injection
through a subcutaneous drug reservoir and then received the opposite
treatment one to four weeks later. Seven of the eight children rated
EMLA superior to placebo. Mean pain scores associated with EMLA cream
use (measured on a visual analog scale) were less than those for
placebo (p less than 0.04). A second group of 14 children requiring
lumbar punctures for intrathecal chemotherapy received EMLA or
placebo cream in an identical fashion to the previous patient group
one hour before the lumbar puncture and then the opposite treatment
one to six weeks later. EMLA cream was preferred by 12 of the 14
children. The pain scores associated with EMLA cream use were lower
(p less than 0.01) than the placebo scores. Four children had not
undergone lumbar punctures before, whereas the other 10 children had
prior experience with this procedure. Pain scores of these two
subgroups were not statistically different, suggesting that prior
experience had no influence on pain evaluation.
The possibility of using EMLA cream to relieve the pain associated with vaccination in infants was evaluated in a randomized, double-blind trial.(15) A total of 155 children (ages ranging from 3 months to 28 months) was enrolled in the study. Most of the patients (98%) received a diphtheria-pertussis-tetanus vaccine. Seventy-nine patients received EMLA cream; the other 76 children received placebo. The cream was applied to the site where the vaccine was to be given and covered with an occlusive dressing for at least 60 minutes before vaccination (amount applied not specified). Pain was assessed using a visual scale; both nurses and parents evaluated the amount of pain, crying, and fear the child displayed in response to the vaccination. Both the nurses and the parents noted the amount of pain and crying as significantly less (P less than 0.003 and p less than 0.001, respectively) among the children who received EMLA cream, but there was no difference between the treatment groups in the scores for fear. The parents of infants who received EMLA cream also reported tenderness around the vaccination site significantly less often than did parents of infants who received placebo (30.3% vs 49.3%, p less than 0.02). While this study demonstrated that EMLA cream was useful in relieving the pain associated with vaccine administration, it did not address whether EMLA use altered the absorption and efficacy of the administered vaccine (see Drug Interactions). In addition, the use of EMLA use altered the absorption and efficacy of the administered vaccine (see Drug Interactions). In addition, the use of EMLA cream will increase costs associated with immunizations and may increase waiting times in physicians' offices since at least 60 minutes of product application time will be required.
Adverse Effects
Adverse effects associated with EMLA cream use have generally
been mild and limited to the transient blanching and erythema of
skin. Mild and transient local skin reactions occurred in 56% of over
1300 patients treated with EMLA cream in clinical trials.(2) Local
effects observed in the trials included blanching 37%, erythema 30%,
alterations in temperature sensation 7%, edema 6%, itching 2%, and
rash, less than 1%. Local reactions generally resolved within 1 or 2
hours. Systemic adverse reactions following appropriate use of EMLA
are unlikely to occur since the plasma levels of lidocaine and
prilocaine following application are 30 to 100 times lower than those
associated with systemic toxicity. (2,16,17) Prilocaine levels are
lower than lidocaine levels due to less protein binding, high tissue
affinity, and higher hepatic metabolism.(17)
Information obtained for the Food and Drug Administration Spontaneous Reporting System for adverse drug reactions indicates that most reactions attributed to EMLA cream continue to be transient local skin reactions. Of note, 54% (36/66) of the reactions were characterized as "no drug effect." Insufficient information is available to determine if this reported lack of effect was related to inappropriate administration of EMLA cream or true lack of patient response.
Other reported complications with EMLA cream use include a two-year-old who chewed the EMLA dressing applied to the back of the hand, swallowing some of the product.(18) It appeared that the upper airway had become effectively anesthetized since the patient was able to undergo tracheal intubation prior to a surgical procedure with only a small dose of an anesthetic agent. Another child was found to have loosened the EMLA dressing on the back of his hand and then proceeded to rub the cream on his face and eyes.(18) It was noted that the cornea may have been anesthetized by the cream and that a corneal abrasion might have occurred. Therefore, use of EMLA cream on young children should be monitored by adults to protect the child from the consequences of inadvertent ingestion or misapplication of the cream.
A case of methemoglobinemia has been reported in a three-month-old male who had EMLA cream under an occlusive dressing applied to the back of the hands and in the cubital regions for five hours.(19) Methemoglobinemia was associated with the use of EMLA since two metabolites of prilocaine have previously been implicated in the development of methemoglobinemia; however, the child was concomitantly receiving a sulfonamide antibiotic which could have also caused the adverse effect.
Drug Interactions
EMLA cream should be used with caution in patients receiving
Class I antiarrhythmic drugs (such as disopyramide, flecainide,
lidocaine, mexiletine, procainamide, quinidine, and tocainide) since
the toxic effects are additive and potentially synergistic.(2)
No clinical studies have assessed whether EMLA cream administration affects the absorption and efficacy of drugs from intramuscular or subcutaneous injection sites.(6) It is known that EMLA cream alters perfusion at application sites because of the blanching and erythema of skin that can occur.(1) Whether this alteration in blood flow significantly affects the absorption of intramuscularly or subcutaneously administered medications remains to be determined. Until adequate information is available regarding the safety and efficacy of EMLA cream prior to intramuscular or subcutaneous medication administration, it should not be used in these situations.
Precautions
To prevent the development of methemoglobinemia, EMLA cream
should not be used in patients with congenital or idiopathic
methemoglobinemia, in patients with glucose-6-phosphate deficiencies
because of their increased susceptibility to methemoglobinemia, and
in infants under the age of 12 months who are receiving treatment
with methemoglobin-inducing drugs.(2,16) Drugs associated with
inducing methemoglobinemia include sulfonamides, acetaminophen,
benzocaine, chloroquine, dapsone, nitrates and nitrites,
nitrofurantoin, nitroglycerin, nitroprusside, phobarbital, phenytoin,
primaquine, and quinine.(20)
EMLA cream is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type (such as lidocaine, prilocaine, mepivicaine, bupivacaine, or etidocaine) or to any other component of the product. Application of EMLA cream to larger areas or for longer times than those recommended could result in sufficient absorption of lidocaine and prilocaine resulting in systemic toxicity.(2) In addition, the manufacturer notes that repeated doses of EMLA cream may increase blood levels of lidocaine and prilocaine. The use of repeated applications of EMLA cream has not been studied; however, it would be prudent to limit the daily amount to the manufacturer's recommended application area.(6) Table 2 provides maximum recommended application areas for infants and children.
Patients with severe hepatic disease are at greater risk of developing toxic plasma concentrations of lidocaine and prilocaine due to their inability to metabolize local anesthetic drugs.
Studies in laboratory animals (guinea pigs) have shown that EMLA cream as an ototoxic effect when instilled into the middle ear. In these same studies, animals exposed to EMLA cream placed only in the external auditory canal showed no abnormality. EMLA cream should not be used in any clinical situation in which its penetration or migration beyond the tympanic membrane into the middle ear is possible.(2)
Conclusions
EMLA cream is an effective topical anesthetic with FDA-approved
labeling as a topical anesthetic for use on normal intact skin for
local analgesia. It is well tolerated and has proven to be useful in
reducing pain in children during venipuncture, lumbar puncture, and
injection through subcutaneous drug reservoirs, particularly due to
the recurrent nature of these procedures in many patients. In most
situations it is as effective as infiltrated lidocaine in producing
local anesthesia without the use of a needle; however, a minimum
application time of 60 minutes is required for EMLA cream to provide
adequate analgesia. If immediate anesthesia is required, an
alternative therapy such as infiltrated lidocaine would need to be
used. EMLA cream may not be as effective in reducing anxiety
associated with a procedure as it is in reducing pain. Controlled
studies of EMLA cream in children under the age of seven years have
shown less overall benefit than in older children. These results
emphasize the importance of emotional and psychological support of
younger children undergoing medical or surgical procedures. Use of
behavioral strategies or premedication where appropriate should also
be considered to reduce a child's anxiety associated with a
procedure.
EMLA cream should not be used in infants less than one month of age or in infants under the age of 12 months who are receiving treatment with methemoglobin-inducing drugs since the risk of significant methemoglobinemia is increased in these populations.
EMLA cream should not be used prior to intramuscular or subcutaneous medication administration (e.g., during routine immunizations) because its use in these situations has not been adequately studied.
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Table 2. EMLA CREAM MAXIMUM RECOMMENDED APPLICATION AREA* For Infants and Children Based on Application to Intact Skin | |
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Body Weight (kg) |
Maximum Application Area (cm2) |
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Up to 10 kg |
100 (10 cm X 10 cm) |
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up to 20 kg |
600 (24 cm X 24 cm) |
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above 20 kg |
2000 (45 cm X 45 cm) |
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References
Renal Failure and Hyperkalemia Associated with Short-Term
Injectable Ketorolac
A 58-year-old black woman with a history of hypertension, type II
diabetes mellitus, and congestive heart failure was admitted with
acute cholecystitis and underwent cholecystectomy. Prior to surgery,
the laboratory values were BUN 21.8 mg/dL, serum creatinine 1.87
mg/dL, and potassium 4.6 mmol/L. Ketorolac therapy, for postoperative
pain control, was initiated with 60 mg intramuscularly, followed by
30 mg every six hours for 6 days for a cumulative dose of 750 mg. The
patient also received intravenous fluid and antibiotics. Fever and
confusion developed on postoperative day 6, and the patient was
returned to the operating room for repair of a wound dehiscence.
After the second visit to the operating room, her condition
deteriorated and worsening renal function (serum creatinine 7.5
mg/dL) and hyperkalemia (potassium 7.4 mmol/L) were noted. Two days
after would repair, she underwent hemodialysis for oliguric acute
renal failure with severe volume overload and hyperkalemia. Death
occurred on postoperative day 9.
A 53-year-old black woman with a history of modified radical mastectomy for intraductal carcinoma two years prior to admission was admitted for a simple mastectomy for recurrent intraductal carcinoma. Ketorolac was used for post-operative pain. The total dose received was 1140 mg. The patient was found to have worsening renal insufficiency with hyperkalemia 10 days later. The baseline serum creatinine of 1.5 mg/dL had been elevated to 2.6 mg/dL; serum potassium levels originally 4.2 mmol/L rose to 6.2 mmol/L. Electrolytes returned to normal within 24 hours of the discontinuation of ketorolac and serum urea nitrogen and creatinine levels returned to baseline within nine days.
___________
Abstracted from: Pearce CJ, Gonzalez FM, Wallin JD. Renal Failure and
Hyperkalemia Associated with Ketorolac Tromethamine. Arch Intern Med.
1993;153:1000-2.
___________
The manufacturer states that renal toxcities have been seen in patients with conditions leading to a reduction in blood volume and/or renal blood flow where prostaglandins have a supportive role in the maintenance of renal perfusion. In such patients, administration of non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate or contribute to acute renal failure. Patients at greatest risk include: those with underlying impaired renal function, heart failure, liver dysfunction; those taking diuretics; those patients who are septic; patients with diabetes mellitus; patients who are in a state of post-operative hypotension; or the elderly.