Analgesia for common procedures

February 2005

Several invasive procedures commonly preformed in pediatric medical practice can be a cause of discomfort and anxiety in infants and children, such as venipuncture, IV cannulation or administration of injectable vaccinations. Some young children are very fearful of receiving a “shot,” and the anticipation and administration of the injection can create significant anxiety for the child, caregiver and perhaps some health care providers. In addition to anxiety at the time of injection, the published literature describes physicians and caregivers withholding routine pediatric immunizations because of immunization administration pain, especially when multiple immunizations are scheduled at one visit. Several pharmaceutical agents can be used to lessen or minimize discomfort from common pediatric procedures. Two products were discussed in this column two years prior (March 2003), and additional data have since become available.

Local anesthetic products

Two products commonly used for local anesthetic action on intact skin are EMLA (lidocaine 2.5% and prilocaine 2.5%) and L-M-X4 (lidocaine 4%, formally known as ELA-Max). They are both available as creams to be applied prior to the procedure. EMLA is also available as cream-containing discs. EMLA is available only by prescription, while L-M-X4 is available over the counter.

EMLA and L-M-X4 have been compared in several published studies. Kleiber compared EMLA and lidocaine 4% in 30 children (7-13 years of age) for IV catheter insertion. This study was conducted in a randomized, single-blind (researcher), crossover manner. Application times included 60 minutes for EMLA and 30 minutes for lidocaine 4%, both with occlusive dressings. The Oucher (0-100 numeric scale) was used to measure pain. There was no difference between the two products and associated pain ratings (mean 20.5-24), nor between the ease of IV cannulation (60%-67%). Several children reported higher pain scale ratings (60–70) with both products, suggesting that some children might be more sensitive to pain. Eichenfield compared EMLA to lidocaine 4% for venipuncture in 117 children (5-17 years of age) in a randomized, double-blind, crossover manner. Study patients were placed into two groups, and each group received either a 30-minute application of both products or a 60-minute application of both products (with crossover at the second visit). EMLA was applied with an occlusive dressing at all visits, while lidocaine 4% was compared with and without an occlusive dressing. To assess pain, a 100-mm visual analog scale tool and the parents’ and blinded research observer’s Observed Behavioral Distress scores were used. No difference in efficacy between the two products was found, including no difference in efficacy between a 30-minute application of lidocaine 4% without an occlusive dressing and a 60-minute application of EMLA with an occlusive dressing. There was no efficacy difference in a 30-minute application of both lidocaine 4% (without occlusion) and EMLA (with occlusion), or a 60-minute application of lidocaine 4% (with occlusion) or EMLA (with occlusion). There was no difference between the products in the difficulty of venipuncture. In a study recently published, Koh compared lidocaine 4% (30-minute application time, with occlusion) with EMLA (60-minute application time, with occlusion) for IV insertions in 60 children (8-17 years of age) in a randomized, double-blind, manner. There was no difference in the pain associated with IV insertion or in the difficulty in IV catheter placement.

Local anesthetic products have also been evaluated for discomfort associated with pediatric immunizations. When evaluating local anesthetic products for this purpose, it is also important to assess the potential effects upon immunization efficacy, as some evidence suggests that lidocaine and prilocaine may have antiviral and antibacterial effects. Fortunately, data from two published studies demonstrate that these potential adverse effects are not clinically significant. One study assessed EMLA application to young infants receiving their first measles-mumps-rubella subcutaneous immunization, evaluating not only analgesic effects, but also antibody response (Halperin S). EMLA was compared with placebo in a randomized, double-blind manner (N = 160). Antibody responses were measured prior to study drug application and at 28 to 35 days after immunization. Pain was measured by the Modified Behavioral Pain Scale. No difference in antibody response was noted between infants receiving EMLA (88.3%-92.3%) or placebo (91.1%-94.9%). Pain was less in infants receiving EMLA as compared with infants receiving placebo (P<.05). Another study compared EMLA with placebo in young infants receiving diphtheria-tetanus-acellular pertussis (DTaP), injectable polio and Haemophilus influenzae type b vaccine and hepatitis B intramuscular immunization in a two-part, randomized, double-blind manner. Antibody response was measured at 6 and 7 months and compared with pre-immunization titers at 0 to 2 months. Pain was measured by the Modified Behavioral Pain Scale and caregiver questionnaire. No difference in antibody response was demonstrated between the groups. Application of EMLA significantly reduced pain from immunization in infants 6 month of age; a significant difference in analgesia was not noted in infants 2 and 4 months of age. The authors attribute this difference to a lower sample size for the younger infants.

Additional methods for analgesia

Clinicians can offer additional methods of analgesia to infants and children, including vapocoolant spray, iontophoresis with lidocaine or sugar solution for younger infants. Vapocoolant spray (Fluori-Methane, dichlorodifluoromethane and trichloromonofluoromethane) has been compared with EMLA and control (distraction) in 62 children (mean age 4.5 years) in a controlled trial for pain due to administration of DTaP immunization (Reis). EMLA was applied 60 minutes prior to immunization, and vapocoolant spray was applied by a spray-saturated cotton ball 15 seconds prior to immunization. Pain control was assessed by monitoring cry duration and use of the Observational Scale of Behavioral Distress. EMLA and vapocoolant spray (both combined with distraction) were equally effective in reducing discomfort, and both treatments were more effective than the control therapy (distraction). This study did not assess antibody response to immunization.

Another method available for local anesthesia is iontophoresis with lidocaine. Iontophoresis uses an electrical current to deliver a topical anesthetic. Lidocaine (Numby Stuff) is applied to the electrode patch and placed on the skin; an electrical current delivered by wire delivers the anesthetic. An advantage of this method includes a rapid onset (10 minutes), which can be important in a busy setting. Disadvantages include the expense of purchasing the necessary equipment and complaints by some children of a mild sensation from the applied electrical current. A controlled trial compared iontophoresis with lidocaine with EMLA in 100 children and adults (mean age 13 years, range 5-21 years) who received venipuncture or IV cannulation (Squire). Iontophoresis was demonstrated to be more effective (P <.05) for minimizing pain than EMLA and required less time (13 minutes for iontophoresis vs. 60 minutes for EMLA). Both treatments were well tolerated, although more children receiving iontophoresis had burning sensations, tingling or erythema. No child receiving iontophoresis withdrew from the study because of these effects. A controlled trial recently published compared a new low-dose lidocaine iontophoresis system (LidoSite) with placebo (iontophoresis of saline placebo) in 548 children (5-17 years of age) for venipuncture or venous cannulation (Zempsky). Lidocaine was delivered by iontophoresis (at a lower electrical dose than other iontophoresis systems) for 10 minutes and was found to be more effective than placebo for all age groups evaluated. Adverse effects did not differ between the study groups and most commonly included mild erythema and edema. Iontophoresis was discontinued in nine children due to pain or burning sensation at the application site. One child suffered a partial-thickness burn while receiving lidocaine because of a defective electrical wire coating. This adverse effect has occurred in other published studies, although uncommonly.

Other analgesic methods evaluated as effective in neonates and young infants receiving venipuncture or other common procedures include orally administered sugar (glucose or sucrose) solutions, tactile stimulation with a bottle or pacifier and holding by caregivers. One published trial compared orally administered glucose 30% with EMLA in 201 neonates receiving venipuncture and found glucose to be more effective (Gradin).

Conclusion

The data discussed above indicate that EMLA and lidocaine 4% (L-M-X4) are effective at minimizing pain from common invasive procedures preformed in children. Several controlled trials have demonstrated equivalent efficacy of EMLA (60-minute application) and lidocaine 4% (30-minute application). Some evidence indicates that 30-minute applications are equally effective for EMLA and lidocaine 4%.

Package labeling for EMLA includes recommendations for use of an occlusive dressing, while labeling for L-M-X4 does not mandate the use of an occlusive dressing. It is likely best to use an occlusive dressing for children receiving both products for practical reasons, such as to prevent accidental removal onto the child’s clothes.

EMLA is only available by prescription, whereas L-M-X4 is available without prescription, and this may present an advantage for L-M-X4 in some situations. EMLA is available in limited supplies and is available more commonly through hospital settings as compared with community practice settings.

Additional data on these products that would be welcome include clarification of minimally effective application durations and an application duration that provides maximal analgesic effect. Some evidence indicates that a 90- to 120-minute application for EMLA may be more effective than a 60-minute application, as dermal penetration correlates with application duration.

Other means of providing pre-procedure analgesia are available to pediatric clinicians, and these methods offer unique advantages and disadvantages. A significant advantage of iontophoresis or vapocoolant spray includes a quicker application time and onset of effect. More data describing the potential for significant adverse effects from iontophoresis and efficacy data for vapocoolant spray would be helpful in clarifying a role for these therapies.

It is possible that all of the above methods are underused by clinicians. Children and their caregivers would likely appreciate additional consideration of these therapies.

For more information:

• Kleiber C, Sorenson M, Whiteside K, et al. Topical anesthetics for intravenous insertion in children: a randomized equivalency study. Pediatrics. 2002;110:758-761.
• Eichenfield LF, Funk A, Fallon-Friedlander S, Cunningham BB. A clinical study to evaluate the efficacy of ELA-Max (4% liposomal lidocaine) as compared with eutectic mixture of local anesthetics cream for pain reduction of venipuncture in children. Pediatrics. 2002;109:1093-1099.
• Koh JL, Harrison D, Myers R, et al. A randomized, double-blind comparison study of EMLA and ELA-Max for topical anesthesia in children undergoing intravenous insertion. Paediatr Anaesth. 2004;14:977-982.
• Halperin SA, McGrath P, Smith B, Houston T. Lidocaine-prilocaine patch decreases the pain associated with the subcutaneous administration of measles-mumps-rubella vaccine but does not adversely affect the antibody response. J Pediatr. 2000;136:789-794.
• Halperin BA, Halperin SA, McGrath P, et al. Use of lidocaine-prilocaine patch to decrease intramuscular injection pain does not adversely affect the antibody response to DTaP-inactivated poliovirus-Haemophilus influenzae type b conjugate and hepatitis B vaccines in infants from birth to six months of age. Pediatr Infect Dis J. 2002;21:399-405.
• Cohen Reis E, Holobkuv R. Vapocoolant spray is equally effective as EMLA cream in reducing immunization pain in school-age children. Pediatrics. 1997;100(6):E5.
• Squire SJ, Kirchhoff KT, Hissong K. Comparing two methods of topical anesthesia used before intravenous cannulation in pediatric patients. J Pediatr Health Care. 2000;14:68-72.
• Zempsky WT, Sullivan J, Paulson DM, Hoath SB. Evaluation of a low-dose lidocaine iontophoresis system for topical anesthesia in adults and children: a randomized, controlled trial. Clin Ther. 2004;26:1110-1119.
• Gradin M, Eriksson M, Holmqvist G, et al. Pain reduction at venipuncture in newborns: oral glucose compared with local anesthetic cream. Pediatrics. 2002;110:1053.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.